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Background and Aims: Several studies have supported the role of innate immune system as a key factor in the sterile inflammation underlying the pathophysiology of atherosclerosis in mice. However, its involvement in humans remains unclear. This study aimed to explore the association between neutrophil count, and the intima-media thickness of common carotid arteries (IMT-CC), as well as the potential impact of long-term dietary interventions on these associations., Methods: A comprehensive analysis was conducted within the framework of the CORDIOPREV study, a long-term secondary prevention study involving dietary interventions with either a Mediterranean or a low-fat diet. The study evaluated the relationship between absolute neutrophil count and neutrophil-related ratios with IMT-CC at baseline and after 5 and 7 years of dietary intervention., Results: At baseline, patients in the highest tertile of neutrophil count had a higher IMT-CC and number of carotid plaques, when compared to lowest tertile (P < .01 and P < .05, respectively). Logistic regression analyses supported this association. Elevated neutrophil count, neutrophil-to-erythrocyte ratio, and neutrophil-to-HDL ratio were associated with an increased likelihood of having an IMT-CC >.9 mm {odds ratio (OR) 1.17 [95% confidence interval (CI) 1.04-1.35], OR 2.21 (95% CI 1.24-4.12), and OR 1.96 (95% CI 1.09-3.55), respectively}, after adjustment for all variables, which was corroborated by linear regression. Furthermore, a linear mixed-effect model analysis from a longitudinal analysis spanning 5 and 7 years revealed an increase in 1 unit of neutrophils/μl at these time points was associated with a mean increase of .004 (.002) mm in the IMT-CC (P = .031) after adjustment for all variables. Interestingly, in patients exhibiting regression in IMT-CC after 7 years of follow-up, those following a Mediterranean diet showed a significant decrease in neutrophil count after 5 and 7 years (both with P < .05), compared to baseline., Conclusions: These findings suggest that neutrophils may represent a promising target for preventing atherosclerosis. A Mediterranean diet could serve as an effective dietary strategy to reduce neutrophil levels and potentially slow the progression of atherosclerosis, offering a new neutrophil-reducing therapy concept. Further research is essential to gain deeper insights into the role of neutrophils in the pathophysiology of atherosclerotic cardiovascular disease in humans., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Malnutrition and sarcopenia are highly prevalent in patients with head neck cancer (HNC). An accurate early diagnosis is necessary for starting nutritional support, as both are clearly associated with clinical outcomes and mortality. We aimed to evaluate the applicability and accuracy of body composition analysis using electrical bioimpedance vectorial analysis (BIVA) for diagnosing malnutrition and sarcopenia in patients with HNC cancer undergoing systemic treatment with chemotherapy or radiotherapy., Methods: Cross-sectional, observational study that included 509 HNC patients. A comprehensive nutritional evaluation that included BIVA was performed., Results: The prevalence of malnutrition was higher in patients that received treatment with chemotherapy (59.2% vs. 40.8%, P < 0.001); increased mortality was observed in malnourished patients (33.3% vs. 20.1%; P < 0.001); ECOG status (1-4) was also worse in malnourished patients (59.2% vs. 22.8% P < 0.001). Body cell mass (BCM) and fat mass were the most significantly associated parameters with malnutrition [OR 0.88 (0.84-0.93) and 0.98 (0.95-1.01), respectively]; BCM and fat free mass index (FFMI) were associated with several aspects including (1) the patient-generated subjective global assessment [OR 0.93 (0.84-0.98) and 0.86 (0.76-0.97), respectively], (2) the presence of sarcopenia [OR 0.81 (0.76-0.87) and 0.78 (0.66-0.92), respectively]. A BCM index (BCMI) < 7.8 in combination with other parameters including FFMI and BCM accurately predicted patients with malnutrition [accuracy 95% CI: 0.803 (0.763-0.839); kappa index: 0.486; AUC: 0.618 (P < 0.01)]. A BCMI