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1.
Sirtuins as Players in the Signal Transduction of Citrus Flavonoids.
Lombardo, GE, Russo, C, Maugeri, A, Navarra, M
International journal of molecular sciences. 2024;(4)
Abstract
Sirtuins (SIRTs) belong to the family of nicotine adenine dinucleotide (NAD+)-dependent class III histone deacetylases, which come into play in the regulation of epigenetic processes through the deacetylation of histones and other substrates. The human genome encodes for seven homologs (SIRT1-7), which are localized into the nucleus, cytoplasm, and mitochondria, with different enzymatic activities and regulatory mechanisms. Indeed, SIRTs are involved in different physio-pathological processes responsible for the onset of several human illnesses, such as cardiovascular and neurodegenerative diseases, obesity and diabetes, age-related disorders, and cancer. Nowadays, it is well-known that Citrus fruits, typical of the Mediterranean diet, are an important source of bioactive compounds, such as polyphenols. Among these, flavonoids are recognized as potential agents endowed with a wide range of beneficial properties, including antioxidant, anti-inflammatory, hypolipidemic, and antitumoral ones. On these bases, we offer a comprehensive overview on biological effects exerted by Citrus flavonoids via targeting SIRTs, which acted as modulator of several signaling pathways. According to the reported studies, Citrus flavonoids appear to be promising SIRT modulators in many different pathologies, a role which might be potentially evaluated in future therapies, along with encouraging the study of those SIRT members which still lack proper evidence on their support.
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2.
Bergamot Byproducts: A Sustainable Source to Counteract Inflammation.
Russo, C, Lombardo, GE, Bruschetta, G, Rapisarda, A, Maugeri, A, Navarra, M
Nutrients. 2024;(2)
Abstract
Chronic inflammation is the result of an acute inflammatory response that fails to eliminate the pathogenic agent or heal the tissue injury. The consequence of this failure lays the foundations to the onset of several chronic ailments, including skin disorders, respiratory and neurodegenerative diseases, metabolic syndrome, and, eventually, cancer. In this context, the long-term use of synthetic anti-inflammatory drugs to treat chronic illnesses cannot be tolerated by patients owing to the severe side effects. Based on this, the need for novel agents endowed with anti-inflammatory effects prompted to search potential candidates also within the plant kingdom, being recognized as a source of molecules currently employed in several therapeutical areas. Indeed, the ever-growing evidence on the anti-inflammatory properties of dietary polyphenols traced the route towards the study of flavonoid-rich sources, such as Citrus bergamia (bergamot) and its derivatives. Interestingly, the recent paradigm of the circular economy has promoted the valorization of Citrus fruit waste and, in regard to bergamot, it brought to light new evidence corroborating the anti-inflammatory potential of bergamot byproducts, thus increasing the scientific knowledge in this field. Therefore, this review aims to gather the latest literature supporting the beneficial role of both bergamot derivatives and waste products in different models of inflammatory-based diseases, thus highlighting the great potentiality of a waste re-evaluation perspective.
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3.
Targets Involved in the Anti-Cancer Activity of Quercetin in Breast, Colorectal and Liver Neoplasms.
Maugeri, A, Calderaro, A, Patanè, GT, Navarra, M, Barreca, D, Cirmi, S, Felice, MR
International journal of molecular sciences. 2023;(3)
Abstract
Phytochemicals have long been effective partners in the fight against several diseases, including cancer. Among these, flavonoids are valuable allies for both cancer prevention and therapy since they are known to influence a large panel of tumor-related processes. Particularly, it was revealed that quercetin, one of the most common flavonoids, controls apoptosis and inhibits migration and proliferation, events essential for the development of cancer. In this review, we collected the evidence on the anti-cancer activity of quercetin exploring the network of interactions between this flavonol and the proteins responsible for cancer onset and progression focusing on breast, colorectal and liver cancers, owing to their high worldwide incidence. Moreover, quercetin proved to be also a potentiating agent able to push further the anti-cancer activity of common employed anti-neoplastic agents, thus allowing to lower their dosages and, above all, to sensitize again resistant cancer cells. Finally, novel approaches to delivery systems can enhance quercetin's pharmacokinetics, thus boosting its great potentiality even further. Overall, quercetin has a lot of promise, given its multi-target potentiality; thus, more research is strongly encouraged to properly define its pharmaco-toxicological profile and evaluate its potential for usage in adjuvant and chemoprevention therapy.
