Red propolis reduces inflammation in cyclophosphamide-induced hemorrhagic cystitis in rats. / El propóleos rojo reduce la inflamación en la cistitis hemorrágica inducida por ciclofosfamida en ratas

Introduction. Cyclophosphamide (CP) is used to treat malignant neoplasias and control autoimmune diseases. Still, one of its metabolites, acrolein, is toxic to the urothelium and can lead to hemorrhagic cystitis and severe discomfort. Objective. To evaluate the ability of red propolis to prevent and treat CP-induced hemorrhagic cystitis in rats. Materials and methods. Red propolis was extracted in 1% gum arabic and administered subcutaneously (sc). In the first experiment, groups IA, IIA, and IIIA and groups IB, IIB, and IIIB received water, gum arabic (GA), or propolis, respectively, for 30 days. Then water (controls) or CP (treatment) was administered i.p. In the second experiment, groups IVA, VA, and VIA received water i.p. while groups IVB, VB, and VIB received CP i.p. This was followed by 5 injections at 2-hour intervals with either water, GA, or propolis. Bladder tissue was examined according to Gray's criteria. Results. The total inflammatory histology score was significantly smaller in group VIB (11.33 ± 2.07). Mild inflammation predominated in group VIB while most of the animals in group IVB had severe inflammation (p=0.0375). Ulcers were predominantly multiple in Groups IVA and VB but rare or absent in Group VIB (p=0.0118). Urothelial cells were mostly absent in groups IVB and VB and present/normal in group VIB (p=0.0052). Fibrin was abundant in groups IVB and VA but mostly absent in group VIB (p=0.0273). Conclusions. Red propolis can reduce inflammation in CP-induced hemorrhagic cystitis in rats.

Introducción. La ciclofosfamida se usa para tratar neoplasias malignas y controlar enfermedades autoinmunitarias, pero uno de sus metabolitos, la acroleína, es tóxico para el urotelio y puede provocar cistitis hemorrágica y malestar grave. Objetivo. Evaluar la capacidad del propóleos rojo para prevenir y tratar la cistitis hemorrágica inducida por ciclofosfamida en ratas. Materiales y métodos. Se extrajo propóleos rojo en goma arábiga al 1 % y se administró por vía subcutánea. En el primer experimento, los grupos IA, IIA, IIIA, IB, IIB y IIIB recibieron agua, goma arábiga y propóleos, respectivamente, durante 30 días. Luego se les administró agua (controles) o el tratamiento (ciclofosfamida) por inyección intraperitoneal. En el segundo experimento, los grupos IVA, VA, VIA recibieron agua por vía intraperitoneal, y los grupos IVB, VB, VIB recibieron el tratamiento por la misma vía, a lo que le siguieron cinco inyecciones con intervalos de dos horas entre ellas, con agua, goma arábiga o propóleos. El tejido de la vejiga se examinó de acuerdo con los criterios de Gray. Resultados. La puntuación total de la inflamación según la histología fue significativamente menor en el grupo VIB (11,33 ± 2,07). La inflamación leve predominó en este grupo, en tanto que la mayoría de los animales del IVB presentó inflamación grave (p=0,0375). Predominaron las úlceras múltiples en los grupos IVA y VB, pero fueron raras o estuvieron ausentes en el VIB (p=0,0118). En general, no se observaron células uroteliales en los grupos IVB y VB, pero sí en el VIB (p=0,0052). La fibrina fue abundante en los grupos IVB y VA, pero predominantemente ausente en el VIB (p=0,0273). Conclusiones. El propóleos rojo puede reducir la inflamación en la cistitis hemorrágica inducida por ciclofosfamida en ratas.

