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Vincenzo Vestuto,1,* Marisa Conte,1,* Mariapia Vietri,1,* Francesca Mensitieri,2 Valentina Santoro,1,3 Anna Di Muro,1 Mariaevelina Alfieri,4 Maria Moros,5,6 Maria Rosaria Miranda,1,3 Chiara Amante,1 Matteo Delli Carri,1 Pietro Campiglia,1 Fabrizio Dal Piaz,2,7 Pasquale Del Gaudio,1 Nunziatina De Tommasi,1,3 Antonietta Leone,1 Ornella Moltedo,1 Giacomo Pepe,1,3 Elisa Cappetta,1 Alfredo Ambrosone1 1Department of Pharmacy, University of Salerno, Fisciano, 84084, Italy; 2Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, 84081, Italy; 3National Biodiversity Future Center (NBFC), Palermo, 90133, Italy; 4Clinical Pathology, Santobono-Pausilipon Children’s Hospital, AORN, Naples, 80122, Italy; 5Instituto de Nanociencia y Materiales de Aragón (INMA), CSIC-Universidad de Zaragoza, Zaragoza, Spain; 6Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain; 7Operative Unit of Clinical Pharmacology, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, Salerno, 84131, Italy*These authors contributed equally to this workCorrespondence: Alfredo Ambrosone; Elisa Cappetta, Department of Pharmacy, University of Salerno, Fisciano, 84084, Italy, Email aambrosone@unisa.it; ecappetta@unisa.itPurpose: Extracellular vesicles (EVs) are promising tools for nanomedicine and nanobiotechnology. The purification of mammalian-derived EVs involves intensive processes, and their therapeutic application raises multiple safety and regulatory issues. Plants have the potential to serve as nonconventional sources of therapeutically relevant EVs. In this context, we recently identified hairy roots (HRs) of medicinal plants as a novel biotechnological platform to produce EVs for human health.Methods: Herein, we report the purification, omics profiling, and bioactivity of EVs isolated from HRs of the medicinal plants S. sclarea and S. dominica. EVs were isolated from conditioned media of HR cultures using differential ultracentrifugation (dUC) and size exclusion chromatography (SEC). The isolated EVs were characterized by nanoparticle tracking analysis (NTA) and electron microscopy. The proteomic and metabolomic profiles of the EVs were determined using mass spectrometry. Uptake studies and bioactivity assays, including confocal microscopy, MTT, flow cytometry, ROS quantification, and untargeted metabolomics analyses, were conducted in SH-SY5Y cells treated with the neurotoxin 6-hydroxydopamine (6-OHDA) to evaluate the therapeutic potential of EVs in an in vitro model of Parkinson’s disease.Results: S. sclarea HRs released nanosized round-shaped EVs with a distinctive molecular signature. HR EVs from S. sclarea and S. dominica revealed conserved cargo of secondary metabolites, predominantly triterpenoids, which are known for their antioxidant properties. We showed that HR EVs are safe, enter the cells, and strongly inhibit apoptosis in a cellular model of Parkinson’s disease. Cellular metabolomics revealed that EVs preserved metabolic homeostasis and mitigated cellular oxidative stress when co-administered with 6-OHDA. Mechanistically, HR EVs inhibited 6-OHDA autoxidation and substantially reduced the accumulation of its oxidative products, which are responsible for 6-OHDA-induced toxicity.Conclusion: Collectively, our findings provide compelling evidence that EVs isolated from the hairy roots of Salvia species are promising, non-mammalian alternative for the design of novel therapies targeting neurological disorders. Keywords: non-mammalian EV source, Salvia extracellular vesicles, hairy roots, nanomedicine, neuroprotection, Parkinson’s disease

Abstract Background Breast cancer manifests as a heterogeneous pathology marked by complex metabolic reprogramming essential to satisfy its energy demands. Oncogenic signals boost the metabolism, modifying fatty acid synthesis and glucose use from the onset to progression and therapy resistant-forms. However, the exact contribution of metabolic dependencies during tumor evolution remains unclear. Methods In this study, we elucidate the connection between FASN and LDHA, pivotal metabolic genes, and their correlation with tumor grade and therapy response using datasets from public repositories. Subsequently, we evaluated the metabolic and proliferative functions upon FASN and LDHA inhibition in breast cancer models. Lastly, we integrated metabolomic and lipidomic analysis to define the contributions of metabolites, lipids, and precursors to the metabolic phenotypes. Results Collectively, our findings indicate metabolic shifts during breast cancer progression, unvealling two distinct functional energy phenotypes associated with aggressiveness and therapy response. Specifically, FASN exhibits reduced expression in advance-grade tumors and therapy-resistant forms, whereas LDHA demonstrates higher expression. Additionally, the biological and metabolic impact of blocking the enzymatic activity of FASN and LDHA was correlated with resistant conditions. Conclusions These observations emphasize the intrinsic metabolic heterogeneity within breast cancer, thereby highlighting the relevance of metabolic interventions in the field of precision medicine.

