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Background Elderly cancer patients are at higher risk of developing cachexia and adverse events due to antineoplastic treatments. Comprehensive Geriatric assessment (CGA) is used to evaluate the health status of elderly to identify impairments/frailty and better assess the risk/benefit ratio of therapeutic decisions. Malnutrition is an independent risk factor that further influences patients’ outcomes and should be systematically screened at hospital admission. The G8 screening tool allows to identify patients who might benefit from CGA and could help clinicians to evaluate nutritional and health status in elderly cancer patients. The Geriatric Nutritional Risk Index (GNRI) and the Mini Nutritional Assessment (MNA) are other standardized nutritional screening tests too. The aim of the study was to demonstrate that the use of a single tool is not enough to assay the real nutritional status of cancer patients. Methods The study involved 533 patients (282 men and 251 women) affected by solid tumor and aged ≥ 70 years old. Patients underwent CGA and MNA to quantify the risk of frailty and malnutrition. Anthropometric assessments, serum levels of albumin, the activities of daily living (ADLs) and Instrumental Activities of Daily Living (IADLs), as well as the rating scale of mental status SPMSQ (Short Portable Mental Status Questionnaire), were also performed. Results. Less than the half of patients had a G8 score and MNA that excluded malnutrition, whereas the most enrolled patients were at high risk for frailty and malnutrition. Anthropometric parameters and serum albumin levels alone were not able to detect malnutrition in all patients, while the association of GNRI with G8, MNA, and CGA scores allowed to specifically determine health risk in 95% of malnourished patients. Conclusions. The malnutrition risk could not be assessed by using a single score. The association of multiple information is required to define malnutrition’s risk among elderly people.

Compassion motivation is associated with increased heart rate variability (HRV), reflecting a calm and self-soothing physiological state. Recent work, however, suggests that this association is dynamic for the specific components of compassion.The present study adopted anodal transcranial direct current stimulation (tDCS) targeting the right insula to see whether this would modulate the sensitivity to suffering and the commitment to engage in helpful actions (i.e., the components of compassion motivation).Ninety-seven healthy individuals underwent 15-min anodal or sham tDCS over the frontotemporal lobe, while watching a video inducing empathic sensitivity and performing a Redistribution Game. Tonic and phasic HRV, dispositional traits, and momentary affects were assessed.Compared to sham condition, anodal stimulation favored significant i) HRV reductions during the video and HRV increases during the Redistribution Game; ii) decreases in self-reported levels of negative affect and increases in positive affect during task when the latter was preceded by the video, without influencing altruistic behavior.Anodal tDCS over the right insula may modulate the engagement phase of compassion by intensifying the psychophysiological sensitivity to signals of distress and protecting from being subjectively overwhelmed by it.

Robustness of nickelocene’s (NiCp2, Cp = cyclopentadienyl) magnetic anisotropy and addressability of its spin states make this molecular magnet attractive as a spin sensor. However, microscopic understanding of its magnetic anisotropy is still lacking, especially when NiCp2 is deposited on a surface to make quantum sensing devices. Quantum chemical calculations of such molecule/solid-state systems are limited to density functional theory (DFT) or DFT+U (Hubbard correction to DFT). We investigate the magnetic behavior of NiCp2 using the equation-of-motion coupled-cluster (EOM-CC) framework. Our first-principle calculations agree well with experimentally derived magnetic anisotropy and susceptibility values. The calculations show that magnetic anisotropy in NiCp2 originates from a large spin-orbit coupling (SOC) between the triplet ground state and the third singlet state, whereas the coupling with lower singlet excited states is negligible. We also considered a set of six ring-substituted NiCp2 derivatives and a model system of the NiCp2/MgO(001) adsorption complex. To gain insight into the electronic structure of these systems, we analyze spinless transition density matrices and their natural transition orbitals (NTOs). The NTO analysis of SOCs explains how spin states and magnetic properties are retained upon modification of the NiCp2 coordination environment and upon its adsorption on a surface. Such resilience of the NiCp2 magnetic behavior supports using NiCp2 as a spin-probe molecule by functionalization of the tip of a scanning tunneling microscope.

