The histone methyltransferase SMYD1 is induced by thermogenic stimuli in adipose tissue.

Aim: To study the expression of histone methyltransferase SMYD1 in white adipose tissue (WAT) and brown adipose tissue and during differentiation of preadipocytes to white and beige phenotypes. Methods: C57BL/6J mice fed a high-fat diet (and exposed to cold) and 3T3-L1 cells stimulated to differentiate into white and beige adipocytes were used. Results: SMYD1 expression increased in WAT of high-fat diet fed mice and in WAT and brown adipose tissue of cold-exposed mice, suggesting its role in thermogenesis. SMYD1 expression was higher in beige adipocytes than in white adipocytes, and its silencing leads to a decrease in mitochondrial content and in Pgc-1α expression. Conclusion: These data suggest a novel role for SMYD1 as a positive regulator of energy control in adipose tissue.

In this study, a protein called SMYD1 was examined in the adipose tissue of mice to understand its role in the development of different types of fat cells. The authors used mice fed a high-fat diet or mice exposed to a cold environment. The experiments were also performed on cultured cells that were stimulated to form specific types of fat cells (white adipocytes, which store energy; or beige adipocytes, which are responsible for releasing energy in the form of heat). The study found that SMYD1 increased in white adipose tissue particularly in response to cold exposure and high-fat diet, suggesting involvement in body temperature regulation. SMYD1 was higher in beige adipocytes than in white fat cells, and when SMYD1 was reduced, there was a decrease in certain factors related to energy control. Overall, these results suggest that SMYD1 plays a novel role in energy regulation in adipose tissues.

Association between Dietary Habits and Severity of Symptoms in Premenstrual Syndrome.

BACKGROUND: Premenstrual syndrome (PMS) is a set of physical, psychological, and emotional symptoms that occur during the luteal phase of the menstrual cycle. The etiopathogenesis of this condition is not fully understood, and several studies suggest a possible role of environmental factors, such as diet. The aim of this work was to investigate the relationship between dietary habits and the occurrence and severity of PMS. METHODS AND RESULTS: Forty-seven women were enrolled in the study. Participants were asked to complete the Daily Record of Severity of Problems (DRSP) to diagnose PMS and to complete a three-day food record during the perimenstrual phase. Thirty women completed the study (16 with PMS and 14 controls). An analysis of the food diaries revealed no differences between the women with PMS and the control subjects in terms of total energy intake (1649 vs. 1570 kcal/day), diet composition, and the consumption of macro- or micronutrients, except for copper, whose consumption was higher in women with PMS than in the control subjects (1.27 ± 0.51 vs. 0.94 ± 0.49 mg/d, p < 0.05). CONCLUSIONS: The data presented here are very preliminary, and only a significant difference in copper intake was found when comparing women with PMS and controls. Larger studies are needed to better define how diet may contribute to the exacerbation of the psychological and somatic symptoms associated with PMS and whether PMS itself may influence macro- or micronutrient intake by changing dietary habits.

Quercetin and Its Derivative Counteract Palmitate-Dependent Lipotoxicity by Inhibiting Oxidative Stress and Inflammation in Cardiomyocytes.

Cardiac lipotoxicity plays an important role in the pathogenesis of obesity-related cardiovascular disease. The flavonoid quercetin (QUE), a nutraceutical compound that is abundant in the "Mediterranean diet", has been shown to be a potential therapeutic agent in cardiac and metabolic diseases. Here, we investigated the beneficial role of QUE and its derivative Q2, which demonstrates improved bioavailability and chemical stability, in cardiac lipotoxicity. To this end, H9c2 cardiomyocytes were pre-treated with QUE or Q2 and then exposed to palmitate (PA) to recapitulate the cardiac lipotoxicity occurring in obesity. Our results showed that both QUE and Q2 significantly attenuated PA-dependent cell death, although QUE was effective at a lower concentration (50 nM) when compared with Q2 (250 nM). QUE decreased the release of lactate dehydrogenase (LDH), an important indicator of cytotoxicity, and the accumulation of intracellular lipid droplets triggered by PA. On the other hand, QUE protected cardiomyocytes from PA-induced oxidative stress by counteracting the formation of malondialdehyde (MDA) and protein carbonyl groups (which are indicators of lipid peroxidation and protein oxidation, respectively) and intracellular ROS generation, and by improving the enzymatic activities of catalase and superoxide dismutase (SOD). Pre-treatment with QUE also significantly attenuated the inflammatory response induced by PA by reducing the release of key proinflammatory cytokines (IL-1ß and TNF-α). Similar to QUE, Q2 (250 nM) also significantly counteracted the PA-provoked increase in intracellular lipid droplets, LDH, and MDA, improving SOD activity and decreasing the release of IL-1ß and TNF-α. These results suggest that QUE and Q2 could be considered potential therapeutics for the treatment of the cardiac lipotoxicity that occurs in obesity and metabolic diseases.

