Assessing the efficacy of gutiferone E in photodynamic therapy for oral candidiasis.

The rise in antifungal resistance and side effects of conventional treatments drive the search for innovative therapies like Photodynamic Therapy (PDT). This study explored the efficacy of PDT mediated by gutiferone, an isolated compound from red propolis, for candidiasis treatment. Multiple evaluation methods were employed, including determining the minimum inhibitory concentration (MIC) via broth microdilution, quantifying biomass using crystal violet detachment, and cell counting through total plate count. PDT mediated by gutiferone was also assessed in five groups of mice, followed by histopathological examination and agar plating of lingual tissue samples. Among the seven Candida species tested, gutiferone displayed efficacy against C. albicans, C. glabrata, and C. tropicalis, with MIC values of 1000 µg/mL. In C. tropicalis biofilms, exposure to gutiferone led to a reduction of 1.61 Log10 CFU/mL. PDT mediated by gutiferone achieved an average reduction of 3.68 Log10 CFU/mL in C. tropicalis biofilm cells, underscoring its potent fungicidal activity. Histopathological analysis revealed fungal structures, such as pseudohyphae and hyphae, in infected groups (G2) and irradiated mice. In contrast, groups treated with gutiferone or subjected to gutiferone-assisted PDT (G5) exhibited only few blastoconidia. Furthermore, CFU/mL assessments in lingual tissue post-treatment demonstrated a significantly lower count (0.30 Log10 CFU/mL) in the G5 group compared to G2 (2.43 Log10 CFU/mL). These findings highlight the potential of PDT mediated by gutiferone as a promising alternative for managing denture stomatitis. Future research and clinical investigations offer the promise of validating its clinical applicability and improving outcomes in the treatment of oral candidiasis.

Ozonated oil is effective at killing Candida species and Streptococcus mutans biofilm-derived cells under aerobic and microaerobic conditions.

This study explores the growth of bacterial, fungal, and interkingdom biofilms under aerobiosis or microaerobic conditions and the effect of ozonated sunflower oil on these biofilms. Candida species and Streptococcus mutans were used to study this interaction due to their importance in oral health and disease as these microorganisms display a synergistic relationship that manifests in the onset of caries and tooth decay. Biofilms were developed in a 96-well microtiter plate at 37ºC for 24 h, under aerobiosis or microaerobic conditions, and treated with ozonated oil for 5 to 120 min. All the microorganisms formed biofilms in both oxygenation conditions. Scanning electron microscopy was used to visualize biofilm morphology. Rodent experiments were performed to verify the oil-related toxicity and its efficacy in oral candidiasis. The growth of all Candida species was increased when co-cultured with S. mutans, whilst the growth of bacterium was greater only when co-cultured with C. krusei and C. orthopsilosis under aerobiosis and microaerobic conditions, respectively. Regardless of the oxygenation condition, ozonated oil significantly reduced the viability of all the tested biofilms and infected mice, showing remarkable microbicidal activity as corroborated with confocal microscopy and minimal toxicity. Thus, ozonated oil therapy can be explored as a strategy to control diseases associated with these biofilms especially in the oral cavity. LAY SUMMARY: We demonstrated that ozonated sunflower oil is effective at killing the biofilms formed by Candida species, by the bacterium Streptococcus mutans, or by both micoorganisms that can interact in the oral cavity, making it a potential therapeutic option for the treatment of these infections.

SVCT2 Is Expressed by Cerebellar Precursor Cells, Which Differentiate into Neurons in Response to Ascorbic Acid.