The search for efficient inhibitors of the SARS-CoV-2 enzymes remains important due to the continuing COVID-19 pandemic. We report the results of computational modeling of the reactions of the SARS-CoV-2 main protease (MPro) with four potential covalent inhibitors. Two of them, carmofur and nirmatrelvir, have been shown experimentally the ability to inhibit MPro. Two other compounds, X77A and X77C, were designed computationally in this work, derived from the structure of X77, a non-covalent inhibitor forming a tight surface complex with MPro. We modified the X77 structure by introducing warheads capable of efficient chemical reactions with the catalytic cysteine residue in the MPro active site. The reactions of the four molecules with MPro were investigated by quantum mechanics/molecular mechanics (QM/MM) calculations. According to calculations, the reactions for all four compounds are exothermic, with sufficiently low barriers, suggesting efficient inhibition of the enzyme. From the chemical perspective, the four compounds react with MPro following three distinct mechanisms. In all cases, the reaction is initiated by a nucleophilic attack of the thiolate group of the deprotonated cysteine residue from the catalytic dyad Cys145-His41 of MPro. In the case of carmofur and X77A, the covalent binding of the thiolate to the ligand involves the formation of the fluoro-uracil leaving group. The reaction with X77C follows the nucleophilic aromatic substitution SNAr mechanism. The reaction of MPro with nirmatrelvir, which has a reactive nitrile group, leads to the formation of the covalent thioimidate adduct with the thiolate of the Cys145 residue in the enzyme active site.

Numerous nutritional approaches aimed at reducing body weight have been devel- oped as a strategy to reduce obesity. Most of these interventions rely on reducing caloric intake or limiting calories access to a few hours per day. In this work, we analyzed the effects of the extended (24 hours/day) or restricted (1 hour/day) access to a cafeteria-style (CAF) diet, on rat body weight and hepatic lipid metabolism, with respect to control rats (CTR) fed with a standard chow diet. The body weight gain of restricted-fed rats was not different from CTR, despite the slightly higher total caloric intake, but resulted significantly lower than extended-fed rats, which showed a CAF diet-induced obesity and a dramatically higher total caloric intake. However, both CAF-fed groups of rats showed, compared to CTR, unhealthy serum and hepatic parameters such as higher serum glucose level, lower HDL values, and increased hepatic triacylglycerol and cholesterol amount. The hepatic expression and activity of key enzymes of fatty acid synthesis, acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS), was similarly reduced in both CAF-fed groups of rats with respect to CTR. Anyway, while in extended-fed rats this reduction was associ- ated to a long-term mechanism involving sterol regulatory element-binding protein-1 (SREBP-1), in restricted-fed animals a short-term mechanism based on PKA and AMPK activation occurred in the liver. Furthermore, hepatic fatty acid oxidation (FAO) and oxidative stress resulted significantly increased in extended, but not in restricted-fed rats, as compared to CTR. Overall, these results demonstrate that al- though limiting the total caloric intake might successfully fight obesity development, the nutritional content of the diet is the major determinant for the health status.

Diet is a major driver of gut microbiota variation and plays a role in metabolic disorders, including metabolic syndrome (MS). Mycorrhized foods from symbiotic agriculture (SA) exhibit improved nutritional properties, but potential benefits have never been investigated in humans. We conducted a pilot interventional study on 60 adults with ≥ 1 risk factors for MS, of whom 33 consumed SA-derived fresh foods and 27 received probiotics over 30 days, with a 15-day follow-up. Stool, urine and blood were collected over time to explore changes in gut microbiota, metabolome, and biochemical, inflammatory and immunologic parameters, previous dietary habits were investigated through a validated food-frequency questionnaire. The baseline microbiota showed alterations typical of metabolic disorders, mainly an increase in Coriobacteriaceae and a decrease in health-associated taxa, which were partly reversed after the SA-based diet. Improvements were observed in metabolome, MS presence (two out of six subjects no longer had MS) or components. Changes were more pronounced with less healthy baseline diets. Probiotics had a marginal, not entirely favorable, effect, although one out of three subjects no longer suffered from MS. These findings suggest that improved dietary patterns can modulate the host microbiota and metabolome, counteracting the risk of developing MS.

