Sandro Malacrida

Hypobaric hypoxia (HH) induces coordinated physiological and molecular responses supporting acclimatization to reduced oxygen availability. However, the temporal integration of blood mRNA and miRNA expression during early HH exposure remains incompletely understood. Eight healthy males were exposed for 72 h to simulated moderate HH (~ 3500 m) in the terraXcube facility. Blood transcriptomic and miRNA profiles were analyzed at baseline and after 12, 24, and 72 h, together with physiological variables, reactive oxygen species (ROS), and circulating inflammatory and endothelial biomarkers. Differential expression analysis revealed a progression from early stress and innate immune responses at 12 h, involving FOSB , CITED4 , and IDO1 , to remodeling of lymphocyte-specific programs at 24 h, including PAX5 , TCF7 , and TNFRSF13C . At 72 h, broader changes involved AP-1 components ( JUN , JUNB , and FOSB ), lymphocyte regulators ( PAX5 and FOXP3 ), and the antioxidant gene SOD2 . Integrated analysis identified predicted miRNA–mRNA pairs displaying inverse expression patterns within these pathways. Notably, miR-486-3p was consistently upregulated and miR-29c-5p downregulated across all time points. Plasma biomarkers remained largely stable, except for a transient increase in ICAM-1 and a marked decrease in TNF-α at 12 h, while ROS increased early and subsequently stabilized. Together, these findings identify distinct but overlapping phases of early HH acclimatization, progressing from stress and innate immune activation to lymphocyte-specific and redox remodeling. The temporal dissociation between coordinated mRNA and miRNA expression changes and limited circulating inflammatory responses indicates that molecular adaptation extends beyond detectable systemic inflammatory activation.

Background/Objectives: Mild cognitive impairment (MCI) is accompanied by olfactory dysfunction, and few interventions target shared chemosensory–cognitive mechanisms. We retrospectively examined whether a 5-week oxygen–ozone major autohemotherapy (MAH) cycle is associated with coupled improvements in olfactory and cognitive performance in adults with MCI. Methods: We analyzed 81 individuals with MCI who completed 10 MAH sessions (twice weekly) and 93 matched healthy controls. In the MCI group, olfactory function was measured before and after MAH using Sniffin’ Sticks^® threshold–discrimination–identification (TDI) scores; global cognition was assessed with the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). We evaluated between-group and pre–post changes and used Spearman correlations to assess olfactory–cognitive coupling. Results: At baseline, MCI participants showed lower TDI and MoCA scores than controls and more hyposmia/anosmia. Following MAH, the proportion of normosmic patients increased from 32.1% to 50.6%, with fewer anosmic cases. TDI scores improved but remained lower than in controls. MMSE scores were unchanged, whereas MoCA total scores increased, with domain-level gains and a significant improvement in Language Repetition. TDI gains were modestly correlated with MoCA total and selected domain changes. Conclusions: In this retrospective cohort, MAH was associated with partial restoration improvements of olfactory function and improved cognitive performance. Correlated olfactory–cognitive changes were observed within the treated MCI group; however, causal attribution to O₂–O₃ MAH cannot be established without randomized, double-blind, sham-controlled trials with coupled olfactory–cognitive gains consistent with a shared, potentially modifiable substrate. Prospective randomized trials are needed to confirm efficacy and clinical utility.

Hepatocellular carcinoma (HCC), the most common form of liver cancer, is frequently diagnosed late due to the absence of symptoms during early disease, thus heavily affecting the overall survival of these patients. Soluble immunological factors persistently produced during cirrhosis have been recognized as promoters of chronic inflammation and neoplastic transformation. The aim of this pilot study was to evaluate the predictive value of the cytokine profiles for HCC development. A Luminex xMAP approach was used for the quantification of 45 proteins in plasma and ascitic fluids of 44 cirrhotic patients without or with HCC of different etiologies. The association with patient survival was also evaluated. Univariate analyses revealed that very low levels of interleukin 5 (IL-5) (<15.86 pg/mL) in ascites and IL-15 (<12.40 pg/mL) in plasma were able to predict HCC onset with an accuracy of 81.8% and a sensitivity of 95.2%. Univariate analyses also showed that HCC, hepatitis B virus/hepatitis C virus infections, low levels of IL-5 and granulocyte-macrophage colony-stimulating factor in ascitic fluids, and high levels of eotaxin-1, hepatocyte growth factor and stromal-cell-derived factor 1α in plasma samples were factors potentially associated with a poor prognosis and decreased survival. Our results suggest a potential protective role of some immune modulators that may act in the peritoneal cavity to counteract disease progression leading to HCC development.

Differences in gustatory sensitivity, nutritional habits, circulating levels of modulators, anthropometric measures, and metabolic assays may be involved in overweight (OW) development. The present study aimed at evaluating the differences in these aspects between 39 OW (19 female; mean age = 53.51 ± 11.17), 18 stage I (11 female; mean age = 54.3 ± 13.1 years), and 20 II (10 female; mean age = 54.5 ± 11.9) obesity participants when compared with 60 lean subjects (LS; 29 female; mean age = 54.04 ± 10.27). Participants were evaluated based on taste function scores, nutritional habits, levels of modulators (leptin, insulin, ghrelin, and glucose), and bioelectrical impedance analysis measurements. Significant reductions in total and subtests taste scores were found between LS and stage I and II obesity participants. Significant reductions in total and all subtests taste scores were found between OW and stage II obesity participants. Together with the progressive increase in plasmatic leptin levels, insulin, and serum glucose, decrease in plasmatic ghrelin levels, and changes in anthropometric measures and nutritional habits along with body mass index, these data for the first time demonstrated that taste sensitivity, biochemical regulators, and food habits play a parallel, concurring role along the stages evolving to obesity.

