The effect of lithium tetraborate as a novel cardioprotective agent after renal ischemia-reperfusion injury

Abstract Epidemiological studies suggest that acute kidney injury has certain effect on myocardial function. In this study, for the first time, we tested a boron compound namely lithium tetraborate an act as an anti-oxidant and anti-inflammatory agent in ischemia-reperfusion injury. For this, we employed an in vivo rat model with kidney ischemia reperfusion injury to evaluate cardiac injury to clarify the mechanisms of lithium tetraborate. The evaluation of cardiac injury through kidney artery occlusion and reperfusion rat model indicated that lithium tetraborate could (1) reduce oxidative stress-induced endothelial dysfunction; (2) attenuate the inflammatory response of cardiac cells; and (3) alleviate the apoptosis and necrosis of myocytes. In summary, lithium tetraborate demonstrates significant therapeutic properties that contribute to the amelioration of cardiac damage, and it could be a promising candidate for future applications in myocardial dysfunction.

Busca por oxidantes quirais para a transformação enantiosseletiva de compostos orgânicos de boro / Search for chiral oxidants for the enantioselective transformation of organic boron compounds

Neste trabalho, avaliou-se o potencial do uso de oxidantes quirais em oxidações enantiosseletivas de compostos orgânicos de boro. É de conhecimento geral que compostos orgânicos de boro, especialmente ésteres e ácidos borônicos são facilmente oxidados por hidroperóxidos em meio básico. No entanto, são escassos na literatura exemplos destas reações de modo enantiosseletivo. A fim de realizar as reações mencionadas, sintetizou-se os hidroperóxidos quirais TADOOH ({(4R,5R)-5-[(hidroperoxidifenil)metil]-2,2-dimetil-1,3-dioxolan-4il}difenilmetanol) e o hidroperóxido quiral derivado de carboidrato, 2,3-dideoxi1-O-oxidanil-4,6-di-O-pivaloil-α-D-eritro-hex-2-enopiranose (di-O-PivOOH). Estes compostos apresentaram resultados interessantes na literatura em oxidações enantiosseletiva de sulfetos orgânicos, em epoxidações de alcenos e em oxidações de Baeyer-Villiger. Inicialmente o potencial oxidativo de ambos hidroperóxidos, bem como a seletividade destes, foi avaliado frente a diversos ésteres borônicos, sendo que somente o TADOOH apresentou resultados promissores. (Ver esquema no PDF) Observou-se uma melhor seletividade do TADOOH frente a ésteres borônicos que possuíam grupos carbonílicos em sua estrutura. Ao submeter o ß-boronil-éster, 3-fenil-3-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)propanoato de etila, à oxidação com o TADOOH em THF utilizando NaOH como base, a -30°C por 1 hora, obteve-se o respectivo álcool com 40% de e.e. Cálculos de DFT para o estado de transição na oxidação dos ésteres borônicos com o TADOOH foram realizados em colaboração com o grupo do Prof. Dr. Ataualpa Albert Carmo Braga. Estes cálculos demonstraram que o estado de transição é estabilizado por uma ligação de hidrogênio não clássica entre o oxigênio da carbonila e umas das ligações C-H dos grupos fenila do TADOOH. Além dos estudos relatados, a reconhecida metodologia de Sharpless na epoxidação assimétrica de alcoóis alílicos foi adaptada para a oxidação enantiosseletiva de ésteres borônicos. Ao trocar o ligante derivado de éster tártarico, normalmente utilizado nas epoxidações de Sharpless, por (-)-efedrina observou-se uma moderada seletividade deste sistema frente ao pinacol l-fenietilboronato. Investigações mais detalhadas demonstraram que a presença do Ti(IV) não era necessária, sendo que a (-)efedrina era a responsável pela ativação e indução quiral nesta reação.