Red propolis reduces inflammation in cyclophosphamide-induced hemorrhagic cystitis in rats / El propóleos rojo reduce la inflamación en la cistitis hemorrágica inducida por ciclofosfamida en ratas

Introduction. Cyclophosphamide (CP) is used to treat malignant neoplasias and control autoimmune diseases. Still, one of its metabolites, acrolein, is toxic to the urothelium and can lead to hemorrhagic cystitis and severe discomfort. Objective.To evaluate the ability of red propolis to prevent and treat CP-induced hemorrhagic cystitis in rats. Materials and methods. Red propolis was extracted in 1% gum arabic and administered subcutaneously (sc). In the first experiment, groups IA, IIA, and IIIA and groups IB, IIB, and IIIB received water, gum arabic (GA), or propolis, respectively, for 30 days. Then water (controls) or CP (treatment) was administered i.p. In the second experiment, groups IVA, VA, and VIA received water i.p. while groups IVB, VB, and VIB received CP i.p. This was followed by 5 injections at 2-hour intervals with either water, GA, or propolis. Bladder tissue was examined according to Gray's criteria. Results. The total inflammatory histology score was significantly smaller in group VIB (11.33 ± 2.07). Mild inflammation predominated in group VIB while most of the animals in group IVB had severe inflammation (p=0.0375). Ulcers were predominantly multiple in Groups IVA and VB but rare or absent in Group VIB (p=0.0118). Urothelial cells were mostly absent in groups IVB and VB and present/normal in group VIB (p=0.0052). Fibrin was abundant in groups IVB and VA but mostly absent in group VIB (p=0.0273). Conclusions. Red propolis can reduce inflammation in CP-induced hemorrhagic cystitis in rats.

Introducción. La ciclofosfamida se usa para tratar neoplasias malignas y controlar enfermedades autoinmunitarias, pero uno de sus metabolitos, la acroleína, es tóxico para el urotelio y puede provocar cistitis hemorrágica y malestar grave. Objetivo. Evaluar la capacidad del propóleos rojo para prevenir y tratar la cistitis hemorrágica inducida por ciclofosfamida en ratas. Materiales y métodos. Se extrajo propóleos rojo en goma arábiga al 1 % y se administró por vía subcutánea. En el primer experimento, los grupos IA, IIA, IIIA, IB, IIB y IIIB recibieron agua, goma arábiga y propóleos, respectivamente, durante 30 días. Luego se les administró agua (controles) o el tratamiento (ciclofosfamida) por inyección intraperitoneal. En el segundo experimento, los grupos IVA, VA, VIA recibieron agua por vía intraperitoneal, y los grupos IVB, VB, VIB recibieron el tratamiento por la misma vía, a lo que le siguieron cinco inyecciones con intervalos de dos horas entre ellas, con agua, goma arábiga o propóleos. El tejido de la vejiga se examinó de acuerdo con los criterios de Gray. Resultados. La puntuación total de la inflamación según la histología fue significativamente menor en el grupo VIB (11,33 ± 2,07). La inflamación leve predominó en este grupo, en tanto que la mayoría de los animales del IVB presentó inflamación grave (p=0,0375). Predominaron las úlceras múltiples en los grupos IVA y VB, pero fueron raras o estuvieron ausentes en el VIB (p=0,0118). En general, no se observaron células uroteliales en los grupos IVB y VB, pero sí en el VIB (p=0,0052). La fibrina fue abundante en los grupos IVB y VA, pero predominantemente ausente en el VIB (p=0,0273). Conclusiones. El propóleos rojo puede reducir la inflamación en la cistitis hemorrágica inducida por ciclofosfamida en ratas.

Immobilization of Amano lipase AK from Pseudomonas fluorescens on different types of chitosan-containing supports: use in the kinetic resolution of rac-indanol.

