Análisis de desbalanceo dinámico mediante el software SKF Aptitude Analyst en conjunto con un estudio de vibraciones en rotor Machinery Fault Simulator

96 p.El presente informe desarrolla un estudio de desbalanceo mecánico en el simulador de fallas del laboratorio de mantenimiento de la escuela de ingeniería civil mecánica, con el fin de estudiar el comportamiento mecánico especialmente en el área de vibraciones mecánicas, con el cual se busque establecer marcos para la prevención y predicción de fallas en equipos rotativos similares en base a la falla por desbalanceo. El estudio dio inicio creando una base de datos inicial para establecer la condición actual del equipo debido a que esta se desconocía y según lo informado no era utilizado regularmente por los docentes ni alumnos, observando que funcionaba correctamente pero no a la perfección, dando a entender que no había recibido algún tipo de ajuste recientemente. Una parte importante fue el sistema de medición y registro de datos en el cual se disponía de un analizador de vibraciones portátil SKF y a su vez se dieron indicaciones de que se había adquirido el software SFK de análisis en la computadora del laboratorio. Al trabajar con un equipo rotativo, se buscó dentro de las normas ISO relacionadas a vibraciones la más adecuada para este tipo de equipo de baja potencia, llegando a que la norma ISO 2372 era la que nos marcaba los márgenes de operación adecuados y óptimos. Ya con todos estos elementos se pudo dar inicio a la generación de fallas dentro del equipo, dado un estudio anterior realizado en la escuela de ingeniería Civil Mecánica, que sentaba las bases para la puesta en marcha del equipo indicaba que el equipo empezaba a sufrir mayores vibraciones notorias de 2 a 4 gr, por lo que se optó por trabajar con masas de pruebas de 4 gr, para posterior a analizar su comportamiento ir aumentando de manera progresiva. Logrando las muestras a 4, 8 y 10 gr (masas seleccionadas) se procede a hacer un análisis comparativo en base a su frecuencia vibratoria Global y sus espectros de onda, en los cuales se observan comportamientos esperados y no esperados en el equipo. Finalmente se busca eliminar la falla del equipo para monitorear su condición después de una serie de ajustes y correcciones con el fin de establecer indicaciones en la solución y diagnóstico de futuras fallas de este tipo o algunas relacionadas dentro del equipo de laboratorio y similares

Estudio de cationes lipofílicos deslocalizados derivados de ácidos poli hidroxi benzoicos como agentes citotóxicos en células de cáncer de mama humanas

