COVID-19: A complex disease with a unique metabolic signature.

Plasma of COVID-19 patients contains a strong metabolomic/lipoproteomic signature, revealed by the NMR analysis of a cohort of >500 patients sampled during various waves of COVID-19 infection, corresponding to the spread of different variants, and having different vaccination status. This composite signature highlights common traits of the SARS-CoV-2 infection. The most dysregulated molecules display concentration trends that scale with disease severity and might serve as prognostic markers for fatal events. Metabolomics evidence is then used as input data for a sex-specific multi-organ metabolic model. This reconstruction provides a comprehensive view of the impact of COVID-19 on the entire human metabolism. The human (male and female) metabolic network is strongly impacted by the disease to an extent dictated by its severity. A marked metabolic reprogramming at the level of many organs indicates an increase in the generic energetic demand of the organism following infection. Sex-specific modulation of immune response is also suggested.

Delirium and IL-6 added to clinical scores improves their performance: a prospective analysis of CALL, PREDI-CO, MRS score applied to a population of patients admitted to internal medicine ward.

This study aimed to evaluate the effectiveness of various scoring systems in predicting in-hospital mortality for COVID-19 patients admitted to the internal medicine ward. We conducted a prospective collection of clinical data from patients admitted to the Internal Medicine Unit at Santa Maria Nuova Hospital in Florence, Italy, with confirmed pneumonia caused by SARS-CoV-2. We calculated three scoring systems: the CALL score, the PREDI-CO score, and the COVID-19 in-hospital Mortality Risk Score (COVID-19 MRS). The primary endpoint was in-hospital mortality. : A total of 681 patients were enrolled in the study, with a mean age of 68.8 ± 16.1 years, and 54.8% of them were male. Non-survivors had significantly higher scores in all prognostic systems compared to survivors (MRS: 13 [12- 15] vs. 10 [8-12]; CALL: 12 [10-12] vs. 9 [7-11]; PREDI-CO: 4 [3-6] vs. 2 [1-4]; all p<0.001). The receiver operating characteristic (ROC) analysis yielded the following area under the curve (AUC) values: MRS 0.85, CALL 0.78, PREDI-CO 0.77. The addition of Delirium and IL6 to the scoring systems improved their discriminative ability, resulting in AUC values of 0.92 for MRS, 0.87 for CALL, and 0.84 for PREDI-CO. The mortality rate increased significantly across increasing quartiles (p<0.001). In conclusion the COVID-19 in-hospital Mortality Risk Score (MRS) demonstrated reasonable prognostic stratification for patients admitted to the internal medicine ward with SARS-CoV-2-induced pneumonia. The inclusion of Delirium and IL6 as additional prognostic indicators in the scoring systems enhanced their predictive performance, specifically in determining in-hospital mortality among COVID-19 patients.

Role of Hydroxytyrosol and Oleuropein in the Prevention of Aging and Related Disorders: Focus on Neurodegeneration, Skeletal Muscle Dysfunction and Gut Microbiota.

Aging is a multi-faceted process caused by the accumulation of cellular damage over time, associated with a gradual reduction of physiological activities in cells and organs. This degeneration results in a reduced ability to adapt to homeostasis perturbations and an increased incidence of illnesses such as cognitive decline, neurodegenerative and cardiovascular diseases, cancer, diabetes, and skeletal muscle pathologies. Key features of aging include a chronic low-grade inflammation state and a decrease of the autophagic process. The Mediterranean diet has been associated with longevity and ability to counteract the onset of age-related disorders. Extra virgin olive oil, a fundamental component of this diet, contains bioactive polyphenolic compounds as hydroxytyrosol (HTyr) and oleuropein (OLE), known for their antioxidant, anti-inflammatory, and neuroprotective properties. This review is focused on brain, skeletal muscle, and gut microbiota, as these systems are known to interact at several levels. After the description of the chemistry and pharmacokinetics of HTyr and OLE, we summarize studies reporting their effects in in vivo and in vitro models of neurodegenerative diseases of the central/peripheral nervous system, adult neurogenesis and depression, senescence and lifespan, and age-related skeletal muscle disorders, as well as their impact on the composition of the gut microbiota.

Beauveria bassiana rewires molecular mechanisms related to growth and defense in tomato.

