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Our research explores serum extracellular circulating miRNAs (ecmiRNAs) involved in dog stress response immediately after the search and rescue (SAR) of missing people. The experimental plan considers four arduous SAR simulations. The SAR dogs are trained by the Alpine School of the Military Force of Guardia di Finanza (Passo Rolle, Italy). The First SAR Trial analyzed dog serum samples at rest time (T0), and immediately after SAR performance (T1) using the miRNome-wide screening next-generation sequencing (NGS). T1 versus T0 NGS results revealed a different expression level of let-7a and let-7f. Subsequently, in a large sample size including: 1st (n = 6), 2nd (n = 6), 3rd (n = 6), and 4th (n = 4) trials, let-7a and let-7f were validated by qPCR. Bioinformatics analysis with TarBase (v.8) and the Diana-mirPath (v.3) revealed a functional role of let-7a and let-7f in the p53 pathway to restore cellular homeostasis. Let-7a and let-7f, highly expressed at T1, could stop MDMs-p53 inhibition inducing the p53 increase in level. In addition, let-7a and let-7f, via p53 post-transcriptional regulation, buffers p53 transcription spikes. During SAR stress, the possibility of p53 preconditioning could explain the phenomenon of “stress hardening” where the tolerance of particular stress increases after preconditioning.

Neurotrophins and inflammatory mediators are known to influence endometrial function, but their interplay in luminal epithelial cells remains poorly characterized. In this study, sheep endometrial luminal epithelial cells (SELECs) were treated with nerve growth factor (NGF), lipopolysaccharide (LPS), or both, and the effects on gene expression and prostaglandin secretion were evaluated. NGF stimulation alone induced a clear transcriptional activation of NGF, neurotrophic receptor tyrosine kinase 1 (NTRK1), p75 neurotrophin receptor (p75NTR), cyclooxygenase 2 (COX2), and steroidogenic acute regulatory protein (STAR). LPS treatment selectively increased Toll-like receptor 4 (TLR4), COX2, and insulin-like growth factor binding protein 6 (IGFBP6). Combined NGF and LPS treatment did not enhance the transcriptional response beyond that induced by NGF alone, except for STAR. However, co-treatment resulted in a modest increase in prostaglandin production, particularly prostaglandin F2α (PGF2α), but not prostaglandin E2 (PGE2), compared to single treatments, suggesting a possible post-transcriptional modulation rather than a transcriptional synergy. These findings indicate that NGF acts as the primary transcriptional driver in SELECs, while LPS contributes selectively and may enhance prostaglandin output. The observed increase in prostaglandin production may involve post-transcriptional mechanisms, although this remains to be confirmed.

Genistein is a natural compound belonging to flavonoids, having antioxidant, anti-inflammatory, and anti-neoplastic properties. Genistein is considered a phytoestrogen. As such, genistein can bind estrogen receptors (ERα and ERβ), although with a lower affinity than that of estradiol. Despite considerable work, the effects of genistein are not well established yet. This review aims to clarify the role of genistein on female and male reproductive functions in mammals. In females, at a high dose, genistein diminishes the ovarian activity regulating several pathway molecules, such as topoisomerase isoform I and II, protein tyrosine kinases (v-src, Mek-4, ABL, PKC, Syk, EGFR, FGFR), ABC, CFTR, Glut1, Glut4, 5α-reductase, PPAR-γ, mitogen-activated protein kinase A, protein histidine kinase, and recently circulating RNA-miRNA. The effect of genistein on pregnancy is still controversial. In males, genistein exerts an estrogenic effect by inducing testosterone biosynthesis. The interaction of genistein with both natural and synthetic endocrine disruptors has a negative effect on testis function. The positive effect of genistein on sperm quality is still in debate. In conclusion, genistein has a potentially beneficial effect on the mechanisms regulating the reproduction of females and males. However, this is dependent on the dose, the species, the route, and the time of administration.

