Discovery and characterization of a new class of NAD+-independent SIRT1 activators.

The activity of sirtuin 1 (SIRT1, a member of the NAD+-dependent deacetylases family) decreases during aging as NAD+ levels naturally decline, thus increasing the risk of several age-associated diseases. Several sirtuin-activating compounds (STACs) have been developed to counteract the age-associated reduction in SIRT1 activity, and some of them are currently under development in clinical trials. STACs induce SIRT1 activation, either through allosteric activation of the enzyme in the presence of NAD+, or by increasing NAD+ levels by inhibiting its degradation or by supplying a key precursor in biosynthesis. In this study, we have identified (E)-2'-des-methyl sulindac analogues as a novel class of STACs that act also in the absence of NAD+, a peculiar behavior demonstrated through enzymatic and mass spectrometry experiments, both in vitro and in cell lines. The activation of the SIRT1 pathway was confirmed in vivo through gene expression and metabolomics analysis. Our data suggest that these compounds could serve as candidate leads for a novel therapeutic strategy aimed at addressing a key metabolic deficiency that may contribute to metabolic and age-associated diseases.

Whole mitochondrial and chloroplast genome sequencing of Tunisian date palm cultivars: diversity and evolutionary relationships.

BACKGROUND: Date palm (Phoenix dactylifera L.) is the most widespread crop in arid and semi-arid regions and has great traditional and socioeconomic importance, with its fruit well-known for its high nutritional and health value. However, the genetic variation of date palm cultivars is often neglected. The advent of high-throughput sequencing has made possible the resequencing of whole organelle (mitochondria and chloroplast) genomes to explore the genetic diversity and phylogenetic relationships of cultivated plants with unprecedented detail. RESULTS: Whole organelle genomes of 171 Tunisian accessions (135 females and 36 males) were sequenced. Targeted bioinformatics pipelines were used to identify date palm haplotypes and genome variants, aiming to provide variant annotation and investigate patterns of evolutionary relationship. Our results revealed the existence of unique haplotypes, identified by 45 chloroplastic and 156 mitochondrial SNPs. Estimation of the effect of these SNPs on genes functions was predicted in silico. CONCLUSIONS: The results of this study have important implications, in the light of ongoing environmental changes, for the conservation and sustainable use of the genetic resources of date palm cultivars in Tunisia, where monoculture threatens biodiversity leading to genetic erosion. These data will be useful for breeding and genetic improvement programs of the date palm through selective cross-breeding.

Hypothalamic NPY-Y1R Interacts with Gonadal Hormones in Protecting Female Mice against Obesity and Neuroinflammation.

We previously demonstrated that Npy1rrfb mice, which carry the conditional inactivation of the Npy1r gene in forebrain principal neurons, display a sexually dimorphic phenotype, with male mice showing metabolic, hormonal and behavioral effects and females being only marginally affected. Moreover, exposure of Npy1rrfb male mice to a high-fat diet (HFD) increased body weight growth, adipose tissue, blood glucose levels and caloric intake compared to Npy1r2lox male controls. We used conditional knockout Npy1rrfb and Npy1r2lox control mice to examine whether forebrain disruption of the Npy1r gene affects susceptibility to obesity and associated disorders of cycling and ovariectomized (ovx) female mice in a standard diet (SD) regimen or exposed to an HFD for 3 months. The conditional deletion of the Npy1r gene increased body weight and subcutaneous white adipose tissue weight in both SD- and HFD-fed ovx females but not in cycling females. Moreover, compared with ovx control females on the same diet regimen, Npy1rrfb females displayed increased microglia number and activation, increased expression of Neuropeptide Y (NPY)-immunoreactivity (IR) and decreased expression of proopiomelanocortin-IR in the hypothalamic arcuate nucleus (ARC). These results suggest that in the ARC NPY-Y1R reduces the susceptibility to obesity of female mice with low levels of gonadal hormones and that this effect may be mediated via NPY-Y1R ability to protect the brain against neuroinflammation.