In this work, it was investigated the potential use of chiral oxidants in organic boron compound oxidation. It is known in the literature, that organic boron compounds can be easily oxidized by hydroperoxides. However, an enantioselective approach in literature is scarce. In order to perform these reactions, hydroperoxide TADOOH ({(4R,5R)-5[(hydroperoxydiphenyl)methyl]-2,2-dimethyl-l,3-dioxolan-4-yl}diphenylmethanol) and carbohydrate derived hydroperoxide, 2,3-dideoxy-1-O-oxidanyl-4,6-di-O-pivaloyl-α-D-erythro-hex-2-enopyranose (di-O-PivOOH), have been synthesized. These compounds showed interesting results in several enantioselective oxidations, as like, organic sulfides oxidation, alkenes epoxidation and Baeyer-Villiger oxidations. The oxidative potential of both hydroperoxides, as well as their selectivity, were evaluated against several boronic esters. Only TADOOH has shown promissing results for further studies. (See Scheme on PDF). Boronic esters containing a carbonyl moiety showed better selectivities with TADOOH, for example, the reaction of ß-boronyl-ester, ethyl 3-phenyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)propanoate, gave the correponding alcohol with 40% e.e. DFT calculations for the transition state in the oxidation of the boronic esters with TADOOH were carried out in collaboration with the group of Prof. Dr. Ataualpa Albert Carmo Braga. These calculations have shown that the transition state is stabilized by a non-classical hydrogen bond between the carbonyl oxygen and one of the C-H bonds of the TADOOH phenyl groups. In addition to the studies, the well-known Sharpless protocol for asymmetric epoxidation of allylic alcohols was adapted in the enantioselective oxidation of boronic esters. By replacing the tartaric ester-derived, commonly used in the Sharpless experiments, for (-)-ephedrine moderate selectivity was observed with pinacol 1-phenylethyl boronate. Further investigations showed that the presence of Ti (IV) was not necessary, and (-)-ephedrine was responsible for the activation and chiral induction in this reaction.

Human umbilical artery smooth muscle exhibits a 2-APB-sensitive capacitative contractile response evoked by vasoactive substances and expresses mRNAs for STIM, Orai and TRPC channels

After depletion of intracellular Ca2+ stores the capacitative response triggers an extracellular Ca2+ influx through store-operated channels (SOCs) which refills these stores. Our objective was to explore if human umbilical artery smooth muscle presented this response and if it was involved in the mechanism of serotonin- and histamine-induced contractions. Intracellular Ca2+ depletion by a Ca2+-free extracellular solution followed by Ca2+ readdition produced a contraction in artery rings which was inhibited by the blocker of Orai and TRPC channels 2-aminoethoxydiphenyl borate (2-APB), suggesting a capacitative response. In presence of 2-APB the magnitude of a second paired contraction by serotonin or histamine was significantly less than a first one, likely because 2-APB inhibited store refilling by capacitative Ca2+ entry. 2-APB inhibition of sarcoplasmic reticulum Ca2+ release was excluded because this blocker did not affect serotonin force development in a Ca2+-free solution. The PCR technique showed the presence of mRNAs for STIM proteins (1 and 2), for Orai proteins (1, 2 and 3) and for TRPC channels (subtypes 1, 3, 4 and 6) in the smooth muscle of the human umbilical artery. Hence, this artery presents a capacitative contractile response triggered by stimulation with physiological vasoconstrictors and expresses mRNAs for proteins and channels previously identified as SOCs.

Effect of cement type and water storage time on the push-out bond strength of a glass fiber post

