Natural products from plants targeting key enzymes for the future development of antidiabetic agents.

Covering: 2000 to January 2023Diabetes is a metabolic disease of serious concern nowadays, with a negative economic impact. In 2021, the International Diabetes Federation estimated that more than 537 million adults live with diabetes, causing over 6.7 million deaths in that year. Intensive scientific research on medicinal plants in the last 100 years reveals that herbal drugs have been an essential source of products for developing antidiabetic agents acting on different physiological targets. This review summarizes recent research from 2000 to 2022 on plant natural compounds affecting selected crucial enzymes (dipeptidyl peptidase IV, diacylglycerol acyltransferase, fructose 1,6-biphosphatase, glucokinase, and fructokinase) involved in glucose homeostasis. Enzyme-aimed treatments usually induce reversible inhibition, irreversible by covalent changes of the objective enzymes, or bind non-covalently but so tightly that their inhibition is irreversible. Depending on the binding site, these inhibitors could be orthosteric or allosteric; in any case, the desired pharmacological action is achieved. One crucial advantage of targeting enzymes in drug discovery is that the required assays are usually simple, using biochemical experiments capable of analyzing enzyme activity.

Factores predictivos de mortalidad e ingreso en la unidad de cuidados intensivos en pacientes con pielonefritis enfisematosa: experiencia de 5 años en un hospital terciario / Predictive factors for mortality and intensive care unit admission in patients with emphysematous pyelonephritis: 5-year experience in a tertiary care hospital

Introduction and objectivesEmphysematous pyelonephritis is a life-threatening infection of the kidney and surrounding tissues associated with a high mortality rate. The aim of this study was to determine predictive factors for mortality and intensive care unit admission in patients with emphysematous pyelonephritis, and to propose a therapeutic algorithm based on current literature and our experience.MethodsA retrospective study was done including patients with emphysematous pyelonephritis in a single center in the north of Mexico from 2011-2016. Demographic, clinical, microbiological and biochemical parameters, therapeutic management, and outcomes were assessed. Factors associated with admission to intensive care unit and mortality were determined. Comparison was assessed using χ2 test for categorical variables, and T-test for numerical variables. Univariate and multivariate logistic regression analyses were performed. Statistical significance was set at p<0.05.ResultsA total of 63 patients were included, of which 55(87.3%) were females, with a mean age of 55.5±12.2 years. The most common comorbidities were diabetes and hypertension. Escherichia coli was the most common isolated microorganism (51.7%) and extended-spectrum beta-lactamase-producing agents were reported in 31.7%. Conservative therapy was provided to 38.7%, double J stent 42.9%, open/percutaneous drainage 12.7%, and nephrectomy 25.3%. Overall mortality and intensive care admission were 20.6% and 36.5%, respectively. In the multivariate analysis, hemodynamic instability (p=0.005), qSOFA≥2 (p=0.003), hypoalbuminemia (p=0.02), and early nephrectomy (p=0.002) were associated with intensive care admission. Huang scale 4 (p=0.006) and early nephrectomy (p=0.001) were associated to mortality.ConclusionsEmphysematous pyelonephritis is a life-threatening disease and evidence of management is based in small case series due to the low incidence of this condition.

Introducción y objetivosLa pielonefritis enfisematosa es una infección del riñón y los tejidos circundantes que pone en riesgo la vida del paciente y se asocia a una elevada tasa de mortalidad. El objetivo de este estudio fue determinar los factores predictivos de mortalidad e ingreso en la unidad de cuidados intensivos en pacientes con pielonefritis enfisematosa, y proponer un algoritmo terapéutico basado en la literatura actual y en nuestra experiencia.MétodosSe realizó un estudio retrospectivo incluyendo los pacientes con pielonefritis enfisematosa en un solo centro del norte de México entre 2011 y 2016. Se evaluaron parámetros demográficos, clínicos, microbiológicos y bioquímicos, el manejo terapéutico y los resultados. Se determinaron los factores asociados con el ingreso a la unidad de cuidados intensivos y la mortalidad. La comparación se evaluó mediante la prueba de chi cuadrado para las variables categóricas, y la prueba t de Student para las variables numéricas. Se realizaron análisis de regresión logística univariante y multivariante. La significación estadística se fijó en p<0,05.ResultadosSe incluyeron 63 pacientes, de los cuales 55 (87,3%) eran mujeres, con una edad media de 55,5±12,2 años. Las comorbilidades más frecuentes fueron la diabetes y la hipertensión. Escherichia coli fue el microorganismo más comúnmente aislado (51,7%) y los agentes productores de betalactamasas de espectro extendido se registraron en el 31,7%. Se administró tratamiento conservador al 38,7%, el uso de catéter doble J en el 42,9%, drenaje abierto/percutáneo en el 12,7% y nefrectomía en el 25,3%. La mortalidad global y el ingreso en cuidados intensivos fueron del 20,6% y el 36,5%, respectivamente. En el análisis multivariante, la inestabilidad hemodinámica (p=0,005), la escala qSOFA≥2 (p=0,003), la hipoalbuminemia (p=0,02) y la nefrectomía temprana (p=0,002) se asociaron con el ingreso en cuidados intensivo

Predictive factors for mortality and intensive care unit admission in patients with emphysematous pyelonephritis: 5-year experience in a tertiary care hospital.