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4.
Intravitreal dexamethasone implant versus anti-vascular endothelial growth factor therapy combined with cataract surgery in patients with diabetic macular oedema: a systematic review with meta-analysis.
Fallico, M, Lotery, A, Maugeri, A, Favara, G, Barchitta, M, Agodi, A, Russo, A, Longo, A, Bonfiglio, V, Avitabile, T, et al
Eye (London, England). 2022;(12):2239-2246
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Abstract
OBJECTIVE To compare outcomes of cataract surgery combined with either anti-Vascular Endothelial Growth Factor (anti-VEGF) therapy or dexamethasone implant (DEX) in patients with diabetic macular oedema (DMO). METHODS Pubmed and Embase databases were searched for studies reporting outcomes of diabetic cataract surgery combined with either anti-VEGF or DEX, with a follow-up ≥3 months. The primary outcome was the mean change in central macular thickness (CMT). Mean change in best corrected visual acuity (BCVA) was considered as a secondary outcome. The mean difference between baseline and post-treatment values (MD) with 95%-Confidence Interval (95%CI) was calculated and meta-analyses were performed. RESULTS Nine-teen studies were included, 8 in the DEX group and 11 in the anti-VEGF group. A significant reduction of macular thickness was shown in the DEX group at 3 months (MD = -98.35 µm; 95% CI, -147.15/-49.54), while mean CMT change was non-significant in the anti-VEGF group (MD = -21.61 µm; 95% CI, -59.46/16.24; test of group differences, P < 0.001). At 3 months, no difference in visual gain was found between the two groups (P = 0.13). CONCLUSIONS In DMO patients, cataract surgery combined with DEX seems to provide better anatomical outcomes compared with cataract surgery combined with anti-VEGF therapy. However, our evidence was limited by significant heterogeneity. Randomised trials comparing these two different combined approaches are warranted.
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5.
Do Nutrients and Nutraceuticals Play a Role in Diabetic Retinopathy? A Systematic Review.
Milluzzo, A, Barchitta, M, Maugeri, A, Magnano San Lio, R, Favara, G, Mazzone, MG, Sciacca, L, Agodi, A
Nutrients. 2022;(20)
Abstract
Diabetic retinopathy (DR) is a multifactorial neuro-microvascular disease, whose prevalence ranges from 25% to 60% of subjects affected by diabetes mellitus, representing the main cause of legal blindness in adults of industrialized countries. The treatment of advanced stage of DR is based on invasive and expensive therapies, while few strategies are available for the early stage or prevention. The mechanisms underlying DR involve a complex interplay between the detrimental effects of hyperglycemia, dyslipidemia, hypoxia, and oxidative stress, providing several pathways potentially targeted by nutrients and nutraceuticals. In this study, we conducted a systematic review of observational and interventional studies, evaluating the effect of nutrients and/or nutraceuticals on the risk of DR and their potential use for the treatment of patients with DR. The analysis of the 41 included studies (27 observational and 14 interventional studies) suggests a promising preventive role of some nutrients, in particular for vitamins B (i.e., B1 and B12), D, and E. However, further investigations are necessary to clarify the potential clinical application of nutraceuticals in the prevention and treatment of DR.
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6.
Fluocinolone acetonide vitreous insert for chronic diabetic macular oedema: a systematic review with meta-analysis of real-world experience.