This study investigated the effects of the cement type and the water storage time on the push-out bond strength of a glass fiber post. Glass fiber posts (Fibrekor, Jeneric Pentron) were luted to post spaces using a self-cured resin cement (C&B Cement [CB]), a glass ionomer cement (Ketac Cem [KC]) or a resin-modified glass ionomer cement (GC FujiCEM [FC]) according to the manufacturers’ instructions. For each luting agent, the specimens were exposed to one of the following water storage times (n=5): 1 day (T1), 7 days (T7), 90 days (T90) and 180 days (T180). Push-out tests were performed after the storage times. Control specimens were not exposed to water storage, but subjected to the push-out test 10 min after post cementation. Data (in MPa) were analyzed by Kruskal-Wallis and Dunn`s test (α=0.05). Cement type and water storage time had a significant effect (p<0.05) on the push-out bond strength. CB showed significantly higher values of retention (p<0.05) than KC and FC, irrespective of the water storage time. Water storage increased significantly the push-out bond strength in T7 and T90, regardless of the cement type (p<0.05). The results showed that fiber posts luted to post spaces with the self-cured resin cement exhibited the best bonding performance throughout the 180-day water storage period. All cements exhibited a tendency to increase the bond strength after 7 and 90 days of water storage, decreasing thereafter.

Este estudo investigou os efeitos do tipo de cimento e do tempo de armazenamento em água na resistência adesiva ao cisalhamento de pinos de fibra. Pinos de fibra de vidro (Fibrekor, JenericPentron) foram cimentados aos condutos radiculares usando o cimento resinoso autopolimerizável (C&B Cement [CB]), o cimento de ionômero de vidro (Ketac Cem [KC]) ou o cimento de ionômero de vidro modificado por resina (GC FujiCEM [FC]) de acordo com as instruções dos fabricantes. Para cada cimento, os espécimes foram expostos a um dos seguintes tempos de armazenamento em água (n=5): 1 dia (T1), 7 dias (T7), 90 dias (T90) e 180 dias (T180). Os testes de resistência adesiva ao cisalhamento foram realizados após os períodos de armazenamento. Os espécimes controles não foram expostos ao armazenamento em água, mas submetidos ao teste de resistência adesiva ao cisalhamento 10 min após a cimentação do pino. Os dados (MPa) foram analisados usando Kruskal-Wallis e teste de Dunn (α=0,05). O tipo de cimento e o tempo de armazenamento em água afetaram significantemente a resistência adesiva ao cisalhamento (p<0,05). CB apresentou valores de retenção significantemente superiores a KC e FC, independentemente do tempo de armazenamento em água. Esse, por sua vez, aumentou significantemente a resistência adesiva ao cisalhamento em T7 e T90, independentemente do tipo de cimento (p<0,05). Os resultados indicaram que os pinos de fibra cimentados aos condutos radiculares com o cimento resinoso autopolimerizável apresentou a melhor performance adesiva durante todo o período de armazenamento em água de 180 dias. Todos os cimentos apresentaram uma tendência a aumentar a resistência adesiva ao cisalhamento após 7 e 90 dias de armazenamento em água, diminuindo posteriormente.

Effect of endodontic sealer and resin luting strategies on pull-out bond strength of glass fiber posts to dentin

The aim of this study was to evaluate the influence of eugenolcontaining endodontic sealers and luting strategy on the pull-out bond strength of glass fiber posts to dentin. Sixty-four bovine incisors were randomly assigned into two groups of 32 specimens each for obturation procedure with gutta-percha only, or with Pulp Canal Sealer EWT. Subsequently, the roots were prepared for the fiber post Reforpost and all specimens of each endodontic sealing procedure were allocated to four groups (n=8), according to the strategies for post cementation: A) Single Bond 2 and RelyX ARC; B) All Bond 2 and C&B cement; C) All Bond 2 and RelyX ARC; D) Single Bond 2 and C&B Cement. The posts were cemented immediately after the endodontic treatment. The pull-out test was performed at a cross-head speed of 0.5 mm/min in a universal testing machine (EMIC). Data (Kgf) were submitted to a two-way ANOVA and Tukey test (p ≤ 0.05). The eugenol-based sealer did not influence the pull-out bond strength of fiber posts regardless of the luting strategy. RelyX ARC showed higher bond strength than C&B Cement when used with Single Bond 2 adhesive system, when the eugenol-based sealer was present. All Bond 2, when associated to all cements studied, promoted similar bond strength, regardless of the eugenol-containing endodontic sealer. In conclusion, eugenolcontaining sealer did not influence the pull-out bond strength values of the resin luting systems for glass fiber post cementation. The bond system and resin cement association from the same manufacturer had similar bond strength values for dentin.