Abstract Background Despite extensive studies on the neurobiological correlates of traumatic brain injury (TBI), little is known about its molecular determinants on long-term consequences, such as dementia and Alzheimer’s disease (AD). Methods Here, we carried out behavioural studies and an extensive biomolecular analysis, including inflammatory cytokines, gene expression and the combination of LC-HRMS and MALDI-MS Imaging to elucidate the targeted metabolomics and lipidomics spatiotemporal alterations of brains from wild-type and APP-SWE mice, a genetic model of AD, at the presymptomatic stage, subjected to mild TBI. Results We found that brain injury does not affect cognitive performance in APP-SWE mice. However, we detected an increase of key hallmarks of AD, including Aβ1-42 levels and BACE1 expression, in the cortices of traumatized transgenic mice. Moreover, significant changes in the expanded endocannabinoid (eCB) system, or endocannabinoidome (eCBome), occurred, including increased levels of the endocannabinoid 2-AG in APP-SWE mice in both the cortex and hippocampus, and N-acylserotonins, detected for the first time in the brain. The gene expression of enzymes for the biosynthesis and inactivation of eCBs and eCB-like mediators, and some of their main molecular targets, also underwent significant changes. We also identified the formation of heteromers between cannabinoid 1 (CB1) and serotonergic 2A (5HT2A) receptors, whose levels increased in the cortex of APP-SWE mTBI mice, possibly contributing to the exacerbated pathophysiology of AD induced by the trauma. Conclusions Mild TBI induces biochemical changes in AD genetically predisposed mice and the eCBome may play a role in the pathogenetic link between brain injury and neurodegenerative disorders also by interacting with the serotonergic system.

Solid Phase Peptide Synthesis (SPPS) is the preferred technique for synthesizing bioactive peptides. However, traditional SPPS generates significant waste and employs hazardous solvents like DMF and DCM. The aim of this research is to investigate solvents and agents of coupling that align with the green chemistry and are suitable for all stages of SPPS. Some solvents, such as p-cymene and anisole, taken into consideration in this work, can be derived from renewable sources like plants and biomass, rendering them environmentally sustainable choices. However, many of these alternative solvents possess different physicochemical properties compared to DMF. To overcome this challenge, solvent mixtures are employed. In this study, we identified a novel green solvent mixture by combining anisole with NOP; its ability to swell different resins and its capability to solubilize all Fmoc protected amino acids was investigated. The same mixture was also assessed with a green coupling agent, TBEC, in combination with ETT as additive. Model peptides Aib-enkephalin and Aib-ACP were synthesized resulting in favorable outcomes in terms of peptide synthesis efficiency, 97.81% and 98.86%, respectively.

Abstract Background Plant-derived nanovesicles (PDNVs) are a novelty in medical and agrifood environments, with several studies exploring their functions and potential applications. Among fruits, apples (sp. Malus domestica) have great potential as PDNVs source, given their widespread consumption, substantial waste production, and recognized health benefits. Notably, apple-derived nanovesicles (ADNVs) can interact with human cell lines, triggering anti-inflammatory and antioxidant responses. This work is dedicated to the comprehensive biochemical characterization of apple-derived nanovesicles (ADNVs) through proteomic and lipidomic analysis, and small RNAs sequencing. This research also aims to shed light on the underlying mechanism of action (MOA) when ADNVs interface with human cells, through observation of intracellular calcium signalling in human fibroblasts, and to tackles differences in ADNVs content when isolated from fruits derived from integrated and organic production methods cultivars. Results The ADNVs fraction is mainly composed of exocyst-positive organelles (EXPOs) and MVB-derived exosomes, identified through size and molecular markers (Exo70 and TET-3-like proteins). ADNVs’ protein cargo is heterogeneous and exhibits a diverse array of functions, especially in plant's protection (favouring ABA stress-induced signalling, pathogen resistance and Reactive Oxygen Species (ROS) metabolism). Noteworthy plant miRNAs also contribute to phytoprotection. In relation with human cells lines, ADNVs elicit spikes of intracellular Ca2+ levels, utilizing the cation as second messenger, and produce an antioxidant effect. Lastly, organic samples yield a substantial increase in ADNV production and are particularly enriched in bioactive lysophospholipids. Conclusions We have conclusively demonstrated that ADNVs confer an antioxidant effect upon human cells, through the initiation of a molecular pathway triggered by Ca2+ signalling. Within ADNVs, a plethora of bioactive proteins, small RNAs, and lipids have been identified, each possessing well-established functions within the realm of plant biology. While ADNVs predominantly function in plants, to safeguard against pathogenic agents and abiotic stressors, it is noteworthy that proteins with antioxidant power might act as antioxidants within human cells. Graphical Abstract