This work explores the level of transparency in reporting the details of computational protocols that is required for practical reproducibility of quantum mechanics/molecular mechanics (QM/MM) simulations. Using the reaction of an essential SARS-CoV-2 enzyme (the main protease) with a covalent inhibitor (carmofur) as a test case of chemical reactions in biomolecules, we carried out QM/MM calculations to determine the structures and energies of the reactants, the product, and the transition state/intermediate using analogous QM/MM models implemented in two software packages, NWChem and Q-Chem. Our main benchmarking goal was to reproduce the key energetics computed with the two packages. Our results indicate that quantitative agreement (within the numerical thresholds used in calculations) is difficult to achieve. We show that rather minor details of QM/MM simulations must be reported in order to ensure the reproducibility of the results and offer suggestions toward developing practical guidelines for reporting the results of biosimulations.

In recent years, lipid metabolism has gained greater attention in several diseases including cancer. Dysregulation of fatty acid metabolism is a key component in breast cancer malignant transformation. In particular, de novo lipogenesis provides the substrate required by the proliferating tumor cells to maintain their membrane composition and energetic functions during enhanced growth. However, it appears that not all breast cancer subtypes depend on de novo lipogenesis for fatty acid replenishment. Indeed, while breast cancer luminal subtypes rely on de novo lipogenesis, the basal-like receptor-negative subtype overexpresses genes involved in the utilization of exogenous-derived fatty acids, in the synthesis of triacylglycerols and lipid droplets, and fatty acid oxidation. These metabolic differences are specifically associated with genomic and proteomic changes that can perturb lipogenic enzymes and related pathways. This behavior is further supported by the observation that breast cancer patients can be stratified according to their molecular profiles. Moreover, the discovery that extracellular vesicles act as a vehicle of metabolic enzymes and oncometabolites may provide the opportunity to noninvasively define tumor metabolic signature. Here, we focus on de novo lipogenesis and the specific differences exhibited by breast cancer subtypes and examine the functional contribution of lipogenic enzymes and associated transcription factors in the regulation of tumorigenic processes.

Continuous and reliable cardiac function monitoring could improve medication adherence in patients at risk of heart failure. This work presents an innovative implantable Fiber Bragg Grating-based soft sensor designed to sense mechanical cardiac activity. The sensor was tested in an isolated beating ovine heart platform, with 3 different hearts operated in wide-ranging conditions. In order to investigate the sensor capability to track the ventricular beats in real-time, two causal algorithms were proposed for detecting the beats from sensor data and to discriminate artifacts. The first based on dynamic thresholds while the second is a hybrid convolutional and recurrent Neural Network. An error of 2.7 +/- 0.7 beats per minute was achieved in tracking the heart rate. Finally, we have confirmed the sensor reliability in monitoring the heart activity of healthy adult minipig with an error systematically lower than 1 Bpm.