Sexual differentiation of microglia.

Sex plays a role in the incidence and outcome of neurological illnesses, also influencing the response to treatments. Despite sexual differentiation of the brain has been extensively investigated, the study of sex differences in microglia, the brain's resident immune cells, has been largely neglected until recently. To fulfill this gap, our laboratory developed several tools, including cellular and animal models, which bolstered in-depth studies on sexual differentiation of microglia and its impact on brain physiology, as well as on the onset and progression of neurological disorders. Here, we summarize the current status of knowledge on the sex-dependent function of microglia, and report recent evidence linking these cells to the sexual bias in the susceptibility to neurological brain diseases.

Randomized clinical trial to assess the mPADSS scale in recovery and home discharge after endoscopy.

BACKGROUND: current clinical practice guidelines recommend the use of objective scales as a criterion for post-endoscopy sedation discharge. OBJECTIVE: to assess the recovery time, complications and patient satisfaction level using the mPADSS scale. MATERIAL AND METHODS: demographic data and medical history were collected. Vital signs, anxiety and abdominal pain were measured pre-endoscopy. Patients were randomized into a control group, discharged according to the usual practice, and the intervention group, who underwent the mPADSS scale every ten minutes, until an objective score was reached. RESULTS: one hundred and eighteen patients were randomized (78 colonoscopies, 32 gastroscopies, three gastro + colonoscopies and 15 endoscopic retrograde cholangiopancreatographies/endoscopic ultrasound [ERCP/USE]). With regard to medical history, there were 36 cases of elevated blood pressure and 19 diabetes cases, 15 with anticoagulant/antiplatelet and 21 with hypnotic/anxiolytic medication. An average of 160 mg of propofol was required per patient, with additional flumazenil and midazolam in 49. There were two episodes of vomiting and three of mild desaturation, all of them in the control group. Sixty patients were included in the control group and 58 in the mPADSS group, who were discharged in 15 and 10 minutes on average respectively (p < 0.005); 24-48h telephone call follow-up data were available for 105 subjects. There were four readmissions (three control and one mPADSS). There were no differences in pain and post-sedation symptoms and the level of satisfaction in terms of attention and duration of stay was similar in both groups. CONCLUSIONS: this study shows the efficiency, safety and patient satisfaction using the mPADSS scale. Thus, its use is recommend.

Relationship between color and betalain content in different thermally treated beetroot products.

Several health benefits are currently attributed to natural pigments that give fruit and vegetables their inherently colorful properties. Color measurements might therefore serve as quick indicators of the potential health-promoting properties of such foods. Nevertheless, the relationship between color and pigment content depends on the type of matrix and pigment, as well as the factors affecting their interaction, which calls for further investigation. Hence, the aim of the present study is to investigate the relationship between color parameters and betalain content in three commonly consumed beetroot products (beetroot juice, beetroot puree and whole beetroot), subjected to thermal treatment. Our results showed a negative correlation between the total betalain content and the color parameters L*, a*, b*, chroma, and hue angle in beetroot juice, beetroot puree and whole beetroot. Two chromatic parameters, a* and chroma, are proposed as the best descriptors for the betalain concentrations of these products. Likewise, the tristimulus L/ab combination for the juice is also suggested as a good descriptor. Our findings highlighted that the relationship between color and total betalain content depended on the beetroot product under assessment, with the strongest correlations found for the juice. Squeezed beetroot was therefore suggested as an alternative to improve this relationship in more complex matrices such as whole cooked beetroots. Useful information from color determination sheds light on the relationship between color and betalain pigments in beetroot, suggesting that color determination could be used as an indicator of betalain content.

Dissecting Adaptation Mechanisms to Contrasting Solar Irradiance in the Mediterranean Shrub Cistus incanus.