Plant roots can exploit beneficial associations with soil-inhabiting microbes, promoting growth and expanding the immune capacity of the host plant. In this work, we aimed to provide new information on changes occurring in tomato interacting with the beneficial fungus Beauveria bassiana. The tomato leaf proteome revealed perturbed molecular pathways during the establishment of the plant-fungus relationship. In the early stages of colonization (5-7 d), proteins related to defense responses to the fungus were down-regulated and proteins related to calcium transport were up-regulated. At later time points (12-19 d after colonization), up-regulation of molecular pathways linked to protein/amino acid turnover and to biosynthesis of energy compounds suggests beneficial interaction enhancing plant growth and development. At the later stage, the profile of leaf hormones and related compounds was also investigated, highlighting up-regulation of those related to plant growth and defense. Finally, B. bassiana colonization was found to improve plant resistance to Botrytis cinerea, impacting plant oxidative damage. Overall, our findings further expand current knowledge on the possible mechanisms underlying the beneficial role of B. bassiana in tomato plants.

Environmental Signals Act as a Driving Force for Metabolic and Defense Responses in the Antarctic Plant Colobanthus quitensis.

During evolution, plants have faced countless stresses of both biotic and abiotic nature developing very effective mechanisms able to perceive and counteract adverse signals. The biggest challenge is the ability to fine-tune the trade-off between plant growth and stress resistance. The Antarctic plant Colobanthus quitensis has managed to survive the adverse environmental conditions of the white continent and can be considered a wonderful example of adaptation to prohibitive conditions for millions of other plant species. Due to the progressive environmental change that the Antarctic Peninsula has undergone over time, a more comprehensive overview of the metabolic features of C. quitensis becomes particularly interesting to assess its ability to respond to environmental stresses. To this end, a differential proteomic approach was used to study the response of C. quitensis to different environmental cues. Many differentially expressed proteins were identified highlighting the rewiring of metabolic pathways as well as defense responses. Finally, a different modulation of oxidative stress response between different environmental sites was observed. The data collected in this paper add knowledge on the impact of environmental stimuli on plant metabolism and stress response by providing useful information on the trade-off between plant growth and defense mechanisms.

Simulated global warming affects endophytic bacterial and fungal communities of Antarctic pearlwort leaves and some bacterial isolates support plant growth at low temperatures.

Antarctica is one of the most stressful environments for plant life and the Antarctic pearlwort (Colobanthus quitensis) is adapted to the hostile conditions. Plant-associated microorganisms can contribute to plant survival in cold environments, but scarce information is available on the taxonomic structure and functional roles of C. quitensis-associated microbial communities. This study aimed at evaluating the possible impacts of climate warming on the taxonomic structure of C. quitensis endophytes and at investigating the contribution of culturable bacterial endophytes to plant growth at low temperatures. The culture-independent analysis revealed changes in the taxonomic structure of bacterial and fungal communities according to plant growth conditions, such as the collection site and the presence of open-top chambers (OTCs), which can simulate global warming. Plants grown inside OTCs showed lower microbial richness and higher relative abundances of biomarker bacterial genera (Allorhizobium-Neorhizobium-Pararhizobium-Rhizobium, Aeromicrobium, Aureimonas, Hymenobacter, Novosphingobium, Pedobacter, Pseudomonas and Sphingomonas) and fungal genera (Alternaria, Cistella, and Vishniacozyma) compared to plants collected from open areas (OA), as a possible response to global warming simulated by OTCs. Culturable psychrotolerant bacteria of C. quitensis were able to endophytically colonize tomato seedlings and promote shoot growth at low temperatures, suggesting their potential contribution to plant tolerance to cold conditions.

Plant defense: ARR11 response regulator as a potential player in Arabidopsis.

Plant growth and response to environmental cues are largely driven by hormones. Salicylic acid (SA)- and jasmonic acid (JA)-mediated defenses have been shown to be effective against different types of attackers. SA-mediated defense is mainly effective against biotrophic pathogens and phloem-feeding insects, whereas JA-mediated defense is effective against necrotrophic pathogens and tissue-damaging insects. Cytokinins (CKs) are classic growth hormones that have also emerged as plant immunity modulators. Evidence pointed out that CKs contribute to the defense responses mediated by SA and JA, acting as hormone modulators of the SA/JA signaling backbone. Recently, we identified in Arabidopsis a type-B response regulator 11 (ARR 11) involved in cytokinin-mediated responses as a novel regulator of the SA/JA cross-talk. Here we investigated plant fitness and resistance against the fungal necrotrophic pathogen Botrytis cinerea in Arabidopsis wild-type Col-8 and defective arr11 mutant following SA, JA, CK single or combined treatment. Our results demonstrated that the CK and SA/JA/CK combination has a positive outcome on plant fitness in both Arabidopsis Col-8 and arr11 mutant,. The triple hormone treatment is efficient in increasing resistance to B. cinerea in Col-8 and this effect is stronger in arr11 mutant. The results will provide not only new background knowledge, corroborating the role of ARR11 in plant-defense related processes, but also new potential opportunities for alternative ways of protecting plants from fungal diseases.

