Pharmaceutical and biomedical analysis, drug discovery, herbal drugs
291
Scopus Publications
Scopus Publications
Powder bergamot juice attenuates skeletal muscle complications in an experimental model of metabolic syndrome Luís Eduardo Sormani, Jordanna Cruzeiro, Matheus Antônio Filiol Belin, Marina de Paula Salomé dos Santos, Juliana Silva Siqueira, Taynara Aparecida Vieira, Núbia Alves Grandini, Murilo Dalarme Tanganini, Thiago Luiz Novaga Palacio, Guilherme Ribeiro Romualdo, Giancarlo Aldini, Camila Renata Corrêa Molecular and Cellular Endocrinology, 2026 Metabolic syndrome (MetS) promotes skeletal muscle complications, which can impair glucose uptake and contribute to the development of diabetes. In contrast, powder bergamot juice (PBJ) possesses bioactive compounds with potential therapeutic applications. To evaluate the effects of PBJ on skeletal muscle complications in an experimental model of metabolic syndrome. Male Wistar rats were fed a control diet (n=20) or a high-sugar fat diet (n=20) with 25% sucrose in drinking water (w/v) for 20 weeks to induce MetS. After this period, animals were then redistributed into two groups (n=7 each): MetS and MetS + PBJ. PBJ was administered by gavage at 250 mg/kg daily for 10 weeks. Systemic metabolic parameters were measured, and lipid content, fatty acid profile, inflammatory and oxidative stress biomarkers, insulin signaling proteins, and histological outcomes were evaluated in the quadriceps. PBJ treatment significantly attenuated systemic adiposity and dyslipidemia. In the quadriceps, PBJ markedly reduced triglyceride accumulation and modulated the fatty acid composition, lowering saturated fatty acid (SFA) levels and increasing the desaturation index. Oxidative stress markers, including malondialdehyde, advanced oxidation protein products, and protein carbonylation, were reduced, while antioxidant defenses were enhanced by upregulating nuclear factor erythroid 2-related factor 2 (NRF-2) signaling. Pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), were significantly decreased and interstitial collagen deposition was also attenuated. Crucially, PBJ modulated the endocrine response and increased total protein expression of glucose transporter type 4 (GLUT-4) without altering IRS-1 phosphorylation. PBJ attenuated skeletal muscle complications resulting from MetS. However, due to the absence of a healthy control group, these findings demonstrate an improvement relative to the diseased condition, but cannot confirm a return to a normal physiological baseline. • PBJ reduces intramuscular triglyceride accumulation and promotes qualitative lipid remodeling by increasing the desaturation index (C16:1/C16:0). • The modulation of the fatty acid profile suggests enhanced sarcolemmal membrane fluidity, facilitating glucose transporter dynamics. • Activation of the NRF-2 pathway by PBJ mitigates oxidative stress and suppresses pro-inflammatory cytokines (TNF-α and IL-6) in skeletal muscle. • PBJ attenuates skeletal muscle fibrosis by reducing interstitial collagen deposition, preserving the tissue's structural integrity and metabolic flexibility. • PBJ modulates the endocrine response and upregulates total muscle GLUT-4 expression through an IRS-1-independent pathway.