Memoria para optar al título de Químico FarmacéuticoEstudios previos han demostrado que derivados del ácido gálico unidos a trifenilfosfonio mediante una cadena alifática de diez carbonos son efectivos agentes citotóxicos, desacoplando la cadena transportadora de electrones del complejo ATP sintasa mitocondrial en células de adenocarcinoma murinas. En el presente trabajo se demostró dicho efecto en células de cáncer de mama humano, así como también se determinó la relación estructura-actividad de derivados de este compuesto. Fueron analizados derivados mono- y di-hidroxilados del ácido benzoico en diferentes líneas celulares de cáncer de mama humanas, las cuales se diferencian en su perfil metabólico y en la expresión de receptores de crecimiento y hormonales. Se observó que dos de los nuevos derivados presentan un mayor efecto citotóxico que los previamente estudiados, los cuales son 2-OH TPP+C10 y Gent TPP+C10, debido a una mayor actividad desacoplante de la fosforilación oxidativa. En forma exhaustiva fueron estudiadas las líneas celulares, MCF7 caracterizada por la presencia de receptores hormonales y la línea MDA-MB-231, la cual posee un fenotipo triple negativo con características metastásica y un metabolismo altamente glicolítico. Se evidenció que los derivados presentan un tropismo mitocondrial, afectando las funciones de este organelo debido a que son capaces de desencadenar una disminución del potencial de transmembrana mitocondrial, lo que conlleva a una disminución de la razón NAD(P)H/NAD(P)+ y una caída del ATP total, parcialmente compensada por la actividad de AMP-kinasa y adenilato kinasa. Como consecuencia, se desencadena una muerte de tipo apoptótica. Además, se observó que los derivados son capaces de inhibir la migración celular en la línea metastásica. La selectividad de estos compuestos fue evaluada al comparar el efecto citotóxico con la línea mamaria epitelial MCF 10F, demostrando que los compuestos 2-OH TPP+C10 y Gent TPP+C10 presentan selectividad a las concentraciones utilizadas, ya que no inducen una muerte significativa a las 48 horas, ni una caída del ATP total en las condiciones analizadas. Como conclusión, todas las moléculas analizadas presentan actividad citotóxica similar en células de cáncer de mama humanas; además, la modificación realizada al grupo farmacóforo la aumentaPrevious studies have shown that gallic acid derivatives bound to an aliphatic chain of ten carbons length to triphenylphosphonium are effective cytotoxic agents, inducing an uncoupler effect to the electron transport chain of the mitochondrial ATPsynthase complex in murine adenocarcinoma cells. The present work displays the effect of these derivatives in human breast cancer cells, as well as the study of the structure-activity relationship derived from these compounds. Mono- and di-hydroxyl derivatives of benzoic acid were analyzed in different human breast cancer cell lines, which differ in their metabolic profile, hormone receptors expression and growth. It was observed that two new derivatives exhibit greater cytotoxic effect than those previously studied, which are: 2-OH TPP+C10 and Gent TPP+C10, due to an increased activity of uncoupling oxidative phosphorylation process. Two cell lines were exhaustively studied, MCF7 characterized by the presence of hormone receptors and MDA-MB-231, which has a triple negative phenotype, metastatic features and a highly glycolytic metabolism. It was demonstrated that the derivatives possess a mitochondrial tropism, affecting the functions of this organelle because they are capable of triggering a decrease in mitochondrial transmembrane potential, leading to a decrease in NAD(P)H/NAD(P)+ ratio and drop of total ATP, partially offset by the activity of AMP-kinase and adenylate kinase. As a result, the intrinsic apoptotic death via is triggered. It was further noted that the derivatives are capable of inhibiting cell migration in metastatic cell line. The selectivity of these compounds was evaluated by comparing the cytotoxic effect with MCF 10F mammary epithelial cell line, showing that compounds 2-OH TPP+C10 and Gent TPP+C10 revealed selectivity at the concentrations used, as they did not induce significant death at 48 hours of treatment, or a drop of the total ATP in the conditions analyzed. In conclusion, all tested molecules shown similar cytotoxic activity on breast human cancer cell lines where, the modification in the pharmacophore moiety increased this activit

Shedding Light on the Dentition and Venom Delivery System of the Rear-Fanged Snake, Galvarinus chilensis chilensis (Serpentes: Dipsadidae: Tachymenini) from Chile

Although the rear-fanged snake Galvarinus chilensis chilensis (formerly named Tachymenis ch. chilensis) causes ophidian accidents with clinical importance in Chile, the anatomical and histological characterizations of the venom delivery system (venom gland and fang) of this species still remain unknown. This study describes the dentition and characteristics of fangs and their ontogenetic variations in G. ch. chilensis. Moreover, histological and histochemistry analyses of the venom glands of this species are presented. Using micro-computed tomography and scanning electron microscopy, the dentitions of neonates, juveniles, and adults were analyzed, and no ontogenetic variations in teeth length and number present in the dentary and maxilla were observed. Moreover, we found three types of basic teeth, with distributional patterns conserved in all ontogenetic categories. The fangs exhibited a groove from the base to the middle. At the end of the groove, prominent ridges are formed. The fang and groove lengths were significantly distinct between ontogenetic categories. No differences between females and males were observed. Histologically, we found that the venom gland is close to the fangs and has a seromucous composition. Our results describe, for the first time, the distributional pattern and characteristics of the dentition and venom delivery system of the poorly studied snake G. ch. chilensis.Fil: Herrera, Yarela. Network For Snake Venom Research And Drug Discovery; Chile. Universidad de Chile; ChileFil: Fuentes Retamal, Sebastián. Network For Snake Venom Research And Drug Discovery; Chile. Universidad de Chile; ChileFil: Kemmerling, Ulrike. Universidad de Chile; ChileFil: Peichoto, María Elisa. Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán". Instituto Nacional de Medicina Tropical; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; ArgentinaFil: Ortiz, Juan Carlos. Universidad de Concepción; ChileFil: Urra, Félix A.. Universidad de Chile; Chile. Network For Snake Venom Research And Drug Discovery; Chil