Amano lipase AK from P. fluorescens was immobilized on different types of chitosan-containing supports. Chitosan lower molecular weight (2.5%), chitosan lower molecular weight/sodium alginate (2.5%/2.5%) and chitosan lower molecular weight/carrageenan (2.5%/2.5%) allowed the highest values of immobilization yields (IY) of 81, 81 and 83%, respectively. Best activity results were achieved using chitosan average molecular weight (5%) and chitosan lower molecular weight/sodium alginate (2.5%/2.5%) as support, with values of 1.40 and 1.30 UpNPB/ggel and with recovery activities of 45.75 and 35.6%, respectively. These derivatives were evaluated in the kinetic resolution of rac-indanol to obtain a key intermediate in the synthesis of a drug used in the treatment of Parkinson's disease. The most efficient derivatives in the kinetic resolution were lipase immobilized on chitosan average molecular weight (5.0%) and chitosan low molecular weight/sodium alginate, the latter leading to obtaining both (S)-indanol and (R)-indanyl acetate with > 99% ee and 50% conversion.

Anxiolytic-like effect of chalcone N-{(4'-[(E)-3-(4-fluorophenyl)-1-(phenyl) prop-2-en-1-one]} acetamide on adult zebrafish (Danio rerio): Involvement of the GABAergic system.

Benzodiazepines are the standard drugs for the treatment of anxiety, but their undesirable side effects make it necessary to develop new anxiolytic drugs. The objective of this study was to evaluate the possible anxiolytic-simile effect of synthetic chalcone N-{(4'-[(E)-3-(4-fluorophenyl)-1-(phenyl) prop-2-en-1-one]} acetamide (PAAPFBA) on adult zebrafish (Danio rerio). PAAPFBA was synthesized with an 88.21% yield and its chemical structure was determined by 1H and 13C NMR. Initially, animals (n = 6/group) were treated (4 or 12 or 40 mg/kg, intraperitoneal) with PAAPFBA and were submitted to acute toxicity and open field tests. Then, other groups (n = 6/each) received PAAPFBA for the analysis of its effect on the Light & Dark Test. The participation of the GABAergic system was also assessed using the GABAA antagonist flumazenil. Molecular docking was performed using the GABAA receptor. The effect of PAAPFBA on anxiety induced by alcohol withdrawal was analyzed. PAAPFBA was non-toxic, reduced the locomotor activity, and showed an anxiolytic-like effect in both models. This effect was reduced by pre-treatment with the flumazenil. In agreement with in vivo studies, molecular docking indicated an interaction between chalcone and the GABAA receptor. The results suggest that PAAPFBA is an anxiolytic agent mediated via the GABAergic system.

Gum arabic and red propolis protecteting colorectal preneoplastic lesions in a rat model of azoxymethane1.

PURPOSE: To evaluate red propolis, gum arabic and L-lysine activity on colorectal preneoplastic lesions induced by azoxymethane (AOM). METHODS: The study featured 4 control groups (I-IV) and 4 experimental groups (V-VIII), totaling 48 rats. Once a week for 2 weeks, animals on control groups received saline, while animals in experimental groups received azoxymethane (15 mg/kg i.p.). The follow up along 16 weeks included daily oral gavage to administer water (I and V), L-lysine (150 mg/kg)(II and VI), própolis (100mg/5ml/kg)(III and VII), or gum arabic (5ml/kg)(IV and VIII). Was performed surgery on the animals in the end of this time in order to collect blood for biological assays (TBARS, GSH), followed by their sacrifice to tissue extract. RESULTS: Oxidative stress (TBARS) and the number of aberrant crypt foci (ACF) in distal colon were lower using própolis (p<0.01 for both parameters). Gum arabic reduced preneoplastic lesions (ACF ≤ 4 crypts) on distal colon and on the entire colon (p<0.05). CONCLUSIONS: Red propolis reduced AOM-induced oxidative stress (TBARS) and total number of ACF in the distal colon. L-lysine neither protected against nor enhanced AOM-induced ACF. Gum arabic reduced the number of ACF.