Modulation of Ferroptosis Biomarkers by Thinned Apple Polyphenols Extract in Acute and Chronic Lung Injuries Rosalba Siracusa, Alessia Arangia, Marika Cordaro, Roberta Fusco, Salvatore Cuzzocrea, Giancarlo Aldini, Daniela Impellizzeri, Rosanna Di Paola, Ramona D'Amico Efood, 2026 Acute and chronic lung injuries are characterized by a large amount of ROS, pro‐inflammatory leukocytes and ferroptosis, resulting in alveolar injury. Nowadays, there is great interest in the bioactive compounds obtained from the waste products deriving from agriculture and the food industry. Thinned young apples are particularly rich in polyphenols, more than 10‐fold with respect to harvested apples, and have antioxidant and anti‐inflammatory activities. Therefore, the aim of this study is to investigate whether modulation of ferroptosis biomarkers by thinned apple polyphenols (TAP) extract was able to reduce lung injuries in two experimental model: acute lung injury (ALI) and bleomycin‐induced idiopathic pulmonary fibrosis (IPF). Our results demonstrated that TAP extract was able to inhibit the ferroptosis, modulating the main biomarkers: malondialdehyde, NADPH oxidase‐4, glutathione peroxidase 4 and ferritin heavy chain 1. This modulation is probably due to Nrf2 activation, negative regulator of ferroptosis, by TAP extract and consequently activating the production of antioxidant enzymes. This induced histological alteration, cytokines release and fibrosis in the alveoli and lung parenchyma. Collectively, these results demonstrated that TAP extract was able to reduce ferroptosis in acute and chronic lung injury models, suggesting it as a potential biomarker for early diagnosis and intervention timely.
The Effect of Carnosine Supplementation on Depressive Symptoms and Health-Related Quality of Life in Individuals With Prediabetes and Well-Controlled Type 2 Diabetes: A Randomized Controlled Trial Robel Hussen Kabthymer, Jack Feehan, Aya Mousa, Giancarlo Aldini, Maximilian de Courten, James Cameron, Barbora de Courten Food Science and Nutrition, 2026 Type 2 diabetes mellitus (T2DM) is commonly associated with mental health disorders such as depression and anxiety. Carnosine, an over‐the‐counter food supplement, may improve depressive symptoms through its anti‐inflammatory properties; however, its effects on depressive symptoms and quality of life in prediabetes or T2DM remain unexplored. This randomized controlled trial aimed to examine whether carnosine supplementation may improve depressive symptoms and quality of life among individuals with prediabetes and well‐controlled T2DM. A total of 38 participants (73.6% male) with a median (IQR) age of 54.8 years (46.2, 59.4) and mean ± SD body mass index (BMI) of 29.0 ± 4.2 kg/m 2 were randomized to carnosine ( n = 18) or placebo ( n = 20) for 14 weeks. None of the patients were diagnosed with depression or anxiety or any other chronic disease other than prediabetes ( n = 20, 52.6%) and T2DM ( n = 18, 47.4%), the latter being well‐controlled with diet or metformin only. Depressive symptoms were measured using the patient health questionnaire (PHQ‐8) and health‐related quality of life was measured with five‐dimension EuroQoL three level (EQ‐5D‐3L) scale. Paired t ‐tests were employed for within‐group comparisons. Analysis of covariance (ANCOVA) was used for between group comparisons adjusted for age, BMI, and baseline values. Carnosine supplementation resulted in improvement of depressive symptoms assessed by total PHQ‐8 score (mean difference = −2.0; 95% CI: −3.9, −0.2; p = 0.03), compared with placebo. However, the eight subcomponents of the PHQ‐8 scale did not show significant changes ( p > 0.05). There were no significant changes both in between‐group and within‐group comparisons in health‐related quality of life scores ( p > 0.05). We demonstrated for the first time that carnosine supplementation resulted in a modest improvement in depressive symptoms in individuals with prediabetes or T2DM. Further studies are needed to corroborate these findings in larger cohorts with more diverse baseline risk profiles. Trial Registration: NCT02917928