Molecular mechanisms that are the base of the strategies adopted by Mediterranean plants to cope with the challenges imposed by limited or excessive solar radiation during the summer season have received limited attention. In our study, conducted on C. incanus plants growing in the shade or in full sunlight, we performed measurements of relevant physiological traits, such as leaf water potential, gas exchange and PSII photochemistry, RNA-Seq with de-novo assembly, and the analysis of differentially expressed genes. We also identified and quantified photosynthetic pigments, abscisic acid, and flavonoids. Here, we show major mechanisms regulating light perception and signaling which, in turn, sustain the shade avoidance syndrome displayed by the 'sun loving' C. incanus. We offer clear evidence of the detrimental effects of excessive light on both the assembly and the stability of PSII, and the activation of a suite of both repair and effective antioxidant mechanisms in sun-adapted leaves. For instance, our study supports the view of major antioxidant functions of zeaxanthin in sunny plants concomitantly challenged by severe drought stress. Finally, our study confirms the multiple functions served by flavonoids, both flavonols and flavanols, in the adaptive mechanisms of plants to the environmental pressures associated to Mediterranean climate.

Dissecting molecular and physiological response mechanisms to high solar radiation in cyanic and acyanic leaves: a case study on red and green basil.

Photosynthetic performance and the expression of genes involved in light signaling and the biosynthesis of isoprenoids and phenylpropanoids were analysed in green ('Tigullio', TIG) and red ('Red Rubin', RR) basil. The aim was to detect the physiological and molecular response mechanisms to high sunlight. The attenuation of blue-green light by epidermal anthocyanins was shown to evoke shade-avoidance responses with consequential effects on leaf morpho-anatomical traits and gas exchange performance. Red basil had a lower mesophyll conductance, partially compensated by the less effective control of stomatal movements, in comparison with TIG. Photosynthesis decreased more in TIG than in RR in high sunlight, because of larger stomatal limitations and the transient impairment of PSII photochemistry. The methylerythritol 4-phosphate pathway promoted above all the synthesis and de-epoxidation of violaxanthin-cycle pigments in TIG and of neoxanthin and lutein in RR. This enabled the green leaves to process the excess radiant energy effectively, and the red leaves to optimize light harvesting and photoprotection. The greater stomatal closure observed in TIG than in RR was due to enhanced abscisic acid (ABA) glucose ester deglucosylation and reduced ABA oxidation, rather than to superior de novo ABA synthesis. This study shows a strong competition between anthocyanin and flavonol biosynthesis, which occurs at the level of genes regulating the oxidation of the C2-C3 bond in the dihydro-flavonoid skeleton.

Effect of oleic acid on store-operated calcium entry in immune-competent cells.

PURPOSE: To study the mechanism by which oleic acid (OA) (C18:1) exerts its beneficial effects on immune-competent cells. Since store-operated Ca2+ entry (SOCE) is a Ca2+ influx pathway involved in the control of multiple physiological processes including cell proliferation, we studied the effect of OA in Ca2+ signals of Jurkat T cells and THP-1 monocytes, paying particular attention to SOCE. METHODS: Changes in [Ca2+]i were measured using the Fura-2 fluorescence dye. Mn2+ uptake was monitored as a rate of quenching of Fura-2 fluorescence measured at the Ca2+-insensitive wavelengths. Thapsigargin was used to induce SOCE in Fura-2-loaded cells. RESULTS: We showed a clear dose-dependent SOCE-inhibitory effect of OA in both cell lines. Such an inhibitory effect was PKC independent and totally restored by albumin, suggesting that OA exerts its effect somewhere in the membrane. We also demonstrated that OA induces increases in [Ca2+]i partly mediated by an extracellular Ca2+ influx through econazole-insensitive channels. Finally, we compared the effect of OA with stearic acid (C18:0), assuming the emerged evidence concerning the link between saturated fats and inflammation disorders. Stearic acid failed to inhibit SOCE, independently on the concentration tested, thus intensifying the physiological relevance of our findings. CONCLUSION: We suggest a physiological pathway for the beneficial effects of OA in inflammation.