Gum arabic and red propolis protecteting colorectal preneoplastic lesions in a rat model of azoxymethane

Abstract Purpose: To evaluate red propolis, gum arabic and L-lysine activity on colorectal preneoplastic lesions induced by azoxymethane (AOM). Methods: The study featured 4 control groups (I-IV) and 4 experimental groups (V-VIII), totaling 48 rats. Once a week for 2 weeks, animals on control groups received saline, while animals in experimental groups received azoxymethane (15 mg/kg i.p.). The follow up along 16 weeks included daily oral gavage to administer water (I and V), L-lysine (150 mg/kg)(II and VI), própolis (100mg/5ml/kg)(III and VII), or gum arabic (5ml/kg)(IV and VIII). Was performed surgery on the animals in the end of this time in order to collect blood for biological assays (TBARS, GSH), followed by their sacrifice to tissue extract. Results: Oxidative stress (TBARS) and the number of aberrant crypt foci (ACF) in distal colon were lower using própolis (p<0.01 for both parameters). Gum arabic reduced preneoplastic lesions (ACF ≤ 4 crypts) on distal colon and on the entire colon (p<0.05). Conclusions: Red propolis reduced AOM-induced oxidative stress (TBARS) and total number of ACF in the distal colon. L-lysine neither protected against nor enhanced AOM-induced ACF. Gum arabic reduced the number of ACF.

Effect of red propolis on hamster cheek pouch angiogenesis in a new sponge implant model.

PURPOSE: To evaluate the effects of red propolis on cheek pouch angiogenesis in a hamster new model sponge implant. METHODS: Forty eight animals divided into eight groups. (Groups I-IV), the animals were treated for 15 days before and 10 days after sponge implantation. (Groups V-VIII), the animals were treated for 10 days after sponge implantation (GI and GV: red propolis 100 mg/kg, GII and GVI: celecoxib 20 mg/kg, GIII and GVII: 1% gum arabic 5 mL/kg, GIV and GVIII: distilled water 5 mL/kg). On the 11th day of implantation, the animals were anesthetized for stereoscopic microscopic imaging and morphometric quantification of angiogenesis (SQAN), followed by histopathological evaluation (H&E). RESULTS: In the SQAN analysis, no significant difference was found between the groups. However, on histology, propolis was found reduce the population of mastocytes in the qualitative analyses (p = 0,013) in the quantitative analyses to reduce the number of blood vessels (p = 0,007), and increase the macrophage count (p = 0,001). CONCLUSION: Red propolis inhibited inflammatory angiogenesis when administered before andcontinuously after sponge implant, and was shown to have immunomodulating effects on inflammatory cells (mastocytes and macrophages) in a new sponge implant hamster model.

Effect of red propolis on hamster cheek pouch angiogenesis in a new sponge implant model

Abstract Purpose: To evaluate the effects of red propolis on cheek pouch angiogenesis in a hamster new model sponge implant. Methods: Forty eight animals divided into eight groups. (Groups I-IV), the animals were treated for 15 days before and 10 days after sponge implantation. (Groups V-VIII), the animals were treated for 10 days after sponge implantation (GI and GV: red propolis 100 mg/kg, GII and GVI: celecoxib 20 mg/kg, GIII and GVII: 1% gum arabic 5 mL/kg, GIV and GVIII: distilled water 5 mL/kg). On the 11th day of implantation, the animals were anesthetized for stereoscopic microscopic imaging and morphometric quantification of angiogenesis (SQAN), followed by histopathological evaluation (H&E). Results: In the SQAN analysis, no significant difference was found between the groups. However, on histology, propolis was found reduce the population of mastocytes in the qualitative analyses (p = 0,013) in the quantitative analyses to reduce the number of blood vessels (p = 0,007), and increase the macrophage count (p = 0,001). Conclusion: Red propolis inhibited inflammatory angiogenesis when administered before andcontinuously after sponge implant, and was shown to have immunomodulating effects on inflammatory cells (mastocytes and macrophages) in a new sponge implant hamster model.

Eugenol derivatives: synthesis, characterization, and evaluation of antibacterial and antioxidant activities.