Fallico, M, Maugeri, A, Lotery, A, Longo, A, Bonfiglio, V, Russo, A, Avitabile, T, Furino, C, Cennamo, G, Barchitta, M, et al
Scientific reports. 2021;(1):4800
Abstract
We conducted a meta-analysis of real-world studies on the 0.19 mg Fluocinolone Acetonide (FAc) intravitreal implant for chronic diabetic macular oedema (DMO), comparing these findings with the Fluocinolone Acetonide for Diabetic Macular Edema (FAME) study. The primary outcome was mean change of best corrected visual acuity (BCVA) at 24 months. Secondary outcomes were 36-month mean BCVA, mean central macular thickness (CMT) change, rates of eyes receiving supplementary intravitreal therapy, cataract surgery, intraocular pressure (IOP)-lowering drops and glaucoma surgery. Mean differences (MDs) with 95% confidence intervals (CIs) were calculated. Nine real-world studies were included. The FAc implant yielded a significantly improved BCVA at 24 and 36 months (24-month MD = 4.52; 95% CI 2.56-6.48; 36-month MD = 8.10; 95% CI 6.34-9.86). These findings were comparable with the FAME study. The FAc implant yielded significantly reduced 24- and 36-month CMT. Pooled proportions of cataract surgery, IOP-lowering drops and glaucoma surgery were 39%, 27% and 3%, respectively, all lower than the FAME study. Pooled estimate of supplementary intravitreal therapy was 39%, higher than the 15.2% of the FAME study. This meta-analysis of real-world studies confirms favorable visual and anatomical outcomes following FAc insert for chronic DMO. In real-life studies more than one third of patients received supplementary intravitreal therapy, an issue that needs to be further explored.
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7.
Epigenetic Mechanisms in Type 2 Diabetes Retinopathy: A Systematic Review.
Milluzzo, A, Maugeri, A, Barchitta, M, Sciacca, L, Agodi, A
International journal of molecular sciences. 2021;(19)
Abstract
Diabetic retinopathy (DR) is one of the main causes of vision loss in middle-aged economically active people. Modifiable (i.e., hyperglycaemia, hypertension, hyperlipidaemia, obesity, and cigarette smoke) and non-modifiable factors (i.e., duration of diabetes, puberty, pregnancy and genetic susceptibility) are involved in the development of DR. Epigenetic mechanisms, modulating the oxidative stress, inflammation, apoptosis, and aging, could influence the course of DR. Herein, we conducted a systematic review of observational studies investigating how epigenetics affects type 2 diabetes retinopathy (T2DR). A total of 23 epidemiological studies were included: 14 studies focused on miRNA, 4 studies on lnc-RNA, one study on both miRNA and lnc-RNA, and 4 studies on global or gene-specific DNA methylation. A direct relation between the dysregulation of miR-21, miR-93, and miR-221 and FPG, HbA1c, and HOMA-IR was identified. A panel of three miRNAs (hsa-let-7a-5p, hsa-miR-novel-chr5_15976, and hsa-miR-28-3p) demonstrated a good sensitivity and specificity for predicting T2DR. Little evidence is available regarding the possible role of the long non-coding MALAT1 dysregulation and MTHFR gene promoter hypermethylation. Despite these initial, encouraging findings potentially suggesting a role of epigenetics in T2DR, the use in clinical practice for the diagnosis and staging of this complication encounters several difficulties and further targeted investigations are still necessary.
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8.
Intravitreal anti-vascular endothelial growth factors, panretinal photocoagulation and combined treatment for proliferative diabetic retinopathy: a systematic review and network meta-analysis.