cutoff of 7.6 was enough for identifying males with malnutrition (P < 0.001), while it should be combined with other parameters in females., Conclusions: Body composition parameters determined by BIVA accurately identify patients with HNC and malnutrition. Phase angle, but other parameters including BCMI, FFMI and BCM provide significant information about nutritional status in patients with HNC., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Background: Numerous studies have reported an association between neutrophils and T2DM, although this relationship remains unclear. This study aims to investigate the interaction of neutrophils and a dietary intervention on T2DM incidence after 60 months of follow-up., Methods: A comprehensive analysis was conducted on the framework of the CORDIOPREV study, which included 462 patients without T2DM at the beginning of the study. They were randomly assigned to either a Mediterranean or a low-fat diet, of whom 107 developed T2DM. Absolute neutrophil counts and other related-ratio, were measured., Results: Kaplan-Meier curves showed that the lowest tertile of basal neutrophils was associated with a reduced likelihood of T2DM incidence when compared to the middle [HR=0.499 (95%CI, 0.287-0.866)] and the highest tertiles [HR=0.442 (95%CI, 0.255-0.768)] in overall population, after adjusting for clinical variables. This association only remained significant in patients who follow a Mediterranean diet when compared the lowest to the middle [HR=0.423 (95% CI, 0.213-0.842)] and the highest tertiles [HR=0.371 (95% CI, 0.182-0.762)]. The predictive capacity yielded an AUC of 0.711 (95%CI: 0.652-0.769), being neutrophils the most important variable in the in the model. Decrease in neutrophils over the 60 months were associated with increased insulin sensitivity index (ISI) (R=-0.31; p=0.019), particularly in patients who followed the Mediterranean diet., Conclusion: These findings suggest that monitoring neutrophils can help prevent the development of T2DM, as a reduction in neutrophil counts could be associated with improved insulin sensitivity. Following a Mediterranean diet might be a potential strategy to reduce the incidence of T2DM by lowering neutrophil levels. Further research is necessary to gain a deeper understanding regarding this mechanism., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Jaboticaba ( Myrciaria jaboticaba ) is a recognizable and unique crop from Brazil. The fruit's byproducts are currently being studied, given their bioactive composition and promising anti-cancer potential. It is not evident, however, if different harvesting seasons can modify the chemical profile and antioxidant capacity of jaboticaba fruit fractions. Furthermore, as there is limited data for jaboticaba's anti-proliferative effects, additional assessments are required to improve the robustness of these findings. Therefore, this study aimed to determine the composition of the peel of jaboticaba collected in two periods (May-off-season, sample 1-and August-October-peak season, sample 2) and test the peel's richest anthocyanin sample against colorectal cancer (CRC) cell lines. To accomplish this, proximate, spectrophotometric, and chromatographic analyses were performed in two freeze-dried samples; and anti-proliferative and/or colony-forming assays were carried out in Caco-2, HT29, and HT29-MTX cells. As a result, sample 2 showed the highest levels of polyphenols overall, including flavonoids and anthocyanins. This sample displayed significative higher contents of cyanidin-3- O -glucoside (48%) and delphinidin-3- O -glucoside (105%), in addition to a superior antioxidant capacity (23% higher). Sample 1 showed higher amounts of total protein, gallic acid (20% higher), and specific carotenoids. An aqueous extract from sample 2 was tested against CRC, showing anti-proliferative effects for Caco-2 cells at 1 and 2 mg/mL concentrations, with IC50 values of 1.2-1.3 mg/mL. Additionally, the extract was able to inhibit cell colony formation when tested at both low and high concentrations. In conclusion, jaboticaba collected in the main season stands out regarding its polyphenol composition and holds potential against cancer cell growth.