Este artigo apresenta os resultados parciais de pesquisa em curso no CNPq que tematiza a memória do futuro em textos culturais midiáticos. O objeto empírico é o vídeo publicitário VW 70 anos/ VW Brasil produzido por tecnologias de Inteligência Artificial compreendido como texto cultural midiático propulsor de memórias. Interroga-se sob a forma de questão-problema: qual o papel que a IA desempenha para a construção de memórias e esquecimentos materializados nesse filme publicitário lido como texto cultural e comunicativo? O objetivo é compreender de que maneira os modos de criação proporcionados pela IA para a publicidade da VW constroem a memória e ou formas de esquecimento a serem consumidos midiática, simbólica, afetiva e socialmente. Como fundamento teórico-metodológico consideram-se os conceitos da Teoria Semiótica da Cultura de Tártu-Moscou articulados a estudos do campo teórico da memória e das Ciências Humanas e Sociais. Pesquisa bibliográfica e documental são mobilizadas para a compreensão de certos princípios da IA. Espera-se demonstrar que o filme publicitário constrói memórias tensionadas a apagamentos de caráter ético-político que promovem a instrumentalização do passado e de suas lembranças.

Abstract Background Early diagnosis of hepatocellular carcinoma (HCC) is essential towards the improvement of prognosis and patient survival. Circulating markers such as α-fetoprotein (AFP) and micro-RNAs represent useful tools but still have limitations. Identifying new markers can be fundamental to improve both diagnosis and prognosis. In this approach, we harness the potential of metabolomics and lipidomics to uncover potential signatures of HCC. Methods A combined untargeted metabolomics and lipidomics plasma profiling of 102 HCV-positive patients was performed by HILIC and RP-UHPLC coupled to Mass Spectrometry. Biochemical parameters of liver function (AST, ALT, GGT) and liver cancer biomarkers (AFP, CA19.9 e CEA) were evaluated by standard assays. Results HCC was characterized by an elevation of short and long-chain acylcarnitines, asymmetric dimethylarginine, methylguanine, isoleucylproline and a global reduction of lysophosphatidylcholines. A supervised PLS-DA model showed that the predictive accuracy for HCC class of metabolomics and lipidomics was superior to AFP for the test set (100.00% and 94.40% vs 55.00%). Additionally, the model was applied to HCC patients with AFP values

Abstract Background Sodium–glucose cotransporter 2 (SGLT2) inhibitors constitute the gold standard treatment for type 2 diabetes mellitus (T2DM). Among them, empagliflozin (EMPA) has shown beneficial effects against heart failure. Because cardiovascular diseases (mainly diabetic cardiomyopathy) are the leading cause of death in diabetic patients, the use of EMPA could be, simultaneously, cardioprotective and antidiabetic, reducing the risk of death from cardiovascular causes and decreasing the risk of hospitalization for heart failure in T2DM patients. Interestingly, recent studies have shown that EMPA has positive benefits for people with and without diabetes. This finding broadens the scope of EMPA function beyond glucose regulation alone to include a more intricate metabolic process that is, in part, still unknown. Similarly, this significantly increases the number of people with heart diseases who may be eligible for EMPA treatment. Methods This study aimed to clarify the metabolic effect of EMPA on the human myocardial cell model by using orthogonal metabolomics, lipidomics, and proteomics approaches. The untargeted and multivariate analysis mimicked the fasting blood sugar level of T2DM patients (hyperglycemia: HG) and in the average blood sugar range (normal glucose: NG), with and without the addition of EMPA. Results Results highlighted that EMPA was able to modulate and partially restore the levels of multiple metabolites associated with cellular stress, which were dysregulated in the HG conditions, such as nicotinamide mononucleotide, glucose-6-phosphate, lactic acid, FA 22:6 as well as nucleotide sugars and purine/pyrimidines. Additionally, EMPA regulated the levels of several lipid sub-classes, in particular dihydroceramide and triacylglycerols, which tend to accumulate in HG conditions resulting in lipotoxicity. Finally, EMPA counteracted the dysregulation of endoplasmic reticulum-derived proteins involved in cellular stress management. Conclusions These results could suggest an effect of EMPA on different metabolic routes, tending to rescue cardiomyocyte metabolic status towards a healthy phenotype. Graphical Abstract