Long-term high-fat diet (HFD) consumption can cause weight gain and obesity, two conditions often associated with hepatic non-alcoholic fatty liver and oxidative stress. Oleoylethanolamide (OEA), a lipid compound produced by the intestine from oleic acid, has been associated with different beneficial effects in diet-induced obesity and hepatic steatosis. However, the role of OEA on hepatic oxidative stress has not been fully elucidated. In this study, we used a model of diet-induced obesity to study the possible antioxidant effect of OEA in the liver. In this model rats with free access to an HFD for 77 days developed obesity, steatosis, and hepatic oxidative stress, as compared to rats consuming a low-fat diet for the same period. Several parameters associated with oxidative stress were then measured after two weeks of OEA administration to diet-induced obese rats. We showed that OEA reduced, compared to HFD-fed rats, obesity, steatosis, and the plasma level of triacylglycerols and transaminases. Moreover, OEA decreased the amount of malondialdehyde and carbonylated proteins and restored the activity of antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, which decreased in the liver of HFD-fed rats. OEA had also an improving effect on parameters linked to endoplasmic reticulum stress, thus demonstrating a role in the homeostatic control of protein folding. Finally, we reported that OEA differently regulated the expression of two transcription factors involved in the control of lipid metabolism and antioxidant genes, namely nuclear factor erythroid-derived 2-related factor 1 (Nrf1) and Nrf2, thus suggesting, for the first time, new targets of the protective effect of OEA in the liver.

Medium-chain fatty acids (MCFA) are dietary components with a chain length ranging from 6 to 12 carbon atoms. MCFA can cross the blood-brain barrier and in the brain can be oxidized through mitochondrial β-oxidation. As components of ketogenic diets, MCFA have demonstrated beneficial effects on different brain diseases, such as traumatic brain injury, Alzheimer's disease, drug-resistant epilepsy, diabetes, and cancer. Despite the interest in MCFA effects, not much information is available about MCFA metabolism in the brain. In this study, with a gas chromatography-mass spectrometry (GC-MS)-based metabolomics approach, coupled with multivariate data analyses, we followed the metabolic changes of U87MG glioblastoma cells after the addition of octanoic (C8), or decanoic (C10) acids for 24 h. Our analysis highlighted significant differences in the metabolism of U87MG cells after the addition of C8 or C10 and identified several metabolites whose amount changed between the two groups of treated cells. Overall, metabolic pathway analyses suggested the citric acid cycle, Warburg effect, glutamine/glutamate metabolism, and ketone body metabolism as pathways influenced by C8 or C10 addition to U87MG cells. Our data demonstrated that, while C8 affected mitochondrial metabolism resulting in increased ketone body production, C10 mainly influenced cytosolic pathways by stimulating fatty acid synthesis. Moreover, glutamine might be the main substrate to support fatty acids synthesis in C10-treated cells. In conclusion, we identified a metabolic signature associated with C8 or C10 addition to U87MG cells that can be used to decipher metabolic responses of glioblastoma cells to MCFA treatment.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia associated with alterations in carbohydrate, lipid, and protein metabolism. The prognosis of T2DM patients is highly dependent on the development of complications, and therefore the identification of biomarkers of T2DM progression, with minimally invasive techniques, is a huge need. In the present study, we applied a 1H-Nuclear Magnetic Resonance (1H-NMR)-based metabolomic approach coupled with multivariate data analysis to identify serum metabolite profiles associated with T2DM development and progression. To perform this, we compared the serum metabolome of non-diabetic subjects, treatment-na&iuml, ve non-complicated T2DM patients, and T2DM patients with complications in insulin monotherapy. Our analysis revealed a significant reduction of alanine, glutamine, glutamate, leucine, lysine, methionine, tyrosine, and phenylalanine in T2DM patients with respect to non-diabetic subjects. Moreover, isoleucine, leucine, lysine, tyrosine, and valine levels distinguished complicated patients from patients without complications. Overall, the metabolic pathway analysis suggested that branched-chain amino acid (BCAA) metabolism is significantly compromised in T2DM patients with complications, while perturbation in the metabolism of gluconeogenic amino acids other than BCAAs characterizes both early and advanced T2DM stages. In conclusion, we identified a metabolic serum signature associated with T2DM stages. These data could be integrated with clinical characteristics to build a composite T2DM/complications risk score to be validated in a prospective cohort.