Biodiversity and Bioprospecting of Fungal Endophytes from the Antarctic Plant Colobanthus quitensis.

Microorganisms from extreme environments are considered as a new and valuable reservoir of bioactive molecules of biotechnological interest and are also utilized as tools for enhancing tolerance to (a)biotic stresses in crops. In this study, the fungal endophytic community associated with the leaves of the Antarctic angiosperm Colobanthus quitensis was investigated as a new source of bioactive molecules. We isolated 132 fungal strains and taxonomically annotated 26 representative isolates, which mainly belonged to the Basidiomycota division. Selected isolates of Trametes sp., Lenzites sp., Sistotrema sp., and Peniophora sp. displayed broad extracellular enzymatic profiles; fungal extracts from some of them showed dose-dependent antitumor activity and inhibited the formation of amyloid fibrils of α-synuclein and its pathological mutant E46K. Selected fungal isolates were also able to promote secondary root development and fresh weight increase in Arabidopsis and tomato and antagonize the growth of pathogenic fungi harmful to crops. This study emphasizes the ecological and biotechnological relevance of fungi from the Antarctic ecosystem and provides clues to the bioprospecting of Antarctic Basidiomycetes fungi for industrial, agricultural, and medical applications.

Profiling metabolites and lipoproteins in COMETA, an Italian cohort of COVID-19 patients.

Metabolomics and lipidomics have been used in several studies to define the biochemical alterations induced by COVID-19 in comparison with healthy controls. Those studies highlighted the presence of a strong signature, attributable to both metabolites and lipoproteins/lipids. Here, 1H NMR spectra were acquired on EDTA-plasma from three groups of subjects: i) hospitalized COVID-19 positive patients (≤21 days from the first positive nasopharyngeal swab); ii) hospitalized COVID-19 positive patients (>21 days from the first positive nasopharyngeal swab); iii) subjects after 2-6 months from SARS-CoV-2 eradication. A Random Forest model built using the EDTA-plasma spectra of COVID-19 patients ≤21 days and Post COVID-19 subjects, provided a high discrimination accuracy (93.6%), indicating both the presence of a strong fingerprint of the acute infection and the substantial metabolic healing of Post COVID-19 subjects. The differences originate from significant alterations in the concentrations of 16 metabolites and 74 lipoprotein components. The model was then used to predict the spectra of COVID-19>21 days subjects. In this group, the metabolite levels are closer to those of the Post COVID-19 subjects than to those of the COVID-19≤21 days; the opposite occurs for the lipoproteins. Within the acute phase patients, characteristic trends in metabolite levels are observed as a function of the disease severity. The metabolites found altered in COVID-19≤21 days patients with respect to Post COVID-19 individuals overlap with acute infection biomarkers identified previously in comparison with healthy subjects. Along the trajectory towards healing, the metabolome reverts back to the "healthy" state faster than the lipoproteome.

A Metabolic Profiling Analysis Revealed a Primary Metabolism Reprogramming in Arabidopsis glyI4 Loss-of-Function Mutant.

Methylglyoxal (MG) is a cytotoxic compound often produced as a side product of metabolic processes such as glycolysis, lipid peroxidation, and photosynthesis. MG is mainly scavenged by the glyoxalase system, a two-step pathway, in which the coordinate activity of GLYI and GLYII transforms it into D-lactate, releasing GSH. In Arabidopsis thaliana, a member of the GLYI family named GLYI4 has been recently characterized. In glyI4 mutant plants, a general stress phenotype characterized by compromised MG scavenging, accumulation of reactive oxygen species (ROS), stomatal closure, and reduced fitness was observed. In order to shed some light on the impact of gly4 loss-of-function on plant metabolism, we applied a high resolution mass spectrometry-based metabolomic approach to Arabidopsis Col-8 wild type and glyI4 mutant plants. A compound library containing a total of 70 metabolites, differentially synthesized in glyI4 compared to Col-8, was obtained. Pathway analysis of the identified compounds showed that the upregulated pathways are mainly involved in redox reactions and cellular energy maintenance, and those downregulated in plant defense and growth. These results improved our understanding of the impacts of glyI4 loss-of-function on the general reprogramming of the plant's metabolic landscape as a strategy for surviving under adverse physiological conditions.