INTRODUCTION AND OBJECTIVES: Emphysematous pyelonephritis is a life-threatening infection of the kidney and surrounding tissues associated with a high mortality rate. The aim of this study was to determine predictive factors for mortality and intensive care unit admission in patients with emphysematous pyelonephritis, and to propose a therapeutic algorithm based on current literature and our experience. METHODS: A retrospective study was done including patients with emphysematous pyelonephritis in a single center in the north of Mexico from 2011 to 2016. Demographic, clinical, microbiological and biochemical parameters, therapeutic management, and outcomes were assessed. Factors associated with admission to intensive care unit and mortality were determined. Comparison was assessed using X2 test for categorical variables, and T-test for numerical variables. Univariate and multivariate logistic regression analyses were performed. Statistical significance was set at P < .05. RESULTS: A total of 63 patients were included, of which 55 (87.3%) were females, with a mean age of 55.5 ±â€¯12.2 years. The most common comorbidities were diabetes and hypertension. Escherichia coli was the most common isolated microorganism (51.7%) and extended-spectrum beta-lactamase-producing agents were reported in 31.7%. Conservative therapy was provided to 38.7%, double J stent 42.9%, open/percutaneous drainage 12.7%, and nephrectomy 25.3%. Overall mortality and intensive care admission were 20.6% and 36.5%, respectively. In the multivariate analysis, hemodynamic instability (P = .005), qSOFA ≥ 2 (P = .003), hypoalbuminemia (P = .02), and early nephrectomy (P = .002) were associated with intensive care admission. Huang scale 4 (P = .006) and early nephrectomy (P = .001) were associated to mortality. CONCLUSIONS: Emphysematous pyelonephritis is a life-threatening disease and evidence of management is based in small case series due to the low incidence of this condition. Hemodynamic instability, hypoalbuminemia, qSOFA ≥ 2, Huang scale ≥3, and early nephrectomy are associated with poor prognosis.

Methods for interpolating missing data in aerobiological databases.

Missing data is a common problem in scientific research. The availability of extensive environmental time series is usually laborious and difficult, and sometimes unexpected failures are not detected until samples are processed. Consequently, environmental databases frequently have some gaps with missing data in it. Applying an interpolation method before starting the data analysis can be a good solution in order to complete this missing information. Nevertheless, there are several different approaches whose accuracy should be considered and compared. In this study, data from 6 aerobiological sampling stations were used as an example of environmental data series to assess the accuracy of different interpolation methods. For that, observed daily pollen/spore concentration data series were randomly removed, interpolated by using different methods and then, compared with the observed data to measure the errors produced. Different periods, gap sizes, interpolation methods and bioaerosols were considered in order to check their influence in the interpolation accuracy. The moving mean interpolation method obtained the highest success rate as average. By using this method, a success rate of the 70% was obtained when the risk classes used in the alert systems of the pollen information platforms were taken into account. In general, errors were mostly greater when there were high oscillations in the concentrations of biotic particles during consecutive days. That is the reason why the pre-peak and peak periods showed the highest interpolation errors. The errors were also higher when gaps longer than 5 days were considered. So, for completing long periods of missing data, it would be advisable to test other methodological approaches. A new Variation Index based on the behaviour of the pollen/spore season (measurement of the variability of the concentrations every 2 consecutive days) was elaborated, which allows to estimate the potential error before the interpolation is applied.