The Carnosine–HNE Michael Adduct as a Redox-Active Species Associated with Nrf2-Dependent Antioxidant and Anti-Inflammatory Responses Alessandra Altomare, Giovanna Baron, Francesca Gado, Larissa Della Vedova, Giulio Ferrario, Lara Davani, Ettore Gilardoni, Rebecca Ferrisi, Clara Mocchetti, Lavpreet Singh, Barbora De Courten, Marina Carini, Rosalba Siracusa, Ramona D’Amico, Rosanna Di Paola, Clelia Dallanoce, Daniela Impellizzeri, Giancarlo Aldini Antioxidants, 2026 Carnosine (CAR), an endogenous histidine-containing dipeptide, exhibits antioxidant and anti-inflammatory activity in various experimental models; however, its molecular mechanism of action remains poorly understood. Here, we demonstrate that the Michael adduct between CAR and 4-hydroxy-2-nonenal (HNE), which has been detected in previous studies in both in vitro and in vivo settings, mediates its bioactivity, particularly its antioxidant and anti-inflammatory responses, through Nrf2 activation. The CAR–HNE adduct was synthesized and its physicochemical, metabolic, and biological properties were evaluated. CAR–HNE exhibited high stability in biological matrices and retained the ability to transfer HNE to thiol nucleophiles at a slow rate under physiologically relevant conditions, consistent with electrophile-mediated Nrf2 activation. This kinetic behavior limits the cytotoxicity typically associated with free HNE while preserving the redox signaling capacity. CAR–HNE induced dose-dependent Nrf2 activation and NF-κB inhibition in cell-based assays without the hormetic toxicity observed for free HNE. Mechanistically, CAR–HNE may act as a redox-tunable electrophilic reservoir, restoring nucleophilic tone and modulating redox-sensitive transcription factors. In vivo, CAR–HNE attenuated DSS-induced colitis more effectively than equimolar doses of either carnosine or HNE alone. Proteomic analyses revealed modulation of canonical Nrf2-dependent antioxidant pathways. Our findings suggest a conceptual shift in carnosine biology: rather than acting as a classical antioxidant or carbonyl quencher, carnosine functions as a precursor of redox-active electrophilic adducts that transduce anti-inflammatory and antioxidant responses via controlled RCS signaling.
Development of an Accurate Double Isotopic Standard LC–MS/MS Method for Hyaluronic Acid Quantification in Biological Matrices Simone Manzi, Alessandra Altomare, Giacomo Mosconi, Maria Serena Rossitto, Luciano Messina, Anna Gallo, Marina Carini, Giancarlo Aldini, Giovanna Baron Analytical Chemistry, 2026 Hyaluronic acid (HA) plays key roles in tissue hydration, repair, and cellular signaling. Its quantification in biological matrices is crucial but challenging due to its endogenous nature and poor mass spectrometric detectability. We developed a robust method based on enzymatic hydrolysis, dual 13C-labeled internal standards, and the standard addition method combined with LC–MS/MS analysis. Samples from bovine vitreous humor and human synovial fluid were depolymerized with recombinant hyaluronidase to generate Δ4-mer oligomers, quantified using 100%- and 50%-13C-labeled HA as internal standards to correct the variabilities of the enzymatic digestion and MS detector. The standard addition method was used to control the matrix effects. The method showed excellent linearity (r2 > 0.99), low estimated LOD (0.147 ± 0.007 μg/mL for bovine vitreous humor and 0.143 ± 0.028 μg/mL for human synovial fluid) and LOQ (0.491 ± 0.022 μg/mL for bovine vitreous humor and 0.475 ± 0.093 μg/mL for human synovial fluid) values, high recovery (>90%), and suitable accuracy. Significant matrix effects were detected, reinforcing the need for the standard addition method. HA concentrations measured were consistent with physiological ranges. This validated strategy offers a reliable tool for HA quantification in complex biological samples, supporting both clinical and pharmaceutical applications.