What Antarctic Plants Can Tell Us about Climate Changes: Temperature as a Driver for Metabolic Reprogramming.

Global warming is strongly affecting the maritime Antarctica climate and the consequent melting of perennial snow and ice covers resulted in increased colonization by plants. Colobanthus quitensis is a vascular plant highly adapted to the harsh environmental conditions of Antarctic Peninsula and understanding how the plant is responding to global warming is a new challenging target for modern cell physiology. To this aim, we performed differential proteomic analysis on C. quitensis plants grown in natural conditions compared to plants grown for one year inside open top chambers (OTCs) which determine an increase of about 4 °C at midday, mimicking the effect of global warming. A thorough analysis of the up- and downregulated proteins highlighted an extensive metabolism reprogramming leading to enhanced photoprotection and oxidative stress control as well as reduced content of cell wall components. Overall, OTCs growth seems to be advantageous for C. quitensis plants which could benefit from a better CO2 diffusion into the mesophyll and a reduced ROS-mediated photodamage.

ALS skin fibroblasts reveal oxidative stress and ERK1/2-mediated cytoplasmic localization of TDP-43.

The main hallmark of many forms of familiar and sporadic amyotrophic lateral sclerosis (ALS) is a reduction in nuclear TDP-43 protein and its inclusion in cytoplasmic aggregates in motor neurons. In order to understand which cellular and molecular mechanisms underlie the mislocalization of TDP-43, we examined human skin fibroblasts from two individuals with familial ALS, both with mutations in TDP-43, and two individuals with sporadic ALS, both without TDP-43 mutations or mutations in other ALS related genes. We found that all ALS fibroblasts had a partially cytoplasmic localization of TDP-43 and had reduced cell metabolism as compared to fibroblasts from apparently healthy individuals. ALS fibroblasts showed an increase in global protein synthesis and an increase in 4E-BP1 and rpS6 phosphorylation, which is indicative of mTORC1 activity. We also observed a decrease in glutathione (GSH), which suggests that oxidative stress is elevated in ALS. ERK1/2 activity regulated the extent of oxidative stress and the localization of TDP-43 in the cytoplasm in all ALS fibroblasts. Lastly, ALS fibroblasts showed reduced stress granule formation in response to H2O2 stress. In conclusion, these findings identify specific cellular and molecular defects in ALS fibroblasts, thus providing insight into potential mechanisms that may also occur in degenerating motor neurons.

GLYI4 Plays A Role in Methylglyoxal Detoxification and Jasmonate-Mediated Stress Responses in Arabidopsis thaliana.

Plant hormones play a central role in various physiological functions and in mediating defense responses against (a)biotic stresses. In response to primary metabolism alteration, plants can produce also small molecules such as methylglyoxal (MG), a cytotoxic aldehyde. MG is mostly detoxified by the combined actions of the enzymes glyoxalase I (GLYI) and glyoxalase II (GLYII) that make up the glyoxalase system. Recently, by a genome-wide association study performed in Arabidopsis, we identified GLYI4 as a novel player in the crosstalk between jasmonate (JA) and salicylic acid (SA) hormone pathways. Here, we investigated the impact of GLYI4 knock-down on MG scavenging and on JA pathway. In glyI4 mutant plants, we observed a general stress phenotype, characterized by compromised MG scavenging, accumulation of reactive oxygen species (ROS), stomatal closure, and reduced fitness. Accumulation of MG in glyI4 plants led to lower efficiency of the JA pathway, as highlighted by the increased susceptibility of the plants to the pathogenic fungus Plectospherella cucumerina. Moreover, MG accumulation brought about a localization of GLYI4 to the plasma membrane, while MeJA stimulus induced a translocation of the protein into the cytoplasmic compartment. Collectively, the results are consistent with the hypothesis that GLYI4 is a hub in the MG and JA pathways.

Physiological response of Posidonia oceanica to heavy metal pollution along the Tyrrhenian coast.

