Gold(I) complexes bearing alkylated 1, 3, 5-triaza-7-phosphaadamantane ligands as thermoresponsive anticancer agents in human colon cells

Overheating can affect solubility or lipophilicity, among other properties, of some an-ticancer drugs. These temperature-dependent changes can improve efficiency and selectivity of the drugs, since they may affect their bioavailability, diffusion through cell membrane or activity. One recent approach to create thermosensitive molecules is the incorporation of fluorine atoms in the chemical structure, since fluor can tune some chemical properties such as binding affinity. Herein we report the anticancer effect of gold derivatives with phosphanes derived from 1, 3, 5-triaza-7-phosphaadamantane (PTA) with long hydrocarbon chains and the homologous fluorinated chains. Besides, we analysed the influence of temperature in the cytotoxic effect. The studied gold(I) complexes with phosphanes derived from PTA showed antiproliferative effect on human colon carcinoma cells (Caco-2/TC7 cell line), probably by inhibiting cellular TrxR causing a dysfunction in the intracellular redox state. In addition, the cell cycle was altered by the activation of p53, and the complexes produce apoptosis through mitochondrial depolarization and the consequent activation of caspase-3. Furthermore, the results suggest that this cytotoxic effect is enhanced by hyperthermia and the presence of polyfluorinated chains. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Fat-to-glucose interconversion by hydrodynamic transfer of two glyoxylate cycle enzyme genes

The glyoxylate cycle, which is well characterized in higher plants and some microorganisms but not in vertebrates, is able to bypass the citric acid cycle to achieve fat-to-carbohydrate interconversion. In this context, the hydrodynamic transfer of two glyoxylate cycle enzymes, such as isocytrate lyase (ICL) and malate synthase (MS), could accomplish the shift of using fat for the synthesis of glucose. Therefore, 20 mice weighing 23.37 +/- 0.96 g were hydrodinamically gene transferred by administering into the tail vein a bolus with ICL and MS. After 36 hours, body weight, plasma glucose, respiratory quotient and energy expenditure were measured. The respiratory quotient was increased by gene transfer, which suggests that a higher carbohydrate/lipid ratio is oxidized in such animals. This application could help, if adequate protocols are designed, to induce fat utilization for glucose synthesis, which might be eventually useful to reduce body fat depots in situations of obesity and diabete

Plan verde para una ciudad patrimonio de la humanidad. Segovia

Segovia's 'Green Plan' is the putting into practice of a methodology for the action, both general and peculiar, in order to defend the town's sustainability. The aim of the Plan is the recovery, preservation and improvement of the landscape and ecological quality of the town and surroundings, starting from the analysis of the urban and peripheral environment, and on the basis of a programme founded upon the comprehensive understanding of environmental aspects. This article describes not only the steps taken for the writing of the Plan and the subsequent elaboration of a proposal for general action, but also the development of this action. The results of the revision and evaluation of the Plan after eight years of execution are also explained, as well as the ensuing strategy for the completion and improvement of the initial Plan.El Plan Verde de Segovia es la puesta en practica de una metodología de actuación general y peculiar para defender la sostenibilidad de la ciudad. El objeto del referido Plan es la recuperación, conservación y mejora de la calidad ecológica y paisajística de la ciudad y su entorno, a partir de un análisis del medio urbano y periurbano, y sobre la base de una programación fundamentada en la visión integral de los aspectos ambientales. El presente articulo describe, tanto los pasos dados para la redacción del plan y la subsiguiente elaboración de una propuesta general de actuación, como el desarrollo de esta ultima. Se expresan también los resultados de la revisión y evaluación del Plan tras ocho años de ejecución y la estrategia derivada para completar y mejorar el Plan inicial

Towards New Comet Missions

The Rosetta observations have greatly advanced our knowledge of the cometary nucleus and its immediate environment. However, constraints on the mission (both planned and unplanned), the only partially successful Philae lander, and other instrumental issues have inevitably resulted in open questions. Surprising results from the many successful Rosetta observations have also opened new questions, unimagined when Rosetta was first planned. We discuss these and introduce several mission concepts that might address these issues. It is apparent that a sample return mission as originally conceived in the 1980s during the genesis of Rosetta would provide many answers but it is arguable whether it is technically feasible even with today’s technology and knowledge. Less ambitious mission concepts are described to address the suggested main outstanding scientific goals