Cistus x incanus L. extract as a complex polyphenolic blend with retained anti-adhesive and anti-inflammatory properties in a model of E. coli-induced UTI following simulated digestion Giulia Martinelli, Nicole Maranta, Giovanna Nicotra, Silvia Francesca Vicentini, Beatrice Bruno, Giovanna Baron, Chiara Di Lorenzo, Safwa Moheb El Haddad, Marco Fumagalli, Carola Pozzoli, Enrico Sangiovanni, Giancarlo Aldini, Mario Dell’Agli, Stefano Piazza Journal of Ethnopharmacology, 2026 ETHNOPHARMACOLOGICAL RELEVANCE: Cistus x incanus L. is a Mediterranean plant traditionally used to treat infective conditions, including urinary tract infections (UTI). However, experimental validation against uropathogenic Escherichia coli (UPEC) is limited. AIM OF THE STUDY: To investigate the antibacterial and anti-inflammatory effects of a hydroalcoholic extract of aerial parts (CE) in an E. coli-induced UTI model, evaluating stability and efficacy after intestinal digestion. MATERIALS AND METHODS: T24 bladder epithelial cells were infected with UPEC CFT073 and treated with CE before and after simulated intestinal digestion (CEd). IL-6 release, bacterial growth, and adhesion were evaluated. Polyphenol content and stability were analyzed using colorimetric assays and LC-MS/MS. A methanol-insoluble fraction (IF) of CE was also tested. RESULTS: for IL-6: 19.05 μg/mL during infection; 1.69 μg/mL with TNF-α). Flavonols remained relatively stable post-digestion, while catechins and procyanidins decreased. IF, rich in glycosidic flavonols and tannins, preserved its anti-inflammatory and antibacterial activity before and after digestion. CONCLUSIONS: These findings support, for the first time, the traditional use of Cistus x incanus in UTI, highlighting its ethnopharmacological relevance in the treatment of urinary infections. The mechanism of action, which includes anti-inflammatory and anti-adhesive activities of the extracts, has been investigated. The efficacy was observed at micromolar concentrations, which are supposed to be reached in vivo consuming Cistus x incanus food supplements. These findings lay groundwork for preclinical UTI models. Moreover, the outcomes in the present study warrant clinical investigations to consolidate our findings.
Proteomics-Driven Mechanistic Insights into the Anti-Inflammatory Potential of Thinned Apple Polyphenols in a DNBS-Induced Colitis Model in Mice Giulio Ferrario, Daniela Impellizzeri, Giovanna Baron, Ramona D’Amico, Giulio Fumagalli, Tommaso Gnasso, Ezio Bombardelli, Marina Carini, Rosanna di Paola, Giancarlo Aldini, Alessandra Altomare Journal of Proteome Research, 2026 Ulcerative colitis (UC) is a multifactorial inflammatory bowel disease (IBD) with increasing incidence worldwide. Current treatments, including NSAIDs and corticosteroids, provide partial symptom relief but are associated with significant side effects, highlighting the need for novel therapies with improved safety profiles. Given the role of oxidative stress and inflammation in driving tissue damage during colitis, natural compounds with antioxidant and anti-inflammatory properties represent promising therapeutic candidates. Thinned apples (TA), an agricultural byproduct, were identified as a valuable source of polyphenols (TAP) with demonstrated anti-inflammatory and antioxidant activities in a cell-based inflammation model. This study evaluates TAP's therapeutic potential in a DNBS-induced colitis mouse model using label-free quantitative proteomics. Proteomic analysis revealed modulation of key pathways affected by TAP treatment, including: (i) activation of antioxidant defense mechanisms; (ii) reversal of DNBS-induced alterations, specifically ferroptosis and heme-toxicity; (iii) suppression of immune responses; and (iv) attenuation of ulcerative features, with downregulation of proteins involved in coagulation, inflammation, and angiogenesis. Overall, TAP showed significant therapeutic effects by targeting oxidative stress and inflammation, supporting its use as a polyphenol-rich extract in health products for UC. Moreover, repurposing TA as a bioactive extract offers an innovative strategy for industrial applications in therapeutic development.