Ascorbic acid (AA) is a known antioxidant that participates in a wide range of processes, including stem cell differentiation. It enters the cell through the sodium-ascorbate co-transporter SVCT2, which is mainly expressed by neurons in the adult brain. Here, we have characterized SVCT2 expression in the postnatal cerebellum in situ, a model used for studying neurogenesis, and have identified its expression in granular precursor cells and mature neurons. We have also detected SVCT2 expression in the cerebellar cell line C17.2 and in postnatal cerebellum-derived neurospheres in vitro and have identified a tight relationship between SVCT2 expression and that of the stem cell-like marker nestin. AA supplementation potentiates the neuronal phenotype in cerebellar neural stem cells by increasing the expression of the neuronal marker ß III tubulin. Stable over-expression of SVCT2 in C17.2 cells enhances ß III tubulin expression, but it also increases cell death, suggesting that AA transporter levels must be finely tuned during neural stem cell differentiation.

Influencia del aceite de coco en enfermos de alzhéimer a nivel cognitivo / How does coconut oil affect cognitive performance in alzheimer patients?

Introducción: la enfermedad de Alzheimer es a día de hoy la demencia neurodegenerativa con mayor prevalencia en el primer mundo. Este hecho, unido a la falta de tratamiento farmacológico que cure la enfermedad, hace que se estudien nuevas estrategias terapéuticas no farmacológicas como es la administración de nutrientes. En este sentido, destaca la posible influencia del aceite de coco como fuente energética alternativa, capaz de frenar la muerte neuronal que se produce de modo progresivo en esta enfermedad. Objetivos: valorar el impacto del aceite de coco a nivel cognitivo en pacientes de alzhéimer, y concretamente en las áreas de orientación, lenguaje-construcción, fijación, cálculo-concentración y memoria. Métodos: estudio prospectivo, longitudinal, cualitativo, analítico y experimental a través de un ensayo clínico, donde se seleccionaron a 44 pacientes con alzhéimer de la zona de la Ribera (Comunidad Valenciana), de los cuales a la mitad se le administró durante 21 días, 40 ml diarios de aceite de coco repartidos entre desayuno (20 ml) y comida (20 ml). Antes y después de la administración del aceite, se les valoró a través del test cognitivo Mini-Examen Cognoscitivo, para determinar los posibles cambios. Resultados: en los enfermos que tomaron el aceite de coco se observó una mejora cognitiva tras finalizar la intervención, siendo estadísticamente significativa en las áreas de orientación y lenguaje-construcción. Conclusiones: el aceite de coco parece mejorar la capacidad cognitiva de los enfermos de alzhéimer, variando la intensidad de la misma en función del área cognitiva (AU)

Introduction: Alzheimer’s disease is one of the most prevalent neurodegenerative dementia in developed world. This fact, coupled with the lack cure, makes new no pharmacological therapeutic strategies such as nutrient management to investigate. In this regard, it stresses the possible influence of coconut oil as alternative energy source capable of stopping the progressively neuronal death that occurs in this disease. Objectives: To assess the cognitive impact of coconut oil in Alzheimer’s patients, and specifi cally in orientation, language-building, fixing, calculation-concentration and memory areas. Methods: Prospective, longitudinal, qualitative, analytical and experimental study through a clinical trial where 44 patients with Alzheimer’s in region of Ribera (Valencia), of which half was selected to receive during 21 days, 40 ml coconut oil daily divided between breakfast (20 ml) and food (20 ml). Before and after administration of the oil, they were evaluated through cognitive test Mini-Mental State Examination to determine possible changes. Results: It was observed in patients who received coconut oil, that cognitive improvement after completion of the intervention, statistically significant improved in the orientation and language-construction areas. Conclusions: Coconut oil appears to improve cognitive abilities of Alzheimer’s patients, with different intensity depending on the cognitive area (AU)

Gene expression changes in colon tissues from colorectal cancer patients following the intake of an ellagitannin-containing pomegranate extract: a randomized clinical trial.