Abstract Many studies have explored the extraction of bioactive compounds from different onion solid wastes, such as bulb, skin, and peel. However, onion leaves have received limited attention despite their potential as a valuable source of nutraceutical compounds. This study aimed to valorise, for the first time, the agricultural waste in the form of spring onion leaves (CN, Cipollotto Nocerino) to obtain antioxidant-rich polyphenolic extracts. A Box–Behnken design (BBD) was used to assess the impact of microwave-assisted extraction (MAE) variables (temperature, time, extraction volume, and ethanol concentration) on total polyphenol content (TPC) measured by Folin–Ciocalteu method and the antioxidant power determined by FRAP assay. Response surface methodology (RSM) was applied, and regression equations, analysis of variance, and 3D response curves were developed. Our results highlighted that the TPC values range from 0.76 to 1.43 mg GAE g−1 dw, while the FRAP values range from 8.25 to 14.80 mmol Fe(II)E g−1 dw. The optimal extraction conditions predicted by the model were 60 °C, 22 min, ethanol concentration 51% (v/v), and solvent volume 11 mL. These conditions resulted in TPC and FRAP values of 1.35 mg GAE g−1 dw and 14.02 mmol Fe(II)E g−1 dw, respectively. Furthermore, the extract obtained under optimized conditions was characterized by UHPLC-ESI-Orbitrap-MS analysis. LC/MS–MS platform allowed us to tentatively identify various compounds belonging to the class of flavonoids, saponins, fatty acids, and lipids. Finally, the ability of CN optimal extract to inhibit the intracellular reactive oxygen species (ROS) release in a hepatocarcinoma cell line using an H2O2-induced oxidative stress model, was evaluated. The results highlighted the potential of CN extract as a valuable source of polyphenols with significant antioxidant properties, suitable for various applications in the food and pharmaceutical industries.

Abstract Background Septoplasty, a common surgical procedure to correct a deviated septum, can be performed under either general anesthesia or deep sedation anesthesia. The choice of anesthesia can influence the duration of anesthesia and surgical outcomes, impacting the feasibility of outpatient procedures. Methods The institutional review board approved the protocol, and we obtained written informed consent from all participants. This retrospective, single-center observational study analyzed data from 586 patients who underwent rhino septoplasty at Santo Stefano Hospital in Prato, Italy, from 2017 to 2021. Patients received either general anesthesia or deep sedation anesthesia. Propensity score matching and inverse probability weighting were used to balance patient characteristics. The main outcome variable was discharge time, with anesthesia time and surgical time as covariates. Statistical analysis was conducted using R software. Results Patients who received deep sedation anesthesia had a significantly shorter duration of anesthesia compared to those who received general anesthesia. A multivariate linear regression model showed that the type of anesthesia had a strong positive association with discharge time, while anesthesia time had a weaker negative association, although not statistically significant. Conclusions Deep sedation anesthesia is associated with a shorter duration of anesthesia compared to general anesthesia during nasal septal surgery, suggesting it could be a more feasible option for outpatient procedures. However, the choice of anesthesia should be tailored to individual patient factors and surgical requirements. Further research is needed to confirm these findings and explore the potential benefits of sedation anesthesia in outpatient nasal septal surgery. Question How do general anesthesia and deep sedation anesthesia compare in terms of duration of anesthesia and surgical outcomes during nasal septal surgery? Findings Our study found that deep sedation anesthesia was associated with a shorter duration of anesthesia compared to general anesthesia in patients undergoing nasal septal surgery. However, there were no significant differences in the duration of the surgical procedure. Meaning The findings suggest that deep sedation anesthesia could potentially make nasal septal surgery more feasible as an outpatient procedure.

