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Coenzyme Q10 (CoQ10) plays a central role in mitochondrial oxidative phosphorylation. Several studies have shown the beneficial effects of dietary CoQ10 supplementation, particularly in relation to cardiovascular health. CoQ10 biosynthesis decreases in the elderly, and consequently, the beneficial effects of dietary supplementation in this population are of greater significance. However, most pharmacokinetic studies have been conducted on younger populations. The aim of this study was to investigate the single-dose bioavailability of different formulations of CoQ10 in a healthy geriatric population. A randomized, three-period, crossover bioavailability study was conducted on 21 healthy older adults (aged 65–74). The treatment was a single dose with a one-week washout period. Three different formulations containing the equivalent of 100 mg of CoQ10 were used: Q10Vital® water-soluble CoQ10 syrup (the investigational product—IP); ubiquinol capsules (the comparative product—CP); and ubiquinone capsules (the standard product—SP). Ubiquinone/ubiquinol was followed in the plasma for 48 h. An analysis of the ratio of the area under the baseline-corrected concentration curve (ΔAUC48) for total CoQ10 and a comparison to SP yielded the following: The bioavailability of CoQ10 in the IP was 2.4-fold higher (95% CI: 1.3–4.5; p = 0.002), while the bioavailability of ubiquinol (CP) was not significantly increased (1.7-fold; 95% CI: 0.9–3.1, p = 0.129). No differences in the redox status of the absorbed coenzyme Q10 were observed between formulations, showing that CoQ10 appeared in the blood mostly as ubiquinol, even if consumed as ubiquinone.

ObjectiveDespite advances in the identification of epigenetic alterations in pancreatic cancer, their biological roles in the pathobiology of this dismal neoplasm remain elusive. Here, we aimed to characterise the functional significance of histone lysine methyltransferases (KMTs) and demethylases (KDMs) in pancreatic tumourigenesis.DesignDNA methylation sequencing and gene expression microarrays were employed to investigate CpG methylation and expression patterns of KMTs and KDMs in pancreatic cancer tissues versus normal tissues. Gene expression was assessed in five cohorts of patients by reverse transcription quantitative-PCR. Molecular analysis and functional assays were conducted in genetically modified cell lines. Cellular metabolic rates were measured using an XF24-3 Analyzer, while quantitative evaluation of lipids was performed by liquid chromatography-mass spectrometry (LC-MS) analysis. Subcutaneous xenograft mouse models were used to evaluate pancreatic tumour growth in vivo.ResultsWe define a new antitumorous function of the histone lysine (K)-specific methyltransferase 2D (KMT2D) in pancreatic cancer. KMT2D is transcriptionally repressed in human pancreatic tumours through DNA methylation. Clinically, lower levels of this methyltransferase associate with poor prognosis and significant weight alterations. RNAi-based genetic inactivation of KMT2D promotes tumour growth and results in loss of H3K4me3 mark. In addition, KMT2D inhibition increases aerobic glycolysis and alters the lipidomic profiles of pancreatic cancer cells. Further analysis of this phenomenon identified the glucose transporter SLC2A3 as a mediator of KMT2D-induced changes in cellular, metabolic and proliferative rates.ConclusionTogether our findings define a new tumour suppressor function of KMT2D through the regulation of glucose/fatty acid metabolism in pancreatic cancer.

Metastasis is one of the leading causes of cancer-related death worldwide. Fascin, a protein that bundles actin filaments to produce protrusions in cancer cells, plays a significant role in the enhancement of cell migration. This protein has been shown that the overexpression of this protein is related to the appearance of different types of cancer, such as colorectal cancer. In this study, we conducted in silico screening of the Enamine library, a compound library with a broad chemical space. Using a ligand-based virtual screening approach based on the pharmacophore model of G2, we identified the predicted inhibitors. First, these compounds were validated by physicochemical analysis. Differential scanning calorimetry (DSF) was used to study the binding between the predicted compounds and fascin protein, followed by an F-actin bundling assay to determine which compounds inhibited the bundling function of fascin. Z1362873773, which exhibited binding to fascin and inhibited F-actin bundling, was further tested in cell cultures to assess its effects on cancer cell viability and migration as well as in organoid models to evaluate potential cytotoxicity. Finally, we established a protocol that can be applied to discover anti-fascin agents from diverse compound libraries. A new molecule has been identified with considerable fascin inhibitory and migration-arresting capacity, which may lead to the development of new therapies to treat cancer.