The clinical evidence of dietary polyphenols as colorectal cancer (CRC) chemopreventive compounds is very weak. Verification in humans of tissue-specific molecular regulation by the intake of polyphenols requires complex clinical trials that allow for the procurement of sufficient pre- and postsupplementation tissue samples. Ellagitannins (ETs), ellagic acid (EA) and their gut microbiota-derived metabolites, the urolithins, modify gene expression in colon normal and cancer cultured cells. We conducted here the first clinical trial with 35 CRC patients daily supplemented with 900 mg of an ET-containing pomegranate extract (PE) and evaluated the expression of various CRC-related genes in normal and cancerous colon tissues before (biopsies) and after (surgical specimens) 5-35 days of supplementation. Tissues were also obtained from 10 control patients (no supplementation) that confirmed a large, gene- and tissue-specific interindividual variability and impact of the experimental protocol on gene expression, with some genes induced (MYC, CD44, CDKN1A, CTNNB1), some repressed (CASP3) and others not affected (KRAS). Despite these issues, the consumption of the PE was significantly associated with a counterbalance effect in the expression of CD44, CTNNB1, CDKN1A, EGFR and TYMs, suggesting that the intake of this PE modulated the impact of the protocol on gene expression in a gene- and tissue-specific manner. These effects were not associated with the individuals' capacity to produce specific urolithins (i.e., metabotypes) or the levels of urolithins and EA in the colon tissues and did not reproduce in vitro effects evidencing the difficulty of demonstrating in vivo the in vitro results.

[Not Available]. / Estudio comparativo de la eficacia y seguridad de una nutrición parenteral formulada con dos lípidos distintos: SMOFlipid® frente a Clinoleic®. Estudio preliminar.

Introducción: la composición lipídica de las fórmulas de nutrición parenteral (NP) se postula como posible factor de evolución clínica.Objetivo: evaluar las diferencias en eficacia y seguridad de dos emulsiones lipídicas en NP.Material y métodos: estudio clínico prospectivo de pacientes posquirúrgicos sometidos a NP durante más de 7 días en un periodo de 2 años. Se administraron de forma indistinta 2 tipos de emulsiones lipídicas: enriquecida con ácidos grasos omega 3 (SMOFlipid Fresenius Kabi®) o con ácido oleico omega 9 (Clinoleic Baxter®). Se analizaron variables epidemiológicas, analíticas, complicaciones infecciosas y mortalidad.Resultados: se estudió un total de 154 pacientes con edad media de 64,36 ± 13,73 años, de los que 95 eran hombres (61%), 78 (51%) recibieron SMOFlipid® y 76 (49%) Clinoleic®. La estancia media fue de 16,91 ± 4,23 días, la duración de la NP 9,68 ± 3,25 días y la mortalidad del 11%. Se diagnosticaron 58 (37%) infecciones. No existieron diferencias significativas en cuanto a los parámetros analíticos lipídicos, hepáticos o nutricionales (medidos al inicio y al 7.º día) ni en su evolución (estancia media, complicaciones infecciosas ni mortalidad) entre los dos grupos de pacientes.Conclusión: los pacientes sometidos a NP presentan similares características evolutivas con independencia de la emulsión lipídica utilizada. La bibliografía actual apunta a un beneficio de la disminución del aporte de ácidos grasos omega 9, pero no se han encontrado diferencias significativas entre las fórmulas comparadas.

[PHARMACONUTRITION IN SEVERELY ILL PATIENT]. / FARMACONUTRICIÓN EN EL PACIENTE GRAVE.

"Pharmaconutrient" is a term applicable to those compounds which. in addition to their nutritional function, play a role as aids in the treatment of patients with severe pathologies, including sepsis, trauma, burns and major surgery, In general, enrichment of enteral an parenteral formulas with pharmaconutrients contribute to positively modulate the inflammatory response, infection and controlling the internal milieu, which in turn can be evaluated through lower mortality, hospital and intensive care units stay, days of mechanical ventilation and other parameters allowing to asses their effects. Arginine, glutamine, nucleotides, omega-3 fatty acids and antioxidant micronutrients, make up the nucleus of pharmaconutrients used with that aim, usually as mixtures of them. In the present review current evidence about the effects, indications, limitations, doses, potential adverse risks and even counter-indications is analysed.

