Renal fibrosis due to multiple cisplatin treatment is exacerbated by kinin B1 receptor antagonism.

Cisplatin is a widely used chemotherapeutic drug, but its side effects are a major limiting factor. Nephrotoxicity occurs in one third of patients undergoing cisplatin treatment. The acute tubular injury caused by cisplatin often leads to a defective repair process, which translates into chronic renal disorders. In this way, cisplatin affects tubular cells, and maladaptive tubules regeneration will ultimately result in tubulointerstitial fibrosis. Kinins are well known for being important peptides in the regulation of inflammatory stimuli, and kinin B1 receptor deficiency and antagonism have been shown to be beneficial against acute cisplatin nephrotoxicity. This study aimed to analyze the effects of kinin B1 receptor deletion and antagonism against repeated cisplatin-induced chronic renal dysfunction and fibrosis. Both the deletion and the antagonism of B1 receptor exacerbated cisplatin-induced chronic renal dysfunction. Moreover, the inhibition of B1 receptor increased tubular injury and tubulointerstitial fibrosis after repeated treatment with cisplatin. The balance between M1/M2 macrophage polarization plays an important role in renal fibrosis. Kinin B1 receptor antagonism had no impact on M1 markers when compared to cisplatin. However, YM1, an M2 marker and an important molecule for the wound healing process, was decreased in mice treated with kinin B1 receptor antagonist, compared to cisplatin alone. Endothelin-1 levels were also increased in mice with B1 receptor inhibition. This study showed that kinin B1 receptor inhibition exacerbated cisplatin-induced chronic renal dysfunction and fibrosis, associated with reduced YM1 M2 marker expression, thus possibly affecting the wound healing process.

Acute and subacute toxicity of the Carapa guianensis Aublet (Meliaceae) seed oil.

Carapa guianensis (Meliaceae), known as Andiroba in Brazil, has been used by Amazon Rainforest indigenous communities for treatment of coughs, convulsions, skin diseases, arthritis, rheumatism, ear infections, to heal wounds and bruises and as an insect repellent. Carapa guianensis seed oil (SO) was evaluated for its acute and subacute toxicity (30 days) by the oral route in Wistar rats. In the acute toxicity test, SO (0.625-5.0g/kg, n=5/sex) did not produce any hazardous symptoms or deaths. The subacute treatment with SO (0.375, 0.75 and 1.5g/kg, n=10/group) failed to change body weight gain, food and water consumption. Hematological analysis showed no significant differences in any of the parameters examined. However, in the biochemical parameters, there was an increase in the alanine aminotransferase (ALT) serum level (29%) in the group SO 1.5g/kg. In addition, absolute and relative liver weights were increased at the doses of 0.75g/kg (23.4 and 19.1%) and 1.5g/kg (18.7 and 33.1%). In conclusion, acute and subacute administration of Carapa guianensis seed oil did not produce toxic effects in male Wistar rats. However, the increase in the ALT serum level and in both absolute and relative liver weights may indicate a possible hepatic toxicity.

A toxicological evaluation of the effect of Carapa guianensis Aublet on pregnancy in Wistar rats.

The effects of the administration of Carapa guianensis Aublet (Meliaceae) seed oil were investigated during pregnancy in female Wistar rats. Five groups of pregnant rats (n=5-9 per group) were treated orally from the 7th to the 14th day of pregnancy (organogenic period), at doses of: 0, 0.375, 0.75, 1.5 and 3.0gkg(-1). On the 20th day of pregnancy, the animals were sacrificed and laparotomized to evaluate reproductive parameters. The results showed that there was no difference between the control and treated groups in terms of the number of live and dead fetuses, the dam-offspring relationship, the weight of the fetus, the weight of the placentae and ovaries, the number of implantation sites, the number of resorption sites, the number of corpora lutea in the ovaries, and the pre- and post-implantation loss rates. It is therefore concluded that administration of Carapa guianensis seed oil did not bring about any toxic effect on pregnancy in Wistar rats.

Renal fibrosis due to multiple cisplatin treatment is exacerbated by kinin B1 receptor antagonism