Epigenome Modulation Induced by Ketogenic Diets.

Ketogenic diets (KD) are dietary strategies low in carbohydrates, normal in protein, and high, normal, or reduced in fat with or without (Very Low-Calories Ketogenic Diet, VLCKD) a reduced caloric intake. KDs have been shown to be useful in the treatment of obesity, metabolic diseases and related disorders, neurological diseases, and various pathological conditions such as cancer, nonalcoholic liver disease, and chronic pain. Several studies have investigated the intracellular metabolic pathways that contribute to the beneficial effects of these diets. Although epigenetic changes are among the most important determinants of an organism's ability to adapt to environmental changes, data on the epigenetic changes associated with these dietary pathways are still limited. This review provides an overview of the major epigenetic changes associated with KDs.

Obesity and Thyroid Cancer Risk: An Update.

Thyroid cancer (TC) is the most common endocrine malignancy worldwide and its incidence has increased dramatically in recent years. In parallel, the prevalence of overweight and obesity has also increased, suggesting a possible link between these two diseases. Indeed, low-grade chronic inflammation, altered cytokine levels, insulin resistance, oxidative stress, and hormonal changes that occur in obese patients are all factors that contribute to the occurrence and growth of TC. In this review, the most recent evidence supporting the potential role of the mechanisms linking obesity to TC will be discussed.

Quantitative but not qualitative flavor recognition impairments in COVID-19 patients.

BACKGROUND: Smell and taste dysfunctions (STDs) are symptoms associated with COVID-19 syndrome, even if their incidence is still uncertain and variable. AIMS: In this study, the effects of SARS-CoV-2 infection on chemosensory function have been investigated using both a self-reporting questionnaire on smell and flavor perception, and a simplified flavor test. METHODS: A total of 111 subjects (19 hospitalized [HOS] and 37 home-isolated [HI] COVID-19 patients, and 55 healthy controls [CTRL]) were enrolled in the study. They received a self-evaluation questionnaire and a self-administered flavor test kit. The flavor test used consists in the self-administration of four solutions with a pure olfactory stimulus (coffee), a mixed olfactory-trigeminal stimulus (peppermint), and a complex chemical mixture (banana). RESULTS: After SARS-CoV-2 infection, HOS and HI patients reported similar prevalence of STDs, with a significant reduction of both smell and flavor self-estimated perception. The aromas of the flavor test were recognized by HI and HOS COVID-19 patients similarly to CTRL; however, the intensity of the perceived aromas was significantly lower in patients compared to controls. CONCLUSION: Data reported here suggests that a chemosensory impairment is present after SARS-CoV-2 infection, and the modified "flavor test" could be a novel self-administering objective screening test to assess STDs in COVID-19 patients. CLINICAL TRIAL REGISTRATION NO: NCT04840966; April 12, 2021, retrospectively registered.

Epigenetic Mechanisms of Endocrine-Disrupting Chemicals in Obesity.