El término farmaconutriente se aplica a aquellos compuestos que poseen un efecto añadido al meramente nutricional y que se utilizan como terapia coadyuvante en pacientes con patologías graves que incluyen sepsis, traumatismos, grandes quemados y enfermos quirúrgicos. En general, con su enriquecimiento en las fórmulas enterales o parenterales se pretende modular positivamente la respuesta inflamatoria, la infección y el control del medio interno, valorables a través de mortalidad, tiempo de estancia en hospital y en UCI, días de ventilación mecánica y otros parámetros que permiten dimensionar los efectos de su utilización. Arginina, glutamina, nucleótidos, ácidos grasos omega-3 y micronutrientes antioxidantes constituyen el núcleo de los farmaconutrientes utilizados con la finalidad antedicha, habitualmente en forma de mezclas. En la presente revisión se analiza la evidencia actual acerca de sus efectos, indicaciones, limitaciones, cantidades a aportar, peligros potenciales e incluso contraindicaciones.

Farmaconutrición en el paciente grave / Pharmaconutrition in severely ill patient

El término farmaconutriente se aplica a aquellos compuestos que poseen un efecto añadido al meramente nutricional y que se utilizan como terapia coadyuvante en pacientes con patologías graves que incluyen sepsis, traumatismos, grandes quemados y enfermos quirúrgicos. En general, con su enriquecimiento en las fórmulas enterales o parenterales se pretende modular positivamente la respuesta inflamatoria, la infección y el control del medio interno, valorables a través de mortalidad, tiempo de estancia en hospital y en UCI, días de ventilación mecánica y otros parámetros que permiten dimensionar los efectos de su utilización. Arginina, glutamina, nucleótidos, ácidos grasos omega-3 y micronutrientes antioxidantes constituyen el núcleo de los farmaconutrientes utilizados con la finalidad antedicha, habitualmente en forma de mezclas. En la presente revisión se analiza la evidencia actual acerca de sus efectos, indicaciones, limitaciones, cantidades a aportar, peligros potenciales e incluso contraindicacione (AU)

'Pharmaconutrient' is a term applicable to those compounds which. in addition to their nutritional function, play a role as aids in the treatment of patients with severe pathologies, including sepsis, trauma, burns and major surgery, In general, enrichment of enteral an parenteral formulas with pharmaconutrients contribute to positively modulate the inflammatory response, infection and controlling the internal milieu, which in turn can be evaluated through lower mortality, hospital and intensive care units stay, days of mechanical ventilation and other parameters allowing to asses their effects. Arginine, glutamine, nucleotides, omega-3 fatty acids and antioxidant micronutrients, make up the nucleus of pharmaconutrients used with that aim, usually as mixtures of them. In the present review current evidence about the effects, indications, limitations, doses, potential adverse risks and even counter-indications is analysed (AU)

Early and Long-term Undernutrition in Female Rats Exacerbates the Metabolic Risk Associated with Nutritional Rehabilitation.

Human studies have suggested that early undernutrition increases the risk of obesity, thereby explaining the increase in overweight among individuals from developing countries who have been undernourished as children. However, this conclusion is controversial, given that other studies do not concur. This study sought to determine whether rehabilitation after undernutrition increases the risk of obesity and metabolic disorders. We employed a published experimental food-restriction model. Wistar female rats subjected to severe food restriction since fetal stage and controls were transferred to a moderately high-fat diet (cafeteria) provided at 70 days of life to 6.5 months. Another group of undernourished rats were rehabilitated with chow. The energy intake of undernourished animals transferred to cafeteria formula exceeded that of the controls under this regime and was probably driven by hypothalamic disorders in insulin and leptin signal transduction. The cafeteria diet resulted in greater relative increases in both fat and lean body mass in the undernourished rats when compared with controls, enabling the former group to completely catch up in length and body mass index. White adipose tissues of undernourished rats transferred to the high-lipid regime developed a browning which, probably, contributed to avoid the obesigenic effect observed in controls. Nevertheless, the restricted group rehabilitated with cafeteria formula had greater accretion of visceral than subcutaneous fat, showed increased signs of macrophage infiltration and inflammation in visceral pad, dyslipidemia, and ectopic fat accumulation. The data indicate that early long-term undernutrition is associated with increased susceptibility to the harmful effects of nutritional rehabilitation, without causing obesity.