Cisplatin is a widely used chemotherapeutic drug, but its side effects are a major limiting factor. Nephrotoxicity occurs in one third of patients undergoing cisplatin treatment. The acute tubular injury caused by cisplatin often leads to a defective repair process, which translates into chronic renal disorders. In this way, cisplatin affects tubular cells, and maladaptive tubules regeneration will ultimately result in tubulointerstitial fibrosis. Kinins are well known for being important peptides in the regulation of inflammatory stimuli, and kinin B1 receptor deficiency and antagonism have been shown to be beneficial against acute cisplatin nephrotoxicity. This study aimed to analyze the effects of kinin B1 receptor deletion and antagonism against repeated cisplatin-induced chronic renal dysfunction and fibrosis. Both the deletion and the antagonism of B1 receptor exacerbated cisplatin-induced chronic renal dysfunction. Moreover, the inhibition of B1 receptor increased tubular injury and tubulointerstitial fibrosis after repeated treatment with cisplatin. The balance between M1/M2 macrophage polarization plays an important role in renal fibrosis. Kinin B1 receptor antagonism had no impact on M1 markers when compared to cisplatin. However, YM1, an M2 marker and an important molecule for the wound healing process, was decreased in mice treated with kinin B1 receptor antagonist, compared to cisplatin alone. Endothelin-1 levels were also increased in mice with B1 receptor inhibition. This study showed that kinin B1 receptor inhibition exacerbated cisplatin-induced chronic renal dysfunction and fibrosis, associated with reduced YM1 M2 marker expression, thus possibly affecting the wound healing process.

Influence of polymeric additives on the mechanical properties of alpha-tricalcium phosphate cement.

Recently, great attention has been paid to calcium phosphate cements, because of their advantages in comparison with conventional calcium phosphate bioceramics employed for bone repairing, regarding in situ handling, and shaping abilities. Nevertheless, the calcium phosphate cements exhibit relatively low mechanical strength. The aim of this work was the improvement of the compressive strength of alpha-tricalcium phosphate-based cement. The hydraulic setting reaction of this system produces a calcium-deficient hydroxyapatite phase suitable for bone repairing: alpha-Ca3(PO4)2 + H2O --> Ca9(HPO4)(PO4)5OH. Mechanical strength can be improved using technological solutions developed for other applications, such as Portland cement and dual-setting glass-ionomers, by using polymeric additives. The additives used in this work were sodium alginate, sodium polyacrylate, and an in situ polymerization system resulting in a polyacrylamide crosslinked hydrogel. Parameters evaluated were setting time, compressive strength before and after immersion in simulated body fluid, density, porosity, crystalline phases, and microstructure. Sodium alginate and sodium polyacrylate were deleterious to both setting time and mechanical strength. When the in situ polymerization system was added, two setting reactions progressed in parallel: the conventional hydraulic reaction and the copolymerization of acrylamide and crosslinking water-soluble monomers. The initial and final setting times of the "dual-setting" cement were 9 and 35 min, respectively, and they can be regulated varying the initiator, catalyst, and monomers concentrations. The initial compressive strength of the dual-setting cement (6.8 MPa at 0 h, and 15.2 MPa at 24 h) is higher than that of unmodified cement. The major crystalline phase after setting is hydroxyapatite. The dual-setting cement seems to be suitable for clinical applications in bone repairing and remodeling.

Triage methodology for the evaluation of implant-bone interfaces.

Stainless steel plugs coated with and without Al2O3, TiO2 and Nb2O5 were inserted into canine femora in order to develop a methodology of rapid identification of appropriate specimens for deeper analysis of implant-bone interfaces. This approach is especially meaningful in areas where research funds are scarce. After a maximum follow-up period of 52 wk, bone segments containing plugs were radiographed using conventional techniques, high resolution techniques (which allowed a good preliminary evaluation) and microradiography. Analysis by X-ray fluorescence spectrometry indicated release of the materials by the implants. Microdensitometry of the microradiographs allowed a precise thickness determination of the tissue formed around the implants.

Alpha-tricalcium phosphate cement: "in vitro" cytotoxicity.

Calcium phosphate-based bioceramics have revolutionized orthopedic and dental repair of damaged parts of the bone system. Among these materials, calcium phosphate-based cements, with hydraulic setting, stand out due to their biocompatibility and in situ hardening, which allow easy manipulation and adaptation to the shape and dimensions of bone defects. An investigation was made of the in vitro cytotoxic effect of calcium phosphate cement based on alpha-tricalcium phosphate, immersed for different lengths of time in simulated body fluid (SBF), based on the ISO-10993 "Biological Evaluation of Medical Devices" standard. The culture medium was Chinese hamster ovary (CHO) cells in contact with diluted cement extracts. The results revealed that the calcium phosphate cement used was cytotoxic and that the material's cytotoxicity decreased the longer the cement was immersed in SBF.

A dimeric ArC2 compound from Peperomia pellucida.

Pellucidin A, a novel dimeric ArC2 compound, together with dill-apiol have been isolated from the aerial parts of Peperomia pellucida. The structure of pellucidin A was established by 1D and 2D NMR spectroscopy (1H-1H COSY; 1H-13C COSY; DEPT; NOESY and double irradiation) and other spectroscopic techniques. The biogenesis of pellucidin A is also briefly discussed.

Flavonoids from Brosimum acutifolium.

