Transcriptional and biochemical changes in mouse liver following exposure to a metal/drug cocktail. Attenuating effect of a selenium-enriched diet.

Real-life pollution usually involves simultaneous co-exposure to different chemicals. Metals and drugs are frequently and abundantly released into the environment, where they interact and bioaccumulate. Few studies analyze potential interactions between metals and pharmaceuticals in these mixtures, although their joint effects cannot be inferred from their individual properties. We have previously demonstrated that the mixture (PC) of the metals Cd and Hg, the metalloid As and the pharmaceuticals diclofenac (DCF) and flumequine (FLQ) impairs hepatic proteostasis. To gain a deeper vision of how PC affects mouse liver homeostasis, we evaluated here the effects of PC exposure upon some biochemical and morphometric parameters, and on the transcriptional profiles of selected group of genes. We found that exposure to PC caused oxidative damage that exceeded the antioxidant capacity of cells. The excessive oxidative stress response resulted in an overabundance of reducing equivalents, which hindered the metabolism and transport of metabolites, including cholesterol and bile acids, between organs. These processes have been linked to metabolic and inflammatory disorders, cancer, and neurodegenerative diseases. Therefore, our findings suggest that unintended exposure to mixtures of environmental pollutants may underlie the etiology of many human diseases. Fortunately, we also found that a diet enriched with selenium mitigated the harmful effects of this combination of toxicants.

Risk of progression of early-stage mycosis fungoides, 10-year experience.

BACKGROUND: Mycosis fungoides is the most frequent form of cutaneous T-cell lymphoma. It is characterized by a chronic, slow, and progressive course, and is associated with mortality rates that depend on several factors, such as clinical staging. A median survival time of up to 13 months is found in patients with advanced stages that require more aggressive treatments, with greater toxicity and higher costs. In Latin America, few prognostic studies of the disease are available. OBJECTIVE: To determine the rate of progression from early stages (IA, IB, IIA) to more advanced stages (> IIB) in patients older than 18 years with mycosis fungoides treated at two medical centers in Colombia between January 1, 2010, and December 31, 2019. METHODS: Retrospective cohort study with a longitudinal design. RESULTS: 112 patients diagnosed with early mycosis fungoides were included. 56.2% were male (n = 63), with a median age of 53 years (IQR 43‒67). The most frequent clinical variant was classic (67.9%; n = 76), followed by folliculotropic (16%; n = 18), and hypopigmented (10.7%; n = 12). The most common first-line treatment was NB-UVB phototherapy (27.7%; n = 31), followed by PUVA phototherapy (25.8%; n = 29%), and topical corticosteroids (25%; n = 28). The global rate of disease progression was 8% (n = 9), with an overall mortality of 12.5% (n = 14). STUDY LIMITATIONS: Its retrospective design and the lack of molecular studies for case characterization. CONCLUSIONS: Early mycosis fungoides is a disease with a good prognosis in most patients, with a progression rate of 8% (n = 9).

Risk of progression of early-stage mycosis fungoides, 10-year experience

Abstract Background Mycosis fungoides is the most frequent form of cutaneous T-cell lymphoma. It is characterized by a chronic, slow, and progressive course, and is associated with mortality rates that depend on several factors, such as clinical staging. A median survival time of up to 13 months is found in patients with advanced stages that require more aggressive treatments, with greater toxicity and higher costs. In Latin America, few prognostic studies of the disease are available. Objective To determine the rate of progression from early stages (IA, IB, IIA) to more advanced stages (> IIB) in patients older than 18 years with mycosis fungoides treated at two medical centers in Colombia between January 1, 2010, and December 31, 2019. Methods Retrospective cohort study with a longitudinal design. Results 112 patients diagnosed with early mycosis fungoides were included. 56.2% were male (n = 63), with a median age of 53 years (IQR 43‒67). The most frequent clinical variant was classic (67.9%; n = 76), followed by folliculotropic (16%; n = 18), and hypopigmented (10.7%; n = 12). The most common first-line treatment was NB-UVB phototherapy (27.7%; n = 31), followed by PUVA phototherapy (25.8%; n = 29%), and topical corticosteroids (25%; n = 28). The global rate of disease progression was 8% (n = 9), with an overall mortality of 12.5% (n = 14). Study limitations Its retrospective design and the lack of molecular studies for case characterization. Conclusions Early mycosis fungoides is a disease with a good prognosis in most patients, with a progression rate of 8% (n = 9).

Proteomic analysis of the hepatic response to a pollutant mixture in mice. The protective action of selenium.