MicroRNAs expression in normal and malignant colon tissues as biomarkers of colorectal cancer and in response to pomegranate extracts consumption: Critical issues to discern between modulatory effects and potential artefacts.

SCOPE: MicroRNAs (miRs) are proposed as colorectal cancer (CRC) biomarkers. Pomegranate ellagic acid and their microbiota metabolites urolithins exert anticancer effects in preclinical CRC models, and target normal and malignant colon tissues in CRC patients. Herein, we investigated whether the intake of pomegranate extract (PE) modified miRs expression in surgical colon tissues versus biopsies from CRC patients. METHODS AND RESULTS: We conducted a randomized, double-blind, controlled trial. Thirty-five CRC patients consumed 900 mg PE daily before surgery. Control CRC patients (no PE intake, n = 10) were included. Our results revealed: (1) significant differences for specific miRs between malignant and normal tissues modifiable by the surgical protocols; (2) opposed trends between -5p and -3p isomolecules; (3) general induction of miRs attributable to the surgery; (4) moderate modulation of various miRs following the PE intake, and (5) no association between tissue urolithins and the observed miRs changes. CONCLUSION: PE consumption appears to affect specific colon tissue miRs but surgery critically alters miRs levels hindering the discrimination of significant changes caused by dietary factors and the establishment of genuine differences between malignant and normal tissues as biomarkers. The components responsible for the PE effects and the clinical relevance of these observations deserve further research.

Resveratrol treatment restores peripheral insulin sensitivity in diabetic mice in a sirt1-independent manner.

SCOPE: Mice with deletion of insulin receptor substrate (IRS) 2 develop hyperglycaemia, impaired hepatic insulin signaling and elevated gluconeogenesis. Protein tyrosine phosphatase 1B (PTP1B) inhibition by resveratrol improves peripheral insulin sensitivity of these mice. Although resveratrol activates Sirtuin1 (Sirt1), the mechanisms underlying its beneficial effects are not totally elucidated. In this study, we have investigated whether Sirt1 mediates the effects of resveratrol in controlling insulin resistance in diabetic mice. METHODS AND RESULTS: We attempted to ameliorate peripheral insulin resistance in two diabetic models, Irs2-deficient (Irs2(-/-)) mice and streptozotocin (STZ)-injected mice by resveratrol treatment or Sirt1 overexpression. Resveratrol improved systemic insulin sensitivity of Irs2-deficient mice. Irs2-deficient mice are characterized by high levels of PTP1B expression in liver and muscle. Interestingly, resveratrol decreased PTP1B in both tissues, thereby restoring IRS1-mediated insulin signaling. Moreover, resveratrol also restored insulin sensitivity and hepatic insulin signaling in STZ-diabetic mice. In contrast, moderate overexpression of Sirt1 neither normalized PTP1B levels nor restored insulin signaling in Irs2-deficient mice or STZ-diabetic mice. CONCLUSION: Resveratrol improves peripheral insulin signaling independently of Sirt1 in diabetic mice in association with the inhibition of PTP1B and, therefore, this polyphenol could be an effective adjuvant for the treatment of diabetes.

Cocoa-rich diet ameliorates hepatic insulin resistance by modulating insulin signaling and glucose homeostasis in Zucker diabetic fatty rats.

