• University of Bari (Bari) PhD student in Functional and Applied Genomics and Proteomics- curriculum Physiology. (2021-present)
• University of Bari (Bari) Master’s Degree / Laurea Magistrale in Cellular and Molecular Biology (2016-2019)
• University of Bari (Bari) Bachelor Degree / Laurea Triennale in Biological Science (2011-2015)
11
Scopus Publications
Scopus Publications
Effect of 4-Week Consumption of “Navelina” Oranges on Serum Lipid Profile in Patients with MASLD: Evidence from a Randomized Clinical Trial Valentina De Nunzio, Giuliano Pinto, Davide Guido, Emanuela Aloisio Caruso, Miriam Cofano, et al. Nutrients, 2026 Background: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) refers to fatty liver disease associated with metabolic syndrome. MASLD causes alterations in lipid metabolism, which can be regulated with a diet rich in polyphenols. The present study aims to evaluate the effects of daily consumption of 400 g of “Navelina” oranges for 4 weeks on serum lipid profiles in a group of 60 patients with MASLD, to identify specific lipid species associated with improvements in hepatic steatosis. Methods: Blood samples were collected from all participants, and biochemical measurements and a serum lipidomic profile were performed. Finally, a Spearman correlation analysis was used to assess the relationships between serum lipidomic fatty acids and biochemical lipid markers. Results: In the experimental treatment arm, serum lipidomic analysis showed a slight decrease in Arachidonic acid (AA) and the Arachidonic acid/Eicosapentaenoic acid ratio (AA/EPA ratio) but no significant interaction between time and treatment was detected. In the same group, Oleic acid, MUFAs and the AA/EPA ratio were significantly and negatively correlated with HDL (r = −0.368, p = 0.046), (r = −0.384, p = 0.036), and (r = −0.522, p = 0.003), respectively. Conversely, EPA and n-3 PUFAs were positively and significantly correlated with HDL (r = 0.447, p = 0.013) and (r = 0.403, p = 0.027) respectively. Conclusions: Furthermore, this study represents one of the first clinical trials to shed a light on the potential association of “Navelina” orange polyphenols on serum fatty acid profiles in patients with MASLD, supporting studies on the nutraceutical effect of oranges on lipid metabolism.
Anti-Fibrotic and Anti-Inflammatory Effects of Hesperidin in an Ex Vivo Mouse Model of Early-Onset Liver Fibrosis Ilenia Saponara, Miriam Cofano, Valentina De Nunzio, Giusy Bianco, Raffaele Armentano, et al. International Journal of Molecular Sciences, 2026 Liver fibrosis is characterized by an excessive accumulation of extracellular matrix (ECM) proteins as a wound-healing response to chronic liver injury, leading to tissue scarring and organ dysfunction. Natural compounds, including phytonutrients and polyphenols, have been shown to exert protective effects by reducing profibrotic biomarkers in vitro and in vivo models. Here, we provide the first evidence that the polyphenol hesperidin (HE) can counteract the onset of fibrotic responses in an ex vivo mouse liver fibrosis model induced by Transforming Growth Factor-β1 (TGF-β1) (5 ng/mL). Notably, HE drives early ECM remodeling in the fibrotic mouse liver tissue. Fibrosis-related parameters were assessed at both the transcriptional and translational levels after treatment with HE at increasing concentrations of 50, 75, and 100 µg/mL. Interestingly, HE at 75 µg/mL exerted the strongest beneficial effect, significantly decreasing the gene expression of α-SMA, SERPINH-1, FN-1, VIM and COL1A1 and counteracting the TGF-β1-induced upregulation of key fibrotic markers, including α-SMA, COL1A2, and VIM, reflecting its capacity to attenuate myofibroblast activation and ECM production and modulating membrane lipid peroxidation. Furthermore, HE inhibited SMAD2 phosphorylation, suggesting that its antifibrotic activity may involve the modulation of the TGF-β/SMAD signaling pathway. Moreover, it promoted an anti-inflammatory response, due to a decrease in IL-1β and IL-6 expression. Our study highlights the potential of the ex vivo model as a platform for evaluating the antifibrotic efficacy of natural molecules, and it suggests significant translational implications and new opportunities for developing innovative therapeutic strategies.