Bioactive compounds are abundant in animals originating from marine ecosystems. Ion channels, which include sodium, potassium, calcium, and chloride, together with their numerous variants and subtypes, are the primary molecular targets of the latter. Based on their cellular targets, these venom compounds show a range of potencies and selectivity and may have some therapeutic properties. Due to their potential as medications to treat a range of (human) diseases, including pain, autoimmune disorders, and neurological diseases, marine molecules have been the focus of several studies over the last ten years. The aim of this review is on the various facets of marine (or marine-derived) molecules, ranging from structural characterization and discovery to pharmacology, culminating in the development of some “novel” candidate chemotherapeutic drugs that target potassium channels.

Lycium barbarum, commonly recognized as goji berry or wolfberry, is highly appreciated not only for its organoleptic and nutritional properties but also as an important source of bioactive compounds such as polysaccharides, carotenoids, phenolics, and various other non-nutritive compounds. These constituents give it a multitude of health benefits, including antioxidant, anti-inflammatory, and anticancer properties. However, the precise biochemical mechanisms responsible for its anticancer effects remain unclear, and the comprehensive composition of goji berry extracts is often insufficiently explored. This study aimed to investigate the biochemical pathways modulated in breast cancer cells by an ethanolic extract of Lycium barbarum fruit (LBE). Following metabolomic profiling using UHPLC-HRMS/MS, we assessed the antitumoral properties of LBE on different breast cancer cell lines. This investigation revealed that LBE exhibited cytotoxic effects, inducing a pro-oxidant effect that triggered pyroptosis activation through endoplasmic reticulum (ER) stress and subsequent activation of the P-IRE1α/XBP1/NLRP3 axis in MCF-7 cells. In addition, LBE did not display cytotoxicity toward healthy human cells but demonstrated antioxidant properties by neutralizing ROS generated by doxorubicin. These findings underscore the potential of LBE as a highly promising natural extract in cancer therapy.

Potassium channels have recently emerged as suitable target for the treatment of epileptic diseases. Among potassium channels, KCNT1 channels are the most widely characterized as responsible for several epileptic and developmental encephalopathies. Nevertheless, the medicinal chemistry of KCNT1 blockers is underdeveloped so far. In the present review, we describe and analyse the papers addressing the issue of KCNT1 blockers’ development and identification, also evidencing the pros and the cons of the scientific approaches therein described. After a short introduction describing the epileptic diseases and the structure–function of potassium channels, we provide an extensive overview of the chemotypes described so far as KCNT1 blockers, and the scientific approaches used for their identification.

The pathogenesis of various gastrointestinal (GI) disorders, including gastritis, ulcers, inflammatory bowel disease (IBD) and cancer, can be linked to oxidative stress. It is known that reactive species carry out a crucial role in the genesis and progression of these pathologies; however, the contribution of ionic channels in their development is still under discussion. The function of ion channels in the gastrointestinal tract influences a variety of cellular processes. Acid-base balance, mucus layer, microbiota and mucosal blood flow are only some of the essential features for maintaining the mucosal integrity of the cellular barrier in the intestine, allowing for the preservation of proper permeability and ensuring tissue homeostasis. As the functional modulation of several ion channels is altered during oxidative stress conditions associated with gastrointestinal inflammation, this review focuses on contributing new insight into the roles of and the relationship between ion channels and oxidative stress in GI diseases. The association between ion channels and oxidative stress conditions could be used in diagnostics and the development of new pharmacological treatments for major gastrointestinal diseases.

Several studies have associated platelets (PLTs) to NSCLC prognosis. To understand the role of PLTs in immunotherapy-treated patients, we used blood samples of NSCLC patients at different TNM stage. We found that PLTs count and the expression of PD-L1 (pPD-L1) were significantly higher in NSCLC patients at Stage IV than Stage I-III and healthy subjects. The presence of high pPD-L1 was associated to upregulated genes for the extracellular matrix organization and tumor immunosuppression. When patients’ survival was correlated to the levels of pPD-L1, longer survival rate was observed, but not when progression disease occurred. The in vitro stimulation of pPD-L1 with Atezolizumab induced CXCL4 release, accompanied by higher levels of TGFβ at the time of drug resistance when the levels of CD16, CD32 and CD64 significantly increased. Leiden-clustering method defined the phenotype of PLTs which showed that the ezrin-radixin-moesin (ERM) family proteins, underlying the PD-L1 signalosome, were involved in high pPD-L1 and higher survival rate. These data imply that Stage IV NSCLC patients characterized by high pPD-L1 are associated with longer progression-free survival rate because the blockade of pPD-L1 by Atezolizumab avoids the exacerbation of a T cell-mediated immune-suppressive environment. pPD-L1 could be an easy-to-use clinical approach to predict ICI responsiveness.