Metals and pharmaceuticals contaminate water and food worldwide, forming mixtures where they can interact to enhance their individual toxicity. Here we use a shotgun proteomic approach to evaluate the toxicity of a pollutant mixture (PM) of metals (As, Cd, Hg) and pharmaceuticals (diclofenac, flumequine) on mice liver proteostasis. These pollutants are abundant in the environment, accumulate in the food chain, and are toxic to humans primarily through oxidative damage. Thus, we also evaluated the putative antagonistic effect of low-dose dietary supplementation with the antioxidant trace element selenium. A total of 275 proteins were affected by PM treatment. Functional analyses revealed an increased abundance of proteins involved in the integrated stress response that promotes translation, the inflammatory response, carbohydrate and lipid metabolism, and the sustained expression of the antioxidative response mediated by NRF2. As a consequence, a reductive stress situation arises in the cell that inhibits the RICTOR pathway, thus activating the early stage of autophagy, impairing xenobiotic metabolism, and potentiating lipid biosynthesis and steatosis. PM exposure-induced hepato-proteostatic alterations were significantly reduced in Se supplemented mice, suggesting that the use of this trace element as a dietary supplement may at least partially ameliorate liver damage caused by exposure to environmental mixtures.

Does Time and Size Matter in Retrograde Intrarenal Surgery? Results Analysis Using a Low-Pressure Technique.

PURPOSE: Kidney stone disease affects 5% of the population and is associated with non-negligible morbidity. Retrograde intrarenal surgery and percutaneous nephrolithotomy are the treatments of choice. We analyzed the results from our patients who underwent retrograde intrarenal surgery at controlled pressure. MATERIALS AND METHODS: We conducted an observational, descriptive, retrospective study of 403 patients who underwent retrograde intrarenal surgery at the Hospital Clínico Universitario Lozano Blesa (Zaragoza, Spain) between January 2013 and December 2019. RESULTS: The mean surgical time was 111.1 minutes, with a mean stone volume of 3.5 cm3 (maximum volume, 38.3 cm3). A total of 70 patients (17.3%) developed postoperative Clavien-Dindo complications-64 minor (91.4%) and 6 major (8.6%). In addition, 28 patients (6.9%) presented with an early complication (<3 months), with urinary tract infection and pyelonephritis being the most common. The stone-free rate was 69.0%, with a retreatment rate of 4.7%. CONCLUSIONS: Sex was statistically significantly related to the onset of minor Clavien postoperative complications (p = 0.001). Similarly, corticosteroid use was associated with the onset of major Clavien complications (p = 0.030). Neither surgical time nor stone volume was found to be statistically significantly related to the onset of Clavien postoperative complications or early complications.

The role of selenium in shaping mice brain metabolome and selenoproteome through the gut-brain axis by combining metabolomics, metallomics, gene expression, and amplicon sequencing.

Selenium (Se) is a trace element crucial for human health. Recently, the impact of Se supplementation on gut microbiota has been pointed out as well as its influence on the expression of certain selenoproteins and gut metabolites. This study aims to elucidate the link between Se supplementation, brain selenoproteins and brain metabolome as well as the possible connection with the gut-brain axis. To this end, an in vivo study with 40 BALB/c mice was carried out. The study included conventional (n=20) and mice model with microbiota depleted by antibiotics (n=20) under a regular or Se supplemented diet. Brain selenoproteome was determined by a transcriptomic/gene expression profile, while brain metabolome and gut microbiota profiles were accomplished by untargeted metabolomics and amplicon sequencing, respectively. The total content of Se in brain was also determined. The selenoproteins genes Dio and Gpx isoenzymes, SelenoH, SelenoI, SelenoT, SelenoV, and SelenoW and 31 metabolites were significantly altered in the brain after Se supplementation in conventional mice, while 11 selenoproteins and 26 metabolites were altered in microbiota depleted mice. The main altered brain metabolites were related to glyoxylate and dicarboxylate metabolism, amino acid metabolism, and gut microbiota that have been previously related with the gut-brain axis (e.g., members of Lachnospiraceae and Ruminococcaceae families). Moreover, specific associations were determined between brain selenoproteome and metabolome, which correlated with the same bacteria, suggesting an intertwined mechanism. Our results demonstrated the effect of Se on brain metabolome through specific selenoproteins gene expression and gut microbiota.