The incidence of obesity has dramatically increased over the last decades. Recently, there has been a growing interest in the possible association between the pandemics of obesity and some endocrine-disrupting chemicals (EDCs), termed "obesogens". These are a heterogeneous group of exogenous compounds that can interfere in the endocrine regulation of energy metabolism and adipose tissue structure. Oral intake, inhalation, and dermal absorption represent the major sources of human exposure to these EDCs. Recently, epigenetic changes such as the methylation of cytosine residues on DNA, post-translational modification of histones, and microRNA expression have been considered to act as an intermediary between deleterious effects of EDCs and obesity development in susceptible individuals. Specifically, EDCs exposure during early-life development can detrimentally affect individuals via inducing epigenetic modifications that can permanently change the epigenome in the germline, enabling changes to be transmitted to the next generations and predisposing them to a multitude of diseases. The purpose of this review is to analyze the epigenetic alterations putatively induced by chemical exposures and their ability to interfere with the control of energy metabolism and adipose tissue regulation, resulting in imbalances in the control of body weight, which can lead to obesity.

Epigenetic regulation of adipogenesis by histone-modifying enzymes.

Many studies investigating the transcriptional control of adipogenesis have been published so far; recently the research is focusing on the role of epigenetic mechanisms in regulating the process of adipocyte development. Histone-modifying enzymes and the histone tails post-transcriptional modifications catalyzed by them, are fundamentally involved in the epigenetic regulation of adipogenesis. In our review, we will discuss recent advances in epigenomic regulation of adipogenesis with a focus on histone-modifying enzymes implicated in the various phases of adipocytes differentiation process from mesenchymal stem cells to mature adipocytes. Understanding adipogenesis, may provide new ways to treat obesity and related metabolic diseases.

Flavor identification inversely correlates with body mass index (BMI).

BACKGROUND AND AIMS: Dietary choices are influenced by several factors including physiological, social, or genetic factors. Among these, flavor is the most important determinant modulating food preferences. The aim of the present study was to assess flavor identification abilities in patients with obesity (Ob) in comparison with matched normal weight (NW) and over-weight (OW) subjects using a specific and validated chemosensory test. METHODS AND RESULTS: The flavor test was administered to 140 Ob patients recruited in the obesity outpatient Unit at the Federico II University hospital and to the same number of NW and OW subjects matched by sex, age, and smoking habit. Flavor score (FS) inversely correlated with BMI. Median [Q1; Q3] FS was significantly higher in NW (14.5 [12; 16]) than in Ob (13 [10; 15] p < 0.001) and not significantly different from OW (14 [12; 16]) individuals. FS was also higher in OW than in Ob subjects (p < 0.005). When separated according to age quartiles, the BMI-related differences in FS were still significant in younger quartiles, while they were abolished in the older. CONCLUSIONS: BMI is a critical factor modulating flavor identification, particularly in young subjects. Further investigations are needed to explore the precise mechanism and the causal relationship between body weight and olfactory dysfunctions. CLINICALTRIAL ID: NCT03506074.

Influences of Age, Sex and Smoking Habit on Flavor Recognition in Healthy Population.

(1) Background: Flavor is one of the main factors influencing food preferences and dietary choices, and a reduction in flavor recognition has been associated with several diseases. A novel quantitative test to assess flavor has been recently developed and validated. The aim of the present work was to define the standard of flavor recognition in the general healthy population. (2) Methods: Three hundred and forty-eight healthy volunteers (18-80 years) performed the flavor test (FT). The test consisted of the oral administration of aqueous aromatic solutions, identifying 21 different compounds. Flavor score (FS) was calculated as the sum of the properly recognized flavors (range 0-21). (3) Results: Normal ranges for FT were produced. Flavor recognition was found to decrease with age. Females obtained slightly higher scores than males, mostly at older ages. Cigarette smoking seemed not to influence flavor recognition. (4) Conclusion: The normal values found for the flavor test in the healthy population will allow its usage as a diagnostic tool in several diseases.

Quercetin and its derivative Q2 modulate chromatin dynamics in adipogenesis and Q2 prevents obesity and metabolic disorders in rats.