This review emphasizes the important role of cross-talk between P53 and microRNAs in physiological stress signaling. P53 responds to stress in a variety of ways ranging from activating survival-promotion pathways to triggering programmed cell death to eliminate damaged cells. In physiological stress generated by any external or internal condition that challenges cell homeostasis, P53 exerts its function as a transcription factor for target genes or by regulating the expression and maturation of a class of small non-coding RNA molecules (miRNAs). The miRNAs control the level of P53 through direct control of P53 or through indirect control of P53 by targeting its regulators (such as MDMs). In turn, P53 controls the expression level of miRNAs targeted by P53 through the regulation of their transcription or biogenesis. This elaborate regulatory scheme emphasizes the relevance of miRNAs in the P53 network and vice versa.

Myxomatous mitral valve disease (MMVD) is the most common acquired cardiac disoder in dogs and a relevant model for human mitral valve disease. However, the molecular drivers of disease progression remain unclear, and reliable biomarkers for early diagnosis still hamper clinical management. This study investigated microRNA (miRNA) expression directly in histologically characterized mitral valve tissues. Formalin-fixed paraffin-embedded samples were obtained from control dogs (n = 7), low-grade MMVD (n = 8), and high-grade MMVD (n = 5). A bioinformatics workflow identified candidate miRNAs converging on extracellular matrix remodeling and canonical signaling pathways, including TGF-β, PI3K–Akt, and MAPK. Selected candidates, let-7 family, miR-98, miR-21, miR-30b, miR-133b, and miR-103, were validated by qPCR. Results revealed a general upregulation of the panel in MMVD compared with controls, with stage-dependent differences between low- and high-grade lesions. In particular, miR-21, let-7b, and miR-133b were markedly increased in advanced disease, while miR-30b emerged as an early-stage marker with potential prognostic value. These findings provide molecular evidence linking miRNA dysregulation to progressive valvular degeneration. By combining histologically defined tissue analysis with stage-based comparisons, this study identifies miRNAs with potential diagnostic and prognostic utility for canine MMVD.

Grape pomace (GP), a by-product of winemaking, is rich in polyphenols and fiber, making it a promising and sustainable feed supplement for ruminants. This study evaluated the safety and productive impact of a 5% GP-supplemented diet (GP5) including non-lactating end-cycle (EC) ewes regularly destined for slaughter and human consumption, and lactating (LAC) ewes, over a 30-day period. Control (CTRL) animals received a standard pellet diet with no GP inclusion. Sampling was performed at four time points (T0, T10, T20, and T30), corresponding to days 0, 10, 20, and 30 of the experimental period. The study assessed clinical status, hematology/biochemistry (T0 and T30), milk composition (T0, T10, T20, and T30), meat quality traits and oxidative stability in EC ewes (T30). Since no significant differences were observed in the CTRL animals, the effects were evaluated within the GP5 group by comparing T0 vs. T30. Meat quality was assessed by comparing EC-GP5 to CTRL at T30. The GP extract showed a high total phenolic content (254.02 ± 20.39 mg GAE/g DW). No clinical or hematological alterations were observed, and most values remained within physiological ranges. Biochemical analysis revealed significant increases in albumin, bilirubin, creatinine, and triglycerides (p < 0.05), with significant decreases in plasma urea and glucose (p < 0.05). In LAC-GP5 ewes, milk urea and lactose concentrations decreased (p < 0.05), while pH increased (p < 0.05), with no significant changes in fat or casein content. These findings are consistent with reduced ruminal propionate availability, leading to decreased hepatic gluconeogenesis and lactose synthesis, with secondary effects on nitrogen metabolism and the acid–base profile of milk. In EC-GP5 ewes, meat quality traits were unaffected, and DPPH scavenging activity did not differ from CTRL (p > 0.05). GP5 was metabolically safe, induced adaptive changes in milk composition, and had no negative effects on meat quality, supporting the valorization of grape pomace as a sustainable feed resource. This trial was designed as a metabolic safety assessment, representing a preliminary step toward future mechanistic and molecular investigations.