Global antioxidant response of meat.

BACKGROUND: The global antioxidant response (GAR) method uses an enzymatic digestion to release antioxidants from foods. Owing to the importance of digestion for protein breakdown and subsequent release of bioactive compounds, the aim of the present study was to compare the GAR method for meat with the existing methodologies: the extraction-based method and QUENCHER. Seven fresh meats were analyzed using ABTS and FRAP assays. RESULTS: Our results indicated that the GAR of meat was higher than the total antioxidant capacity (TAC) assessed with the traditional extraction-based method. When evaluated with GAR, the thermal treatment led to an increase in the TAC of the soluble fraction, contrasting with a decreased TAC after cooking measured using the extraction-based method. The effect of thermal treatment on the TAC assessed by the QUENCHER method seemed to be dependent on the assay applied, since results from ABTS differed from FRAP. CONCLUSION: Our results allow us to hypothesize that the activation of latent bioactive peptides along the gastrointestinal tract should be taken into consideration when evaluating the TAC of meat. Therefore, we conclude that the GAR method may be more appropriate for assessing the TAC of meat than the existing, most commonly used methods. © 2016 Society of Chemical Industry.

Antioxidant Capacity of Beetroot: Traditional vs Novel Approaches.

Red beetroot has been ranked among the 10 most potent antioxidant vegetables, although only extraction-based methods have been used to evaluate its total antioxidant capacity. Therefore, the present study aims at comparing the traditional extraction-based method with two more recent approaches (QUENCHER -QUick, Easy, New, CHEap and Reproducible- and GAR -global antioxidant response method), in order to establish their suitability in the case of beetroot. Our results indicate that the total antioxidant capacity of beetroot would be underestimated when using extraction-based procedures, since both QUENCHER and GAR methods resulted in a higher total antioxidant capacity. The effect of a thermal treatment on the total antioxidant capacity of beetroot varies among the methods evaluated and our findings suggest different compounds responsible for the total antioxidant capacity detected in each pre-processing method. Remarkably, the present study demonstrates that the traditional extraction-based method seems useful to screen for (changes in) the "bioavailable" antioxidant potential of the root.

Tetradian oscillation of estrogen receptor α is necessary to prevent liver lipid deposition.

In the liver of female mice, the transcriptional activity of estrogen receptor (ER) α oscillates in phase with the 4-d-long estrous cycle. Here systemic, genome-wide analysis demonstrates that ER tetradian oscillation is necessary to generate pulses of expression in genes for fatty acid and cholesterol synthesis. This ER-dependent metabolic programming changes with pregnancy and after cessation of ovarian function due to age or surgical menopause, suggesting that ER signaling is optimized to coordinate liver functions with the energetic requirements of each reproductive stage. Alterations of amplitude and frequency of the tetradian cycle, as observed after surgical menopause, age, or specific ablation of the hepatic Igf-1 gene, are associated with liver fat deposition. Appropriate hormone replacement therapy reinstating the oscillatory activity of liver ER prevents the effect of surgical menopause on fat deposition in liver.

Spatial and temporal epidemiology of clinical malaria in Cambodia 2004-2013.