Recently the attention of the scientific community has focused on the ability of polyphenols to counteract adverse epigenetic regulation involved in the development of complex conditions such as obesity. The aim of this study was to investigate the epigenetic mechanisms underlying the anti-adiposity effect of Quercetin (3,3',4',5,7-pentahydroxyflavone) and of one of its derivatives, Q2 in which the OH groups have been replaced by acetyl groups. In 3 T3-L1 preadipocytes, Quercetin and Q2 treatment induce chromatin remodeling and histone modifications at the 5' regulatory region of the two main adipogenic genes, c/EBPα and PPARγ. Chromatin immunoprecipitation assays revealed a concomitant increase of histone H3 di-methylation at Lys9, a typical mark of repressed gene promoters, and a decrease of histone H3 di-methylation at Lys 4, a mark of active transcription. At the same time, both compounds inhibited histone demethylase LSD1 recruitment to the 5' region of c/EBPα and PPARγ genes, a necessary step for adipogenesis. The final effect is a significant reduction in c/EBPα and PPARγ gene expression and attenuated adipogenesis. Q2 supplementation in rats reduced the gain in body weight and in white adipose tissue, as well as the increase in adipocyte size determined by high fat diet. Moreover, Q2 improved dyslipidemia, glucose tolerance and decreased the hepatic lipid accumulation by activating the expression of beta-oxidation related genes. Our data suggest that Q2, as well as Quercetin, has the potential to revert the unfavorable epigenomic profiles associated with obesity onset. This opens the possibility to use these compounds in targeted prevention strategies against obesity.

The co-activator-associated arginine methyltransferase 1 (CARM1) gene is overexpressed in type 2 diabetes.

PURPOSE: We examined the expression of a panel of epigenetic enzymes catalyzing histone tails post-transcriptional modifications, together with effectors of metabolic and inflammatory alterations, in type 2 diabetes. METHODS: Cross-sectional, case-control study of 21 people with type 2 diabetes and 21 matched controls. Total RNA was extracted from white cells and reverse transcribed. PCR primer assays for 84 key genes encoding enzymes known to modify genomic DNA and histones were performed. Western blot was performed on lysates using primary antibodies for abnormally expressed enzymes. Hormones and cytokines were measured by multiplex kits. A Bayesian network was built to investigate the relationships between epigenetic, cytokine, and endocrine variables. RESULTS: Co-activator-associated aRginine Methyltransferase 1 (CARM1) expression showed a five-fold higher median value, matched by higher protein levels, among patients who also had increased GIP, IL-4, IL-7, IL-13, IL-17, FGF basic, G-CSF, IFN-γ, and TNFα and decreased IP-10. In a Bayesian network approach, CARM1 expression showed a conditional dependence on diabetes, but was independent of all other variables nor appeared to influence any. CONCLUSIONS: Increased CARM1 expression in type 2 diabetes suggests that epigenetic mechanisms are altered in human diabetes. The impact of lifestyle and pharmacological treatment on regulation of this enzyme should be further investigated.

Aptamer Chimeras for Therapeutic Delivery: The Challenging Perspectives.

Nucleic acid-based aptamers have emerged as efficient delivery carriers of therapeutics. Thanks to their unique features, they can be, to date, considered one of the best targeting moieties, allowing the specific recognition of diseased cells and avoiding unwanted off-target effects on healthy tissues. In this review, we revise the most recent contributes on bispecific and multifunctional aptamer therapeutic chimeras. We will discuss key examples of aptamer-mediated delivery of nucleic acid and peptide-based therapeutics underlying their great potentiality and versatility. Achieved objectives and challenges will be highlighted as well.

Nucleic Acid Aptamers Targeting Epigenetic Regulators: An Innovative Therapeutic Option.

Epigenetic mechanisms include DNA methylation, posttranslational modifications of histones, chromatin remodeling factors, and post transcriptional gene regulation by noncoding RNAs. All together, these processes regulate gene expression by changing chromatin organization and DNA accessibility. Targeting enzymatic regulators responsible for DNA and chromatin modifications hold promise for modulating the transcriptional regulation of genes that are involved in cancer, as well as in chronic noncommunicable metabolic diseases like obesity, diabetes, and cardiovascular diseases. Increasingly studies are emerging, leading to the identification of specific and effective molecules targeting epigenetic pathways involved in disease onset. In this regard, RNA interference, which uses small RNAs to reduce gene expression and nucleic acid aptamers are arising as very promising candidates in therapeutic approach. Common to all these strategies is the imperative challenge of specificity. In this regard, nucleic acid aptamers have emerged as an attractive class of carrier molecules due to their ability to bind with high affinity to specific ligands, their high chemical flexibility as well as tissue penetration capability. In this review, we will focus on the recent progress in the field of aptamers used as targeting moieties able to recognize and revert epigenetics marks involved in diseases onset.