Fallico, M, Maugeri, A, Lotery, A, Longo, A, Bonfiglio, V, Russo, A, Avitabile, T, Pulvirenti, A, Furino, C, Cennamo, G, et al
Acta ophthalmologica. 2021;(6):e795-e805
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Abstract
PURPOSE To conduct a systematic review with network meta-analysis (NMA) of randomized clinical trials (RCTs) comparing panretinal photocoagulation (PRP) versus anti-vascular endothelial growth factor (VEGF) treatment alone or in combination with PRP, for proliferative diabetic retinopathy (PDR). METHODS PubMed, Medline and Embase databases were searched for RCTs comparing PRP versus intravitreal anti-VEGF therapy and/or combined PRP and intravitreal anti-VEGF for PDR. The primary outcome measures were the mean best corrected visual acuity (BCVA) change and the regression of neovascularization. Mean change of central macular thickness (CMT), the subgroup analyses of patients without diabetic macular oedema (DME) and the rate of vitreous haemorrhage and vitrectomy were secondary outcomes. Frequentist NMAs were performed. RESULTS Twelve RCTs were included. For the 12-month mean BCVA change, NMA showed a better visual outcome in both the anti-VEGF group and combined group compared to PRP [anti-VEGF vs PRP, mean difference (MD) = 3.42; standard error (SE) = 1.5; combined vs PRP, MD = 3.92; SE = 1.65], with no difference between combined group and anti-VEGF (MD = -0.50; SE = 1.87). No difference in neovascularization regression was found between PRP and anti-VEGF alone or in combination with PRP, but there was significant inconsistency (p = 0.016). Subgroup analyses in patients without DME yielded no difference for the 12-month visual outcome between the three interventions, but with significant inconsistency (p = 0.005). CONCLUSION This NMA showed limited evidence of comparable efficacy in terms of neovascularization regression between PRP and anti-VEGF therapy alone or in combination with PRP, but better visual outcomes were associated with anti-VEGF use. Intravitreal anti-VEGF therapy could be a valid therapeutic option in association with PRP.
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Bergamottin and 5-Geranyloxy-7-methoxycoumarin Cooperate in the Cytotoxic Effect of Citrus bergamia (Bergamot) Essential Oil in Human Neuroblastoma SH-SY5Y Cell Line.
Maugeri, A, Lombardo, GE, Musumeci, L, Russo, C, Gangemi, S, Calapai, G, Cirmi, S, Navarra, M
Toxins. 2021;(4)
Abstract
The plant kingdom has always been a treasure trove for valuable bioactive compounds, and Citrus fruits stand out among the others. Bergamottin (BRG) and 5-geranyloxy-7-methoxycoumarin (5-G-7-MOC) are two coumarins found in different Citrus species with well-acknowledged pharmacological properties. Previously, they have been claimed to be relevant in the anti-proliferative effects exerted by bergamot essential oil (BEO) in the SH-SY5Y human neuroblastoma cells. This study was designed to verify this assumption and to assess the mechanisms underlying the anti-proliferative effect of both compounds. Our results demonstrate that BRG and 5-G-7-MOC are able to reduce the proliferation of SH-SY5Y cells, inducing apoptosis and increasing cell population in sub-G0/G1 phase. Moreover, we demonstrated the pro-oxidant activity of the two coumarins that increased reactive oxygen species and impaired mitochondrial membrane potential. From a molecular point of view, BRG and 5-G-7-MOC were able to modulate apoptosis related factors at both protein and gene levels. Lastly, we evaluated the synergistic effect of their combination, finding that the highest synergy was observed at a concentration ratio similar to that occurring in the BEO, supporting our initial hypothesis. Taken together, our results deepen the knowledge regarding the effect of BRG and 5-G-7-MOC in SH-SY5Y cells, emphasizing the relevance of their cooperation in achieving this effect.
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10.
The Effects of Dietary Interventions on DNA Methylation: Implications for Obesity Management.
Maugeri, A
International journal of molecular sciences. 2020;(22)
Abstract
Previous evidence from in vivo and observational research suggested how dietary factors might affect DNA methylation signatures involved in obesity risk. However, findings from experimental studies are still scarce and, if present, not so clear. The current review summarizes studies investigating the effect of dietary interventions on DNA methylation in the general population and especially in people at risk for or with obesity. Overall, these studies suggest how dietary interventions may induce DNA methylation changes, which in turn are likely related to the risk of obesity and to different response to weight loss programs. These findings might explain the high interindividual variation in weight loss after a dietary intervention, with some people losing a lot of weight while others much less so. However, the interactions between genetic, epigenetic, environmental and lifestyle factors make the whole framework even more complex and further studies are needed to support the hypothesis of personalized interventions against obesity.