Shedding Light on the Dentition and Venom Delivery System of the Rear-Fanged Snake, Galvarinus chilensis chilensis (Serpentes: Dipsadidae: Tachymenini) from Chile

Although the rear-fanged snake Galvarinus chilensis chilensis (formerly named Tachymenis ch. chilensis) causes ophidian accidents with clinical importance in Chile, the anatomical and histological characterizations of the venom delivery system (venom gland and fang) of this species still remain unknown. This study describes the dentition and characteristics of fangs and their ontogenetic variations in G. ch. chilensis. Moreover, histological and histochemistry analyses of the venom glands of this species are presented. Using micro-computed tomography and scanning electron microscopy, the dentitions of neonates, juveniles, and adults were analyzed, and no ontogenetic variations in teeth length and number present in the dentary and maxilla were observed. Moreover, we found three types of basic teeth, with distributional patterns conserved in all ontogenetic categories. The fangs exhibited a groove from the base to the middle. At the end of the groove, prominent ridges are formed. The fang and groove lengths were significantly distinct between ontogenetic categories. No differences between females and males were observed. Histologically, we found that the venom gland is close to the fangs and has a seromucous composition. Our results describe, for the first time, the distributional pattern and characteristics of the dentition and venom delivery system of the poorly studied snake G. ch. chilensis

Antiproliferative and proapoptotic activities of aza-annulated naphthoquinone analogs

© 2018 1,4-Naphthoquinone derivatives have been widely documented with regard to their biological properties, and particularly their anticancer activities. In the 9,10-anthraquinone family, aza-annulation involving one of the carbonyl oxygen atoms has afforded more potent, possibly less toxic analogues. We recently carried out different modifications on the naphthoquinone skeleton to generate 3-chloro-2-amino- and 3-chloro-2-(N-acetamido)-1,4-naphthoquinone and 3,4-dihydrobenzo[f]quinoxalin-6(2H)-one derivatives. These three series of compounds were now tested against normal human fibroblasts and six human cancer cell lines. Some of the dihydrobenzoquinoxalinone derivatives were not only more potent than their 1,4-naphthoquinone counterparts, but also exhibited 10- to 14-fold selectivity between bladder carcinoma and normal cells and were equipotent with the non-selective reference drug used (etoposide). The fusion of an additional azaheterocycle to the 1,4-naphthoquinone nucleus modu

FRI-1 Is an Anti-Cancer Isoquinolinequinone That Inhibits the Mitochondrial Bioenergetics and Blocks Metabolic Shifts by Redox Disruption in Breast Cancer Cells

Since breast cancer (BC) cells are dependent on mitochondrial bioenergetics for promoting proliferation, survival, and metastasis, mitochondria highlight as an important target for anticancer drug discovery. FRI-1, methyl 1, 3-dimethyl-5, 8-dioxo-5, 8-dihydro-4-isoquinolinecarboxylate, was previously described as a selective cytotoxic compound on cancer cell lines, however, details on the mechanism of action remain unknown. In this work, we describe that FRI-1 inhibits mitochondrial bioenergetics, producing apoptosis in MCF7 and MDA-MB-231 BC cell lines. FRI-1 decreases the maximal oxygen consumption rate (OCR), Δψm, NADH, and ATP levels, with a notable increase of mitochondrial reactive oxygen species (ROS) production, promoting AMPK activation with pro-survival effects. Moreover, FRI-1 inhibits the metabolic remodeling to glycolysis induced by oligomycin. In isolated tumoral mitochondria, FRI-1 increases Complex I and III-dependent OCR state 2, and this is sensitive to rotenone and antimycin A inhibitor additions, suggesting a redox cycling event. Remarkably, α-ketoglutarate and lipoic acid supplementation reversed and promoted, respectively, the FRI-1-induced apoptosis, suggesting that mitochondrial redox disruption affects 2-oxoglutarate dehydrogenase (OGDH) activity, and this is involved in their anticancer mechanism. Consistent with this, the combination of FRI-1 and CPI-613, a dual inhibitor of redox-sensible tricarboxylic acid (TCA) cycle enzymes PDH and OGDH, produced extensive BC cell death. Taken together, our results suggest that FRI-1 exhibits anticancer effects through inhibition of mitochondrial bioenergetics by redox disruption in BC cells