Among gynecological cancers, endometrial cancer is the most common in developed countries. Extracellular vesicles (EVs) are cell-derived membrane-surrounded vesicles that contain proteins involved in immune response and apoptosis. A deep proteomic approach can help to identify dysregulated extracellular matrix (ECM) proteins in EVs correlated to key pathways for tumor development. In this study, we used a proteomics approach correlating the two acquisitions—data-dependent acquisition (DDA) and data-independent acquisition (DIA)—on EVs from the conditioned medium of four cell lines identifying 428 ECM proteins. After protein quantification and statistical analysis, we found significant changes in the abundance (p < 0.05) of 67 proteins. Our bioinformatic analysis identified 26 pathways associated with the ECM. Western blotting analysis on 13 patients with type 1 and type 2 EC and 13 endometrial samples confirmed an altered abundance of MMP2. Our proteomics analysis identified the dysregulated ECM proteins involved in cancer growth. Our data can open the path to other studies for understanding the interaction among cancer cells and the rearrangement of the ECM.

Microplastics have garnered an infamous reputation as a sorbate for many concerning environmental pollutants and as a delivery vehicle for the aquatic food chain through the ingestion of these contaminated small particulates. While sorption mechanisms have been extensively studied for polycyclic aromatic hydrocarbons, polycyclic aromatic sulfur heterocycles (PASHs) have not been investigated, partly due to their low concentrations in aquatic ecosystems. Herein, an analytical methodology is presented for the analysis of dibenzothiophene, benzo[b]naphtho[1,2-b]thiophene, benzo[b]naphtho[2,1-b]thiophene, benzo[b]naphtho[2,3-b]thiophene, chryseno[4,5-bcd]thiophene and dinaphtho[1,2-b:1′,2′-d]thiophene at relevant environmental concentrations based on solid phase extraction and high-performance liquid chromatography. The sorption uptake behavior and the sorption kinetics of the three benzo[b]napthothiophene isomers were then investigated on nylon microplastics to provide original information on their environmental fate and avoid human contamination through the food chain. The obtained information might also prove relevant to the development of successful remediation approaches for aquatic ecosystems.

Lycium barbarum, known as goji berry or wolfberry, is a fruit long associated with health benefits, showing a plethora of effects ranging from antioxidant, anticancer, anti-inflammatory, and immunomodulatory effects. Its potential is attributed to the significant presence of polysaccharides, glycopeptides, polyphenols, flavonoids, carotenoids, and their derivatives. These compounds effectively counteract the action of free radicals, positively influencing cellular balance and intracellular signaling, contributing to overall cell health and function acting on multiple molecular pathways. Several fractions extracted from goji berries demonstrate antitumor properties, particularly effective against breast cancer, without showing cytotoxic effects on normal human cells. Hence, the review explored the fundamental traits of bioactive elements in Lycium barbarum and their potential in cancer treatment and, specifically, breast cancer. It focused on elucidating wolfberry’s influenced biochemical pathways, its synergism with anticancer drugs, and its potential to alleviate the side effects associated with existing cancer treatments.

IntroductionThe management of severe COVID-19-induced acute respiratory distress syndrome (C-ARDS) often involves deep sedation. This study evaluated the efficacy of sevoflurane, a volatile anesthetic, as an alternative to traditional intravenous sedation in this patient population.MethodsThis single-center, retrospective cohort study enrolled 112 patients with C-ARDS requiring invasive mechanical ventilation. A propensity score matching model was utilized to pair 56 patients receiving sevoflurane sedation with 56 patients receiving intravenous sedation. The primary outcome was mortality, with secondary outcomes being changes in oxygenation (PaO2/FiO2 ratio), pulmonary compliance, and levels of D-Dimer, CRP, and creatinine.ResultsThe use of sevoflurane was associated with a statistically significant reduction in mortality (OR 0.40, 95% CI 0.18–0.87, beta = −0.9, p = 0.02). In terms of secondary outcomes, an increase in the PaO2/FiO2 ratio and pulmonary static compliance was observed, although the results were not statistically significant. No significant differences were noted in the levels of D-Dimer, CRP, and creatinine between the two groups.ConclusionOur findings suggest an association between the use of sevoflurane and improved outcomes in C-ARDS patients requiring invasive mechanical ventilation. However, due to the single-center, retrospective design of the study, caution should be taken in interpreting these results, and further research is needed to corroborate these findings. The study offers promising insights into potential alternative sedation strategies in the management of severe C-ARDS.