Eugenol is the major component of clove essential oil and has demonstrated relevant biological potential with well-known antimicrobial and antioxidant action. Therefore, this work carried out the synthesis, purification, characterization, and evaluation of the antioxidant and antibacterial potential of 19 eugenol derivatives. The derivatives were produced by esterification reactions in the hydroxyl group (-OH) of eugenol with different carboxylic acids and also by addition reactions in the double bond of the allyl group. The derivatives had a promising antibacterial potential, including a lower minimum inhibitory concentration of 500 µg/mL than eugenol (1000 µg/mL). In addition, the derivatives were active against bacterial strains (Escherichia coli, Staphylococcus aureus) that eugenol itself showed no activity, thus increasing the spectrum of antibacterial action. As for the antioxidant activity, it was observed that the derivatives that involved esterification reactions in the hydroxyl group (-OH) of the eugenol molecule's phenol resulted in a significant reduction of the antioxidant action (IC50 > 100 µg/mL) when compared with the eugenol precursor molecule (IC50 = 4.38 µg/mL). On the other hand, the structural changes located in the double bond affected much more smoothly the capacity of capturing radicals than the starting molecule, also being obtained derivatives with proximal antioxidant capacity (IC50 = 19.30 µg/mL) to commercial standards such as Trolox (IC50 = 16.00 µg/mL).

Biflorin induces cytotoxicity by DNA interaction in genetically different human melanoma cell lines.

Cancer is a public health problem and the second leading cause of death worldwide. The incidence of cutaneous melanoma has been notably increasing, resulting in high aggressiveness and poor survival rates. Taking into account the antitumor activity of biflorin, a substance isolated from Capraria biflora L. roots that is cytotoxic in vitro and in vivo, this study aimed to demonstrate the action of biflorin against three established human melanoma cell lines that recapitulate the molecular landscape of the disease in terms of genetic alterations and mutations, such as the TP53, NRAS and BRAF genes. The results presented here indicate that biflorin reduces the viability of melanoma cell lines by DNA interactions. Biflorin causes single and double DNA strand breaks, consequently inhibiting cell cycle progression, replication and DNA repair and promoting apoptosis. Our data suggest that biflorin could be considered as a future therapeutic option for managing melanoma.

Recent Advances in Lipase-Mediated Preparation of Pharmaceuticals and Their Intermediates.

Biocatalysis offers an alternative approach to conventional chemical processes for the production of single-isomer chiral drugs. Lipases are one of the most used enzymes in the synthesis of enantiomerically pure intermediates. The use of this type of enzyme is mainly due to the characteristics of their regio-, chemo- and enantioselectivity in the resolution process of racemates, without the use of cofactors. Moreover, this class of enzymes has generally excellent stability in the presence of organic solvents, facilitating the solubility of the organic substrate to be modified. Further improvements and new applications have been achieved in the syntheses of biologically active compounds catalyzed by lipases. This review critically reports and discusses examples from recent literature (2007 to mid-2015), concerning the synthesis of enantiomerically pure active pharmaceutical ingredients (APIs) and their intermediates in which the key step involves the action of a lipase.

Oncocalyxone A functions as an anti-glycation agent in vitro.

Advanced glycation endproducts (AGE) are the result of post-translational changes to proteins, which ultimately compromise their structure and/or function. The identification of methods to prevent the formation of these compounds holds great promise in the development of alternative therapies for diseases such as diabetes. Plants used in traditional medicine are often rich sources of anti-glycation agents. Therefore, in this study, we investigated the anti-glycation activity of one such compound, Oncocalyxone A (Onco A). Using spectrofluorimetric techniques, we determined that Onco A inhibits AGE formation in a concentration-dependent manner. Its IC50 value (87.88 ± 3.08 µM) was almost two times lower than the standard anti-glycation compound aminoguanidine (184.68 ± 4.85 µM). The excellent anti-glycation activity of Onco A makes it an exciting candidate for the treatment of diseases associated with excessive accumulation of AGE. However, additional studies are necessary to identify its mechanism of action, as well as the in vivo response in suitable model organisms.