O objetivo desse estudo foi avaliar a influencia de cimentos endodonticos a base de eugenol e estrategia de cimentacao resinosa na resistencia a tracao de pinos de fibra de vidro a dentina. Sessenta e quatro incisivos bovinos foram aleatoriamente divididos em dois grupos com 32 especimes para cada procedimento de obturacao, com o cimento a base de eugenol Pulp Canal Sealer EWT ou somente com guta percha pela tecnica termoplastificada. Apos, realizou-se o prepare do conduto radicular para o pino de fibra Reforpost e posteriormente, as amostras de cada procedimento obturador foram separadas em quarto grupos (n=8), considerando as estrategias para cimentacao do pino: A) Adper Single Bond 2 e RelyX ARC; B) All Bond 2 e C&B cement; C) All Bond 2 e RelyX ARC; D) Adper Single Bond 2 e C&B Cement. Os pinos foram imediatamente cimentados apos o tratamento endodontico. Dessa maneira, o teste de pull-out foi realizado a uma velocidade de 0.5 mm/min em maquina de ensaio universal (EMIC DL2000). Os dados (Kgf) A analise estatistica foi realizada pelos testes ANOVA de dois fatores e teste de Tukey (p ≤ 0.05). O cimento endodontico contend eugenol nao influenciou a resistencia de uniao a tracao (pull-out) dos pinos de fibra, independente da estrategia de cimentacao. O RelyX ARC ofereceu maior resistencia de uniao do pino a dentina, comparado ao C&B Cement quanto utilizado com o Adper Single Bond 2, na presenca do cimento endodontico contendo eugenol. O All Bond 2 quando associado a todos os cimentos estudados promoveram uma resistencia de uniao semelhante, independente do conteudo de eugenol na cimentacao endodontica. Em conclusao, o cimento endodontico a base de eugenol nao influenciou na resistencia a tracao de pinos de fibra a dentina. A associacao de sistema adesivo e cimento resinoso do mesmo fabricante apresentou valores de resistencia de uniao semelhantes na cimentacao de pinos de fibra.

Boron neutron capture therapy in cancer: past, present and future

Undifferentiated thyroid cancer (UTC) is a very aggressive tumor with no effective treatment, since it lacks iodine uptake and does not respond to radio or chemotherapy. The prognosis of these patients is bad, due to the rapid growth of the tumor and the early development of metastasis. Boron neutron capture therapy (BNCT) is based on the selective uptake of certain boron non-radioactive compounds by a tumor, and the subsequent irradiation of the area with an appropriate neutron beam. 10B is then activated to 11B, which will immediately decay releasing alpha particles and 7Li, of high linear energy transfer (LET) and limited reach. Clinical trials are being performed in patients with glioblastoma multiforme and melanoma. We have explored its possible application to UTC. Our results demonstrated that a cell line of human UTC has a selective uptake of borophenylalanine (BPA) both in vitro and after transplantation to nude mice. Treatment of mice by BNCT led to a complete control of growth and cure of 100 percent of the animals. Moreover dogs with spontaneous UTC also have a selective uptake of BPA. At the present we are studying the biodistribution of BPA in patients with UTC before its application in humans.

O câncer indiferenciado de tiróide (CIT) é um tumor muito agressivo sem tratamento efetivo, uma vez que não capta iodo e não responde à radio ou quimioterapia. O prognóstico desses pacientes é ruim, devido ao rápido crescimento do tumor e surgimento precoce de metástases. A terapia por captura de nêutrons de boro (TCNB) é baseada na captação seletiva de certos compostos de boro não-radioativos pelo tumor, e à subsequente irradiação da área com um feixe de nêutrons apropriado. O 10B é então ativado para 11B, cujo decaimento imediato libera partículas alfa e 7Li, de alta transferência linear de energia (TLE) e alcance limitado. Ensaios clínicos estão sendo conduzidos em pacientes com glioblastoma multiforme e melanoma, e nós estamos explorando sua possível aplicação no CIT. Nossos resultados demonstram que uma linhagem celular do CIT humano mostra captação seletiva de borofenilalanina (BPA) tanto in vitro como após transplante em camundongos "nude". O tratamento de camundongos com TCNB leva a um controle completo do crescimento tumoral e à cura em 100 por cento dos animais. Além disso, cães com CIT espontâneo também apresentam captação seletiva de BPA. No momento, estamos estudando a biodistribuição de BPA em pacientes com CIT, antes de sua aplicação em humanos.