The Parotoid Gland Secretion from Peruvian Toad Rhinella horribilis (Wiegmann, 1833): Chemical Composition and Effect on the Proliferation and Migration of Lung Cancer Cells

Since Rhinella sp. toads produce bioactive substances, some species have been used in traditional medicine and magical practices by ancient cultures in Peru. During several decades, the Rhinella horribilis toad was confused with the invasive toad Rhinella marina, a species documented with extensive toxinological studies. In contrast, the chemical composition and biological effects of the parotoid gland secretions (PGS) remain still unknown for R. horribilis. In this work, we determine for the first time 55 compounds from the PGS of R. horribilis, which were identified using HPLC-MS/MS. The crude extract inhibited the proliferation of A549 cancer cells with IC50 values of 0.031 +/- 0.007 and 0.015 +/- 0.001 mu g/mL at 24 and 48 h of exposure, respectively. Moreover, it inhibited the clonogenic capacity, increased ROS levels, and prevented the etoposide-induced apoptosis, suggesting that the effect of R. horribilis poison secretion was by cell cycle blocking before of G2/M-phase checkpoint. Fraction B was the most active and strongly inhibited cancer cell migration. Our results indicate that the PGS of R. horribilis are composed of alkaloids, bufadienolides, and argininyl diacids derivatives, inhibiting the proliferation and migration of A549 cells.ANID PCI-Biotechnology Redbio0027 FONDEQUIP EQM 170023 lineas de apoyo a la investigacion financiadas por ICBM (2020) Universidad de Talca ANID 2219122

Novel benzoate-lipophilic cations selectively induce cell death in human colorectal cancer cell lines

Introduction: Colorectal cancer (CRC) is a critical health issue worldwide. The high rate of liver and lung metastasis associated with CRC creates a significant barrier to effective and efficient therapy. Tumour cells, including CRC cells, have metabolic alterations, such as high levels of glycolytic activity, increased cell proliferation and invasiveness, and chemo- and radio-resistance. However, the abnormally elevated mitochondrial transmembrane potential of these cells also provides an opportunity to develop drugs that selectively target the mitochondrial functions of tumour cells. Methods: In this work, we used a new batch of benzoic acid esters with cytotoxic activities attached to the triphenylphosphonium group as a vehicle to target tumour mitochondria and improve their activity. We evaluated the cytotoxicity, selectivity, and mechanism of action of these derivatives, including the effects on energy stress-induced apoptosis and metabolic behaviour in the human CRC cell lines HCT-15 and COLO-205. Results: The benzoic acid derivatives selectively targeted the tumour cells with high potency and efficacy. The derivatives induced the uncoupling of the oxidative phosphorylation system, decreased the transmembrane potential, and reduced ATP levels while increasing AMPK activation, thereby triggering tumour cell apoptosis in both tumour cell lines tested. Conclusion: The benzoic acid derivatives studied here are promising candidates for assessing in vivo models of CRC, despite the diverse metabolic characteristics of these tumour cells.Consejo Nacional de Ciencia y Tecnologia (CONACyT) Comisión Nacional de Investigación Cientifica y Tecnológica (CONICYT) FONDECYT 11160281 FONDECYT 1180296 FONDECYT 1130189 Academy Insertion Grant 791220004 Vicerrectoría de Investigación y Desarrollo, Universidad de Chile (Enlace) ENL022/16 Comisión Nacional de Investigación Cientifica y Tecnológica (CONICYT) FONDECYT 11160281 Comisión Nacional de Investigación Cientifica y Tecnológica (CONICYT) CONICYT FONDECYT 1180296 1130189 Universidad de Chile (Enlace) ENL022/1

Complex mitochondrial dysfunction induced by TPP+-gentisic acid and mitochondrial translation inhibition by doxycycline evokes synergistic lethality in breast cancer cells