BACKGROUND: Artemisinin-resistant Plasmodium falciparum malaria has recently been identified on the Thailand-Cambodia border and more recently in parts of Thailand, Myanmar and Vietnam. There is concern that if this resistance were to spread, it would severely hamper malaria control and elimination efforts worldwide. Efforts are currently underway to intensify malaria control activities and ultimately eliminate malaria from Cambodia. To support these efforts, it is crucial to have a detailed picture of disease burden and its major determinants over time. METHODS: An analysis of spatial and temporal data on clinical malaria in Cambodia collected by the National Centre for Parasitology, Entomology and Malaria Control (CNM) and the Department of Planning and Health Information, Ministry of Health Cambodia from 2004 to 2013 is presented. RESULTS: There has been a marked decrease of 81% in annual cases due to P. falciparum since 2009 coinciding with a rapid scale-up in village malaria workers (VMWs) and insecticide-treated bed nets (ITNs). Concurrently, the number of cases with Plasmodium vivax has greatly increased. It is estimated that there were around 112,000 total cases in 2012, 2.8 times greater than the WHO estimate for that year, and 68,000 in 2013 (an annual parasite incidence (API) of 4.6/1000). With the scale-up of VMWs, numbers of patients presenting to government facilities did not fall and it appears likely that those who saw VMWs had previously accessed healthcare in the private sector. Malaria mortality has decreased, particularly in areas with VMWs. There has been a marked decrease in cases in parts of western Cambodia, especially in Pailin and Battambang Provinces. In the northeast, the fall in malaria burden has been more modest, this area having the highest API in 2013. CONCLUSION: The clinical burden of falciparum malaria in most areas of Cambodia has greatly decreased from 2009 to 2013, associated with roll-out of ITNs and VMWs. Numbers of cases with P. vivax have increased. Possible reasons for these trends are discussed and areas requiring further study are highlighted. Although malaria surveillance data are prone to collection bias and tend to underestimate disease burden, the finding of similar trends in two independent datasets in this study greatly increased the robustness of the findings.

Sexual dimorphism of metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver condition. MASLD is a sexually dimorphic condition, with its development and progression influenced by sex chromosomes and hormones. Estrogens typically protect against, whereas androgens promote, MASLD. Therapeutic approaches for a sex-specific personalized medicine include estrogen replacement, androgen blockers, and novel drugs targeting hormonal pathways. However, the interactions between hormonal factors and inherited genetic variation impacts MASLD risk, necessitating more tailored therapies. Understanding sex disparities and the role of estrogens could improve MASLD interventions and management, whereas clinical trials addressing sex differences are crucial for advancing personalized treatment. This review explores the underappreciated impact of sexual dimorphism in MASLD and discusses the potential therapeutic application of sex-related hormones.

The de novo, chromosome-level genome assembly of the sweet chestnut (Castanea sativa Mill.) Cv. Marrone Di Chiusa Pesio.

OBJECTIVES: The sweet chestnut Castanea sativa Mill. is the only native Castanea species in Europe, and it is a tree of high economic value that provides appreciated fruits and valuable wood. In this study, we assembled a high-quality nuclear genome of the ancient Italian chestnut variety 'Marrone di Chiusa Pesio' using a combination of Oxford Nanopore Technologies long reads, whole-genome and Omni-C Illumina short reads. DATA DESCRIPTION: The genome was assembled into 238 scaffolds with an N50 size of 21.8 Mb and an N80 size of 7.1 Mb for a total assembled sequence of 750 Mb. The BUSCO assessment revealed that 98.6% of the genome matched the embryophyte dataset, highlighting good completeness of the genetic space. After chromosome-level scaffolding, 12 chromosomes with a total length of 715.8 and 713.0 Mb were constructed for haplotype 1 and haplotype 2, respectively. The repetitive elements represented 37.3% and 37.4% of the total assembled genome in haplotype 1 and haplotype 2, respectively. A total of 57,653 and 58,146 genes were predicted in the two haplotypes, and approximately 73% of the genes were functionally annotated using the EggNOG-mapper. The assembled genome will be a valuable resource and reference for future chestnut breeding and genetic improvement.

Diacylglycerol-containing oleic acid induces increases in [Ca(2+)](i) via TRPC3/6 channels in human T-cells.