Tratamiento del cáncer por captura neutrónica de boro: su aplicación al carcinoma indiferenciado de tiroides / Boron neutron capture therapy applied to undifferentiated thyroid carcinoma

El cáncer indiferenciado de tiroides es un tumor muy agresivo, de muy mal pronóstico y sin tratamiento efectivo. La terapia por captura neutrónica de boro (BNCT) podría ser una alternativa para el tratamiento de esta enfermedad. Se basa en la captación selectiva de boro por el tumor y su activación por un haz de neutrones. El boro activado libera un núcleo de litio-7 y una partícula alfa, las cuales tienen una alta transmisión linear de energía (linear energy transfer, LET) y un alcance de 5-9 µm, destruyendo el tumor. En estudios previos hemos mostrado que la línea celular humana de cáncer indiferenciado de tiroides (ARO) tiene una captación selectiva de borofenilalanina (10BPA) tanto in vitro como después de ser implantada en ratones NIH nude. También demostramos en estos animales inyectados con BPA e irradiados con un haz de neutrones térmicos, un 100% de control sobre el crecimiento tumoral y un 50% de cura histológica. En trabajos posteriores mostramos que la porfirina 10BOPP tetrakis-carborane carboxylate ester de 2,4-bis-(a,b-dihydroxyethyl)-deutero-porphyrin IX) cuando es inyectada 5-7 días antes que el BPA se obtiene una concentración tumoral de boro de aproximadamente el doble que el BPA solo (45-38 ppm vs. 20 ppm). La posterior irradiación con neutrones mostró un 100% de remisión completa en animales con tumores cuyo volumen pre-tratamiento era de 50 mm3 o menor. Los perros padecen CIT espontáneo, con un comportamiento biológico similar al humano, y una captación selectiva de BPA, abriendo la posibilidad de su tratamiento por BNCT

Undifferentiated thyroid carcinoma (UTC) is an aggressive tumor with a poor prognosis due to the lack of an effective treatment. Boron neutron capture therapy (BNCT) is based on the selective uptake of boron by the tumor and its activation by a neutron beam, releasing lithium-7 and an alpha particle that will kill the tumor cells by their high linear energy transfer (LET). In previous studies we have shown a selective uptake of borophenylalanine (10BPA) in a human UTC cell line (ARO) and in NIH nude mice implanted with this cell line. When these animals were injected with BPA and irradiated with an appropriated neutron beam, we observed a 100% of tumor growth control and a 50 % of histological cure when the initial tumor volume was 50 mm3 or less. Further studies with BOPP (tetrakis-carborane carboxylate ester of 2,4-bis-(a, b-dihydroxyethyl)-deutero-porphyrin IX) showed that when this porphyrin was injected 5-7 days before BPA, and the animals were sacrificed 60 min after the i.p. injection of BPA, a significant increase in boron uptake by the tumor was found (45-38 ppm with both compounds vs. 20 ppm with BPA alone). The application of BNCT using the combination of boron compounds showed a 100% of complete remission in tumors with initial volumes under 50 mm3. Dogs suffer spontaneous UTC, with a similar biological behavior to the human tumor, and a selective uptake of BPA. These results open the possibility of applying BNCT to UTC

El kininógeno de alto peso molecular: su participación en la respuesta inflamatoria y en la angiogénesis. Propiedades y posible aplicación terapéutica / High molecular weight kininogen in inflammation and angiogenesis: a review of its properties and therapeutic applications