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Binge eating disorder (BED) is the most frequent eating disorder, for which current pharmacotherapies show poor response rates and safety concerns, thus highlighting the need for novel treatment options. The lipid-derived messenger oleoylethanolamide (OEA) acts as a satiety signal inhibiting food intake through the involvement of central noradrenergic and oxytocinergic neurons. We investigated the anti-binge effects of OEA in a rat model of binge-like eating, in which, after cycles of intermittent food restrictions/refeeding and palatable food consumptions, female rats show a binge-like intake of palatable food, following a 15-min exposure to their sight and smell (“frustration stress”). Systemically administered OEA dose-dependently (2.5, 5, and 10 mg kg−1) prevented binge-like eating. This behavioral effect was associated with a decreased activation (measured by mapping the expression of c-fos, an early gene widely used as a marker of cellular activation) of brain areas responding to stress (such as the nucleus accumbens and amygdala) and to a stimulation of areas involved in the control of food intake, such as the VTA and the PVN. These effects were paralleled, also, to the modulation of monoamine transmission in key brain areas involved in both homeostatic and hedonic control of eating. In particular, a decreased dopaminergic response to stress was observed by measuring dopamine extracellular concentrations in microdialysates from the nucleus accumbens shell, whereas an increased serotonergic and noradrenergic tone was detected in tissue homogenates of selected brain areas. Finally, a decrease in corticotropin-releasing factor (CRF) mRNA levels was induced by OEA in the central amygdala, while an increase in oxytocin mRNA levels was induced in the PVN. The restoration of a normal oxytocin receptor density in the striatum paralleled the oxytocinergic stimulation produced by OEA. In conclusion, we provide evidence suggesting that OEA might represent a novel potential pharmacological target for the treatment of binge-like eating behavior.

The application of non-targeted serum metabolomics profiling represents a noninvasive tool to identify new clinical biomarkers and to provide early diagnostic differentiation, and insight into the pathological mechanisms underlying hepatocellular carcinoma (HCC) progression. In this study, we used proton Nuclear Magnetic Resonance (1H-NMR) Spectroscopy and multivariate data analysis to profile the serum metabolome of 64 HCC patients, in early (n = 28) and advanced (n = 36) disease stages. We found that 1H-NMR metabolomics profiling could discriminate early from advanced HCC patients with a cross-validated accuracy close to 100%. Orthogonal partial least squares discriminant analysis (OPLS-DA) showed significant changes in serum glucose, lactate, lipids and some amino acids, such as alanine, glutamine, 1-methylhistidine, lysine and valine levels between advanced and early HCC patients. Moreover, in early HCC patients, Kaplan&ndash, Meier analysis highlighted the serum tyrosine level as a predictor for overall survival (OS). Overall, our analysis identified a set of metabolites with possible clinical and biological implication in HCC pathophysiology.

It is widely accepted that chronic stress may alter the homeostatic mechanisms of body weight control. In this study, we followed the metabolic changes occurring in mice when chronic stress caused by psychosocial defeat (CPD) is associated with ad libitum exposure to a palatable high-fat diet (HFD). In this model, CPD mice consumed more HFD than unstressed (Un) mice without gaining body weight. We focused on metabolic processes involved in weight control, such as de novo lipogenesis (DNL), fatty acid β-oxidation (FAO), and thermogenesis. The activity and expression of DNL enzymes were reduced in the liver and white adipose tissue of mice consuming the HFD. Such effects were particularly evident in stressed mice. In both CPD and Un mice, HFD consumption increased the hepatic expression of the mitochondrial FAO enzyme carnitine palmitoyltransferase-1. In the liver of mice consuming the HFD, stress exposure prevented accumulation of triacylglycerols; however, accumulation of triacylglycerols was observed in Un mice under the same dietary regimen. In brown adipose tissue, stress increased the expression of uncoupling protein-1, which is involved in energy dissipation, both in HFD and control diet-fed mice. We consider increased FAO and energy dissipation responsible for the antiobesity effect seen in CPD/HFD mice. However, CPD associated with HFD induced hepatic oxidative stress.-Giudetti, A. M., Testini, M., Vergara, D., Priore, P., Damiano, F., Gallelli, C. A., Romano, A., Villani, R., Cassano, T., Siculella, L., Gnoni, G. V., Moles, A., Coccurello, R., Gaetani, S. Chronic psychosocial defeat differently affects lipid metabolism in liver and white adipose tissue and induces hepatic oxidative stress in mice fed a high-fat diet.