Hesperidin Is a Promising Nutraceutical Compound in Counteracting the Progression of NAFLD In Vitro Miriam Cofano, Ilenia Saponara, Valentina De Nunzio, Giuliano Pinto, Emanuela Aloisio Caruso, et al. International Journal of Molecular Sciences, 2025 Non-alcoholic fatty liver disease (NAFLD) is characterized by an accumulation of fat in hepatocytes, and it may progress, under additional triggering factors, to non-alcoholic steatohepatitis (NASH). Effective strategies to counteract this progression are essential, especially considering that at the moment, there is a lack of approved pharmacological therapies. Our previous study showed that the daily consumption of Navelina oranges significantly reduced hepatic steatosis in patients with Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD). Starting with our previous study, here, we have investigated the molecular targets through which Hesperidin (HE), a citrus flavanone, is able to prevent the progression of NAFLD to NASH using an in vitro model. In Hepa-RG cells exposed to NAFLD Promoting Agents, HE reduced lipid droplet accumulation (~35%) and suppressed de novo lipogenesis, with decreased expression of FASN (0.62 ± 0.06 vs. 0.39 ± 0.03 at 100 µg/mL) and SCD1 (0.05 ± 0.001 vs. 0.03 ± 0.004 at 50 µg/mL). HE also enhanced fatty acid oxidation by increasing SIRT1 (0.73 ± 0.16 vs. 2.36 ± 0.10 at 50 µg/mL) and PGC1α (0.71 ± 0.03 vs. 0.89 ± 0.003 at 50 µg/mL). In LX-2 cells, HE downregulated COL1A1 (1.48 ± 0.10 vs. 0.90 ± 0.11 at 100 µg/mL) and α-SMA (1.21 ± 0.16 vs. 0.76 ± 0.07 at 75 µg/mL) and upregulated MMP3 (0.64 ± 0.05 vs. 0.98 ± 0.07) and MMP9 (0.99 ± 0.005 vs. 2.61 ± 0.16 at 100 µg/mL). In conclusion, HE may offer a promising approach for NAFLD/NASH prevention and treatment, demonstrating in vitro its potential to reduce hepatic steatosis and fibrosis.
The Antiaging Potential of Dietary Plant-Based Polyphenols: A Review on Their Role in Cellular Senescence Modulation Matteo Centonze, Emanuela Aloisio Caruso, Valentina De Nunzio, Miriam Cofano, Ilenia Saponara, et al. Nutrients, 2025 Aging is a complex biological process characterized by a progressive decline in physiological functions and an increased risk of chronic diseases. A key mechanism of this process is cellular senescence, the permanent arrest of the cell cycle in response to stress or damage, which contributes to the accumulation of dysfunctional cells in tissues. Recent research has highlighted the role of polyphenols, bioactive compounds present in numerous plant-based foods, in positively modulating these processes. Polyphenols exert antioxidant effects, regulate gene expression and improve mitochondrial function, helping to delay cellular aging and prevent age-related diseases. In addition, some polyphenols exhibit senolytic properties, selectively eliminating senescent cells and promoting tissue regeneration. This review summarizes the current evidence on the effects of polyphenols on aging and cellular senescence, exploring the underlying molecular mechanisms and discussing their potential in nutritional strategies aimed at promoting healthy aging.
Delta-9 desaturase reduction in gastrointestinal cells induced to senescence by doxorubicin Valentina De Nunzio, Emanuela Aloisio Caruso, Matteo Centonze, Giuliano Pinto, Miriam Cofano, et al. FEBS Open Bio, 2025 The condition of cellular senescence has specific features, including an altered lipid metabolism. Delta‐9 desaturase (Δ9) catalyzes the conversion of saturated fatty acids, such as palmitic acid and stearic acid, into their monounsaturated forms, palmitoleic and oleic acid, respectively. Δ9 activity is important for most lipid functions, such as membrane fluidity, lipoprotein metabolism and energy storage. The present study aimed to investigate differences in the expression of Δ9 in senescence‐induced pancreatic (MIA‐PaCa‐2 and PANC‐1) and hepatic (Hepa‐RG and HLF) cancer cell lines. Cellular senescence was induced by growing cells in the presence of the chemotherapic drug doxorubicin. Senescence status was determined by the senescence‐associated beta‐galactosidase activity assay kit combined with the p21 and senescence associated secretory phenotype protein assay. Δ9 was downregulated in all senescence‐induced cell lines compared to control cells, in both the lipidomic analysis and when measuring protein levels via western blotting. Hence, our findings demonstrate that the study of membrane lipid composition and the expression levels of Δ9 could potentially form the basis for future applications investigating the state of cellular senescence.