Does Time and Size Matter in Retrograde Intrarenal Surgery? Results Analysis Using a Low-Pressure Technique

Purpose: Kidney stone disease affects 5% of the population and is associated with non-negligible morbidity. Retrograde intrarenal surgery and percutaneous nephrolithotomy are the treatments of choice. We analyzed the results from our patients who underwent retrograde intrarenal surgery at controlled pressure. Materials and Methods: We conducted an observational, descriptive, retrospective study of 403 patients who underwent retrograde intrarenal surgery at the Hospital Clínico Universitario Lozano Blesa (Zaragoza, Spain) between January 2013 and December 2019. Results: The mean surgical time was 111.1 minutes, with a mean stone volume of 3.5 cm3 (maximum volume, 38.3 cm3). A total of 70 patients (17.3%) developed postoperative Clavien-Dindo complications—64 minor (91.4%) and 6 major (8.6%). In addition, 28 patients (6.9%) presented with an early complication (<3 months), with urinary tract infection and pyelonephritis being the most common. The stone-free rate was 69.0%, with a retreatment rate of 4.7%. Conclusions: Sex was statistically significantly related to the onset of minor Clavien postoperative complications (p = 0.001). Similarly, corticosteroid use was associated with the onset of major Clavien complications (p = 0.030). Neither surgical time nor stone volume was found to be statistically significantly related to the onset of Clavien postoperative complications or early complications (AU)

A selenium-enriched diet helps to recover liver function after antibiotic administration in mice.

Antibiotic (Abx) treatments or inadvertent exposure to Abx-contaminated food and water can adversely affect health. Many studies show strong correlations between Abx and liver damage pointing to gut dysbiosis as a contributing factor because the gut microbiota (GM) forms a complex network with liver. Selenium (Se) is a beneficial micronutrient able to shape the composition of the GM. We analyzed here the ability of a low dose (120 µg/kg bodyweight/day) Se-enriched diet to ameliorate the effects of a 7-day intervention with an Abx-cocktail over the global health and the homeostasis of cholesterol and bile acids in the mouse liver. We found that Se restored lipid metabolism preventing the increased synthesis and accumulation of cholesterol caused by Abx treatment. Integrating these results with previous metataxonomic and metabolomic data in same mice, we conclude that part of the effect of Se against liver dysfunction (cholesterol and bile acids metabolism and transport) could be mediated by the GM. We provide data that contribute to a more complete view of the molecular mechanisms underlying the beneficial action of Se on health, pointing to a possible use of low doses of Se as a functional food additive (prebiotic) to prevent the negative effects of antibiotics.

Omic methodologies for assessing metal(-loid)s-host-microbiota interplay: A review.

Omic methodologies have become key analytical tools in a wide number of research topics such as systems biology, environmental analysis, biomedicine or food analysis. They are especially useful when they are combined providing a new perspective and a holistic view of the analytical problem. Methodologies for microbiota analysis have been mostly focused on genome sequencing. However, information provided by these metagenomic studies is limited to the identification of the presence of genes, taxa and their inferred functionality. To achieve a deeper knowledge of microbial functionality in health and disease, especially in dysbiosis conditions related to metal and metalloid exposure, the introduction of additional meta-omic approaches including metabolomics, metallomics, metatranscriptomics and metaproteomics results essential. The possible impact of metals and metalloids on the gut microbiota and their effects on gut-brain axis (GBA) only begin to be figured out. To this end new analytical workflows combining powerful tools are claimed such as high resolution mass spectrometry and heteroatom-tagged proteomics for the absolute quantification of metal-containing biomolecules using the metal as a "tag" in a sensitive and selective detector (e.g. ICP-MS). This review focus on current analytical methodologies related with the analytical techniques and procedures available for metallomics and microbiota analysis with a special attention on their advantages and drawbacks.

Proteomic profile of the effects of low-dose bisphenol A on zebrafish ovaries.

Human exposure to bisphenol-A (BPA) is largely unavoidable because BPA is an environmental contaminant found in soil, water, food and indoor dust. The safety of authorized BPA amounts in consumer products is under question because new studies have reported adverse effects of BPA at doses far below that previously established by the NOAEL (50 µg/kg per day). To protect public health, the consequences of low-dose BPA exposure in different organs and organismal functions must be further studied to generate relevant data. This study attempted to investigate the effects and potential molecular mechanisms of short-term exposure to 1 µg/L BPA on zebrafish ovarian follicular development. We observed only minor changes at the histopathological level with a small (3 %) increase in follicular atresia. However, a shotgun proteomics approach indicated deep alterations in BPA-exposed ovarian cells, including induction of the oxidative stress response, metabolic shifts and degradome perturbations, which could drive oocytes towards premature maturation. Based on these results, it could be suggested that inadvertent exposure to small concentrations of BPA on a continuous basis causes alteration in biological processes that are essential for healthy reproduction.

Pedro Ximenez sun-dried grape must: a dietary supplement for a healthy longevity.

