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Hypovitaminosis D has become a pandemic, being observed in all ethnicities and age groups worldwide. Environmental factors, such as increased air pollution and reduced ultraviolet B (UVB) irradiation, as well as lifestyle factors, i.e., decreased outdoor activities and/or poor intake of vitamin D-rich food, are likely involved in the etiology of a dramatic reduction of vitamin D circulating levels. The insufficiency/deficiency of vitamin D has long been known for its association with osteoporosis and rickets. However, in the last few decades it has become a serious public health concern since it has been shown to be independently associated with various chronic pathological conditions such as cancer, coronary heart disease, neurological diseases, type II diabetes, autoimmune diseases, depression, with various inflammatory disorders, and with increased risk for all-cause mortality in the general population. Prevention strategies for these disorders have recently involved supplementation with either vitamin D2 or vitamin D3 or their analogs at required daily doses and tolerable upper-limit levels. This review will focus on the emerging evidence about non-classical biological functions of vitamin D in various disorders.

Melatonin, an indoleamine hormone produced and secreted at night by pinealocytes and extra-pineal cells, plays an important role in timing circadian rhythms (24-h internal clock) and regulating the sleep/wake cycle in humans. However, in recent years melatonin has gained much attention mainly because of its demonstrated powerful lipophilic antioxidant and free radical scavenging action. Melatonin has been proven to be twice as active as vitamin E, believed to be the most effective lipophilic antioxidant. Melatonin-induced signal transduction through melatonin receptors promotes the expression of antioxidant enzymes as well as inflammation-related genes. Melatonin also exerts an immunomodulatory action through the stimulation of high-affinity receptors expressed in immunocompetent cells. Here, we reviewed the efficacy, safety and side effects of melatonin supplementation in treating oxidative stress- and/or inflammation-related disorders, such as obesity, cardiovascular diseases, immune disorders, infectious diseases, cancer, neurodegenerative diseases, as well as osteoporosis and infertility.

Plant polyphenols exert anti-inflammatory activity through both anti-oxidant effects and modulation of pivotal pro-inflammatory genes. Recently, Citrus bergamia has been studied as a natural source of bioactive molecules with antioxidant activity, but few studies have focused on molecular mechanisms underlying their potential beneficial effects. Several findings have suggested that polyphenols could influence cellular function by acting as activators of SIRT1, a nuclear histone deacetylase, involved in the inhibition of NF-κB signaling. On the basis of these observations we studied the anti-inflammatory effects produced by the flavonoid fraction of the bergamot juice (BJe) in a model of LPS-stimulated THP-1 cell line, focusing on SIRT1-mediated NF-κB inhibition. We demonstrated that BJe inhibited both gene expression and secretion of LPS-induced pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) by a mechanism involving the inhibition of NF-κB activation. In addition, we showed that BJe treatment reversed the LPS-enhanced acetylation of p65 in THP-1 cells. Interestingly, increasing concentrations of Sirtinol were able to suppress the inhibitory effect of BJe via p65 acetylation, underscoring that NF-κB-mediated inflammatory cytokine production may be directly linked to SIRT1 activity. These results suggest that BJe may be useful for the development of alternative pharmacological strategies aimed at reducing the inflammatory process.

Genetic polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) enzyme may influence DNA methylation. Alterations in DNA methylation patterns of genes involved in the regulation of the cell cycle, DNA repair, cell adherence and metastasis process are known to contribute to cancer development. In this study, the influence of the MTHFR C677T and A1298C gene polymorphisms on global DNA methylation and site-specific methylation on p16 and O6-methylguanine-DNA methyltransferase (MGMT) gene promoters was investigated in patients with oral squamous cell cancer (OSCC). To this aim, methylation studies were carried out by using genomic DNA isolated from saliva samples of 58 OSCC patients and 90 healthy controls. The frequency of the CT/AC and TT/AA genotypes was significantly higher in patients than in controls. Whereas no difference in global DNA methylation levels was observed between patients and controls, a higher frequency of methylation at both p16 and MGMT gene promoters was detected in patients compared with controls. A significant association between MTHFR gene polymorphisms and p16 and MGMT gene promoter methylation was found. The frequency of p16 and MGMT methylation was around 60% in patients with either the CT/AC or TT/AA genotype. Our results suggest that hypermethylation of cancer-related genes may be affected by MTHFR polymorphisms.