Etiología de la gangrena de Fournier como factor pronóstico de mortalidad: análisis de 121 casos / Etiology of Fournier gangrene as a prognostic factor in mortality: Analysis of 121 cases

Objetivo: Evaluar el origen de la gangrena de Fournier (GF) como factor pronóstico de morbimortalidad. Material y métodos: Los pacientes que acudieron a nuestra clínica con diagnóstico de GF entre 2010 y 2017 se incluyeron de forma retrospectiva. Los pacientes fueron categorizados según el origen de la infección. Se determinaron 3 factores de gravedad en cada grupo: duración de la estancia hospitalaria (días), índice de gravedad de GF y mortalidad. Se realizó un análisis de regresión logística para evaluar los datos. Resultados: De los 130 pacientes evaluados, el origen se estableció en 121 con base en la historia clínica y los hallazgos radiológicos y quirúrgicos. Treinta y cinco pacientes tuvieron un origen intestinal con una mortalidad del 20,68%, en 46 el origen fue testicular y la mortalidad del 2,22%, en 12 pacientes el origen fue urinario, con una mortalidad del 0%, y 28 pacientes tenían enfermedad de origen cutáneo y una mortalidad del 16,6%. El origen testicular fue el más frecuente (38%), además de presentar una estancia hospitalaria y un índice de gravedad de FG más bajo y una mortalidad menor que aquellos con enfermedad de origen intestinal (p = 0,022). Conclusiones: El origen de la infección tiene un valor pronóstico significativo en la mortalidad del paciente

Objective: Evaluate the origin of Fournier gangrene (FG) as a prognostic factor of morbidity and mortality. Material and methods: Patients who came to our clinic with a diagnosis of FG from 2010 to 2017 were included retrospectively. Patients were categorized depending on the origin of the infection. Three severity factors were determined in each group: days of hospital stay, the FG severity index, and mortality. Logistic regression test was performed to analyze the data. Results: Of the 130 patients evaluated, the origin was established in 121 based on the clinical history and radiological and surgical findings. Thirty-five patients had an intestinal origin with a mortality of 20.68%, 46 patients had a testicular origin with a mortality of 2.22%, 12 patients had a urinary origin with a mortality of 0%, and 28 patients with a cutaneous origin with a mortality of 16.6%. The testicular origin was the most frequent (38%) in addition to presenting a lower hospital stay, a lower FG severity index, and a lower mortality than those with an intestinal origin (P = .022). Conclusions: The origin of the infection has a significant prognostic value in the mortality of the patient

Etiology of Fournier gangrene as a prognostic factor in mortality: Analysis of 121 cases. / Etiología de la gangrena de Fournier como factor pronóstico de mortalidad: análisis de 121 casos.

OBJECTIVE: Evaluate the origin of Fournier gangrene (FG) as a prognostic factor of morbidity and mortality. MATERIAL AND METHODS: Patients who came to our clinic with a diagnosis of FG from 2010 to 2017 were included retrospectively. Patients were categorized depending on the origin of the infection. Three severity factors were determined in each group: days of hospital stay, the FG severity index, and mortality. Logistic regression test was performed to analyze the data. RESULTS: Of the 130 patients evaluated, the origin was established in 121 based on the clinical history and radiological and surgical findings. Thirty-five patients had an intestinal origin with a mortality of 20.68%, 46 patients had a testicular origin with a mortality of 2.22%, 12 patients had a urinary origin with a mortality of 0%, and 28 patients with a cutaneous origin with a mortality of 16.6%. The testicular origin was the most frequent (38%) in addition to presenting a lower hospital stay, a lower FG severity index, and a lower mortality than those with an intestinal origin (P=.022). CONCLUSIONS: The origin of the infection has a significant prognostic value in the mortality of the patient.

Increasing resolution of airborne pollen forecasting at a discrete sampled area in the southwest Mediterranean Basin.

Daily fluctuations of the airborne pollen concentrations produce variations on symptomatology in allergic population. Such fluctuations are influenced by local vegetal coverage, flowering phenology, geography and climatology. Since 1991, airborne pollen of Malaga province (southern Spain) has been monitored in 7 different locations. Malaga station has been kept operational uninterruptedly throughout the studied period, while the rest of the stations only worked in periods of 2-4 years. Weekly, its pollen information is updated online to inform the population in order to prevent allergic diseases. Increasing the spatial resolution of pollen information would be very useful for allergic population living at unsampled locations. Due to the impossibility of keeping operational a high number of pollen stations covering the whole province of Malaga, the aim of this study is to create spatial models to extrapolate and forecast the pollen concentrations to Malaga province by using the concentrations registered at the capital as unique input. To do so, the relationships obtained between the airborne pollen concentrations detected at Malaga city and those detected at the other stations have been used to elaborate models for the main pollen types registered at the province. These models were spatially interpolated all over the province by using co-kriging techniques and the Compensated Thermicity Index as covariable. As result of this work, pollen distribution of the 8 most prevalent taxa has been depicted all over the whole Malaga province and an allergy alert system has been set up to extrapolate pollen information from Malaga to the whole province.

Role of Wnt/ß-catenin signaling in hepatocellular carcinoma, pathogenesis, and clinical significance.