Polyphenols in red wine are bioactive compounds with positive effects on health and disease prevention. White grape musts and wines have a lower concentration of phenolic compounds compared to the red ones and are therefore considered less beneficial to health. In Andalucía, a region located in the South West of Spain, Pedro Ximenez white grapes are desiccated under the sun for a week before they are pressed and the juice (must) is obtained. This ancient procedure increases the variety and content of polyphenols present in the Pedro Ximenez must (PXM). We incorporated PXM into the daily diet of aged Mus spretus mice (24 months) and investigated their properties by comparing several parameters determined in these old mice with those measured in young mice (two months old). Biochemical, histological, and transcriptional analyses indicated that PXM exhibited potent antioxidant properties, promoted the normalization of the biotransforming ability of several cytochromes, i.e., the P450 family, in the liver, and regularized hepatic apoptosis, promoting proliferation instead. Our data indicated that PXM possesses a profound ability to promote liver regeneration in terms of both the structure and the function, thus contributing to a healthy aging process.

Protective effect of Pedro-Ximénez must against p,p'-DDE-induced liver damages in aged Mus spretus mice.

Aging is characterized by deterioration of biomolecules and impaired stress responses that make the elderly especially vulnerable to environmental pollutants. The pesticide p,p'-DDE is a DDT derivative that generates great concern because of its wide distribution and its harmful effects on both human health and the environment. We analyzed here the biological responses elicited by p,p'-DDE exposure in the liver of aged Mus spretus mice. Data demonstrate that the elderly constitute a population especially sensitive to this noxious environmental pollutant. We also demonstrated here that the daily consumption of sun-dried Pedro Ximénez (PX) white-grape must (PXM) protects the liver of aged mice from both the age and the damages caused by p,p'-DDE exposure. The PXM activity was exerted through the restoration of the hepatic metabolisms of lipids and carbohydrates and, probably, is a consequence of the ability of this polyphenol-rich mixture to avoid oxidative stress. Nutritional interventions including PXM, which ameliorates the effects of unavoidable exposure to pesticides in our food, are helpful tools that can help elderly populations to enjoy a healthy and expanded lifetime.

Inner-Sphere Oxygen Activation Promoting Outer-Sphere Nucleophilic Attack on Olefins.

Alkoxylation and hydroxylation reactions of 1,5-cyclooctadiene (cod) in an iridium complex with alcohols and water promoted by the reduction of oxygen to hydrogen peroxide are described. The exo configuration of the OH/OR groups in the products agrees with nucleophilic attack at the external face of the olefin as the key step. The reactions also require the presence of a coordinating protic acid (such as picolinic acid (Hpic)) and involve the participation of a cationic diolefin iridium(III) complex, [Ir(cod)(pic)2 ]+ , which has been isolated. Independently, this cation is also involved in easy alkoxy group exchange reactions, which are very unusual for organic ethers. DFT studies on the mechanism of olefin alkoxylation mediated by oxygen show a low-energy proton-coupled electron-transfer step connecting a superoxide-iridium(II) complex with hydroperoxide-iridium(III) intermediates, rather than peroxide complexes. Accordingly, a more complex reaction, with up to four different products, occurred upon reacting the diolefin-peroxide iridium(III) complex with Hpic. Moreover, such hydroperoxide intermediates are the origin of the regio- and stereoselectivity of the hydroxylation/alkoxylation reactions. If this protocol is applied to the diolefin-rhodium(I) complex [Rh(pic)(cod)], free alkyl ethers ORC8 H11 (R=Me, Et) resulted, and the reaction is enantioselective if a chiral amino acid, such as l-proline, is used instead of Hpic.

Activating a Peroxo Ligand for C-O Bond Formation.

Dioxygen activation for effective C-O bond formation in the coordination sphere of a metal is a long-standing challenge in chemistry for which the design of catalysts for oxygenations is slowed down by the complicated, and sometimes poorly understood, mechanistic panorama. In this context, olefin-peroxide complexes could be valuable models for the study of such reactions. Herein, we showcase the isolation of rare "Ir(cod)(peroxide)" complexes (cod=1,5-cyclooctadiene) from reactions with oxygen, and then the activation of the peroxide ligand for O-O bond cleavage and C-O bond formation by transfer of a hydrogen atom through proton transfer/electron transfer reactions to give 2-iradaoxetane complexes and water. 2,4,6-Trimethylphenol, 1,4-hydroquinone, and 1,4-cyclohexadiene were used as hydrogen atom donors. These reactions can be key steps in the oxy-functionalization of olefins with oxygen, and they constitute a novel mechanistic pathway for iridium, whose full reaction profile is supported by DFT calculations.