The β3-AR agonist BRL37344 ameliorates the main symptoms of X-linked nephrogenic diabetes insipidus in the mouse model of the disease Serena Milano, Ilenia Saponara, Andrea Gerbino, Monica Carmosino, Maria Svelto, et al. Journal of Cellular and Molecular Medicine, 2024 X‐linked nephrogenic diabetes insipidus (X‐NDI) is a rare congenital disease caused by inactivating mutations of the vasopressin type‐2 receptor (AVPR2), characterized by impaired renal concentrating ability, dramatic polyuria, polydipsia and risk of dehydration. The disease, which still lacks a cure, could benefit from the pharmacologic stimulation of other GPCRs, activating the cAMP‐intracellular pathway in the kidney cells expressing the AVPR2. On the basis of our previous studies, we here hypothesized that the β3‐adrenergic receptor could be such an ideal candidate. We evaluated the effect of continuous 24 h stimulation of the β3‐AR with the agonist BRL37344 and assessed the effects on urine output, urine osmolarity, water intake and the abundance and activation of the key renal water and electrolyte transporters, in the mouse model of X‐NDI. Here we demonstrate that the β3‐AR agonism exhibits a potent antidiuretic effect. The strong improvement in symptoms of X‐NDI produced by a single i.p. injection of BRL37344 (1 mg/kg) was limited to 3 h but repeated administrations in the 24 h, mimicking the effect of a slow‐release preparation, promoted a sustained antidiuretic effect, reducing the 24 h urine output by 27%, increasing urine osmolarity by 25% and reducing the water intake by 20%. At the molecular level, we show that BRL37344 acted by increasing the phosphorylation of NKCC2, NCC and AQP2 in the renal cell membrane, thereby increasing electrolytes and water reabsorption in the kidney tubule of X‐NDI mice. Taken together, these data suggest that human β3‐AR agonists might represent an effective possible treatment strategy for X‐NDI.
β3-Adrenoceptor as a new player in the sympathetic regulation of the renal acid–base homeostasis Serena Milano, Ilenia Saponara, Andrea Gerbino, Dominga Lapi, Ludovica Lela, et al. Frontiers in Physiology, 2024 Efferent sympathetic nerve fibers regulate several renal functions activating norepinephrine receptors on tubular epithelial cells. Of the beta-adrenoceptors (β-ARs), we previously demonstrated the renal expression of β3-AR in the thick ascending limb (TAL), the distal convoluted tubule (DCT), and the collecting duct (CD), where it participates in salt and water reabsorption. Here, for the first time, we reported β3-AR expression in the CD intercalated cells (ICCs), where it regulates acid–base homeostasis. Co-localization of β3-AR with either proton pump H+-ATPase or Cl−/HCO3− exchanger pendrin revealed β3-AR expression in type A, type B, non-A, and non-B ICCs in the mouse kidney. We aimed to unveil the possible regulatory role of β3-AR in renal acid–base homeostasis, in particular in modulating the expression, subcellular localization, and activity of the renal H+-ATPase, a key player in this process. The abundance of H+-ATPase was significantly decreased in the kidneys of β3-AR−/− compared with those of β3-AR+/+ mice. In particular, H+-ATPase reduction was observed not only in the CD but also in the TAL and DCT, which contribute to acid–base transport in the kidney. Interestingly, we found that in in vivo, the absence of β3-AR reduced the kidneys’ ability to excrete excess proton in the urine during an acid challenge. Using ex vivo stimulation of mouse kidney slices, we proved that the β3-AR activation promoted H+-ATPase apical expression in the epithelial cells of β3-AR-expressing nephron segments, and this was prevented by β3-AR antagonism or PKA inhibition. Moreover, we assessed the effect of β3-AR stimulation on H+-ATPase activity by measuring the intracellular pH recovery after an acid load in β3-AR-expressing mouse renal cells. Importantly, β3-AR agonism induced a 2.5-fold increase in H+-ATPase activity, and this effect was effectively prevented by β3-AR antagonism or by inhibiting either H+-ATPase or PKA. Of note, in urine samples from patients treated with a β3-AR agonist, we found that β3-AR stimulation increased the urinary excretion of H+-ATPase, likely indicating its apical accumulation in tubular cells. These findings demonstrate that β3-AR activity positively regulates the expression, plasma membrane localization, and activity of H+-ATPase, elucidating a novel physiological role of β3-AR in the sympathetic control of renal acid–base homeostasis.