Hepatocellular carcinoma (HCC) is one of the most common primary hepatic malignancies and one of the fastest-growing causes of cancer-related mortality in the United States. The molecular basis of HCC carcinogenesis has not been clearly identified. Among the molecular signaling pathways implicated in the pathogenesis of HCC, the Wnt/ß-catenin signaling pathway is one of the most frequently activated. A great effort is under way to clearly understand the role of this pathway in the pathogenesis of HCC and its role in the transition from chronic liver diseases, including viral hepatitis, to hepatocellular adenomas (HCAs) and HCCs and its targetability in novel therapies. In this article, we review the role of the ß-catenin pathway in hepatocarcinogenesis and progression from chronic inflammation to HCC, the novel potential treatments targeting the pathway and its prognostic role in HCC patients, as well as the imaging features of HCC and their association with aberrant activation of the pathway.

End-of-life decisions in emergency patients: prevalence, outcome and physician effect.

BACKGROUND: End-of-life decisions (EOLD) represent potentially highly consequential decisions often made in acute situations, such as 'do not attempt resuscitation' (DNAR) choices at emergency presentation. AIM: We investigated DNAR decisions in an emergency department (ED) to assess prevalence, associated patient characteristics, potential medical and economic consequences and estimate contributions of patients and physicians to DNAR decisions. DESIGN: Single-centre retrospective observation, including ED patients with subsequent hospitalization between 2012 and 2016. Primary outcome was a DNAR decision and associated patient characteristics. Secondary outcomes were mortality, admission to intensive care unit and use of resources. METHODS: Associations between DNAR and patient characteristics were analysed using logistic mixed effects models, results were reported as odds ratios (OR). Median odds ratios (MOR) were used to estimate patient and physician contributions to variability in DNAR. RESULTS: Patients of 10 458 were attended by 315 physicians. DNAR was the choice in 23.3% of patients. Patients' characteristics highly associated with DNAR were age (OR = 4.0, 95% CI = 3.6-4.3) and non-trauma presentation (OR = 2.3, 95% CI = 1.9-2.9). In-hospital mortality was significantly higher (OR = 5.4, CI = 4.0-7.3), and use of resources was significantly lower (OR = 0.7, CI = 0.6-0.8) in patients choosing DNAR. There was a significant effect on DNAR by both patient (MOR = 1.8) and physician (MOR = 2.0). CONCLUSIONS: DNAR choices are common in emergency patients and closely associated with age and non-trauma presentation. Mortality was significantly higher, and use of resources significantly lower in DNAR patients. Evidence of a physician effect raises questions about the choice autonomy of emergency patients in the process of EOLD.

Survival and preference of cotton boll weevil adults for alternative food sources / Sobrevivência e preferência para exploração de recursos de adultos do bicudo do algodoeiro

Abstract Plants that have potential as alternative food source (floral nectar, pollen and plant tissues) to the boll weevil during the intercropping season were evaluated considering the prevalent conditions of Cerrado in the Central Brazil. Initially, we tested the nutritional adequacy for the survival of the insect of flower resource (pollen and nectar) provided by eight plant species (fennel, mexican sunflower, castor bean, okra, hibiscus, sorghum, pigeonpea and sunn hemp). Subsequently, we tested if the resources provided by the selected plants continued to be exploited by the boll weevil in the presence of cotton plant, its main food source average longevity of boll weevil adults was significantly longer when they were fed on hibiscus’ flowers (166.6 ± 74.4) and okra flowers (34.7 ± 28.9) than when they fed on flowers of other six species. Subsequently, the preference of the boll weevil in the use of resources was compared between okra or hibiscus and cotton plants, in dual choice experiments. Boll weevils preferred plants of the three species in the reproductive stages than those in vegetative stages. Although the cotton plant in the reproductive stage was the most preferred plant of all, boll weevils preferred flowering okra and hibiscus than cotton at the vegetative stage.

Resumo Plantas que podem ser uma fonte potencial de recursos alimentares (néctar floral, pólen e tecidos vegetais) para o bicudo do algodoeiro durante a entressafra foram avaliadas, considerando as condições ambientais prevalentes na região de Cerrado do Brasil Central. Primeiro, testamos a adequação nutricional dos recursos (pólen e néctar) fornecidos por oito espécies de plantas (erva-doce, margaridão, mamona, quiabo, hibisco, sorgo, feijão guandu e crotalária) como único recurso alimentar para a sobrevivência do inseto. Posteriormente, nós avaliamos se os recursos fornecidos pelas plantas selecionadas continuaram a serem explorados pelo bicudo na presença do algodoeiro, seu recurso alimentar principal. A longevidade média do bicudo do algodoeiro foi significativamente maior quando eles foram alimentados com flores de hibisco (166,6 ± 74,4) e quiabo (34,7 ± 28,9) do que quando alimentados com flores das outras seis espécies. Em seguida, a preferência do bicudo no uso de recursos foi comparada contrastando o quiabo e o hibisco com o algodão, em experimentos de dupla escolha. Os bicudos preferiram as plantas das três espécies na fase reprodutiva em relação àquelas em estádios vegetativos. Embora a preferência por plantas de algodão na fase reprodutiva tenha sido maior, os bicudos preferiram plantas em floração de quiabo e hibisco quando estas foram contrastadas com o algodão na fase vegetativa.