The mitochondrion has emerged as a promising therapeutic target for novel cancer treatments because of its essential role in tumorigenesis and resistance to chemotherapy. Previously, we described a natural compound, 10-((2,5-dihydroxybenzoyl)oxy)decyl) triphenylphosphonium bromide (GA-TPP+C10), with a hydroquinone scaffold that selectively targets the mitochondria of breast cancer (BC) cells by binding to the triphenylphosphonium group as a chemical chaperone; however, the mechanism of action remains unclear. In this work, we showed that GA-TPP+C10 causes time-dependent complex inhibition of the mitochondrial bioenergetics of BC cells, characterized by (1) an initial phase of mitochondrial uptake with an uncoupling effect of oxidative phosphorylation, as previously reported, (2) inhibition of Complex I-dependent respiration, and (3) a late phase of mitochondrial accumulation with inhibition of alpha-ketoglutarate dehydrogenase complex (alpha KGDHC) activity. These events led to cell cycle arrest in the G1 phase and cell death at 24 and 48 h of exposure, and the cells were rescued by the addition of the cell-penetrating metabolic intermediates l-aspartic acid beta-methyl ester (mAsp) and dimethyl alpha-ketoglutarate (dm-KG). In addition, this unexpected blocking of mitochondrial function triggered metabolic remodeling toward glycolysis, AMPK activation, increased expression of proliferator-activated receptor gamma coactivator 1-alpha (pgc1 alpha) and electron transport chain (ETC) component-related genes encoded by mitochondrial DNA and downregulation of the uncoupling proteins ucp3 and ucp4, suggesting an AMPK-dependent prosurvival adaptive response in cancer cells. Consistent with this finding, we showed that inhibition of mitochondrial translation with doxycycline, a broad-spectrum antibiotic that inhibits the 28 S subunit of the mitochondrial ribosome, in the presence of GA-TPP+C10 significantly reduces the mt-CO1 and VDAC protein levels and the FCCP-stimulated maximal electron flux and promotes selective and synergistic cytotoxic effects on BC cells at 24 h of treatment. Based on our results, we propose that this combined strategy based on blockage of the adaptive response induced by mitochondrial bioenergetic inhibition may have therapeutic relevance in BC.Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT), CONICYT FONDECYT: 1180296, 21150774, 3170813

Derivatives of alkyl gallate triphenylphosphonium exhibit antitumor activity in a syngeneic murine model of mammary adenocarcinoma

We previously demonstrated that alkyl gallates coupled to triphenylphosphine have a selective and efficient antiproliferative effect by inducing mitochondria] uncoupling in vitro due to the increased mitochondrial trans membrane potential of tumor cells. Therefore, in this work, the in vivo antitumor activities of alkyl gallate triphenylphosphonium derivatives (TPP+ C-8, TPP+C10 and TPP+ C-12) were evaluated in a syngeneic murine model of breast cancer. We found that TPP+ C-10 increased the cytosolic ADP/ATP ratio and significantly increased the AMP levels in a concentration-dependent manner in TA3/Ha murine mammary adenocarcinoma cells. Interestingly, TPP+ C-10 induced a decrease in the levels of cellular proliferation markers and promoted caspase-3 activation in tumor-bearing mice. Additionally, TPP+ C-10 inhibited tumor growth in the syngeneic mouse model. Importantly, 30 days of intraperitoneal (i.p.) administration of the combination of TPP+ C-10 (10 mg/kg/48 h) and the antibiotic doxycycline (10 mg/kg/24 h) completely eliminated the subcutaneous tumor burden in mice (n = 6), without any relapses at 60 days post-treatment. This enhancement of the individual activities of TPP+C10 and doxycycline is due to the uncoupling of oxidative phosphorylation by TPP+ C-10 and the inhibition of mitochondrial biogenesis by doxycycline, as demonstrated by loss of mitochondrial mass and overexpression of PGC1-ct as an adaptive response. Moreover, i.p. administration of TPP+ C-10 (10 mg/kg/24 h) to healthy mice did not produce toxicity or damage in organs important for drug metabolism and excretion, as indicated by hematological, biochemical and histological assessments. These findings suggest that the combination of TPP+ C-10 with doxycycline is a valuable candidate therapy for breast cancer management. (C) 2017 Elsevier Inc. All rights reserved.FONDECYT 1130772 VID ENL022/16 ERANET-LAC ELAC2014/HID328 CONICYT Ph.D. fellowshi