Recent literature data have highlighted the important role of hypovitaminosis D in pregnancy complications and prenatal/perinatal health. Vitamin D action takes place through vitamin D receptor (VDR) activation. Two single nucleotide polymorphisms of VDR gene, FokI and BsmI, have been reported to affect VDR molecular signaling and be associated with several disorders, including hypertension. We carried out a case-control study aimed to assess vitamin D serum levels together with the distribution of VDR FokI and BsmI in a population of 116 pregnant women with gestational hypertension (GH) and 69 normotensive pregnant women (CTR). Hypovitaminosis D was largely prevalent both in GH (81%) and CTR (69%) pregnant women. Vitamin D insufficiency (10-30 ng/ml) had a similar frequency in both cohorts (GH 60% vs CTR 58%), while vitamin D deficiency (<10 ng/ml) was more frequent in GH cohort than in CTR one (21% vs 11%). Regression analysis showed that GH was significantly (p = 0.031) linked to vitamin D status. Vitamin D deficiency was associated with a threefold-increased risk of developing GH, while a normal vitamin D status was protective against this pregnancy disorder. The VDR FF/bB haplotype was the most frequent in GH cohort, and resulted to increase by two folds the risk for GH. Notably, hypovitaminosis D was found in 92% of FF/bB GH pregnant women, 27% of which had deficient vitamin D levels compared with 11% of their normotensive counterparts. Despite being preliminary, these findings suggest that genotyping of pregnant women for VDR polymorphisms may be useful for a tailored vitamin D supplementation strategy.

Androgen independency is associated with poor prostate cancer (PCa) survival. Here we report that silencing of transglutaminase-2 (TG2) expression by CRISPR-Cas9 is associated with upregulation of androgen receptor (AR) transcription in PCa cell lines. Knockout of TG2 reversed the migratory potential and anchorage independency of PC3 and DU145 cells and revealed a reduced level of mucin-1 (MUC1) RNA transcript through unbiased multi-omics profiling, which was restored by selective add-back of the truncated TG2 isoform (TGM2_v2). Silencing of AR resulted into increased MUC1 in TG2KO PC3 cells showing that TG2 affects transcriptional regulation of MUC1 via repressing AR expression. Treatment of PC3 WT cell line with TG2 inhibitor ZDON led to a significant increase in AR expression and decrease in MUC1. ZDON also blocked the formation of MUC1-multimers labelled with TG amine-donor substrates in reducing conditions, revealing for the first time a role for TG2, which we show to be externalised via extracellular vesicles, in MUC1 stabilisation via calcium-dependent transamidation. A specific antibody towards TGM2_v2 revealed its restricted nuclear location compared to the canonical long form of TG2 (TGM2_v1), which is predominantly cytosolic, suggesting that this form contributes to the previously suggested TG2-mediated NF-κB activation and AR transcriptional repression. As TGM2_v2 transcription was increased in biopsies of early-stage prostate adenocarcinoma (PRAD) patients compared to subjects presenting inflammatory prostatitis, and total TG2 protein expression significantly increased in PRAD versus normal tissue, the role of TG2 and its truncated form as a prostate malignancy marker is suggested. In conclusion, this investigation has provided the first unbiased discovery of a novel pathway mediated by TG2 via MUC1, which is shown to contribute to androgen insensitivity and malignancy of PCa cells and be upregulated in PCa biopsies, with potential relevance to cancer immune evasion.

Balanitis xerotica obliterans (BXO) is a chronic inflammatory skin disorder, considered the male genital variant of lichen sclerosus. Anti-inflammatory drugs are commonly used in BXO. We evaluated the effects of an innovative formulation of ozonated olive oil with vitamin E acetate (OZOILE®) on the inflammatory status and tissue remodeling in male children with BXO. The mRNA transcripts of proteins involved either in inflammation or in dynamics of tissue regeneration were analyzed by quantitative real-time PCR, in foreskins affected by BXO removed from patients untreated or treated with OZOILE® cream for 7 days before circumcision. We found a significant reduction in mRNA levels of IL-1β, TNF-α, INF–γ, transglutaminase 2 and NOS2 in foreskins treated with OZOILE® in comparison to untreated ones (p < 0.001). No significant differences were observed in NF-κB activation in the specimens obtained from treated and untreated patients. Hence, OZOILE® treatment up-regulated hypoxia-inducible factor (HIF)-1alpha, vascular endothelial growth factor (VEGF) and E-cadherin gene expression (p < 0.001). The treatment with OZOILE® showed effective results in children affected by BXO by reducing the inflammatory process and stimulating mechanisms for tissue regeneration of the foreskin. A randomized clinical trial on a large number of children affected by BXO might be useful to verify the efficacy of topical treatment with OZOILE®.