β3 Adrenergic Receptor Agonist Mirabegron Increases AQP2 and NKCC2 Urinary Excretion in OAB Patients: A Pleiotropic Effect of Interest for Patients with X-Linked Nephrogenic Diabetes Insipidus Serena Milano, Fatima Maqoud, Monica Rutigliano, Ilenia Saponara, Monica Carmosino, et al. International Journal of Molecular Sciences, 2023 We previously reported the novel finding that β3-AR is functionally expressed in the renal tubule and shares its cellular localization with the vasopressin receptor AVPR2, whose physiological stimulation triggers antidiuresis by increasing the plasma membrane expression of the water channel AQP2 and the NKCC2 symporter in renal cells. We also showed that pharmacologic stimulation of β3-AR is capable of triggering antidiuresis and correcting polyuria, in the knockout mice for the AVPR2 receptor, the animal model of human X-linked nephrogenic diabetes insipidus (XNDI), a rare genetic disease still missing a cure. Here, to demonstrate that the same response can be evoked in humans, we evaluated the effect of treatment with the β3-AR agonist mirabegron on AQP2 and NKCC2 trafficking, by evaluating their urinary excretion in a cohort of patients with overactive bladder syndrome, for the treatment of which the drug is already approved. Compared to baseline, treatment with mirabegron significantly increased AQP2 and NKCC2 excretion for the 12 weeks of treatment. This data is a step forward in corroborating the hypothesis that in patients with XNDI, treatment with mirabegron could bypass the inactivation of AVPR2, trigger antidiuresis and correct the dramatic polyuria which is the main hallmark of this disease.
TRPML1-Induced Lysosomal Ca2+ Signals Activate AQP2 Translocation and Water Flux in Renal Collecting Duct Cells Simona Ida Scorza, Serena Milano, Ilenia Saponara, Maira Certini, Roberta De Zio, et al. International Journal of Molecular Sciences, 2023 Lysosomes are acidic Ca2+ storage organelles that actively generate local Ca2+ signaling events to regulate a plethora of cell functions. Here, we characterized lysosomal Ca2+ signals in mouse renal collecting duct (CD) cells and we assessed their putative role in aquaporin 2 (AQP2)-dependent water reabsorption. Bafilomycin A1 and ML-SA1 triggered similar Ca2+ oscillations, in the absence of extracellular Ca2+, by alkalizing the acidic lysosomal pH or activating the lysosomal cation channel mucolipin 1 (TRPML1), respectively. TRPML1-dependent Ca2+ signals were blocked either pharmacologically or by lysosomes’ osmotic permeabilization, thus indicating these organelles as primary sources of Ca2+ release. Lysosome-induced Ca2+ oscillations were sustained by endoplasmic reticulum (ER) Ca2+ content, while bafilomycin A1 and ML-SA1 did not directly interfere with ER Ca2+ homeostasis per se. TRPML1 activation strongly increased AQP2 apical expression and depolymerized the actin cytoskeleton, thereby boosting water flux in response to an hypoosmotic stimulus. These effects were strictly dependent on the activation of the Ca2+/calcineurin pathway. Conversely, bafilomycin A1 led to perinuclear accumulation of AQP2 vesicles without affecting water permeability. Overall, lysosomal Ca2+ signaling events can be differently decoded to modulate Ca2+-dependent cellular functions related to the dock/fusion of AQP2-transporting vesicles in principal cells of the CD.