Alterations in brain amino acid metabolism and inhibitory effects on PKC are possibly correlated with anticonvulsant effects of the isomeric mixture of α- and ß-amyrin from Protium heptaphyllum.

CONTEXT: α- and ß-Amyrin (AMY) from Protium heptaphyllum (Aubl) March (Burseraceae) is found in Brazil and used in diverse inflammation-related diseases. This species presents a central action, as previously described. OBJECTIVE: The objectives were to evaluate the anticonvulsant effect of AMY in mice and to verify the mechanism of action. MATERIAL AND METHODS: Seizures were induced by pentylenetetrazole followed by acute or subchronic treatments (5-25 mg/kg, p.o. and i.p.) and determination of brain amino acids (10 and 25 mg/kg, i.p., 7 d). RESULTS: In the acute treatment, AMY (10, 25, and 50 mg/kg, p.o.) increased the latency to the first convulsion (FC) by 30, 44, and 40% and time to death (TD) by 36, 52, and 42%, respectively. When administered intraperitoneally, the same doses increased FC by 62, 75, and 73% and TD by 76, 82, and 119%, respectively. Combined with polymixin or staurosporine, AMY (25 mg/kg, i.p.) increased TD by 61 and 63%, respectively, as related to each drug alone. When subchronically administered (25 and 50 mg/kg, i.p.) increased FC by 75 and 101% and TD by 86 and 124%, respectively. AMY increased taurine (116 and 76%) and tyrosine concentrations (135 and 110%) in basal ganglia and hippocampus, respectively, and decreased by 68, 65, and 62% glutamate, aspartate, and GABA in basal ganglia. CONCLUSION: Thus, the AMY anticonvulsant activity is related to the GABAergic system and may be linked to the inhibition of the signaling cascade of PKC as well as to alterations in amino acids metabolism.

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.

Larvicidal activity against Aedes aegypti of pacharin from Bauhinia acuruana.

The aim of the present study was to evaluate the activity of pacharin isolated from the ethanol extract from roots of Bauhinia acuruana on third-instar larvae of Aedes aegypti Linn. (Diptera: Culicidae). The crude ethanol extract showed larvicidal activity at the concentration of 500 µg/mL. Given this larvicidal activity, this extract was submitted to chromatographic fractionation on a silica gel column eluted with n-hexane, dichloromethane, ethyl ether, ethyl acetate, and methanol in order to isolate the active compound(s). Pacharin, obtained in pure form from fraction eluted with ethyl ether, was evaluated for their larvicidal effects against A. aegypti. In these bioassays, the larvae were exposed at concentrations of 500, 250, 100, 50, and 25 µg/mL of the crude ethanol extract or pacharin. After 24 h, the number of dead larvae was counted and the LC50 values for larval mortality were calculated. Pacharin showed LC50 value of 78.9 ± 1.8 µg/mL. The structure of isolated compound was identified on the basis of their spectral data (IR, 1D- and 2D-NMR) and by comparison with literature spectral data. The results indicate pacharin as a potential natural larvicide.

Carvacrol decreases neuronal excitability by inhibition of voltage-gated sodium channels.

The monoterpenoid carvacrol (1) is present in many essential oils of plants and has attracted attention because of its beneficial biological activities, especially analgesic activity. However, the mechanism of action of 1 remains unknown. The present study aimed to explore the mechanisms whereby 1 produces its effects on the peripheral nervous system. Carvacrol reversibly blocked the excitability of the rat sciatic nerve in a concentration-dependent manner with an IC(50) value of 0.50 ± 0.04 mM. At 0.6 mM, 1 increased the rheobase from 3.30 ± 0.06 V to 4.16 ± 0.14 V and the chronaxy from 59.6 ± 1.22 µs to 75.0 ± 1.82 µs. Also, 1 blocked the generation of action potentials (IC(50) 0.36 ± 0.14 mM) of the intact dorsal root ganglion (DRG) neurons without altering the resting potential and input resistance. Carvacrol reduced the voltage-gated sodium current of dissociated DRG neurons (IC(50) 0.37 ± 0.05 mM). In this study it has been demonstrated that 1 blocks neuronal excitability by a direct inhibition of the voltage-gated sodium current, which suggests that this compound acts as a local anesthetic. The present findings add valuable information to help understand the mechanisms implicated in the analgesic activity of carvacrol.