Insulin resistance is the primary characteristic of type 2 diabetes and results from insulin signaling defects. Cocoa has been shown to exert anti-diabetic effects by lowering glucose levels. However, the molecular mechanisms responsible for this preventive activity and whether cocoa exerts potential beneficial effects on the insulin signaling pathway in the liver remain largely unknown. Thus, in this study, the potential anti-diabetic properties of cocoa on glucose homeostasis and insulin signaling were evaluated in type 2 diabetic Zucker diabetic fatty (ZDF) rats. Male ZDF rats were fed a control or cocoa-rich diet (10%), and Zucker lean animals received the control diet. ZDF rats supplemented with cocoa (ZDF-Co) showed a significant decrease in body weight gain, glucose and insulin levels, as well as an improved glucose tolerance and insulin resistance. Cocoa-rich diet further ameliorated the hepatic insulin resistance by abolishing the increased serine-phosphorylated levels of the insulin receptor substrate 1 and preventing the inactivation of the glycogen synthase kinase 3/glycogen synthase pathway in the liver of cocoa-fed ZDF rats. The anti-hyperglycemic effect of cocoa appeared to be at least mediated through the decreased levels of hepatic phosphoenolpyruvate carboxykinase and increased values of glucokinase and glucose transporter 2 in the liver of ZDF-Co rats. Moreover, cocoa-rich diet suppressed c-Jun N-terminal kinase and p38 activation caused by insulin resistance. These findings suggest that cocoa has the potential to alleviate both hyperglycemia and hepatic insulin resistance in type 2 diabetic ZDF rats.

Cocoa-rich diet attenuates beta cell mass loss and function in young Zucker diabetic fatty rats by preventing oxidative stress and beta cell apoptosis.

We have recently shown that cocoa flavanols may have anti-diabetic potential by promoting survival and function of pancreatic beta-cells in vitro. In this work, we investigated if a cocoa-rich diet is able to preserve beta-cell mass and function in an animal model of type 2 diabetes and the mechanisms involved. Our results showed that cocoa feeding during the prediabetic state attenuates hyperglycaemia, reduces insulin resistant, and increases beta cell mass and function in obese Zucker diabetic rats. At the molecular level, cocoa-rich diet prevented beta-cell apoptosis by increasing the levels of Bcl-xL and decreasing Bax levels and caspase-3 activity. Cocoa diet enhanced the activity of endogenous antioxidant defenses, mainly glutathione peroxidase, preventing thus oxidative injury induced by the pre-diabetic condition and leading to apoptosis prevention. These findings provide the first in vivo evidence that a cocoa-rich diet may delay the loss of functional beta-cell mass and delay the progression of diabetes by preventing oxidative stress and beta-cell apoptosis.

Influence of n-3 polyunsaturated fatty acids enriched lipid emulsions on nosocomial infections and clinical outcomes in critically ill patients: ICU lipids study.

OBJECTIVE: n-3 polyunsaturated fatty acids (contained in fish oil) have been shown to beneficially influence infection rate and clinical outcomes in surgical patients probably due to their immunomodulatory action. In contrast, study results of fish oil administration in critically ill patients are controversial. The aim of this study was to investigate the effects of n-3 polyunsaturated fatty acids on the prevalence of nosocomial infections and clinical outcomes in medical and surgical critically ill patients. DESIGN: Prospective, multicenter, randomized, comparative, double-blind study. SETTING: Seventeen Spanish ICUs during 4 years. SUBJECTS: A total of 159 medical and surgical intensive care patients with Acute Physiology and Chronic Health Evaluation II score more than or equal to 13, expected to require total parenteral nutrition for at least 5 days. INTERVENTIONS: Patients received total parenteral nutrition prepared either with a lipid emulsion containing 10% fish oil or a fish oil-free lipid emulsion. The prevalence of nosocomial infections was detected during 28 days of ICU stay. Patients were followed 6 months after discharge from the ICU for length of hospital stay, hospital mortality, and 6-month mortality. MEASUREMENTS AND MAIN RESULTS: The number of patients with nosocomial infections was significantly reduced in the fish oil-receiving group (21.0% vs 37.2%, p = 0.035) and the predicted time free of infection was prolonged (21 ± 2 vs 16 ± 2 d, p = 0.03). No significant differences were detected for ICU, hospital, and 6-month mortality. CONCLUSIONS: The results show that administration of n-3 polyunsaturated fatty acids reduces the risk of nosocomial infections and increases the predicted time free of infections in critically ill medical and surgical patients. The administration of n-3 polyunsaturated fatty acids was safe and well tolerated.