Highly selective and sensitive fluorescence detection of Zn(2+) and Cd(2+) ions by using an acridine sensor.

Fluorescence spectroscopy investigations of the new acridine derivative bis(N,N-dimethylaminemethylene)acridine (3) show remarkable selectivity and sensitivity towards Zn(2+) and Cd(2+) ions in methanol and for the latter even in water. Through the chelation of the metal ions the present PET effect is quenched, significantly enhancing the emission intensity of the fluorophore. In solution, the bonding situation is studied by fluorescence and NMR spectroscopy, as well as ESI-TOF mass-spectrometry measurements. The solid state environment is investigated by X-ray diffraction and computational calculations. Here, we can show the complexation of the zinc and cadmium ions by the methylene bridged amine receptors as well as by the nitrogen atom of the acridine system.

Survival and preference of cotton boll weevil adults for alternative food sources.

Plants that have potential as alternative food source (floral nectar, pollen and plant tissues) to the boll weevil during the intercropping season were evaluated considering the prevalent conditions of Cerrado in the Central Brazil. Initially, we tested the nutritional adequacy for the survival of the insect of flower resource (pollen and nectar) provided by eight plant species (fennel, mexican sunflower, castor bean, okra, hibiscus, sorghum, pigeonpea and sunn hemp). Subsequently, we tested if the resources provided by the selected plants continued to be exploited by the boll weevil in the presence of cotton plant, its main food source average longevity of boll weevil adults was significantly longer when they were fed on hibiscus' flowers (166.6 ± 74.4) and okra flowers (34.7 ± 28.9) than when they fed on flowers of other six species. Subsequently, the preference of the boll weevil in the use of resources was compared between okra or hibiscus and cotton plants, in dual choice experiments. Boll weevils preferred plants of the three species in the reproductive stages than those in vegetative stages. Although the cotton plant in the reproductive stage was the most preferred plant of all, boll weevils preferred flowering okra and hibiscus than cotton at the vegetative stage.

Proteasome inhibition reverses hedgehog inhibitor and taxane resistance in ovarian cancer.

The goal of this study was to determine whether combined targeted therapies, specifically those against the Notch, hedgehog and ubiquitin-proteasome pathways, could overcome ovarian cancer chemoresistance. Chemoresistant ovarian cancer cells were exposed to gamma-secretase inhibitors (GSI-I, Compound E) or the proteasome inhibitor bortezomib, alone and in combination with the hedgehog antagonist, LDE225. Bortezomib, alone and in combination with LDE225, was evaluated for effects on paclitaxel efficacy. Cell viability and cell cycle analysis were assessed by MTT assay and propidium iodide staining, respectively. Proteasome activity and gene expression were determined by luminescence assay and qPCR, respectively. Studies demonstrated that GSI-I, but not Compound E, inhibited proteasome activity, similar to bortezomib. Proteasome inhibition decreased hedgehog target genes (PTCH1, GLI1 and GLI2) and increased LDE225 sensitivity in vitro. Bortezomib, alone and in combination with LDE225, increased paclitaxel sensitivity through apoptosis and G2/M arrest. Expression of the multi-drug resistance gene ABCB1/MDR1 was decreased and acetylation of α-tubulin, a marker of microtubule stabilization, was increased following bortezomib treatment. HDAC6 inhibitor tubastatin-a demonstrated that microtubule effects are associated with hedgehog inhibition and sensitization to paclitaxel and LDE225. These results suggest that proteasome inhibition, through alteration of microtubule dynamics and hedgehog signaling, can reverse taxane-mediated chemoresistance.