Phenolic composition of artichoke waste and its antioxidant capacity on differentiated Caco-2 cells

Artichoke waste represents a huge amount of discarded material. This study presents the by-products (bracts, exterior leaves, and stalks) of the “Blanca de Tudela” artichoke variety as a potential source of phenolic compounds with promising antioxidant properties. Artichoke residues were subjected to different extraction processes, and the antioxidant capacity and phenolic composition of the extracts were analyzed by spectrophotometric methods and high performance liquid chromatography (HPLC) analyses, respectively. The most abundant polyphenols in artichoke waste were chlorogenic acid, luteolin-7-O-rutinoside, and luteolin-7-O-glucoside. Minor quantities of cynarin, luteolin, apigenin-7-O-glucoside, apigenin-7-O-rutinoside, and naringenin-7-O-glucoside were also found. The antioxidant activity of the obtained extracts determined by ABTS [2, 2’-azinobis (3-ethylbenzothiazoline-6-sulphonic acid)], DPPH (2, 2-diphenyl-1-pycrilhydracyl), and FRAP (Ferric Ion Reducing Antioxidant Power) was highly correlated with the total concentration of phenolic compounds. Chlorogenic acid, luteolin-7-O-glucoside, and luteolin-7-O-rutinoside, the most abundant compounds in 60% methanol extracts, are the components most responsible for the antioxidant activity of the artichoke waste extracts. The extract with the best antioxidant capacity was selected to assay its antioxidant potential on a model intestinal barrier. This action of the hydroxycinnamic acids on intestinal cells (Caco-2) was confirmed. In summary, artichoke waste may be considered a very interesting ingredient for food functionalization and for therapeutic purposes

Therapeutic molecules for osteoarthritis treatment. role of phloretin, ipriflavone and raloxifene in lipopolysaccharide induced osteoarthritic chondrocytes

Purpose: The search of novel molecules for the treatment of osteoarthritis (OA) is complex as any new therapeutic approach should encompass these requirements: inhibition of cartilage degradation, protection of bone and inhibition of inflammation. In the last years, different drugs have been proposed though most of them did not succeed in fulfil these requirements. Moreover, few of them have been encapsulated in drug delivery systems to improve their therapeutic potential to achieve a sustained or controlled release compared to the administration of equivalent doses of the free compounds. Nanoscience has arisen in the last decades as a potential field of study in drug delivery because nanomaterials may overcome the main current limitations to achieve an efficient and localized drug delivery by improving the targeted delivery and providing a sustained or controlled delivery to prolong the therapeutic effect. On the other hand, different polyphenols and aromatic organic compounds are known to possess anti-inflammatory, antioxidant and bone density-building properties..

Obesity induced by a pair-fed high fat sucrose diet: methylation and expression pattern of genes related to energy homeostasis.

BACKGROUND: The expression of some genes controlling energy homeostasis could be regulated by epigenetic mechanisms that may play a role in body weight regulation. Thus, it is known that various nutritional factors affect DNA methylation. In order to assess whether the macronutrient composition of the diet could be related to the epigenetic regulation of gene expression and with obesity development, we investigated the effects on methylation and expression patterns of two pair-fed isocaloric diets in rats: control (rich in starch) and HFS (rich in fat and sucrose). RESULTS: The pair-fed HFS diet induced higher weight gain and adiposity as compared to the controls as well as liver triglyceride accumulation and oxidative stress. Feeding the HFS diet impaired glucose tolerance and serum triglycerides and cholesterol. Liver glucokinase expression, a key glycolytic gene, remained unaltered, as well as the mRNA values of fatty acid synthase and NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 6 (NDUFB6) in liver and visceral adipocytes, which regulate lipogenesis and mitochondrial oxidative metabolism, respectively. Liver expression of hydroxyacyl-coenzyme A dehydrogenase (HADHB), a key gene of beta-oxidation pathway, was higher in the HFS-fed animals. However, the methylation status of CpG islands in HADHB and glucokinase genes remained unchanged after feeding the HFS diet. CONCLUSIONS: These results confirm that the distribution and type of macronutrients (starch vs. sucrose, and percent of fat) influence obesity onset and the associated metabolic complications. HFS diets produce obesity independently of total energy intake, although apparently no epigenetic (DNA methylation) changes accompanied the modifications observed in gene expression