Angiogenesis inhibition by green propolis and the angiogenic effect of L-lysine on bladder cancer in rats.

PURPOSE: To determine the effects of water-soluble derivative of green propolis in bladder cancer angiogenesis in rats given N-butyl-(-4-hydroxybutyl) nitrosamine (BBN). METHODS: Nine groups were established, where six of them (Groups 1 to 6), the animals received 0.05% BBN in their drinking water for 14 weeks. From the 32nd to the 40th week, Groups 1, 2, 3 and 4 were treated respectively with water, L-lysine (300 mg/kg/day), celecoxib (30 mg/kg/day) and propolis (300 mg/kg/day). Groups 5 and 6 were given propolis and L-lysine from the 1st to the 40th week (150 mg/kg/day). Microvascular density was determined by histological sections stained for the marker CD-31 and analyzed with specific software. RESULTS: The microvascular density in bladder carcinomas was lower (p<0.01) in rats receiving propolis than in controls given carcinogen only. On the other hand, the microvascular density of tumors in rats receiving carcinogen and L-lysine for 40 weeks from the beginning of carcinogen treatment was significantly higher (p<0.01) than in the corresponding controls. CONCLUSION: Water-soluble derivative of propolis inhibits angiogenesis in BBN-induced rat bladder cancer, while L-lysine treatment stimulates angiogenesis if initiated concurrently with BBN.

Angiogenesis inhibition by green propolis and the angiogenic effect of L-lysine on bladder cancer in rats / Inibição da angiogênese pela própolis verde e efeito angiogênico da L-lisina no câncer de bexiga em ratos

PURPOSE: To determine the effects of water-soluble derivative of green propolis in bladder cancer angiogenesis in rats given N-butyl-(-4-hydroxybutyl) nitrosamine (BBN). METHODS: Nine groups were established, where six of them (Groups 1 to 6), the animals received 0.05% BBN in their drinking water for 14 weeks. From the 32nd to the 40th week, Groups 1, 2, 3 and 4 were treated respectively with water, L-lysine (300 mg/kg/day), celecoxib (30 mg/kg/day) and propolis (300 mg/kg/day). Groups 5 and 6 were given propolis and L-lysine from the 1st to the 40th week (150 mg/kg/day). Microvascular density was determined by histological sections stained for the marker CD-31 and analyzed with specific software. RESULTS: The microvascular density in bladder carcinomas was lower (p<0.01) in rats receiving propolis than in controls given carcinogen only. On the other hand, the microvascular density of tumors in rats receiving carcinogen and L-lysine for 40 weeks from the beginning of carcinogen treatment was significantly higher (p<0.01) than in the corresponding controls. CONCLUSION: Water-soluble derivative of propolis inhibits angiogenesis in BBN-induced rat bladder cancer, while L-lysine treatment stimulates angiogenesis if initiated concurrently with BBN.