Mycalin A (MA) is a polybrominated C-15 acetogenin isolated from the marine sponge Mycale rotalis. Since this substance displays a strong antiproliferative bioactivity towards some tumour cells, we have now directed our studies towards the elucidation of the MA interactome through functional proteomic approaches, (DARTS and t-LIP-MS). DARTS experiments were performed on Hela cell lysates with the purpose of identifying MA main target protein(s); t-LiP-MS was then applied for an in-depth investigation of the MA–target protein interaction. Both these techniques exploit limited proteolysis coupled with MS analysis. To corroborate LiP data, molecular docking studies were performed on the complexes. Finally, biological and SPR analysis were conducted to explore the effect of the binding. Mortalin (GRP75) was identified as the MA’s main interactor. This protein belongs to the Hsp70 family and has garnered significant attention due to its involvement in certain forms of cancer. Specifically, its overexpression in cancer cells appears to hinder the pro-apoptotic function of p53, one of its client proteins, because it becomes sequestered in the cytoplasm. Our research, therefore, has been focused on the possibility that MA might prevent this sequestration, promoting the re-localization of p53 to the nucleus and facilitating the apoptosis of tumor cells.

Endocrine disruptors (EDCs) are chemicals that interfere with the endocrine system. EDC exposure may contribute to the development of obesity, type 2 diabetes, and cardiovascular diseases by impacting the composition of an infant’s gut microbiota during the first 1000 days of life. To explore the relationship between maternal urinary levels of Bisphenol-A and phthalates (UHPLC-MS/MS), and the composition of the infant gut microbiota (16S rDNA) at age 12 months (T3) and, retrospectively, at birth (T0), 1 month (T1), and 6 months (T2), stool samples from 20 infants breastfed at least once a day were analyzed. Metataxonomic bacteria relative abundances were correlated with EDC values. Based on median Bisphenol-A levels, infants were assigned to the over-exposed group (O, n = 8) and the low-exposed group (B, n = 12). The B-group exhibited higher gut colonization of the Ruminococcus torques group genus and the O-group showed higher abundances of Erysipelatoclostridium and Bifidobacterium breve. Additionally, infants were stratified as high-risk (HR, n = 12) or low-risk (LR, n = 8) exposure to phthalates, based on the presence of at least three phthalates with concentrations exceeding the cohort median values; no differences were observed in gut microbiota composition. A retrospective analysis of gut microbiota (T0–T2) revealed a disparity in β-diversity between the O-group and the B-group. Considering T0–T3, the Linear Discriminant Effect Size indicated differences in certain microbes between the O-group vs. the B-group and the HR-group vs. the LR-group. Our findings support the potential role of microbial communities as biomarkers for high EDC exposure levels. Nevertheless, further investigations are required to deeply investigate this issue.

Summary: Skeletal muscle (SM) pain and fatigue are common in Fabry disease (FD). Here, we undertook the investigation of the energetic mechanisms related to FD-SM phenotype. A reduced tolerance to aerobic activity and lactate accumulation occurred in FD-mice and patients. Accordingly, in murine FD-SM we detected an increase in fast/glycolytic fibers, mirrored by glycolysis upregulation. In FD-patients, we confirmed a high glycolytic rate and the underutilization of lipids as fuel. In the quest for a tentative mechanism, we found HIF-1 upregulated in FD-mice and patients. This finding goes with miR-17 upregulation that is responsible for metabolic remodeling and HIF-1 accumulation. Accordingly, miR-17 antagomir inhibited HIF-1 accumulation, reverting the metabolic-remodeling in FD-cells. Our findings unveil a Warburg effect in FD, an anaerobic-glycolytic switch under normoxia induced by miR-17-mediated HIF-1 upregulation. Exercise-intolerance, blood-lactate increase, and the underlying miR-17/HIF-1 pathway may become useful therapeutic targets and diagnostic/monitoring tools in FD.