The COVID-19 pandemic has hugely impacted many different aspects of human health, and vaccination is one of the most effective weapons to manage it. However, many different factors, such as age, gender, comorbidities and lifestyles, play a role in the response to infections and vaccines. We carried out this study to evaluate the potential role played by some individual factors in the production of anti-COVID-19 antibodies in the light of personalized and future vaccinology. We conducted an observational study consisting of a retrospective phase, exploiting previous data about anti-COVID-19 antibody responses, with a prospective phase to investigate individual variables through the use of a questionnaire. The antibody response after the COVID-19 vaccination was inversely related to old age, increased BMI and the number of smoking years, while a positive correlation was found with moderate alcohol consumption and especially with circulating levels of vitamin D, as clearly shown by the multivariate regression analysis. Our study showed that a number of variables are involved in the COVID-19 vaccine antibody response. These findings are very important and can be considered in the light of a future and personalized vaccinology.

Electromagnetic radiation emitted by commonly used devices became an issue for public health because of their harmful effects. Notably, 2.45 GHz electromagnetic radiation exposure has been associated with DNA damage and alterations in the central nervous system. We here investigated the effects of 2.45 GHz electromagnetic radiation on cell redox status by using human SH-SY5Y neuroblastoma cells, which were differentiated to neuronal-like cells, and peripheral blood mononuclear cells (PBMCs), which were exposed to an antenna emitting 2.45 GHz electromagnetic radiation for 2, 24, and 48 h. We evaluated cell viability and mitochondrial activity alterations by measuring reactive oxygen species (ROS), mitochondrial transmembrane potential (ΔΨm), NAD+/NADH ratio, mitochondrial transcription factor A (mtTFA), and superoxide dismutase 1 (SOD1) gene transcript levels. We also investigated apoptosis and autophagy, evaluating B-cell lymphoma 2 (BCL2), BCL2-associated X protein (BAX), and microtubule-associated protein 1A/1B-light chain 3 (LC3) gene transcript levels. Cell viability was significantly reduced after 24–48 h of exposure to radiation. ROS levels significantly increased in radiation-exposed cells, compared with controls at all exposure times. ΔΨm values decreased after 2 and 24 h in exposed SH-SY5Y cells, while in PBMCs, values decreased soon after 2 h of exposure. Alterations were also found in the NAD+/NADH ratio, mtTFA, SOD1, LC3 gene expression, and BAX/BCL2 ratio. Our results showed that neuron-like cells are more prone to developing oxidative stress than PBMCs after 2.45 GHz electromagnetic radiation exposure, activating an early antioxidant defense response.

Background and Objectives: Diabetes mellitus (DM) and hypertension (HT) are characterized by cell damage caused by inflammatory and metabolic mechanisms induced by alteration in reduction-oxidative status. Serum advanced oxidation protein products (AOPP) are new markers of protein damage induced by oxidative stress. We evaluated serum levels of AOPP in a cohort of patients with DM and HT, with or without renal complications, compared with a control healthy population. Materials and Methods: The study group comprised of 62 patients with type 2 DM and 56 with HT. The 62 patients affected by DM were further distinguished in 24 subjects without renal impairment, 18 with diabetic nephropathy (DN), 20 with chronic kidney disease (CKD) stage 2–3 secondary to DN. The subgroup of 56 patients with primary HT comprised 26 subjects without renal complications and 30 with CKD (stage 2–3) secondary to HT. Thirty healthy controls, matched for age and sex, were recruited among blood donors. Results: Increased AOPP levels were found in DM patients compared with healthy subjects, although not significantly. This index was higher and more significant in patients with DN and CKD secondary to DN than in DM patients without nephropathy (p < 0.05) or controls (p < 0.0001). Patients with HT and with kidney impairment secondary to HT also had significantly higher AOPP serum levels than controls (p < 0.01 and p < 0.0001, respectively). There were no significant differences in mean AOPP levels among DM and HT patients. Conclusion: Our study showed that oxidative stress was higher in diabetic or hypertensive subjects than in healthy controls and, in particular, it appeared to be more severe in patients with renal complications. We suggest that the assessment of AOPP in diabetic and hypertensive patients may be important to predict the onset of renal failure and to open a new perspective on the adoption of antioxidant molecules to prevent CKD in those settings.