Targeted metabolic profiling of pomegranate polyphenols and urolithins in plasma, urine and colon tissues from colorectal cancer patients.

SCOPE: Urolithins are bioactive metabolites produced by the gut microbiota from ellagitannins (ETs) and ellagic acid (EA). We investigated whether urolithins could be detected in colon tissues from colorectal cancer (CRC) patients after pomegranate extract (PE) intake. METHODS AND RESULTS: CRC patients (n = 52) were divided into controls and PEs consumers (900 mg/day for 15 days) before surgical resection. PEs with low (PE-1) and high (PE-2) punicalagin:EA ratio were administered. Twenty-three metabolites, but no ellagitannins, were detected in urine, plasma, normal (NT) or malignant (MT) colon tissues using UPLC-ESI-QTOF-MS/MS (UPLC, ultra performance liquid chromatography; QTOF, quadrupole TOF). Free EA, five EA conjugates, gallic acid and 12 urolithin derivatives were found in colon tissues. Individual and total metabolites levels were higher in NT than in MT, independently of the PE consumed. The maximal mean concentration (1671 ± 367 ng/g) was found in NT after consumption of PE-1 and the lowest concentration (42.4 ± 10.2 ng/g) in MT with PE-2. Urolithin A or isourolithin A were the main urolithins produced (54 and 46% patients with urolithin A or isourolithin A phenotype, respectively). High punicalagin content (PE-2) hampered urolithins formation. CONCLUSION: Significant levels of EA derivatives and urolithins are found in human colon tissues from CRC patients after consumption of pomegranate. Further studies are warranted to elucidate their biological activity.

Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: a template-based approach--part 2.

Previous efforts by our group have established pyrazolo[1,5-a]pyrimidine as a viable core for the development of potent and selective CDK inhibitors. As part of an effort to utilize the pyrazolo[1,5-a]pyrimidine core as a template for the design and synthesis of potent and selective kinase inhibitors, we focused on a key regulator in the cell cycle progression, CHK1. Continued SAR development of the pyrazolo[1,5-a]pyrimidine core at the C5 and C6 positions, in conjunction with previously disclosed SAR at the C3 and C7 positions, led to the discovery of potent and selective CHK1 inhibitors.

Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: a template-based approach--part 1.

The synthesis and hit-to-lead SAR development of a pyrazolo[1,5-a]pyrimidine hit 4 is described leading to a series of potent, selective CHK1 inhibitors such as compound 17r. In the Letter, the further utility of the pyrazolo[1,5-a]pyrimidine template for the development of potent, selective kinase inhibitors is detailed.

Modelo experimental de hiperlipidemia con el empleo de caseína y grasas saturadas / Experimental model of hyperlipidaemia with the use of casein and saturated fats

En el presente trabajo se evaluó el efecto hiperlipídico de una dieta combinada de caseína y grasas saturadas, en un modelo biológico conformado por ratas Wistar. Se integraron tres grupos experimentales de seis animales cada uno: el primero (grupo control) consumió una dieta convencional; el segundo, una dieta convencional combinada con caseína y grasa de cerdo al 20 por ciento y el tercero, la dieta convencional suplementada solamente con grasa de cerdo al por ciento. Fueron cuantificados el colesterol y los triacilglicéridos por métodos enzimáticos en tres momentos diferentes: al comienzo del estudio, a los 15 días y al finalizar este. El incremento de peso corporal, una vez finalizada la investigación, no mostró diferencias significativas entre los grupos de experimentación. El grupo de la dieta combinada elevó el perfil lipídico más eficientemente que el que solo consumió grasas saturadas, lo cual confirma que el modelo experimental de hiperlipidemia inducida por dieta suplementada con caseína y grasas saturadas es el más eficaz para la elevación del perfil lipídico