IntroductionThe aim of this study was to explore the usefulness of the determination of free light chains (FLC) in serum as a biomarker of flare in patients with systemic lupus erythematosus (SLE) and to analyze the differences in their discriminatory capacity with complement C3 and C4.MethodsThis was a prospective cohort study. The definition of flare was based on the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Flare Index. The discriminatory capacity of FLC and C3 and C4 levels was compared using receiver operating characteristic (ROC) curves and the area under the curve (AUC).ResultsForty-six patients were enrolled. Patients with SLE flare showed significantly lower C3 (p = 0.025) and C4 levels (p = 0.028), as well as a higher concentration of lambda light chains (λ-LC) (p = 0.028) compared with the non-flare group. λ-LC, as opposed to kappa light chains and total light chains, demonstrated a discriminatory capacity for detecting the presence of SLE flare (AUC 0.781), with 100% sensitivity, 65% specificity, and 69.6% of patients correctly classified for a cutoff point of ≥ 19.5 mg/L. Complement C3 and C4 also showed a high discriminatory capacity for SLE flare (AUC 0.804 and 0.837, respectively). Comparing λ-LC, C3, and C4, the last one demonstrates better discriminatory capacity for SLE flare with the highest AUC (0.837; 95% CI 0.663–1.000).Conclusionsλ-LC have good discriminatory capacity for SLE flare and could be useful as a biomarker of SLE exacerbation.Key Points• The usefulness of free light chains as a biomarker could be compared with complement.• Lambda free light chains have good discriminatory capacity for SLE flare.• Free light chains are a promising marker of SLE activity

•Coenzyme Q10 (CoQ10) preparations show high differences in bioavailability in humans.•Physiological unknown factors affect CoQ10 bioavailability in humans.•Composition of vehicle in CoQ10 preparations affects bioavailability in humans.•Addition of antioxidants to CoQ10 preparations can decrease bioavailability.•For each individual, best CoQ10 preparation must be empirically determined. Bioavailability of supplements with coenzyme Q10 (CoQ10) in humans seems to depend on the excipients of formulations and on physiological characteristics of the individuals. The aim of this study was to determine which factors presented in CoQ10 supplements affect the different response to CoQ10 in humans. We tested seven different supplement formulations containing 100 mg of CoQ10 in 14 young, healthy individuals. Bioavailability was measured as area under the curve of plasma CoQ10 levels over 48 h after ingestion of a single dose. Measurements were repeated in the same group of 14 volunteers in a double-blind crossover design with a minimum of 4 wk washout between intakes. Bioavailability of the formulations showed large differences that were statistically significant. The two best absorbable formulations were soft-gel capsules containing ubiquinone (oxidized CoQ10) or ubiquinol (reduced CoQ10). The matrix used to dissolve CoQ10 and the proportion and addition of preservatives such as vitamin C affected the bioavailability of CoQ10. Although control measurements documented that all formulations contained 100 mg of either CoQ10 or ubiquinol, some of the participants showed high and others lower capacity to reach high increase of CoQ10 in blood, indicating the participation of individual unknown physiological factors. This study highlights the importance of individually adapted selection of best formulations to reach the highest bioavailability of CoQ10 in humans.

The mycelium is an organised cellular network that develops according to a functionally coherent plan. As it expands, the mycelium is capable of modulating the relative abundance of different cell types to suit the prevailing environmental conditions. This versatile pattern of multicellular development involves sophisticated environmental sensing and intercellular communication systems that have barely been recognised. This review describes an insight into our current understanding of the signalling molecules and mechanisms that take part in the ordered and timely emergence of various cell types and their biological significance. The prospects that this emerging knowledge may offer for the sustainable control of fungal colonisation or dispersal will also be considered.

This article empirically explores the relationship existing between the online reputation and tourism competitiveness of Spanish coastal tourism destinations. It is based on big data from comments made by tourists in social media. The existing literature suggests that, in theory, a destination's online reputation plays a key role in promoting its competitiveness. However, the results obtained in this study reflect, for the Spanish case, that this effect is today still very small and other determinants of competitiveness exist that are more relevant in promoting a true competitive advantage of destinations.