The impact of natural CO2 emissions in the development of geothermal areas is presently gaining more attention than ever before. In Italian geothermal fields, a reduction in the natural CO2 emissions has been observed. This paper reviews and provides an analysis of the historical production data of boric acid from 1818 to 1867 used to calculate the natural emissions of CO2 associated with boric acid production that pre-dates the use of geothermal resources for power production, which started in 1913. Boric acid was already being extracted from the natural geothermal fluids in geysers and natural ponds emitting steam and gases. After 1827 the ‘lagone coperto’ (covered lake) equipment optimized production, and the drilling of shallow wells (20–30 m) starting in 1836, which further increased the quantity of its extraction. The first geothermal reservoir was developed at the turn of the century and the Larderello geothermal field began to grow. The use of deep wells, keeping pace with the power production, led to the gradual disappearance of the natural ponds and the ‘lagoni’ (lakes) in the historical area, so the residual natural emission of CO2 is presently restricted to diffuse soil emission. Comparisons of the ancient CO2 emissions with those of the Geothermal Power Plant (GPP) in the Larderello area show that both amounts are in the same order of magnitude, suggesting a balance between the depletion of natural emissions and geothermal activity.

Hepatic de novo lipogenesis (DNL), the process by which carbohydrates are converted into lipids, is strictly controlled by nutritional and hormonal status. 3,5-Diiodo-L-thyronine (T2), a product of the 3,5,3'-triiodo-L-thyronine (T3) peripheral metabolism, has been shown to mimic some T3 effects on lipid metabolism by a short-term mechanism independent of protein synthesis. Here, we report that T2, administered for 1 week to hypothyroid rats, increases total fatty acid synthesis from acetate in isolated hepatocytes. Studies carried out on liver subcellular fractions demonstrated that T2 not only increases the activity and the expression of acetyl-CoA carboxylase and fatty acid synthase but also of other proteins linked to DNL such as the mitochondrial citrate carrier and the cytosolic ATP citrate lyase. Parallelly, T2 stimulates the activities of enzymes supplying cytosolic NADPH needed for the reductive steps of DNL. With respect to both euthyroid and hypothyroid rats, T2 administration decreases the hepatic mRNA level of SREBP-1, a transcription factor which represents a master regulator of DNL. However, when compared to hypothyroid rats T2 significantly increases, without bringing to the euthyroid value, the content of both mature (nSREBP-1), and precursor (pSREBP-1) forms of the SREBP-1 protein as well as their ratio. Moreover, T2 administration strongly augmented the nuclear content of ChREBP, another crucial transcription factor involved in the regulation of lipogenic genes. Based on these results, we can conclude that in the liver of hypothyroid rats the transcriptional activation by T2 of DNL genes could depend, at least in part, on SREBP-1- and ChREBP-dependent mechanisms. © 2019 IUBMB Life, 2019.

The pathogenesis of cancer involves multiple molecular alterations at the level of genome, epigenome, and stromal environment, resulting in several deregulated signal transduction pathways. Metabolites are not only end products of gene and protein expression but also a consequence of the mutual relationship between the genome and the internal environment. Considering that metabolites serve as a comprehensive chemical fingerprint of cell metabolism, metabolomics is emerging as the method able to discover metabolite biomarkers that can be developed for early cancer detection, prognosis, and response to treatment. Urine represents a noninvasive source, available and rich in metabolites, useful for cancer diagnosis, prognosis, and treatment monitoring. In this chapter, we reported the main published evidences on urinary metabolic biomarkers in the studied cancers related to hepatopancreatic and urinary tract with the aim at discussing their promising role in clinical practice.