Gamma oryzanol modulates hepatic lipids expression and regulates integrated pathways in liver disease pathophysiology under a high sugar fat diet Juliana Silva Siqueira, Camila Renata Correa, Gilda Aiello, Thiago Luiz Novaga Palacio, Jordanna Cruzeiro, Estela Oliveira Lima, Hendrew Jesus Barbosa Campos de Souza, Fabiane Valentini Francisqueti-Ferron, Marina Carini, Giancarlo Aldini, Alfonsina D’Amato Scientific Reports, 2025 Diets high in simple carbohydrates and saturated fats increase the risk of liver diseases. Gamma oryzanol (ORY), a compound found in rice bran, shows promise in addressing metabolic liver diseases, though its impact on lipid pathways requires further exploration. This study evaluated the effects of ORY in rats submitted to a high sugar-fat (HSF) diet using a multiomics approach to unravel its impact on lipid metabolism and associated pathways. Male Wistar rats were fed a control (CTRL), HSF, or HSF + ORY (0.5% w/w) diet for 30 weeks. Hepatic lipid profiling was performed using high-resolution mass spectrometry. Proteins and lipids were integrated into molecular pathway analyses. miR-122 expression was assessed by qRT-PCR, while oxidative stress markers were measured via colorimetric assays. The HSF diet altered 233 lipids compared to CTRL, while ORY supplementation modulated 84 lipids relative to the HSF group, with 39 lipids showing opposing regulatory profiles. Integrating proteomic data revealed key pathways in MAFLD pathophysiology affected by ORY. Additionally, ORY regulated miR-122 expression linked to lipid metabolism and reduced oxidative stress, demonstrating its potential to mitigate HSF-induced liver damage. ORY modulates hepatic lipid profiles and influences integrated metabolic networks, suggesting a significant role in MAFLD prevention and treatment.
Ligand-induced conformations and dynamic allosteric motions of IDO1 affecting the recruitment of a protein signaling partner Alice Coletti, Elisa Bianconi, Sofia Rossini, Alessandra Altomare, Andrea Butticè, Daniele Mazzoletti, Giada Mondanelli, Andrea Carotti, Giancarlo Aldini, Riccardo Miggiano, Ciriana Orabona, Joshua Salafsky, Antonio Macchiarulo Communications Chemistry, 2025 Indoleamine 2,3-dioxygenase 1 (IDO1) is a moonlight protein endowed with catalytic and signaling functions. It plays a pivotal role in the immune breaking mechanism leading to immunosuppression in cancer microenvironment. Intense research efforts have been devoted to designing catalytic inhibitors for developing immunotherapies, yet neglecting the enzyme’s signaling function. A few IDO1 inhibitors have reached the clinical stage, including navoximod, epacadostat and linrodostat. Using second harmonic generation analysis (SHG) and molecular dynamics simulations, here we show that these clinical inhibitors can induce distinct allosteric motions in the enzyme that affect the stability of the transient signaling complex between IDO1 and Src tyrosine kinase. Next generation sequencing demonstrates that, despite sharing a similar ability to inhibit the enzyme’s catalytic function, all three catalytic inhibitors modulate the IDO1’s signaling function in different ways, regulating distinct transcriptomes in SKOV3 cells. Indoleamine 2,3-dioxygenase 1 (IDO1) is crucial in cancer-related immunosuppression, yet its signaling function remains underexplored in immunotherapy development. Here, the authors use second harmonic generation analysis and molecular dynamics simulations to reveal that clinical IDO1 inhibitors differentially modulate its signaling, impacting distinct transcriptomes.
