👤 G Monteleone

Neonicotinoid pesticides, including acetamiprid (ACE), are widely used in agriculture and pose increasing concerns due to their persistence in the environment and potential human exposure mainly through diet. Available evidence suggests that ACE may disrupt adipocyte function and promote metabolic dysfunctions such as obesity; however, there is limited research on how ACE negatively affects adipose tissue (AT) in men and women. This study utilizes an Twenty-four subjects with severe obesity (11 men and 13 women) undergoing bariatric surgery were recruited from St. Andrea University Hospital (Rome, Italy). Visceral adipose tissue biopsies were collected and either treated with ACE or left untreated for further gene and protein expression analysis by RT-qPCR and Western blot, respectively. In addition, adipocytokines secretion, reactive oxygen species production, and free fatty acid release were measured in adipose tissue culture media using commercial or in house assays. Our findings demonstrate that ACE induces distinct sex-dependent alterations in lipid metabolism, Adipokines regulation, and inflammatory pathways. Specifically, it significantly lowers PPARγ gene expression but raises protein levels, particularly in men. Free fatty acid release increases and Hormone Sensitive Lipase (HSL) drops in both sexes, while Lipoprotein Lipase (LPL) decreases only in women. ACE also promotes inflammation mainly in women, increasing TNF-α, NF-κB, and reactive oxygen species. These results show that the neonicotinoid ACE worsens AT dysfunction via inflammatory and metabolic pathways in a sex-specific way, likely leading to different risks of obesity-related complications. Overall, these findings provide a mechanistic basis for understanding the toxicological risk of neonicotinoids, highlighting the importance of sex-specific assessment in evaluating metabolic risks of environmental pesticide exposure. Show less

In the tumor microenvironment, Cancer Associated Fibroblasts (CAFs) become activated by cancer cells and increase their secretory activity to produce soluble factors that contribute to tumor cells proliferation, invasion and dissemination to distant organs. The pro-tumorigenic transcription factor STAT3 and its canonical inducer, the pro-inflammatory cytokine IL-6, act conjunctly in a positive feedback loop that maintains high levels of IL-6 secretion and STAT3 activation in both tumor and stromal cells. Here, we demonstrate that STAT3 is essential for the pro-tumorigenic functions of murine breast cancer CAFs both in vitro and in vivo, and identify a STAT3 signature significantly enriched for genes encoding for secreted proteins. Among these, ANGPTL4, MMP13 and STC-1 were functionally validated as STAT3-dependent mediators of CAF pro-tumorigenic functions by different approaches. Both in vitro and in vivo CAFs activities were moreover impaired by MMP13 inhibition, supporting the feasibility of a therapeutic approach based on inhibiting STAT3-induced CAF-secreted proteins. The clinical potential of such an approach is supported by the observation that an equivalent CAF-STAT3 signature in humans is expressed at high levels in breast cancer stromal cells and characterizes patients with a shorter disease specific survival, including those with basal-like disease. Show less

Osteochondromas represent the largest group of benign tumors of bone. Multiple osteochondromatosis or hereditary multiple exostoses (EXT) is an autosomal dominant inherited disorder characterized by the presence of multiple benign cartilage-capped exostoses. EXT is genetically heterogeneous with at least 3 chromosomal loci: EXT1 (8q24.1), EXT2 (11p11-p13), and EXT3 (19p). In <5% of EXT patients, the inactivation of both copies of EXT alleles (LOH) is associated with malignant transformation. We have analyzed the EXT1 and EXT2 genes in 9 unrelated EXT families and in a patient with a sporadic osteochondroma, all originating from Italy. Four families show an EXT1 mutation, consisting of a small deletion in 3 of them and a small insertion in the 4th. All these mutations lead to premature termination of translation and thus a truncated EXT1 protein. Three families presented EXT2 mutations consisting of nucleotide substitutions leading to alterations of the third intron splice-site, to an amino acid substitution and to a nonsense mutation. All these mutations cosegregate with the disease phenotype. The sporadic osteochondroma patient carried a novel missense mutation in exon 11 of EXT2 gene, leading to an amino acid substitution. Seven of these mutations have never been described before. EXT2 missense mutations were also confirmed by amino acids conservation between human and mouse and by analysis of a healthy control population. In conclusion, our study provide further evidence that loss of function of the EXT1 or EXT2 gene is the main cause of EXT supporting the putative tumor-suppressor function of these genes. Show less