4'-Hydroxy-7,8-[2-(2-hydroxyisopropyl)dihydrofuran]flavan and 4',7-dihydroxy-8-(3,3-dimethylallyl)flavan, together with 10 known plant constituents, were obtained from the trunk bark of Brosimum acutifolium. Their structures were elucidated by spectroscopic methods, including 2D NMR spectroscopic techniques.

Ethnopharmacology, phytochemistry and pharmacology: a successful combination in the study of Croton cajucara.

Phytochemical and pharmacological studies of Croton cajucara were oriented by traditional medicine. The stem bark of the mature plant is a rich source of clerodane-type diterpenes: trans-dehydrocrotonin (DCTN), trans-crotonin (CTN), cis-cajucarin B, cajucarin A, cajucarinolide and two novel clerodanes, trans-cajucarin B and sacacarin. In young (18-month-old) plants, the triterpene acetyl aleuritolic acid (AAA) was the major stem bark component and in these the diterpene DCTN was not present. The highest concentration of DCTN (1.4% of dry bark) was detected in 4-6 year-old plants, while 3-year-old plants contained only 0.26% of this diterpene. Three steroids (beta-sitosterol, stigmasterol and sitosterol-3-O-beta-glucoside), two flavonoids (kaempferol 3,4', 7-trimethyl ether and 3,7-dimethyl ether) and one diterpene (cajucarinolide) were isolated from the leaves of this Croton. The main pharmacological activity was correlated with DCTN. This clerodane produced anti-inflammatory and antinociceptive effects and a significant hypoglycemia in alloxan-induced diabetic rats. The compound also reduced the index of gastric lesions induced by restraint-in-cold. Dose-related DCTN and CTN inhibited in vivo the basal acid secretion in pylorus-ligature rats and oxyntic glands isolated from rabbit gastric mucosa, DCTN, CTN or AAA decreased in vitro uptake basal acid secretion induced by histamine and measured with the 14C-aminopyrine uptake method. Uniquely DCTN inhibited 14C-AP uptake induced by bethanechol. The terpenoids, DCTN and AAA, and the chloroform extract of 6-month-old plants reduced gastrointestinal transit in mice. The effects of DCTN and CTN on the survival of mice bearing Sarcoma 180 and Ehrlich carcinoma ascitic tumors, on the proliferation of cultured cells and TNFalpha were determined. DCTN was also evaluated for a possible antioestrogenic activity using the immature rat as a model system for bioassay of oestrogen and for an anti-implantation effect in regularly cycling rats. The biological experiments, using the plant extracts and the terpenoids DCTN, CTN and AAA, are herein discussed.

Artificial articular cartilage: mechanoelectrical transduction under dynamic compressive loading.

The search for biomaterials to be used as an artificial articular cartilage in joint restoration is a challenging research area. Because the articular cartilage plays a fundamental role in joint function, the biomaterial has to be able to mimic the behavior of the natural healthy surface. Articular cartilage is a biphasic material composed by a solid extracellular matrix and a fluid phase, the synovial fluid. When the tissue is pressed, there is a mechanoelectrical transduction that is believed to modulate the cellular activity of chondrocytes, being fundamental for tissue repair. This work aimed at the development of hydrogels for use as an artificial articular cartilage. Hydrogels with negative groups fixed in the macromolecular network were obtained by copolymerizing 2-hydroxyethyl methacrylate with acrylic acid. The obtained hydrogels showed a mechanoelectrical transduction under dynamic compressive loading with potential amplitude increasing with fixed charge density values.

In vitro evaluation of open heart surgery tubing coated with heparin and lipid.

The aim of this work was to evaluate in vitro the tromboresistence, hemolysis tendency, platelet adhesion, cytotoxicity, physicochemical properties, and stability of open-heart tubing coated with fractionated heparin-benzalkonium chloride and/or lipid dipalmitoyl L-alpha-phosphatidylcholine (DPPC). The tendency for clot formation and platelet adhesion was greater in noncoated and lipid-coated tubing than in heparin-coated tubing. There were no significant differences between the hemolytic potentials of coated and noncoated tubing. The coatings were stable during the time of the experiment. The coatings did not present cytotoxicity and physicochemical alterations.

Characterization of coatings for open-heart surgery tubing with heparin and lipid.

The aim of this study was to compare qualitative and quantitative methods for coating characterization on internal surfaces of polyvinyl chloride (PVC) tubing used in procedures of extracorporeal circulation. The methods of characterization included optical microscopy (OM) after dyeing with toluidine blue, scanning electron microscopy (SEM), atomic force microscopy (AFM) and energy dispersive spectrometry (EDS). OM after sample dyeing was excellent in allowing early detection of any absence or irregularities of coatings among the used methods. SEM was the most effective in observing the structure and thickness either in heparin coatings or in lipid coatings. AFM provided a good evaluation of the surface topography. A conjunction of all methods is recommended for complete characterization. The quantification methods based on colorimetric tests were efficient in determining the concentrations of heparin and lipid on internal surface tubes, the coating stability and the reproducibility of the results.