Heavy metal (HM) pollution of marine coastal areas is a big concern worldwide. The marine phanerogam Posidonia oceanica (L.) Delile is widely considered to be a sensitive bioindicator of water pollution due to its ability to sequester trace elements from the environment. The analysis of specific biomarkers, like reactive oxygen species scavengers, could allow us to correlate the physiological response of P. oceanica meadows to water pollution. In this study, we analysed the activity of some antioxidant enzymes and the expression level of the corresponding genes in the leaves of P. oceanica plants harvested from four meadows distributed along the Tyrrhenian coast; lipid peroxidation and the expression level of two genes related to HM response, metallothionein-2b and chromethylase, were also measured. The results of biochemical and molecular analyses were correlated with the concentration of some HMs, such as Cr, Cd, Cu, Ni and Pb, measured in P. oceanica leaves. We found a very strong antioxidant response in plants from the Murelle meadow whose HM concentration was the lowest for most of the analysed HMs, particularly Cu.

Proteomic Analysis of MeJa-Induced Defense Responses in Rice against Wounding.

The role of jasmonates in defense priming has been widely recognized. Priming is a physiological process by which a plant exposed to low doses of biotic or abiotic elicitors activates faster and/or stronger defense responses when subsequently challenged by a stress. In this work, we investigated the impact of MeJA-induced defense responses to mechanical wounding in rice (Oryza sativa). The proteome reprogramming of plants treated with MeJA, wounding or MeJA+wounding has been in-depth analyzed by using a combination of high throughput profiling techniques and bioinformatics tools. Gene Ontology analysis identified protein classes as defense/immunity proteins, hydrolases and oxidoreductases differentially enriched by the three treatments, although with different amplitude. Remarkably, proteins involved in photosynthesis or oxidative stress were significantly affected upon wounding in MeJA-primed plants. Although these identified proteins had been previously shown to play a role in defense responses, our study revealed that they are specifically associated with MeJA-priming. Additionally, we also showed that at the phenotypic level MeJA protects plants from oxidative stress and photosynthetic damage induced by wounding. Taken together, our results add novel insight into the molecular actors and physiological mechanisms orchestrated by MeJA in enhancing rice plants defenses after wounding.

Epidemiology of Chronic Pain in the Latium Region, Italy: A Cross-Sectional Study on the Clinical Characteristics of Patients Attending Pain Clinics.

In Italy, chronic pain affects more than a quarter of the population, whereas the average European prevalence is 21%. This high prevalence might be due to the high percentage of Italian people who do not receive treatment, even after the passing of law 38/2010 (the right to access pain management in Italy), which created a regional network for the diagnosis and treatment of noncancer chronic pain. Italian epidemiologic studies on chronic pain are scanty, and this observational, multicenter, cross-sectional study is the first to investigate the clinical characteristics of patients who attended the pain management clinics in the Latium Region, Italy, for the management of their noncancer chronic pain. A total of 1,606 patients (mean age 56.8 years, standard deviation ± 11.4), 67% women, were analyzed. Severe pain was present in 54% of the sample. Women experienced pain and had it in two or more sites more often than men (57% vs. 50%, p = .02; and 55.2% vs. 45.9%, p < .001, respectively). Chronic pain was musculoskeletal (45%), mixed (34%), and neuropathic (21%). In more than 60% of the cases, chronic pain was continuous, and in 20% it had lasted for more than 48 months; long-lasting pain was often neuropathic. Low back (33.4%) and lower limbs (28.2%) were the main locations. Severe intensity of pain was statistically significantly associated with female gender (odds ratio [OR] 1.39; 95% confidence interval [CI] 1.06-1.84); with International Classification of Diseases, Ninth Revision, codes for chronic pain syndrome (OR 2.14; 95% CI 1.55-2.95); and with continuous pain (OR 2.02; 95% CI 1.54-2.66). Neuropathic pain and mixed pain were significantly associated with number of sites, and a trend seemed to be present (OR 2.11 and 3.02 for 2 and 3 + sites; 95% CI 1.59-2.79 and 2.00-4.55, respectively).

Tyrosinase-Treated Hydroxytyrosol-Enriched Olive Vegetation Waste with Increased Antioxidant Activity Promotes Autophagy and Inhibits the Inflammatory Response in Human THP-1 Monocytes.

Treatment of olive vegetation waste with tyrosinase immobilized on multiwalled carbon nanotubes increased the antioxidant activity as a consequence of the conversion of phenols to corresponding catechol derivatives, as evaluated by DPPH, Comet assay, and micronucleus analyses. During this transformation, 4-hydroxyphenethyl alcohol (tyrosol) was quantitatively converted to bioactive 3,4-dihydroxyphenethyl alcohol (hydroxytyrosol). The hydroxytyrosol-enriched olive vegetation waste also promoted autophagy and inhibited the inflammatory response in human THP-1 monocytes.