Vitamin C modulates the interaction between adipocytes and macrophages

Scope: Increased adiposity is related with monocyte infiltration into the adipose tissue that accentuates inflammation. Antioxidant treatments emerge as approaches to counteract this phenomenon. Methods and results: Cocultures of differentiated 3T3-L1 adipocytes and RAW264.7 macrophages were incubated for 24-72 h with/without 100 nM insulin and/or 200 μM vitamin C (VC). Nitric oxide (NO) secretion (24 h) was measured. Also, expression (24 h) and secretion (72 h) of MCP-1, leptin and apelin were analyzed. NO secretion was significantly inhibited by insulin and VC only in cocultures. MCP-1 expression/secretion was enhanced in cocultures. Insulin incubation reduced MCP-1 expression in both cultures and VC only in controls. Both treatments inhibited MCP-1 secretion in cocultures. Apelin gene expression was induced in cocultures. Insulin induced apelin mRNA expression, but VC inhibited its expression in cocultures under insulin treatment. Apelin secretion was notably induced by insulin and inhibited by VC in cocultures. Leptin expression was decreased in coculture, while presented no effects by VC. Conclusion: VC importantly modulates the established pro-inflammatory state in the interaction between adipocytes and macrophages

Vitamin C inhibits leptin secretion and some glucose/lipid metabolic pathways in primary rat adipocytes

Antioxidant-based treatments are emerging as an interesting approach to possibly counteract obesity fat accumulation complications, since this is accompanied by an increased systemic oxidative stress. The aim of this study was to analyze specific metabolic effects of vitamin C (VC) on epididymal primary rat adipocytes. Cells were isolated and incubated for 72 h in culture medium, in the absence or presence of 1.6 nM insulin, within a range of VC concentrations (5-1000 microM). Glucose- and lipid-related variables as well as the secretion/expression patterns of several obesity-related genes were assessed. It was observed that VC dose dependently inhibited glucose uptake and lactate production, and also reduced glycerol release in both control and insulin-treated cells. Also, VC caused a dramatic concentration-dependent fall in leptin secretion especially in insulin-stimulated cells. In addition, VC (200 microM) induced Cdkn1a and Casp8, partially inhibited Irs3, and together with insulin drastically reduced Gpdh (listed as Gpd1 in the MGI database) gene expressions. Finally, VC and insulin down-regulatory effects were observed on extracellular and intracellular reactive oxygen species production respectively. In summary, this experimental assay describes a specific effect of VC in isolated rat adipocytes on glucose and fat metabolism, and on the secretion/expression of important obesity-related proteins

Fat intake leads to differential response of rat adipocytes to glucose, insulin and ascorbic acid

Antioxidant-based treatments have emerged as novel and interesting approaches to counteract fat accumulation in obesity and associated metabolic disturbances. Adipocytes from rats that were fed on chow or high-fat diet (HFD) for 50 d were isolated (primary adipocytes) and incubated (72 h) on low (LG; 5.6 mmol/L) or high (HG; 25 mmol/L) glucose levels, in the presence or absence of 1.6 nmol/L insulin and 200 μmol/L vitamin C (VC). Adipocytes from HFD-fed animals presented lower insulin-induced glucose uptake, lower lactate and glycerol release, and lower insulin-induced secretion of some adipokines as compared with controls. HG treatment restored the blunted response to insulin regarding apelin secretion in adipocytes from HFD-fed rats. VC treatment inhibited the levels of nearly all variables, irrespective of the adipocytes' dietary origin. The HG treatment reduced adipocyte viability, and VC protected from this toxic effect, although more drastically in control adipocytes. Summing up, in vivo chow or HFD intake determines a differential response to insulin and glucose treatments that appears to be dependent on the insulin-resistance status of the adipocytes, while VC modifies some responses from adipocytes independently of the previous dietary intake of the animals