High-fat diet unveils an enhancer element at the Ped/Pea-15 gene responsible for epigenetic memory in skeletal muscle.

BACKGROUND: The impact of nutrition on the evolution towards type 2 diabetes has recently received increasing attention because of the effect on chromatin structure and gene expression. PURPOSE: Evaluate the effect of high-fat diet on chromatin remodelling and expression of Ped/Pea-15, a gene commonly overexpressed in individuals at risk of type 2 diabetes. METHODS: We used mouse and cell models to investigate Ped/Pea-15 transcriptional regulation by high-fat diet and glucose, respectively. Chromatin structure and histone modification marks were assessed by Micrococcal Nuclease Protection and Chromatin Immunoprecipitation assays. RESULTS: Sixteen-week exposure of C57BL/6J mice to a high-fat diet impaired glucose tolerance and enhanced Ped/Pea-15 expression in their skeletal muscle tissue. This effect was associated with increased chromatin accessibility at specific regulatory sites at the Ped/Pea-15 gene. In particular, the region at -1900 to -1300 bp from Ped/Pea-15 transcription start site was revealed to feature enhancer activity as demonstrated by its function in the luciferase assay, increased p300 recruitment and H3K4me1 and H3K27Ac levels, all marks of functionally active enhancers. Returning mice to a standard chow diet was accompanied by rapid loss of acetylation of K27 on histone H3 and p300 recruitment at Ped/Pea-15. In contrast, the increased H3K4me1, which accompanied the high-fat diet exposure, remained stable. Incubation of muscle cells in culture medium supplemented with 25 mM glucose (HG) increased Ped/Pea-15 mRNA expression and H3K4me1 at the enhancer region. These effects became measurable upon 72 h of exposure to the HG medium and were not rescued upon returning the cells to the 5 mM glucose-containing medium. Interestingly, after 25 mM and sequential 5 mM glucose treatments, re-exposure of the same cells to HG medium further enhanced Ped/Pea-15 expression and increased H3K4me1 above the levels induced by the initial HG challenge already upon 24 h. CONCLUSION: Transient exposure to HFD or HG unveiled the presence of an enhancer element at the Ped/Pea-15 gene. Epigenetic changes imposed at this region by diets, which impair glucose tolerance generate metabolic memory of the nutritional injury and leave Ped/Pea-15 induction in a poised state.

Isoquercetin as an Adjunct Therapy in Patients With Kidney Cancer Receiving First-Line Sunitinib (QUASAR): Results of a Phase I Trial.

Sunitinib is the most commonly prescribed drug for advanced renal cell carcinoma in the first-line setting and has been associated with multiple adverse events related to its on-and off-target effects, including hand and foot syndrome and fatigue. It was hypothesized that sunitinib-induced fatigue may be related to off target inhibition of the AMPK enzyme, which results in impairment of energy-producing processes at a systemic level. Quercetin is a naturally occurring flavonol with established AMPK-stimulating activity. While clinical use of quercetin is limited by its poor bio-availability, quercetin-3-O-ß-d-glucopyranoside, that is isoquercetin, has an improved pharmacokinetic profile. On the grounds of the in vitro stimulatory activity with respect to AMPk, we hypothesized that oral isoquercetin could improve fatigue in kidney cancer patients receiving sunitinib. Given the lack of data on the safety of isoquercetin given concomitantly with sunitinib, we conducted a phase I trial to assess the safety of GMP manufactured isoquercetin given at two dose levels (450 and 900 mg a day). In the 12-patient study cohort included in this study, isoquercetin was administered concomitantly with 50 mg sunitinib for a median 81 days (IQR, 75.5, 86.5). None of the 12 patients required isoquercetin suspension or isoquercetin dose reduction because of adverse events. No abnormalities in ECG, heart or lower limbs doppler ultrasound were detected. A statistically significant improvement was reported for the FACIT fatigue score (6.8 points; 95% CI: 2.8-10.8; p = 0.002) and for the FACIT Adverse Events score (18.9 points; 95% CI: 9.1-28.8; p < 0.001) after isoquercetin consumption vs. baseline. In this phase I trial, isoquercetin was remarkably safe, with a preliminary signal of activity in terms of improvement of sunitinib adverse events.