Though most of the studies have focused on the effects of free fatty acids on T-cell activation, fatty acids incorporated into plasma membrane phospholipids may also affect cell signaling via diacylglycerol (DAG), generally produced by phospholipid hydrolysis. In the present study, we have synthesized a DAG-containing oleic acid and studied its implication in the modulation of calcium signaling in human Jurkat T-cells. 1-palmitoyl-2-oleoyl-sn-glycerol (POG) induced a dose-dependent increase in [Ca(2+)](i). This effect was due to the presence of oleic acid at the sn-2 position as no differences were observed between POG and 1-stearoly-2-oleoyl-sn-glycerol (SOG). However, the substitution of oleic acid with arachidonic acid at the sn-2 position of the DAG moiety exerted a different response on the increases in [Ca(2+)](i) in these cells. POG-evoked increases in [Ca(2+)](i) were not due to its metabolites. Furthermore, POG-induced increases in [Ca(2+)](i) were due to the opening of TRPC3/TRPC6 channels as silencing of TRPC3 and TRPC6 genes by shRNA abolished calcium entry. Moreover, disruption of lipid rafts with methyl-ß-cyclodextrin completely abolished POG-evoked increases in [Ca(2+)](i). In conclusion, our results demonstrate that oleic acid can influence T-lymphocyte functions, in the conjugated form of DAG, via opening TRPC3/6 channels.

Diet and Fertility Status: Relevance in Health and Disease.

The prevalence of obesity and other metabolic disorders is increasing worldwide [...].

Sex, Nutrition, and NAFLD: Relevance of Environmental Pollution.

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease and represents an increasing public health issue given the limited treatment options and its association with several other metabolic and inflammatory disorders. The epidemic, still growing prevalence of NAFLD worldwide cannot be merely explained by changes in diet and lifestyle that occurred in the last few decades, nor from their association with genetic and epigenetic risk factors. It is conceivable that environmental pollutants, which act as endocrine and metabolic disruptors, may contribute to the spreading of this pathology due to their ability to enter the food chain and be ingested through contaminated food and water. Given the strict interplay between nutrients and the regulation of hepatic metabolism and reproductive functions in females, pollutant-induced metabolic dysfunctions may be of particular relevance for the female liver, dampening sex differences in NAFLD prevalence. Dietary intake of environmental pollutants can be particularly detrimental during gestation, when endocrine-disrupting chemicals may interfere with the programming of liver metabolism, accounting for the developmental origin of NAFLD in offspring. This review summarizes cause-effect evidence between environmental pollutants and increased incidence of NAFLD and emphasizes the need for further studies in this field.

Neurocognitive assessment in microgravity: review of tools and benefits of increasing their clinical validity for long duration missions.

INTRODUCTION: Clinical complications are not expected in current space missions; however, for future long-duration missions to the Moon and Mars, a new perspective may be needed - a more clinical approach. Different risks, both environmental, such as radiation, accidents, and biopsychological, including neurological problems, represent potential sources of subsequent neurocognitive deficits. AIMS: This study aims to review research studies published to this date in microgravity conditions using existing spaceflight neurocognitive assessment batteries. This study also discusses the different risks of neuropsychological impairment in spaceflight and the potential benefits of increasing the clinical validity of these tools with neurological clinical samples on Earth for future long-duration missions. METHOD: A PRISMA guidelines-based review of specialized literature on neurocognitive assessment batteries and human spaceflight was performed. Different factors including type of tool or battery used, sample size, mission duration, etc. were included in this review. After the scrutiny of 192 articles, a total of 27 studies were detailed in the review outcome. RESULTS: Results showed that neuropsychological function research target has changed over the years, with working memory and perception studies being predominant in the 80s and 90s while reaction time being more frequent in recent research. We also found a lack of language-related research in microgravity and the predominance of two neurocognitive assessment batteries in microgravity research. CONCLUSIONS: With this study, we want to emphasize the importance of increasing the clinical validity of neurocognitive or neuropsychological assessment tools to be used in space, especially in long-duration missions because in this type of mission the risk of suffering a brain injury or neurological condition increases due to multiple factors. Testing these tools with neurological clinical samples and using machine learning, predictive systems may help crews in early detection of potential clinical, neurological, or neurocognitive problems during these long-duration missions to Mars and beyond.