In the current research it was evaluated the hyperlipidic effect of a combined diet with casein andsaturated fats, in a biological model conformed by Wistar's rats. Three experimental groups wereintegrated with six animals in each one. The first group (control group) consumed a conventionaldiet; the second group, a conventional diet combined with casein and pig fat at 20 %; and the thirdone, the same conventional diet supplemented just with pig fat at 20 %.The cholesterol andtriacylglycerols were quantified by means of enzymatic methods in three different moments: at thebeginning of the study, after 15 days and at the end of this. The increase of body weight, once itwas finished the research, didn't show significant differences among the experimental groups. Thegroup of the combined diet increased its lipidic profile more efficiently than the group that justconsumed saturated fats, which confirms that the experimental model of induced hyperlipidaemiaby supplemented diet with casein and saturated fats is the most effective for the elevation of lipidicprofile.

Electroacupuntura en el tratamiento de la colitis ulcerosa experimental en ratas Sprague Dawley / Electro acupuncture in the treatment of experimental ulcerous colitis in Sprague Dawley rats

Se realizó un estudio sobre la efectividad terapéutica de laelectroacupuntura (EA) en la colitisulcerosa (CU) provocadaexperimentalmente en ratas Sprague Dawley por administraciónintracolónica de una disolución de ácido acético al 4%. El experimento serealizó en 57 ratas distribuidas en tres grupos: Grupo I (control placebo), alque se administró solución salina fisiológica mediante instilaciónintracolónica, Grupo II (control no tratado) y Grupo III (estudio), integrado ambos por animales en que se reprodujo artificialmente la colitis ulcerosa. El estudio histopatológico de muestras tomadas mediante biopsias permitió corroborar la instauración de la entidad. Los acupuntos seleccionados fueron LI-4 (Hegu) y ST-36 (Zusanli) y la aplicación de la EA se realizó a las 24, 48 y 72 horas posteriores a la reproducción experimental de la CU. En lascondiciones del estudio se comprobó que una sesión de EA a las 24 horasposteriores a la reproducción de la entidad, posee efecto anti inflamatorio ymejora notablemente la lesión tisular, no siendo eficaz en los tratamientosrealizados a las 48 y 72 horas, influyendo en ello el mecanismo detransducción. Mediante el estudio histopatológico de muestras tomadasmediante biopsias se puede evaluar el estado de la mucosa en la CU y surespuesta al tratamiento mediante EA, sin necesidad de acudir a otrosprocedimientos más sofisticados y costosos. Se comprobó que el modeloexperimental utilizado es adecuado para estudios sobre esta afección(AU)

Occurrence of urolithins, gut microbiota ellagic acid metabolites and proliferation markers expression response in the human prostate gland upon consumption of walnuts and pomegranate juice.

Epidemiology supports the important role of nutrition in prostate cancer (PCa) prevention. Pomegranate juice (PJ) exerts protective effects against PCa, mainly attributed to PJ ellagitannins (ETs). Our aim was to assess whether ETs or their metabolites ellagic acid and urolithins reach the human prostate upon consumption of ET-rich foods and to evaluate the effect on the expression of three proliferation biomarkers. Sixty-three patients with BPH or PCa were divided into controls and consumers of walnuts (35 g walnuts/day) or pomegranate (200 mL PJ/day) for 3 days before surgery. Independently of the ETs source, the main metabolite detected was urolithin A glucuronide, (3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one glucuronide) (up to 2 ng/g) together with the traces of urolithin B glucuronide, (3-hydroxy-6H-dibenzo[b,d]pyran-6-one glucuronide) and dimethyl ellagic acid. The small number of prostates containing metabolites was likely caused by clearance of the compounds during the fasting. This was corroborated in a parallel rat study and thus the presence of higher quantities of metabolites at earlier time points cannot be discarded. No apparent changes in the expression of CDKN1A, MKi-67 or c-Myc were found after consumption of the walnuts or PJ. Our results suggest that urolithin glucuronides and dimethyl ellagic acid may be the molecules responsible for the beneficial effects of PJ against PCa.