Camptocormia: cifosis lumbar adquirida progresiva reductible / Camptocormia: Progressive and acquired reducible lumbar kyphosis

La camptocormia es una enfermedad invalidante para el paciente que la presenta pues le limita en sus actividades de la vida diaria, así como para la marcha. Es una entidad poco frecuente, relativamente conocida, y en la que se debe pensar ante la presencia de una cifosis lumbar adquirida, progresiva y reductible en un paciente de edad avanzada. Su diagnóstico es fundamentalmente clínico y se confirma tras realización de pruebas complementarias como TAC de columna y RNM. El tratamiento en muchos casos no resulta muy efectivo y se basa en prescripción de rehabilitación, ortesis, productos de apoyo o ayudas técnicas para la marcha y tratamiento farmacológico sintomático. Presentamos el caso de una mujer de 81 a˜nos remitida desde el servicio de neurología, que fue valorada y tratada en nuestro servicio con mejoría de la clínica y de su patrón de marcha y postural (AU)

Camptocormia is a disabling disease that limits activities of daily living in affected individuals as well as their gait. It is uncommon but relatively well-known disease that should be considered in patients with progressive and reducible lumbar kyphosis acquired at advanced age. The diagnosis is mainly clinical and is confirmed by complementary tests such as spinal computed tomography and magnetic resonance imaging. Treatment is often ineffective and is based on rehabilitation, the use of orthoses, supports or technical aids for walking, and symptomatic drug therapy. We report the case of an 81-year-old woman who was referred by the neurology service and was evaluated and treated in our service. The patient showed improvements in her clinical symptoms, posture and gait (AU)

Phenological and geographical influence in the concentration of selected bioactive 4-phenylcoumarins and chlorogenic acid in Hintonia latiflora leaves.

ETHNOPHARMACOLOGICAL RELEVANCE: Hintonia latiflora is a Mexican medicinal plant with well-documented ethnomedical record comprising more than 400 years; in modern Mexico is used for treating several maladies such as diabetes and gastric ulcers. Although the pharmacological actions of the stem-bark and leaves have been demonstrated, the phenological and geographical effect on the concentration of active principles remains unexplored. AIM OF THE STUDY: The main goals of this study were to analyze the amount of selected 4-phenylcoumarins and chlorogenic acid in the leaves in order to assess the best harvesting period, and consequently their pharmacological efficacy. In addition, the preclinical antidiabetic efficacy of the infusion of the leaves was corroborated using standard pharmacological tests. MATERIALS AND METHODS: The aqueous extracts from the leaves of Hintonia latiflora were prepared by infusion. For phenological and geographical comparison, leaves of Hintonia latiflora were collected in two different regions in Chihuahua and Michoacán. The material was analyzed by UPLC applying an analytical method that developed and validated for this purpose following the ICH guidelines. Investigation of the antidiabetic action was accomplished using an acute hypoglycemic test and oral glucose and sucrose tolerance tests. RESULTS: The validated analytical method was successfully applied for quantifying chlorogenic acid (1) and 4-phenylcoumarins (2-5) in the leaves of 12 different batches (1-12) during one-year period, and seven different batches for each geographical region; the concentration of the metabolites at the phenological cycle was significantly different, their concentration increased during the pre-senescence phase whereas in the leaf renovation stage the highest concentration of 2-5 was reached. The overall analysis of the active compounds concentration between the two populations investigated seems to be less important than the phenological variations. The aqueous extract of the leaves of Hintonia latiflora exerted its antidiabetic effect by different mechanisms showing comparable effect to the organic extract. CONCLUSIONS: The findings of the present investigation reveal that the best harvest season for the leaves of Hintonia latiflora is between the leaves renovation and senescence stages avoiding the flowering period. In addition, no significant differences were found among the two different geographical populations analyzed. The infusions of the leaves, rich in 4-phenylcoumarins and chlorogenic acid, showed comparable antidiabetic action than the organic extract.

Palladin promotes invasion of pancreatic cancer cells by enhancing invadopodia formation in cancer-associated fibroblasts.

The stromal compartment surrounding epithelial-derived pancreatic tumors is thought to have a key role in the aggressive phenotype of this malignancy. Emerging evidence suggests that cancer-associated fibroblasts (CAFs), the most abundant cells in the stroma of pancreatic tumors, contribute to the tumor's invasion, metastasis and resistance to therapy, but the precise molecular mechanisms that regulate CAFs behavior are poorly understood. In this study, we utilized immortalized human pancreatic CAFs to investigate molecular pathways that control the matrix-remodeling and invasion-promoting activity of CAFs. We showed previously that palladin, an actin-associated protein, is expressed at high levels in CAFs of pancreatic tumors and other solid tumors, and also in an immortalized line of human CAFs. In this study, we found that short-term exposure of CAFs to phorbol esters reduced the number of stress fibers and triggered the appearance of individual invadopodia and invadopodial rosettes in CAFs. Molecular analysis of invadopodia revealed that their composition resembled that of similar structures (that is, invadopodia and podosomes) described in other cell types. Pharmacological inhibition and small interfering RNA knockdown experiments demonstrated that protein kinase C, the small GTPase Cdc42 and palladin were necessary for the efficient assembly of invadopodia by CAFs. In addition, GTPase activity assays showed that palladin contributes to the activation of Cdc42. In mouse xenograft experiments using a mixture of CAFs and tumor cells, palladin expression in CAFs promoted the rapid growth and metastasis of human pancreatic tumor cells. Overall, these results indicate that high levels of palladin expression in CAFs enhance their ability to remodel the extracellular matrix by regulating the activity of Cdc42, which in turn promotes the assembly of matrix-degrading invadopodia in CAFs and tumor cell invasion. Together, these results identify a novel molecular signaling pathway that may provide new molecular targets for the inhibition of pancreatic cancer metastasis.