Redox homeostasis is a vital process the maintenance of which is assured by the presence of numerous antioxidant small molecules and enzymes and the alteration of which is involved in many pathologies, including several neurodegenerative disorders. Among the different enzymes involved in the antioxidant response, SOD1 and DJ-1 have both been associated with the pathogenesis of amyotrophic lateral sclerosis and Parkinson’s disease, suggesting a possible interplay in their mechanism of action. Copper deficiency in the SOD1-active site has been proposed as a central determinant in SOD1-related neurodegeneration. SOD1 maturation mainly relies on the presence of the protein copper chaperone for SOD1 (CCS), but a CCS-independent alternative pathway also exists and functions under anaerobic conditions. To explore the possible involvement of DJ-1 in such a pathway in vivo, we exposed Drosophila melanogaster to anoxia and evaluated the effect of DJ-1 on fly survival and SOD1 levels, in the presence or absence of CCS. Loss of DJ-1 negatively affects the fly response to the anoxic treatment, but our data indicate that the protective activity of DJ-1 is independent of SOD1 in Drosophila, indicating that the two proteins may act in different pathways.

During recent decades, model organisms such as Drosophila melanogaster have made it possible to study the effects of different environmental oxygen conditions on lifespan and oxidative stress. However, many studies have often yielded controversial results usually assigned to variations in Drosophila genetic background and differences in study design. In this study, we compared longevity and ROS levels in young, unmated males of three laboratory wild-type lines (Canton-S, Oregon-R and Berlin-K) and one mutant line (Sod1n1) as a positive control of redox imbalance, under both normoxic and hypoxic (2% oxygen for 24 h) conditions. Lifespan was used to detect the effects of hypoxic treatment and differences were analysed by means of Kaplan–Meier survival curves and log-rank tests. Electron paramagnetic resonance spectroscopy was used to measure ROS levels and analysis of variance was used to estimate the effects of hypoxic treatment and to assess ROS differences between strains. We observed that the genetic background is a relevant factor involved in D. melanogaster longevity and ROS levels. Indeed, as expected, in normoxia Sod1n1 are the shortest-lived, while the wild-type strains, despite a longer lifespan, show some differences, with the Canton-S line displaying the lowest mortality rate. After hypoxic stress these variances are amplified, with Berlin-K flies showing the highest mortality rate and most evident reduction of lifespan. Moreover, our analysis highlighted differential effects of hypoxia on redox balance/unbalance. Canton-S flies had the lowest increase of ROS level compared to all the other strains, confirming it to be the less sensitive to hypoxic stress. Sod1n1 flies displayed the highest ROS levels in normoxia and after hypoxia. These results should be used to further standardize future Drosophila research models designed to investigate genes and pathways that may be involved in lifespan and/or ROS, as well as comparative studies on specific mutant strains.

Editorial: Human Molecular and Physiological Responses to Hypoxia

The aim of the present scoping review was to evaluate the impact of experimental meal loads or observational diet changes/habits on taste tests in both healthy subjects and patients. A systematic search performed in PubMed, Scopus, and Institute for Scientific Information (ISI) Web of Science electronic databases retrieved, respectively 2981, 6258, and 7555 articles from January 2000 to December 2020. A total of 17 articles were included for full-text review. Literature results were stratified according to the observational/interventional approach, the involvement of healthy subjects or patients, the taste test, and the meal/dietary changes. The present scoping review reinforced the notions postulating that certain taste tests (for example focusing on fatty acid, salt, or sugar) might be specifically influenced by the nutritional intervention and that other ones might be susceptible to a wide span of changes beyond the extent of tastant included in the specific food changes. This could also depend on the inhomogeneity of literature trend: The short duration of the intervention or the random type of meal load, unsuitability of the taste test chosen, and the presence of underlying disorders. Future studies for a better comprehension of taste tests reliability in relation to specific food changes are thus to be fostered.

Single-nucleotide polymorphisms (SNPs) in the TERT gene can affect telomere length and TERT expression and have been associated with risk and/or outcome for several tumors, but very few data are available about their impact on rectal cancer. Eight SNPs (rs2736108, rs2735940, rs2736098, rs2736100, rs35241335, rs11742908, rs2736122 and rs2853690), mapping in regulatory and coding regions of the TERT gene, were studied in 194 rectal cancer patients to evaluate their association with constitutive telomere length, circulating TERT mRNA levels, response to neoadjuvant chemoradiotherapy (CRT) and disease outcome. At diagnosis, the rs2736100CC genotype was associated with longer telomeres measured pre-CRT, while the rs2736100CC, rs2736108TT and rs2735940AA were associated with greater telomere erosion evaluated post-CRT. The rs2736108CC and rs2853690AA/GG genotypes, respectively associated with lower telomere erosion and lower levels of circulating TERT post-CRT, were also independently associated with a better response to therapy [OR 4.6(1.1–19.1) and 3.0(1.3–6.9)]. Overall, post-CRT, low levels (≤ median value) of circulating TERT and its stable/decreasing levels compared to those pre-CRT, were independently associated with a better response to therapy [OR 5.8(1.9–17.8) and 5.3(1.4–19.4), respectively]. Furthermore, post-CRT, patients with long telomeres (>median value) and low levels of circulating TERT had a significantly lower risk of disease progression [HR 0.4(0.1–0.9) and 0.3(0.1–0.8), respectively]. These findings suggest that TERT SNPs could be a useful tool for improving the selection of patients who could benefit from CRT and support the role of telomere length and circulating TERT mRNA levels as useful markers for monitoring the response to therapy and disease outcome in rectal cancer patients.