OBJETIVO: Determinar os efeitos da própolis verde solúvel em água na angiogênese de câncer de bexiga em ratos que receberam n-butil-(-4-hidroxibutil) nitrosamina (BBN). METODOS: Nove grupos foram estabelecidos, onde em seis destes (grupos de 1 a 6) os animais receberam BBN a 0,05% em água de beber por 14 semanas. Na 32ª semana das 40 semanas, os grupos 1, 2, 3 e 4 foram tratados respectivamente com água, L lisina (300 mg/kg/dia), celecoxibe (30 mg/kg/dia) e própolis (300 mg/kg/dia). Os grupos 5 e 6 receberam própolis e L lisina da 1ª a 40ª semana (150 mg/ kg/dia). A densidade microvascular foi determinada por cortes histológicos corados pelo CD-31 e analisados por programa de computador específico. RESULTADOS: A densidade microvascular em carcinomas de bexiga foi menor com p<0,01 nos ratos que receberam própolis do que nos carcinomas do grupo controle que recebeu apenas carcinógeno. Por outro lado, a densidade microvascular de tumores de ratos que receberam carcinógeno e L-Lisina por 40 semanas desde o início do carcinógeno foi significantemente maior com p<0,01 que a densidade microvascular dos tumores de seu respectivo grupo controle. CONCLUSÃO: A própolis verde solúvel em água inibiu a angiogênese em câncer de bexiga induzido pelo BBN, enquanto a L- lisina estimulou a angiogênese quando iniciada juntamente com o BBN.

Antispasmodic effects of a new kaurene diterpene isolated from Croton argyrophylloides on rat airway smooth muscle.

OBJECTIVES: The effects of rel-(1S,4aS,7S,8aS)-7-(1-vinyl)-tetradecahydro-1,4a-dimethylphenanthrene-7,8a-carbolactone-1-carboxylic acid (TCCA), a new ent-kaurene diterpene isolated from Croton argyrophylloides, on rat tracheal preparations were investigated. METHODS: Tracheae were removed and cut into two-cartilage segments that were mounted in organ baths containing Tyrode's solution. RESULTS: TCCA reduced the contractions induced by electrical field stimulation, relaxed K(+)-induced contractions, and inhibited both phasic and tonic components of the K(+)- and ACh-induced contractions. TCCA reduced the serotonin-induced contraction, abolished that evoked by K(+) in the presence of epinephrine, and also reduced the ACh-induced contractions under Ca(2+)-free conditions. TCCA blocked contractions that depend on divalent cation inflow through voltage-operated Ca(2+) channels (VOCCs) and receptor-operated Ca(2+) channels (ROCCs), but had greater potency to block VOCC- than ROCC-dependent contractions or contractions induced by ACh in Ca(2+)-free conditions. TCCA relaxed the phorbol 12,13 dibutyrate (1 µm) induced contraction, but with slight potency. CONCLUSIONS: TCCA induces an antispasmodic effect through several mechanisms including blockade of either VOCCs (with greater potency) or ROCCs, blockade of IP(3)-induced Ca(2+) release from sarcoplasmic reticulum (with intermediate potency) and reduction of the sensitivity of contractile proteins to Ca(2+).

Chemoprevention with green propolis green propolis extracted in L-lysine versus carcinogenesis promotion with L-lysine in N-Butyl-N-[4-hydroxybutyl] nitrosamine (BBN) induced rat bladder cancer.

PURPOSE: To determine the effects of green propolis extracted in L-lysine (WSDP) and of L- lysine for 40 weeks on induced rat bladder carcinogenesis. METHODS: The animals (groups I, II, III, IV, V and VI) received BBN during 14 weeks. Group I was treated with propolis 30 days prior received BBN, and then these animals were treated daily with propolis; Groups II and III was treated with subcutaneous and oral propolis (respectively) concurrently with BBN. The animals of Group IV were treated L-lysine; Group V received water subcutaneous; and Group VI received only to BBN. Among the animals not submitted to carcinogenesis induction, Group VII received propolis, Group VIII received L-lysine and Group IX received water. RESULTS: The carcinoma incidence in Group I was lower than that of control (Group VI). The carcinoma multiplicity in Group IV was greater than in Group VI. All animals treated with L-lysine developed carcinomas, and they were also more invasive in Group IV than in controls. On the other hand, Group VIII showed no bladder lesions. CONCLUSION: The WSDP is chemopreventive against rat bladder carcinogenesis, if administered 30 days prior to BBN , and that L-lysine causes promotion of bladder carcinogenesis.