Fiber reinforced calcium phosphate cement.

The term calcium phosphate cement was introduced by Gruninger et al. (1). This type of cement can be prepared by reacting a calcium phosphate salt with an aqueous solution, which causes it to set by the crossing of the precipitated crystals. These cements offer a series of advantages that allow their use as grafts and substitutes of damaged parts of the bone system. However, these cements have low mechanical strength compared to human bones. This work studied the influence of the use of polyamide fibers in the mechanical properties of a calcium phosphate cement based on alpha-tricalcium phosphate as well as the mechanisms involved in the increase of mechanical strength. The results demonstrate the feasibility of the use of polymeric fibers to increase mechanical strength and the need for coupling agents for the effective performance of the fibers as reinforcement in these materials.

Auxiliary total artificial heart: A compact electromechanical artificial heart working simultaneously with the natural heart.

Leading international institutions are designing and developing various types of ventricular assist devices (VAD) and total artificial hearts (TAH). Some of the commercially available pulsatile VADs are not readily implantable into the thoracic cavity of smaller size patients because of size limitation. The majority of the TAH dimensions requires the removal of the patients' native heart. A miniaturized artificial heart, the auxiliary total artificial heart (ATAH), is being developed in these authors' laboratories. This device is an electromechanically driven ATAH using a brushless direct current (DC) motor fixed in a center metallic piece. This pusher plate-type ATAH control is based on Frank-Starling's law. The beating frequency is regulated through the change of the left preload, assisting the native heart in obtaining adequate blood flow. With the miniaturization of this pump, the average sized patient can have the surgical implantation procedure in the right thoracic cavity without removing the native heart. The left and right stroke volumes are 35 and 32 ml, respectively. In vitro tests were conducted, and the performance curves demonstrate that the ATAH produces 5 L/min of cardiac output at 180 bpm (10 mmHg of left inlet mean pressure and 100 mm Hg of left outlet mean pressure). Taking into account that this ATAH is working along with the native heart, this output is more than satisfactory for such a device.

Potencial acaricida do óleo de andiroba Carapa guianensis Aubl. sobre fêmeas adultas ingurgitadas de Anocentor nitens Neumann, 1897 e Rhipicephalus sanguineus Latreille, 1806 / Acaricide potencial of andiroba (Carapa guianensis Aubl.) oil on engorged adult females of Anocentor nitens (Neumann, 1897) and Rhipicephalus sanguineus (Latreille, 1806)

Avaliou-se o potencial acaricida in vitro do óleo da semente da andiroba (Carapa guianensis) sobre fêmeas ingurgitadas de Anocentor nitens (n=210) e Rhipicephalus sanguineus (n=140), coletadas manualmente, respectivamente, de equinos e de cães naturalmente infestados. Para o teste de imersão, empregaram-se cinco diluições do óleo de andiroba, 100 por cento, 50 por cento, 30 por cento, 25 por cento e 10 por cento, em água destilada, utilizando-se tween 80 como dispersante. No teste com A. nitens, foram usadas três repetições para cada diluição, utilizando-se 10 fêmeas ingurgitadas para cada tratamento. No teste com R. sanguineus, usaram-se duas repetições, e formaram-se, ainda, dois grupos-controle para cada espécie de ixodídeo, um com água destilada e outro com tween 80 mais água destilada. Após os testes, as fêmeas foram mantidas em laboratório sob temperatura ambiente. Observou-se mortalidade das fêmeas ingurgitadas e redução de postura, neste caso, com ovos inférteis, demonstrando eficácia de 100 por cento nas duas espécies em todas as diluições testadas. Os dados obtidos evidenciaram a potencialidade do uso do extrato de andiroba contra A. nitens e R. sanguineus.

In vitro acaricide potential of the oil from andiroba seed (Carapa guianensis) was evaluated on engorged females of Anocentor nitens (n=210) and Rhipicephalus sanguineus (n=140) manually collected, from horses and dogs naturally infested, respectively. Five dilutions, 100 percent, 50 percent, 30 percent, 25 percent, and 10 percent of andiroba seed oil in deionized water, using tween 80 as dispersant, were employed for the engorged females immersion test. For A. nitens test, three repetitions were made with each dilution, using 10 engorged females for each treatment, and two repetitions for R. sanguineus test. Two control groups were used for each tick species, one with deionized water and another one with tween 80 and deionized water. After the tests, the females were kept in the laboratory under room temperature. Engorged female mortality and oviposition reduction were observed with infertile eggs, showing 100 percent of efficacy in the two species in all tested dilutions. The obtained data demonstrated the potential use of andiroba seed extract against A. nitens and R. sanguineus.