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Q-Der: a next-generation CoQ10 analogue supercharging neuroprotection by combating oxidative stress and enhancing mitochondrial function
Full text linkBackground: Mitochondrial dysfunction and oxidative stress are central mechanisms in the progression of neurodegenerative diseases. This study first evaluated the toxicity of Q-Der (Q10-diacetate), a derivative of Coenzyme Q10, in HT22 hippocampal neurons under normal and oxidative stress conditions. Methods: HT22 cells were treated with Q-Der at 2.5, 5 and 10 μM with and without rotenone. Mitochondrial superoxide production (Mitosox), gene expression (via qRT-PCR), and protein levels (via Western blot) were measured. Morphological analyses were performed using transmission (TEM) and scanning (SEM) electron microscopes. Results: Q-Der significantly reduced mitochondrial superoxide levels, particularly at 5 μM, and upregulated key mitochondrial biogenesis genes, including PGC-1α and TFAM. Additionally, it restored the expression of MT-ND1 and MT-COI, which were downregulated by rotenone. Western blot results showed a significant recovery in CV-ATP5A (complex V) expression (p < 0.05), preserving mitochondrial ATP production. Morphological analyses further confirmed Q-Der's ability to maintain cellular and mitochondrial structure under stress conditions. Conclusion: These findings suggest that Q-Der is non-toxic under normal conditions and protects against oxidative stress, supporting its potential as a therapeutic agent for neurodegenerative diseases
PRODUZIONE DI METABOLITI SECONDARI DI ORIGINE VEGETALE A PARTIRE DA COLTURE IN VITRO DI CALLI DALLA POLPA DI FRUTTA DI DIVERSE POMACEAE (VALUTAZIONE DELL’ATTIVITÀ BIOLOGICA DEI METABOLITI SECONDARI OTTENUTI DA COLTURE IN VITRO DI CELLULE DI POLPA DI CALLO)
No full textThis doctoral thesis focused on evaluating the biological activities of hydroalcoholic extracts derived from callus pulp cultures of three selected apples: Cydonia oblonga Mill., Mela Rosa Marchigiana, and Malus pumila cv Miller (Annurca Campana Apple).
For each apple, the research followed the following workflow: (1) establishment of callus cultures and extract preparation, (2) qualitative-quantitative chemical characterization of SM extracts, and (3) evaluation of their biological activity.
In Cydonia oblonga Mill., the hydroalcoholic extract, previously found to be rich in phenolic and triterpenic compounds, demonstrated a potent anti-inflammatory effect in in vitro models of LPS-stimulated RAW 264.7 macrophages and HaCaT keratinocytes. Results indicated significant reductions in NO production, and pro-inflammatory gene expression (iNOS, IL-6, IL-1β, ikBα, ICAM). Moreover, the extract reduced the radical oxygen species levels in the hydrogen peroxide (H2O2) and tert-butyl hydroperoxide- (TBHP) injured HaCaT keratinocytes, revealing an important antioxidant activity.
For Mela Rosa Marchigiana, callus cultures from sub-cultures maintained high triterpenic acid content and bioactivity over the years. Comparative analysis with previous extracts confirmed consistent antioxidant, and anti-inflammatory effects, as demonstrated through cell-free (DPPH, ABTS, and ORAC) and cell-based assays (LPS-stimulated RAW 264.7 macrophages and H2O2 injured HaCaT keratinocytes).
In Malus pumila cv Miller, two callus cultures were cultivated under darkness and photoperiod conditions. The selected conditions for generating the two types of calli facilitated the production of substantial amounts of triterpenic compounds. Both calli primarily exhibit anti-inflammatory and genoprotective effects (tested using the lipoxygenase inhibition activity assay and LPS-stimulated RAW 264.7 macrophages, and the nicking assay, respectively) while showing lower antioxidant activity (evaluated by DPPH, ABTS, and ORAC assays). The callus cultivated in light conditions was chosen for encapsulation in a nanocarrier, which allowed for the assessment of its anti-inflammatory activity in a cellular model of ferroptosis on HaCaT cells. The results highlight the promise of Annurca Apple Callus extract in addressing oxidative stress and inflammation linked to excess iron. The nanocarrier system greatly improves its therapeutic effectiveness, as evidenced by gene expression analysis showing that the encapsulated extract can modulate the expression of genes associated with the ferroptosis process (COX-2, GPX-4, NrF2, IL-6, and TNF-α).
