👤 Gian Gaetano Tartaglia

The progressive accumulation of physiological stress as we age, known as allostatic load, is linked to an increased risk of dementia. Fostering brain resilience through physical exercise can counteract allostatic load and improve adaptation to age-related brain alterations. Fibronectin type III domain-containing protein 5 (FNDC5)/irisin is a neuroprotective exercise-linked hormone found in extracellular vesicles (EV-FNDC5/irisin). Here, we sought to analyse EV-FNDC5/irisin in ageing as a promising biomarker of brain resilience. We measured exercise-associated factors, including EV-FNDC5/irisin, brain-derived neurotrophic factor (BDNF), and cathepsin B in the serum of 31 young (18-28 years) and 19 older subjects (65-79 years). Levels of FNDC5/irisin in serum-derived EVs are markedly reduced in older subjects compared to young ( Show less

Chronic lymphocytic leukemia (CLL) is divided into unmutated (UM-CLL) and mutated (M-CLL) subtypes depending on somatic hypermutation (SHM) frequency in their immunoglobulin heavy chain V (IGHV) region. We previously demonstrated that CD27bright memory B cells (MBCs) are germinal center (GC)-dependent with higher mutation rate, whereas CD27dull MBCs accumulate fewer mutations and originate independently from the GC. We conducted a meta-transcriptomic analysis on bulk RNA data from 116 individuals combining four CLL cohorts and healthy B cell subsets (naïve, CD27dull and CD27bright MBCs) to decipher the transcriptional and mechanistic functions of CLL subtypes. CD27bright MBCs showed more transcriptional similarity to M-CLL rather than UM-CLL. Functional enrichment analysis revealed that LPL, ZNF667 and ZNF667-AS1 are potential informative biomarkers for stratification of CLL subtypes. They are part of the mechanistic regulatory pathways of CLL pathology through cholesterol and Epithelial Mesenchymal Transition (EMT) regulation. We applied markers for the GC B-cell substages to map in silico the CLL cohorts to their potential GC B cell counterpart. UM-CLL represented transcriptional mimicry to an early intermediary GC substage whereas M-CLL mimicked later substages in the GC. This could potentially explain the IGHV mutational status of M-CLL as well as hypothesize that CLL subtypes could derive from a GC-dependent pathway. Show less

To assess the cross-talk between immune cells and respiratory tract during SARS-CoV-2 infection, we analyzed the relationships between the inflammatory response induced by SARS-CoV-2 replication and immune cells phenotype in a reconstituted organotypic human airway epithelium (HAE). The results indicated that immune cells failed to inhibit SARS-CoV-2 replication in the HAE model. In contrast, immune cells strongly affected the inflammatory profile induced by SARS-CoV-2 infection, dampening the production of several immunoregulatory/inflammatory signals (e.g., IL-35, IL-27, and IL-34). Moreover, these mediators were found inversely correlated with innate immune cell frequency (NK and γδ T cells) and directly with CD8 T cells. The enriched signals associated with NK and CD8 T cells highlighted the modulation of pathways induced by SARS-CoV-2 infected HAE. These findings are useful to depict the cell-cell communication mechanisms necessary to develop novel therapeutic strategies aimed to promote an effective immune response. Show less

Insulin is a key hormone that controls glucose homeostasis. In liver, insulin suppresses gluconeogenesis by inhibiting the transcriptions of phosphoenolpyruvate carboxylase (PEPCK) and glucose-6-phosphatase (G6Pase) genes. In insulin resistance and type II diabetes there is an elevation of hepatic gluconeogenesis, which contributes to hyperglycemia. To search for novel genes that negatively regulate insulin signaling in controlling metabolic pathways, we screened a cDNA library derived from the white adipose tissue of ob/ob mice using a reporter system comprised of the PEPCK promoter placed upstream of the alkaline phosphatase gene. The mitogen-activated dual specificity protein kinase phosphatase 3 (MKP-3) was identified as a candidate gene that antagonized insulin suppression on PEPCK gene transcription from this screen. In this study, we showed that MKP-3 was expressed in insulin-responsive tissues and that its expression was markedly elevated in the livers of insulin-resistant obese mice. In addition, MKP-3 can activate PEPCK promoter in synergy with dexamethasone in hepatoma cells. Furthermore, ectopic expression of MKP-3 in hepatoma cells by adenoviral infection increased the expression of PEPCK and G6Pase genes and led to elevated glucose production. Taken together, our data strongly suggests that MKP-3 plays a role in regulating gluconeogenic gene expression and hepatic gluconeogenesis. Therefore, dysregulation of MKP-3 expression and/or function in liver may contribute to the pathogenesis of insulin resistance and type II diabetes. Show less