Determination of diflubenzuron residues in milk and cattle tissues / Determinação de resíduos de diflubenzuron em leite e tecidos bovinos

Diflubenzuron (DFB) is used to control ectoparasitic infestation by inhibiting larvae development in the manure and feces of treated animals. It is also currently been used to control tick infestations. In this study, milk and tissues from cattle treated orally with DFB for a 77-120 day period with a commercial product containing the compound were analyzed for the presence of residues. DFB residues were determined by using extraction with acetonitrile, cleanup with C18 SPE and chromatographic analysis by HPLC with UV detection (254nm). DFB was not detected in any of the analysed samples (<0.006mg kg-1 for fat, <0.014mg kg-1 for muscle, <0.015mg kg-1 for kidney, <0.016mg kg-1 for liver and <0.0006mg kg-1 for milk). In this manner, the use of this compound, according to the manufacturer's suggested doses may result in cattle milk, liver, kidneys, fat and muscles being considered safe regarding the presence of DFB residues.

O diflubenzuron (DFB) é um inibidor de desenvolvimento de insetos que inibe a síntese de quitina com atividade ovicida e larvicida e está sendo utilizado na pecuária para o controle do carrapato. Leite e tecidos provenientes de bovinos tratados por um período de 77 a 120 dias com um produto comercial contendo DFB foram analisados quanto à presença de resíduos. Os resíduos de DFB foram determinados utilizando-se extração com acetonitrila, limpeza por SPE C18 e cromatografia líquida de alta eficiência com detecção por UV (254nm). DFB não foi detectado em nenhuma das amostras analisadas (<0.006mg kg-1 para gordura, <0,014mg kg-1 para músculo, <0,015mg kg-1 para rim, <0,016mg kg-1 para fígado e <0.0006mg kg-1 para leite). Dessa forma, a utilização do princípio ativo conforme recomendado pelo fabricante e em níveis suficientes para se obter o efeito larvicida desejado deve resultar em leite, fígado, rins, gordura e músculos que podem ser considerados seguros para o consumo em termos da presença DFB.

Gastroprotective effect of Hintonia latiflora and Hintonia standleyana aqueous extracts and compounds.

ETHNOPHARMACOLOGICAL RELEVANCE: The stem-barks of Hintonia latiflora and Hintonia standleyana, locally known as "copalchi", are used for treating several maladies such as diabetes and gastrointestinal complaints, including gastric ulcers. Although the antidiabetic properties have been demonstrated, the gastroprotective action remains unexplored. AIM OF THE STUDY: The main goals of this study were to establish the potential acute toxicity and the gastroprotective activity of aqueous extracts and compounds from Hintonia latiflora and Hintonia standleyana in order to demonstrate their preclinical efficacy for the treatment of gastric ulcers in Mexican folk medicine. MATERIALS AND METHODS: The aqueous extracts from the stem-barks (HLSB and HSSB) and leaves (HLL and HSL) from Hintonia latiflora and Hintonia standleyana were prepared by infusion. Investigation of the acute toxicity was accomplished by the Lorke method. The gastroprotective effect was assessed by means of a conventional ethanol-induced gastric injury model in rats using carbenoxolone as positive control. 5-O-[ß-D-apiofuranosyl-(1→6)-ß-D-glucopyranosyl]-7-methoxy-3',4'-dihydroxy-4-phenylcoumarin (1) and chlorogenic acid (2) were also assayed. Preliminary mechanism of action of the tested compounds was analyzed using the same pharmacological models but pretreating the animals with N(G)-nitro-L-arginine methyl ester (L-NAME), N-ethylmaleimide (NEM) and indomethacin. RESULTS: Investigation of the acute toxicity revealed that infusions of the leaves and stem-barks of both Hintonia species were not toxic to mice (LD(50)>5000 mg/kg in all cases). HLSB, HSSB, HLL and HSL provoked a significant gastroprotective effect [80.5±3.35% (ED(50)=184.7 mg/kg), 80.26±3.96%, 75.1±7.26% (ED(50)=109.1 mg/kg), 76.85±3.17% (ED(50)=149.7 mg/kg) of gastroprotection respectively]. Compounds 1 and 2, present in all the extracts, were also active [68.85±8.4% (ED(50)=15 mg/kg), 74.04±4.4% (ED(50)=26 mg/kg) of gastroprotection respectively] and their mode of action involved non-protein sulfhydryl endogenous (NP-SH) compounds, since only pretreatment with NEM inhibited their gastroprotective action. CONCLUSIONS: The present investigation tends to support the ethnomedical use of HLSB, HSSB for treating gastric ulceration. Since HLL and HSL were also active, the leaves could be use alternatively, which in terms of natural resources conservation is an outstanding finding, considering that the plant populations of both Hintonia are scarce and in danger of extinction. Mainly two compounds (1 and 2) are important active principles of the plants.