Overall, this study highlights the potential of callus culture technology for producing bioactive SMs with pharmaceutical, cosmetic, and nutraceutical applications. It also emphasizes the importance of optimizing culture conditions and leveraging advanced delivery systems to maximize the therapeutic potential of plant-derived compounds. These findings pave the way for scalable and sustainable production strategies in bioactive compound research and industry applications
A proposito di MOG e salute: recensione a F. Curi, La tutela del benessere lavorativo negli enti pubblici e privati, Giappichelli, 2024
No full textIMPACT OF CLOZAPINE ON ADIPOSE AND SKELETAL MUSCLE CELLS: IMPLICATIONS FOR METABOLIC SIDE EFFECTS
No full textClozapine (CLZ), a second-generation antipsychotic (SGA), is particularly effective in the treatment of schizophrenia, but its use has been restricted to patients who do not respond to other medications due to severe side effects such as cardiomyopathy, seizures and agranulocytosis, weight gain, insulin resistance, cardiovascular disease and metabolic syndrome through mechanisms that are not yet fully understood.
The first chapter of this thesis presents a paper accepted with revision, demonstrating that CLZ inhibits mitochondrial biogenesis by reducing PGC1α expression, mitochondrial DNA content, and mitochondrial mass as early as day 3 (T3). Also, the expression of the mitochondrial main proteins was altered by CLZ treatment. At T3, cells displayed elevated ATP levels, which were partially reduced by rotenone, a complex I inhibitor, suggesting a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS). Despite the inhibition of mitochondrial biogenesis, the treatment with CLZ does not induce a compensatory increase in glycolytic activity. Instead, CLZ-treated cells show a slight decrease in glycolysis but exhibit enhanced mitochondrial function, characterized by increased expression of electron transport chain complexes, elevated mitochondrial membrane potential, and improved mitochondrial activity. Notably, CLZ stimulates the respiratory capacity linked to ATP synthesis and increases the functionality of complex II.
Therefore, CLZ suppresses mitochondrial biogenesis in differentiating SW872 cells, which nevertheless maintained adequate ATP levels using an unexpected strategy which was associated with enhanced oxygen consumption driven by lipid substrate-dependent stimulation of complexes I and II, an event associated with increased mitochondrial membrane potential, ATP synthesis and mitochondrial ROS generation.
Building on the findings of Chapter 1, Chapter 2 extends the investigation to myotubes, a cell model with specific metabolic susceptibilities, to further elucidate CLZ-induced metabolic side effects across different cell types that are both implicated in metabolic dysregulation. This study has been the subject of a paper that is now under consideration for publication.
It has been reported that exposure to CLZ has also been associated with potentially important adverse reactions in the skeletal muscle cells (Barbosa et al., 2022). Indeed, some reports indicate that CLZ promotes myopathy associated with muscle weakness. Most importantly, the use of CLZ has also been associated with the development of rhabdomyolysis, i.e., a condition characterized by the breakdown of skeletal muscle tissue and the release of myoglobin, into the bloodstream. Although CLZ-induced rhabdomyolysis is a rare event, some clinicians suggest that patients under CLZ treatment should be monitored for the appearance of signs of myopathy (Béchard et al., 2022), especially when concomitantly taking other drugs increasing the risk of rhabdomyolysis (e.g., statins), or with previous history of muscle-related adverse effects. To date, a small number of studies have been carried out on the myotoxic effects of the drug in vitro and on the mechanisms underlying the muscle-related adverse effects.
In the study reported in chapter 2, C2C12 derived myotubes were used to fill some of these gaps. The results show that CLZ interferes with myogenic differentiation by being selectively toxic to differentiated myotubes, but not to proliferating myoblasts. According to this evidence, micromolar concentrations of CLZ trigger massive apoptosis in myotubes, an event occurring under conditions in which the drug fails to promote toxic effects in myoblasts as well as in reserve cells. Consistent results were also obtained in primary myotubes.