Background and rationalePolydrug use is a widespread phenomenon, especially among adolescents and young adults. Synthetic cathinones are frequently consumed in combination with other drugs of abuse. However, there is very little information regarding the consequences of this specific consumption pattern.ObjectivesThe aim of this review is to introduce this topic and highlight the gaps in the existing literature. In three different sections, we focus on specific interactions of synthetic cathinones with alcohol, cannabinoids, and the stimulants nicotine and cocaine. We then dedicate a section to the existence of sex and gender differences in the effects of synthetic cathinones and the long-term psychophysiological consequences of adolescent and prenatal exposure to these drugs.Major findingsEpidemiological studies, case reports, and results obtained in animal models point to the existence of pharmacological and pharmacokinetic interactions between synthetic cathinones and other drugs of abuse. This pattern of polyconsumption can cause the potentiation of negative effects, and the dissociation between objective and subjective effects can increase the combined use of the drugs and the risk of toxicity leading to serious health problems. Certain animal studies indicate a higher vulnerability and effect of cathinones in females. In humans, most of the users are men and case reports show long-term psychotic symptoms after repeated use.ConclusionsThe co-use of synthetic cathinones and the other drugs of abuse analyzed indicates potentiation of diverse effects including dependence and addiction, neurotoxicity, and impaired cognition and emotional responses. The motivations for and effects of synthetic cathinone use appear to be influenced by sex/gender. The long-term consequences of their use by adolescents and pregnant women deserve further investigation.

Women and men differ in a wide variety of behavioral traits and in their vulnerability to developing certain mental disorders. This review endeavors to explore how recent preclinical and clinical research findings have enhanced our understanding of the factors that underlie these disparities. We start with a brief overview of some of the important genetic, molecular, and hormonal determinants that contribute to the process of sexual differentiation. We then discuss the importance of animal models in studying the mechanisms responsible for sex differences in neuropsychiatric disorders (e.g., drug dependence) - with a special emphasis on experimental models based on the neurodevelopmental and \"three hits\" hypotheses. Next, we describe the most common brain phenotypes observed in vivo with magnetic resonance imaging. We discuss the challenges in interpreting these phenotypes vis-à-vis the underlying neurobiology and revisit the known sex differences in brain structure from birth, through adolescence, and into adulthood. This is followed by a presentation of pertinent clinical and epidemiological data that point to important sex differences in the prevalence, course, and expression of psychopathologies such as schizophrenia, and mood disorders including major depression and posttraumatic stress disorder. Recent evidence implies that mood disorders and psychosis share some common genetic predispositions and neurobiological bases. Therefore, modern research is emphasizing dimensional representation of mental disorders and conceptualization of schizophrenia and major depression as a continuum of cognitive deficits and neurobiological abnormalities. Herein, we examine available evidence on cerebral sexual dimorphism to verify if sex differences vary quantitatively and/or qualitatively along the psychoses-depression continuum. Finally, sex differences in the prevalence of posttraumatic disorder and drug abuse have been described, and we consider the genomic and molecular data supporting these differences.

Traumatic brain injury (TBI) incidence rises during adolescence because during this critical neurodevelopmental period some risky behaviors increase. The purpose of this study was to assess the contribution of cannabinoid receptors (CB1 and CB2), blood brain barrier proteins (AQP4) and astrogliosis markers (vimentin) to neurological deficit and brain edema formation in a TBI weight drop model in adolescent male mice. These molecules were selected since they are known to change shortly after lesion. Here we extended their study in three different timepoints after TBI, including short (24h), early mid-term (72h) and late mid-term (two weeks). Our results showed that TBI induced an increase in brain edema up to 72 h after lesion that was directly associated with neurological deficit. Neurological deficit appeared 24 h after TBI and was completely recovered two weeks after trauma. CB1 receptor expression decreased after TBI and was negatively correlated with edema formation and behavioral impairments. CB2 receptor increased after injury and was associated with high neurological deficit whereas no correlation with edema was found. AQP4 increased after TBI and was positively correlated with edema and neurological impairments as occurred with vimentin expression in the same manner. The results suggest that CB1 and CB2 differ in the mechanisms to resolve TBI and also that some of their neuroprotective effects related to the control of reactive astrogliosis may be due to the regulation of AQP4 expression on the end-feet of astrocytes.