Histidine-Containing Dipeptides in Obesity and Cardiometabolic Health: A Systematic Scoping Review Saeede Saadati, Robel Hussen Kabthymer, Giancarlo Aldini, Thilini R. Thrimawithana, Julie E. Stevens, Kathy Ngyuen, Arshad Majid, Simon M. Bell, Jack Feehan, Aya Mousa, Barbora de Courten Obesity Reviews, 2025 BackgroundHistidine‐containing dipeptides (HCDs) have been reported to have anti‐inflammatory and antidiabetic properties. Yet, no previous reviews have examined the impact of HCDs on Type 2 diabetes (T2D) risk factors (e.g., obesity) and progression (e.g., microvascular and macrovascular complications). In this scoping review, we aimed to thoroughly examine the evidence on the effects of HCDs, particularly carnosine, which is the most studied HCD, on T2D risk factors and complications and the underlying mechanisms of action.MethodsWe systematically searched Ovid‐Medline, Embase, CINAHL, Scopus, Web of Science, and Cochrane Library from inception to December 2023. We included experimental studies (animal models and cell studies), observational studies, and randomized controlled trials (RCTs) investigating the mechanism of action of HCDs and the effects of supplementation in individuals with obesity and/or T2D.ResultsThe primary literature search yielded 10,973 articles and 121 studies were eligible for inclusion. HCDs have been shown to mitigate inflammation and improve lipid profile and glycemic control in obesity and T2D with or without microvascular and macrovascular complications. However, most studies are experimental, focusing on elucidating the potential mechanisms of action of HCDs, with limited observational data or RCTs of individuals with obesity and/or T2D. No RCTs have investigated the effects of HCDs in individuals with neuropathy, retinopathy, cerebrovascular disease, and cardiovascular disease within a diabetic context.ConclusionsAlthough the existing evidence, predominantly from preclinical studies, generally supports the use of HCDs for improving cardiometabolic health, further human studies, especially RCTs with adequately powered sample sizes, are needed.
Cardioprotective Effect of Gamma-Oryzanol on Myocardium Proteome of Rats Submitted to Diet-Induced Obesity Jéssica Leite Garcia, Alfonsina D'Amato, Juliana Silva Siqueira, Fabiane Valentini Francisqueti‐Ferron, Cristina Schmitt Gregolin, Silméia Garcia Zanati Bazan, Artur Junio Togneri Ferron, Luis Eduardo Sormani, Taynara Aparecida Vieira, Bianca Pereira Lopes, Dijon Henrique Salomé de Campos, Guilherme Ribeiro Romualdo, Giancarlo Aldini, Camila Renata Correa Molecular Nutrition and Food Research, 2025
AR-A014418-based dual Glycogen Synthase Kinase 3β/Histone Deacetylase inhibitors as potential therapeutics for Alzheimer's disease Alan Santini, Elisa Tassinari, Alessandra Altomare, Manuela Loi, Elisabetta Ciani, Stefania Trazzi, Rebecca Piccarducci, Simona Daniele, Claudia Martini, Barbara Pagliarani, Andrea Tarozzi, Matteo Bersani, Francesca Spyrakis, Daniela Danková, Eleonora Poeta, Simone Raimondi, Lara Davani, Giancarlo Aldini, Vincenza Andrisano, Angela De Simone, Andrea Milelli European Journal of Medicinal Chemistry, 2025
Carnosine supplementation and retinal oxidative parameters in a high-calorie diet rat model Rogil Jose de Almeida Torres, Fernando Moreto, Andrea Luchini, Rogerio Joao de Almeida Torres, Sofia Pimentel Longo, Ricardo Aurino Pinho, Seigo Nagashima, Lucia de Noronha, Artur Junio Togneri Ferron, Carol Cristina Vagula de Almeida Silva, Camila Renata Correa, Giancarlo Aldini, Ana Lucia Anjos Ferreira BMC Ophthalmology, 2023
New Insights into Bitopic Orthosteric/Allosteric Ligands of Cannabinoid Receptor Type 2 Rebecca Ferrisi, Beatrice Polini, Caterina Ricardi, Francesca Gado, Kawthar A. Mohamed, Giovanna Baron, Salvatore Faiella, Giulio Poli, Simona Rapposelli, Giuseppe Saccomanni, Giancarlo Aldini, Grazia Chiellini, Robert B. Laprairie, Clementina Manera, Gabriella Ortore International Journal of Molecular Sciences, 2023
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