In conclusion, the results reported in this thesis may help to shed light on the detailed molecular mechanisms explaining some of the adverse metabolic effects induced by CLZ
Role of 11β-Hydroxysteroid Dehydrogenase and Mineralocorticoid Receptor on Alzheimer's Disease Onset: A Systematic Review
Full text linkThe role of 11β-HSD1 in Alzheimer's disease (AD) has garnered significant attention due to its involvement in glucocorticoid metabolism, neuroinflammation, and cognitive decline. This review explores the current understanding of 11β-HSD1 in AD, examining genetic, preclinical, and clinical research. Genetic studies have identified 11β-HSD1 polymorphisms that may influence AD risk, although findings remain inconsistent. Mechanistically, 11β-HSD1 promotes neurodegeneration through the dysregulation of glucocorticoid activity, contributing to hippocampal atrophy, amyloid plaque formation, and tau pathology. Preclinical studies have shown that 11β-HSD1 inhibitors offer neuroprotective effects, including enhanced cognitive function, reduced inflammation, and improved mitochondrial activity. However, clinical trials, including those involving ABT-384 and Xanamem, have produced mixed results, with no substantial cognitive improvements despite effective enzyme inhibition. These inconsistencies highlight the complexity of AD and the challenges in translating preclinical findings into clinical outcomes. Moreover, while 11β-HSD1 inhibition holds therapeutic potential, other strategies targeting neuroinflammation, autophagy, and glucocorticoid signaling are also being explored. Ongoing research is focusing on optimizing 11β-HSD1 inhibitors, identifying biomarkers for patient selection, and investigating combination therapies to enhance treatment efficacy. Ultimately, 11β-HSD1's role in AD presents a promising therapeutic target, but further studies are required to fully understand its potential in managing the disease
A Ricardian Analysis of the Impacts of Climate Change on Agricultural Crop Production in Myanmar
No full textThis study employs a Ricardian analytic framework to investigate the current and projected impacts of changes in temperature and precipitation on Myanmar’s agricultural sector. By analysing 330 pieces of 2017–2022 township-level data on crop productivity and 1990–2020 climate data, we estimate the economic effects of climate change on Myanmar’s agricultural crop production. The analysis reveals that the climate’s impacts on agriculture exhibit significant heterogeneity across different seasons and farm types. Most notably, increases in summer temperatures correlate with substantial crop revenue losses, highlighting the vulnerabilities faced during this critical growing season. Projections using three climate models (PCM, CGCM3, and CSIRO) indicate that climate change’s impact on agriculture will intensify through the 21st century, with estimates pointing to revenue declines in summer and winter of up to -25.85% and potential gains of approximately 23.02% during monsoon season. These projections highlight the precarious nature of agricultural productivity in Myanmar, where fluctuations in temperature and precipitation patterns can lead to marginal changes in crop revenues. Overall, the findings stress the urgent need for substantial investment in agricultural preparedness, adaptation strategies and integrated climate-change-mitigation policies to safeguard food security and enhance resilience in Myanmar’s agricultural sector amid escalating climatic challenges
Cola di Rienzo mago
No full textL’Anonyme romain raconte qu’à la mort de Cola di Rienzo, en 1354, on trouva parmi ses effets personnels un miroir dans lequel était enfermé un démon. D’autres témoignages (Clément VI, Pétrarque et Cola lui-même) associent le grand orateur à la magie. Sa réputation de magicien est liée à son rapport au passé, à sa proximité avec les hérétiques, à son penchant pour le millénarisme et à son interprétation symbolique d’un monde dont il croit qu’il peut être transformé par le pouvoir des mots
CRONACHE CERETANE Atti del Seminario sulla storia degli scavi e delle collezioni archeologiche disperse Viterbo, 30 marzo – Cerveteri, 21 aprile – Roma, 27 maggio 2023
No full textIl volume raccoglie gli Atti del Convegno sulla storia degli scavi e delle collezioni archeologiche disperse di Cerveteri, tenutosi tra Viterbo, Cerveteri e Roma, tra marzo e aprile del 2023, organizzato dalle Università di Roma Sapienza, Tuscia e Urbino e dalla direzione del Parco Archeologico di Cerveteri e Tarquini
Il sito di età romana di Roncosambaccio di Fano (PU)
No full textIn località Crocefisso di Roncosambaccio di Fano furono recuperati, tra vari
materiali, alcuni frammenti architettonici di ordine dorico in arenaria che vennero
da subito messi in relazione con una villa rustica o un santuario cronologicamente
precedente rispetto alla fondazione della colonia augustea di Fanum
Fortunae. Le vicende che portarono al recupero dei reperti, mancando una
documentazione a riguardo, sono ancora oggi di difficile ricostruzione e controversa
risulta anche la reale entità dei ritrovamenti. Le tappe della riscoperta
sono ricostruibili, tuttavia, attraverso le testimonianze dirette dei proprietari dei
terreni e grazie all’impegno profuso da parte di chi, in passato, si è interessato
all’argomento. In questa sede è proposta un’analisi del sito dal punto di vista
topografico e architettonico insieme a una breve trattazione del materiale ceramico
proveniente dal medesimo scavo
La necropoli di Monte Abatone dalle indagini della Fondazione Lerici ai nuovi scavi: verso una ricomposizione del quadro culturale
No full textA short picture is presented of the archaeological discoveries and geophysical researches carried out at the Monte Abatone necropolis (Caere) by the Lerici Foundation in the 1950s, and of the later start of the ‘Monte Abatone Project’, aiming to set up a complete edition of all the funerary contexts brought to light by Lerici. Wide space is devoted to the new field researches in the western part of the necropolis, close to the Campana Tumulus, and on its borders: the discoveries make it able to focus on methods of occupation of the space of the necropolis, and to sketch a new picture of the sequence and diffusion of some tomb types