Lack of short-term increase in serum mediators of fibrogenesis and in non-invasive markers of liver fibrosis in HIV/hepatitis C virus-coinfected patients starting maraviroc-based antiretroviral therapy.

The aim of this study was to analyze serum changes in mediators of fibrogenesis and in non-invasive markers of liver fibrosis among HIV/HCV-coinfected patients starting maraviroc (MVC)-based antiretroviral therapy. Patients included in this prospective pilot study met the following criteria: (1) HIV-infection, (2) detectable serum HCV-RNA, and ((3) started MVC. Transforming growth factor-ß1 (TGF-beta1), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were measured in serum samples at baseline and 6 months after starting MVC. AST-to-platelet ratio index (APRI) was assessed at the same time points. Twenty-four patients were analyzed. Median (IQR) serum levels at baseline and after 6 months on MVC of TGF-beta1 were 27,295 (20,562-36,844) and 33,753 (18,973-46,130) pg/mL (p=0.116), of MMP-2 were 216 (186-274) and 241 (194-306) ng/mL (p=0.247), and of TIMP-1 were 237 (170-284) and 216 (171-271) ng/mL (p=0.415). APRI levels were 0.99 (0.53-3.46) at baseline and 0.83 (0.48-2.34) at 6 months (p=0.16). Serum mediators of liver fibrogenesis and fibrosis do not change significantly in HIV/HCV-coinfected patients in the short-term after starting MVC. As TGF-beta1 levels have been shown to increase over time in HCV infection and liver fibrosis worsens rapidly in HIV/HCV coinfection, these parameters seem to evolve in a different way in MVC-treated patients.

Germinación in vitro de híbridos de Vanilla planifolia y V. pompona / In vitro germination of Vanilla planifolia and V. pompona hybrids

El cultivo de la vainilla se lleva a cabo ampliamente por medio de propagación clonal, de manera asexual por cortes de tallos y la producción de frutos se realiza por autopolinización. Esta práctica inhibe la variación genética y la emergencia de nuevos individuos por recombinación sexual. Por lo anterior, se considera necesario realizar cruzas por propagación sexual entre especies para obtener nuevos individuos con características deseables para el cultivo. En el presente trabajo se obtuvieron híbridos de dos especies de vainilla como parte de un programa de mejoramiento genético. En general, las semillas híbridas obtenidas que presentaron mayor porcentaje de germinación fueron las cruzas interespecíficas interespecíficos de V. planifolia y V. pompona (85%), seguido de la cruza inversa V. planifolia y V. pompona (57,9%). Las semillas producto de V. pompona autopolinizada obtuvieron valores muy bajos de germinación (10,8%), mientras que las obtenidas de V. planifolia autopolinizada no presentaron germinación. El medio de cultivo más eficiente en todos los tratamientos fue el Murashige & Skoog (MS) adicionado con 400 mg/L-1 de glutamina y 80 mg/L-1 de sulfato de adenina.

The cultivation of vanilla is extensive clonal asexual propagation by cuttings and fruit production by artificial self-pollination. This feature tends to inhibit the genetic variation and the emergence of new individuals by sexual recombination. Therefore, sexual propagation between species it is considered necessary to obtain new individuals with desirable characteristics for cultivation. In this paper we were able to obtain hybrids of two species of vanilla. In general, the hybrids seeds obtained whit the higher germination percentage were interspecific crosses of V. planifolia and V. pompona (85%), followed by reverse cross V. planifolia and V. pompona (57.9%). Seeds obtained of V. pompona self-pollination were very low germination (10.8%) while those obtained from V. planifolia self-pollination showed no germination in any media culture. The most efficient medium for all treatments was the Murashige & Skoog (MS) supplemented whit 400 mg/L-1glutamine and 80 mg/L-1 of adenine sulfate.