The plasma kallikrein-kinin system (KKS) participates in the pathogenesis of inflammatory reactions involved in cellular injury, coagulation, fibrinolysis, kinin formation, complement activation, cytokine secretion and release of proteases. It has been shown that KKS activation in the systemic inflammatory response syndrome results in decrease of its component plasma proteins. Similar changes have been documented in diabetes, sepsis, children with vasculitis, allograft rejection, disseminated intravascular coagulation, patients with recurrent pregnancy losses, hereditary angioedema, adult respiratory distress syndrome and coronary artery disease. Direct involvement of the KKS in the pathogenesis of experimental acute arthritis and acute and chronic enterocolitis has been documented by previous studies from our laboratory using experimental animal models. It has been found that in HK deficient Lewis rats, experimental IBD was much less severe. We showed a genetic difference in kininogen structure between resistant Buffalo and susceptible Lewis rats, which results in accelerated cleavage of HK and it is responsible for the susceptibility to the inflammatory process in the Lewis rats. It has been demostrated that therapy with a specific plasma kallikrein inhibitor (P8720) modulated the experimental enterocolitis, arthritis and systemic inflammation. Furthermore, it has been shown that a bradykinin 2 receptor (B2R) antagonist attenuates the inflammatory changes in the same animal model. We have showed that a monoclonal antibody targeting HK decreases angiogénesis and arrests tumor growth in a syngeneic animal model. In summary, these results indicate that the plasma KKS plays a central role in the pathogenesis of chronic intestinal inflammation, arthritis and angiogenesis.

Se ha demostrado la participación del sistema plasmático de kalikreína-kininas (KKS) en el proceso inflamatorio, el cual incluye reacciones de daño celular, coagulación y fibrinólisis, formación de kininas, activación del complemento, secreción de citoquinas y liberación de proteasas. El KKS se encuentra activado en el síndrome de respuesta inflamatoria sistémica con una disminución en la concentración plasmática de las proteínas que lo constituyen. También se ha demostrado una activación similar en la diabetes, choque séptico, vasculitis en infantes, enfermedad injerto-huésped, coagulación intravascular diseminada, pacientes con abortos de repetición, angioedema hereditario, el síndrome de estrés respiratorio del adulto y enfermedad coronaria arterial. Mediante el uso de modelos animales experimentales, nuestro laboratorio ha demostrado una participación directa del KKS en la patogénesis de la artritis experimental aguda y la enterocolitis aguda y crónica. Se ha demostrado que en la rata tipo Lewis, cuando es deficiente de kininógeno de alto peso molecular (HK), la enfermedad inflamatoria intestinal es menos severa comparada con la presentada en ratas con niveles normales de HK como la Buffalo. Nosotros mostramos una diferencia entre el gene que codifica la molécula del kininógeno de la rata tipo Buffalo (resistentes) y Lewis (susceptibles), que resulta en un incremento de la actividad proteolítica de kalikreína sobre su substrato HK, lo cual predispone a las ratas Lewis al desarrollo de la enfermedad inflamatoria crónica. Se ha demostrado una disminución en las manifestaciones inflamatorias sistémicas de la enterocolitis y artritis experimental mediante el uso de un inhibidor específico de la kalikreína (P8720). Además, el antagonista del receptor 2 de la bradikinina (BR2) atenuó los cambios inflamatorios en el mismo modelo animal. Asimismo, se ha demostrado que las ratas Lewis deficientes de kininógeno desarrollaron inflamación intestinal sistémica menos severa. Mediante el uso del anticuerpo monoclonal C11C1 contra HK se logró una disminución de la angiogenesis y, consecuentemente, el crecimiento tumoral. En conclusión, los resultados demuestran que el sistema plasmático de KKS desempeña un papel preponderante en la patogénesis de la artritis reumatoide, la enfermedad intestinal crónica y en el proceso angiogénico.