👤 Monica Cattaneo

Depression and anxiety during pregnancy are major public health concerns with lasting consequences for mother and child. Although the gut microbiome contributes to stress and mood regulation, its role in preconceptional stress and transgenerational outcomes remains unclear. Here, we examined behavioral, microbial, and thalamic transcriptional effects of preconceptional social isolation rearing (SIR) in female mice and tested whether maternal probiotic supplementation mitigates these alterations. SIR females displayed increased anxiety-like and social-avoidant behavior, reduced gut microbial diversity, depletion of Odoribacter, Tuzzerella, and Alloprevotella, and enrichment of Bacteroides and Lachnospiraceae. A multispecies probiotic (Lactobacillus rhamnosus HN001, L. acidophilus La-14, Bifidobacterium lactis HN019) reversed these behavioral and microbial changes. Adult offspring of SIR dams showed sex-dependent behavioral deficits and microbial alterations partly reflecting maternal patterns. Prenatal SIR was associated with reduced thalamic Bdnf expression in offspring and altered Grin2a/2b selectively in males. In contrast, prenatal probiotic exposure exerted broader transcriptional effects and restored Bdnf levels in SIR offspring. SIR-induced increases in Lachnospiraceae were transmitted to offspring, whereas reductions in Ruminococcaceae were normalized by maternal probiotic treatment. Predicted functional profiling indicated sex-dependent modulation of microbial pathways related to tryptophan and central carbon metabolism. These findings demonstrate enduring transgenerational effects of preconceptional stress on the gut-brain axis and support maternal probiotic supplementation as a potential strategy to mitigate stress-induced dysregulation. Show less

Stressful life events (SLE) are associated with an increased likelihood of developing depression. However, the underlying mechanisms and the long-lasting consequences of SLE exposure during adolescence, a critical period for physical, sexual, and behavioural maturation, are largely unknown. Recent studies suggest that they might be mediated by aberrant epigenetic mechanisms, such as alterations in DNA methylation, histone modifications and the expression of microRNAs. This systematic review aims at investigating the epigenetic markers affected by SLE during adolescence and their (causal) contribution to the onset of depression later in life. In line with the PRISMA 2020 guidelines and following a pre-registered protocol (CRD42023441784), PubMed, Web of Science and Embase were screened and 30 studies, including both rodents (n = 19) and humans (n = 11), met the pre-defined inclusion criteria. The preclinical findings converge on SLE-related changes in DNA methylation of Bdnf gene and alterations in microRNAs implicated in the regulation of Bdnf- and glucocorticoid-related pathways. The clinical studies focused primarily on DNA methylation and microRNAs alterations. Whilst a consensus on specific SLE-related epigenetic modifications did not emerge, novel pathways, including extracellular vesicle (EV) miRNAs, should be further investigated to be employed as biomarkers for preventive screening. Overall, our systematic review provides early suggestive evidence on the role of epigenetic mechanisms in mediating the effects of SLE in adolescence and the consequent onset of depression-relevant symptoms in later life. However, the paucity and the heterogeneity of the findings highlight the need for additional studies to address this fundamental research question and provide solid evidence for causality. Show less

Depression is a leading cause of global disability and is increasingly recognized as a multifactorial disorder characterized by fundamental disruptions in neuroplasticity, including diminished hippocampal neurogenesis, impaired synaptic plasticity, and dysregulated stress-response systems. Given the limited efficacy of conventional pharmacological treatments, lifestyle-based interventions-most notably physical exercise-have gained considerable attention for their antidepressant effects, partly mediated by secreted exerkines. Among these, adiponectin has emerged as a particularly compelling candidate linking metabolic regulation to neuroplasticity and mood. Recent evidence suggests that adiponectin contributes to the antidepressant effects of exercise by modulating hippocampal neurogenesis, neuroinflammation, and brain-derived neurotrophic factor (BDNF) signalling. Despite these advances, the mechanisms by which adiponectin influences depression remain incompletely understood. This review synthesizes current knowledge on adiponectin's role in depression pathophysiology, with emphasis on its capacity to enhance neuroplasticity and hippocampal neurogenesis, and its potential to mediate exercise-induced antidepressant effects via defined molecular pathways. Building on these insights, we discuss adiponectin's translational promise as both a predictive biomarker of treatment response and a novel therapeutic target. By integrating preclinical and clinical evidence, this review offers a comprehensive perspective on adiponectin's involvement in depression while identifying critical gaps to guide future mechanistic research. Show less