Epigenetic Signature: A New Player as Predictor of Clinically Significant Prostate Cancer (PCa) in Patients on Active Surveillance (AS).

Widespread prostate-specific antigen (PSA) testing notably increased the number of prostate cancer (PCa) diagnoses. However, about 30% of these patients have low-risk tumors that are not lethal and remain asymptomatic during their lifetime. Overtreatment of such patients may reduce quality of life and increase healthcare costs. Active surveillance (AS) has become an accepted alternative to immediate treatment in selected men with low-risk PCa. Despite much progress in recent years toward identifying the best candidates for AS in recent years, the greatest risk remains the possibility of misclassification of the cancer or missing a high-risk cancer. This is particularly worrisome in men with a life expectancy of greater than 10-15 years. The Prostate Cancer Research International Active Surveillance (PRIAS) study showed that, in addition to age and PSA at diagnosis, both PSA density (PSA-D) and the number of positive cores at diagnosis (two compared with one) are the strongest predictors for reclassification biopsy or switching to deferred treatment. However, there is still no consensus upon guidelines for placing patients on AS. Each institution has its own protocol for AS that is based on PRIAS criteria. Many different variables have been proposed as tools to enrol patients in AS: PSA-D, the percentage of freePSA, and the extent of cancer on biopsy (number of positive cores or percentage of core involvement). More recently, the Prostate Health Index (PHI), the 4 Kallikrein (4K) score, and other patient factors, such as age, race, and family history, have been investigated as tools able to predict clinically significant PCa. Recently, some reports suggested that epigenetic mapping differs significantly between cancer patients and healthy subjects. These findings indicated as future prospect the use of epigenetic markers to identify PCa patients with low-grade disease, who are likely candidates for AS. This review explores literature data about the potential of epigenetic markers as predictors of clinically significant disease.

Selenium supplementation modulates apoptotic processes in thyroid follicular cells.

Selenium (Se) is an essential micronutrient modulating several physiopathological processes in the human body. The aim of the study is to characterize the molecular effects determined by Se-supplementation in thyroid follicular cells, using as model the well-differentiated rat thyroid follicular cell line FRTL5. Experiments have been performed to evaluate the effects of Se on cell growth, mortality and proliferation and on modulation of pro- and antiapoptotic pathways. The results indicate that Se-supplementation improves FRTL5 growth rate. Furthermore, Se reduces the proportion of cell death and modulates both proapoptotic (p53 and Bim) and antiapoptotic (NF-kB and Bcl2) mRNA levels. In addition, incubation with high doses of Na-Se might prevent the ER-stress apoptosis induced by tunicamycin, as assessed by membrane integrity maintenance, reduction in caspase 3/7 activities, and reduction in Casp-3 and PARP cleavage. Taken together, these results provide molecular evidences indicating the role of Se supplementation on cell death and apoptosis modulation in thyroid follicular cells. These observations may be useful to understand the effects of this micronutrient on the physiopathology of the thyroid gland. © 2016 BioFactors, 43(3):415-423, 2017.

Sunshine vitamin and thyroid.

Vitamin D exerts its canonical roles on the musculoskeletal system and in the calcium/phosphorus homeostasis. In the last years, increasing evidences suggested several extra-skeletal actions of this hormone, indicating that vitamin D may produce effects in almost all the body tissues. These are mediated by the presence of vitamin D receptor (VDR) and thanks to the presence of the 1-α-hydroxylase, the protein that converts the 25-hydroxyvitamin (calcidiol) to the active form 1,25-dihydroxyvitamin (calcitriol). Several studies evaluated the possible role of vitamin D in the pathogenesis of thyroid diseases, and this review will focus on the available data of the literature evaluating the association between vitamin D and thyroid function, vitamin D and autoimmune thyroid diseases, including Hashimoto's thyroiditis, Graves' disease and post-partum thyroiditis, and vitamin D and thyroid cancer.