Osteosarcoma (OS) and extraskeletal osteosarcoma (EOS) in dogs exhibit histological similarities but differ in anatomical origin, which poses a challenge to diagnostic accuracy. We adopted a marker-first strategy to enhance molecular classification by selecting RUNX2, KPNA2, and SATB2, three validated immunohistochemical (IHC) markers, as primary targets. Bioinformatic screening identified the miR-30 family as the only miRNA group predicted to coordinately regulate RUNX2, KPNA2, and SATB2, justifying its prioritization for expression analysis. RT-qPCR on FFPE tissues from 14 OS, 19 EOS, and 10 healthy controls revealed that miR-30a was significantly downregulated in OS and inversely correlated with RUNX2 nuclear expression, confirmed by IHC. MiR-30e also showed high diagnostic accuracy, while miR-30b and miR-30c distinguished EOS from OS. Non-seed interaction modeling (i.e., outside the canonical “seed” region, spanning nucleotides 2–8 of the miRNA) suggested divergent regulatory affinities within the PI3K/AKT/RUNX2 axis among miR-30 family members. MiR-30a and miR-30e exhibited the highest diagnostic power (LR+ 7.7 and 6.8, respectively), supporting their role as biomarkers. These results highlight a miR–30–centered regulatory axis with relevance for diagnosis and molecular stratification of canine osteogenic tumors.

Cell-free miRNAs, called circulating miRNAs (cmiRNAs), can act in a paracrine manner by facilitating a diversity of signaling mechanisms between cells. Real-time qPCR is the most accepted method for quantifying miRNA expression levels. The use of stable miRNA endogenous control (EC) for qPCR data normalization allows an accurate cross-sample gene expression comparison. The appropriate selection of EC is a crucial step because qPCR data can change drastically when normalization is performed using an unstable versus a stable EC. To find EC cmiRNA with stable expression in search and rescue (SAR) working dogs, we explored the serum miRNome by Next-Generation Sequencing (NGS) at T0 (resting state) and T1 immediately after SAR performance (state of physiologically recovered stress). The cmiRNAs selected in the NGS circulating miRNome as probable ECs were validated by qPCR, and miRNA stability was evaluated using the Delta Ct, BestKeeper, NormFinder, and GeNorm algorithms. Finally, RefFinder was used to rank the stability orders at both T0 and T1 by establishing miR-320 and miR-191 as the best-circulating ECs. We are confident that this study not only provides a helpful result in itself but also an experimental design for selecting the best endogenous controls to normalize gene expression for genes beyond circulating miRNAs.

Resilience is conceived as a dynamic developmental process involving the achievement of positive adaptation within the context of significant adversity. Resilience is not a unique ability but rather a set of capacities of a system put in place to absorb a disturbance and to reorganize while trying to retain the same function, structure, and identity. This review describes the characteristics and the molecular mechanisms of resilience to understand the core elements of resilience and its indicators. The objectives of this review are: (1) to define some of the leading environmental stressors and clarify the mechanism of vulnerability or resilience outcomes; (2) to clarify some of the prominent epigenetic modulations mediating resilience or vulnerability as a stress response; (3) to highlight the neural mechanisms related to stress resilience since the central nervous system is a highly dynamic structure characterized by an everlasting plasticity feature, which therefore has the opportunity to modify resilience. The review aims to introduce the reader to the concept of resilience seen as an ability acquired in life and not only inherited from birth.

The aging process is a multifactorial biological phenomenon starting at birth and persisting throughout life, characterized by a decline in physiological functions and adaptability. This decline results in the diminished capacity of aging organisms to respond to environmental changes and stressors, leading to reduced efficiency in metabolic, immune, and hormonal functions. As behavioral flexibility wanes, older individuals face longer recovery times and increased vulnerability to diseases. While early research proposed nine core hallmarks of mammalian aging, recent studies have expanded this framework to twelve key characteristics: epigenetic changes, genomic instability, telomere shortening, loss of proteostasis, altered metabolism, mitochondrial dysfunction, cellular senescence, disrupted intercellular communication, stem cell depletion, immune system dysfunction, accumulation of toxic metabolites, and dysbiosis. Given the growing interest in the aging area, we propose to add a new hallmark: impaired water homeostasis. This potential hallmark could play a critical role in aging processes and might open new directions for future research in the field. This review enhances our understanding of the physiological aspects of aging in dogs, suggesting new clinical intervention strategies to prevent and control issues that may arise from the pathological degeneration of these hallmarks.