Aging is influenced by genetic determinants and comorbidities, among which diabetes increases the risk for heart failure with preserved ejection fraction. There is no therapy to prevent heart dysfunction in aging and diabetic individuals. In previous studies, a single administration of the longevity-associated variant (LAV) of the human BPIFB4 gene halted heart decline in older and type 2 diabetic mice. Here, we asked whether orally administered LAV-BPIFB4 protein replicates these benefits. In two controlled, randomized studies, 18-month-old male C57BL/6 J mice and 9-week-old C57BLKS/J-Leprdb/Leprdb/Dock7 + [db/db] mice of both sexes underwent baseline echocardiography. They then received a recombinant purified LAV-BPIFB4 protein (3 µg/animal, every three days) or vehicle by gavage. After 30 days, the animals underwent echocardiography, and the hearts were collected post-termination for histology. All the animals completed the study except one female diabetic mouse, which was culled prematurely because tooth malocclusion caused eating problems. There was no effect of the LAV-BPIFB4 protein on body weight in the two studies or glycosuria in the diabetic study. In aging mice, LAV-BPIFB4 increased myocardial Bpifb4 expression, improving heart contractility and capillarity while reducing perivascular fibrosis and senesce. In male diabetic mice, LAV-BPIFB4 therapy improved systolic function, microvascular density, and senescence, whereas the benefit was limited to systolic function in females. This study shows the feasibility and efficacy of a variant protein associated with human longevity in contrasting pivotal risk factors for heart failure in animal models. The diabetic study revealed that sex influences the treatment efficacy. Show less

The human formyl-peptide receptor 2 (FPR2) is activated by an array of ligands. By phospho-proteomic analysis we proved that FPR2 stimulation induces redox-regulated phosphorylation of many proteins involved in cellular metabolic processes. In this study, we investigated metabolic pathways activated in FPR2-stimulated CaLu-6 cells. The results showed an increased concentration of metabolites involved in glucose metabolism, and an enhanced uptake of glucose mediated by GLUT4, the insulin-regulated member of GLUT family. Accordingly, we observed that FPR2 transactivated IGF-IR Show less

DNA methylation (DNAm) is an epigenetic mark with essential roles in disease development and predisposition. Here, we created genome-wide maps of methylation quantitative trait loci (meQTL) in three peripheral tissues and used Mendelian randomization (MR) analyses to assess the potential causal relationships between DNAm and risk for two common neurodegenerative disorders, i.e. Alzheimer's disease (AD) and Parkinson's disease (PD). Genome-wide single nucleotide polymorphism (SNP; ~5.5M sites) and DNAm (~850K CpG sites) data were generated from whole blood (n=1,058), buccal (n=1,527) and saliva (n=837) specimens. We identified between 11 and 15 million genome-wide significant (p<10 Show less

JNCL is a recessively inherited, childhood-onset neurodegenerative disease most-commonly caused by a approximately 1 kb CLN3 mutation. The resulting loss of battenin activity leads to deposition of mitochondrial ATP synthase, subunit c and a specific loss of CNS neurons. We previously generated Cln3Deltaex7/8 knock-in mice, which replicate the common JNCL mutation, express mutant battenin and display JNCL-like pathology. To elucidate the consequences of the common JNCL mutation in neuronal cells, we used P4 knock-in mouse cerebella to establish conditionally immortalized CbCln3 wild-type, heterozygous, and homozygous neuronal precursor cell lines, which can be differentiated into MAP-2 and NeuN-positive, neuron-like cells. Homozygous CbCln3Deltaex7/8 precursor cells express low levels of mutant battenin and, when aged at confluency, accumulate ATPase subunit c. Recessive phenotypes are also observed at sub-confluent growth; cathepsin D transport and processing are altered, although enzyme activity is not significantly affected, lysosomal size and distribution are altered, and endocytosis is reduced. In addition, mitochondria are abnormally elongated, cellular ATP levels are decreased, and survival following oxidative stress is reduced. These findings reveal that battenin is required for intracellular membrane trafficking and mitochondrial function. Moreover, these deficiencies are likely to be early events in the JNCL disease process and may particularly impact neuronal survival. Show less

The BRCA2 gene is mutated in familial breast and ovarian cancer, and its product is implicated in DNA repair and transcriptional regulation. Here we identify a protein, EMSY, which binds BRCA2 within a region (exon 3) deleted in cancer. EMSY is capable of silencing the activation potential of BRCA2 exon 3, associates with chromatin regulators HP1beta and BS69, and localizes to sites of repair following DNA damage. EMSY maps to chromosome 11q13.5, a region known to be involved in breast and ovarian cancer. We show that the EMSY gene is amplified almost exclusively in sporadic breast cancer (13%) and higher-grade ovarian cancer (17%). In addition, EMSY amplification is associated with worse survival, particularly in node-negative breast cancer, suggesting that it may be of prognostic value. The remarkable clinical overlap between sporadic EMSY amplification and familial BRCA2 deletion implicates a BRCA2 pathway in sporadic breast and ovarian cancer. Show less