Background: Colorectal cancer (CRC) continues to be a major health concern in today's world. Despite conflictive findings, evidence supports systemic inflammation's impact on CRC patients' survival rates. Therefore, this study aims to assess the prognostic role of the innate immune system in patients with CRC., Method: A total of 449 patients were included, with a 5-year follow-up period, and absolute neutrophil counts and their related ratios were measured., Results: The non-survival group had increased levels of white blood cells, neutrophils (both p <0.001), and monocytes (p=0.038), compared to the survival group, along with other neutrophil-related ratios. We observed increased mortality risk in patients in the highest tertile of white blood cells [HR=1.85 (1.09-3.13), p<0.05], neutrophils [HR=1.78 (95% CI: 1.07-2.96), p<0.05], and monocytes [HR=2.11 (95% CI: 1.22-3.63)], compared to the lowest tertile, after adjusting for all clinicopathological variables. Random forest analysis identified neutrophils as the most crucial variable in predicting survival rates, having an AUC of 0.712, considering all clinicopathological variables. A positive relationship between neutrophil counts and metastasis was observed when neutrophil counts are considered continuous (β=0.92 (0.41), p<0.05) and tumor size (width) when neutrophils were considered as logistic variable (T1 vs T3) [OR=1.42, (95% CI: 1.05-1.98), p<0.05]., Conclusion: This study offers comprehensive insights into the immune factors that impact the prognosis of CRC, emphasizing the need for personalized prognostic tools., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Garcia-Flores, Dawid De Vera, Pilo, Rego, Gomez-Casado, Arranz-Salas, Hierro Martín, Alcaide, Torres, Ortega-Gomez, Boughanem and Macias-Gonzalez.)

Background: Several studies have suggested secreted frizzled-related protein 2 (SFRP2) gene as a potential clinical biomarker in colorectal cancer (CRC). However, its diagnostic role remains unclear. In this study, we aimed to investigate the significance of SFRP2 methylation levels in a large cohort of biological specimens (including blood, adipose and colonic tissues) from patients with CRC, thereby potentially identifying new biomarker utility., Methods: We examined the expression (by qPCR) and methylation status (by 450 K DNA array and DNA pyrosequencing) of the SFRP2 gene in healthy participants (N = 110, aged as 53.7 (14.2), 48/62 males/females) and patients with CRC (N = 85, aged 67.7 (10.5), 61/24 males/females), across different biological tissues, and assessing its potential as a biomarker for CRC. Additionally, we investigated the effect of recombinant human SFRP2 (rhSFRP2) as a therapeutic target, on cell proliferation, migration, and the expression of key genes related to carcinogenesis and the Wnt pathway., Results: Our findings revealed that SFRP2 promoter methylation in whole blood could predict cancer stage (I + II vs. III + IV) (AUC = 0.653), lymph node invasion (AUC = 0.692), and CRC recurrence (AUC = 0.699) in patients with CRC (all with p < 0.05). Furthermore, we observed a global hypomethylation of SFRP2 in tumors compared to the adjacent area (p < 0.001). This observation was validated in the TCGA-COAD and TCGA-READ cohorts, demonstrating overall hypermethylation (both with p < 0.001) and low expression (p < 0.001), as shown in publicly available scRNA-Seq data. Notably, neoadjuvant-treated CRC patients exhibited lower SFRP2 methylation levels compared to untreated patients (p < 0.05) and low promoter SFRP2 methylation in untreated patients was associated with poor overall survival (p < 0.05), when compared to high methylation. Finally, treatment with 5 µg of rhSFRP2 treatment in CRC cells (HCT116 cells) inhibited cell proliferation (p < 0.001) and migration (p < 0.05), and downregulated the expression of AXIN2 (p < 0.01), a gene involved in Wnt signaling pathway., Conclusions: These findings establish promoter methylation of the SFRP2 gene as a prognostic candidate in CRC when assessed in blood, and as a therapeutic prognostic candidate in tumors, potentially valuable in clinical practice. SFRP2 also emerges as a therapeutic option, providing new clinical and therapeutical avenues., (© 2024. The Author(s).)

Introduction: Bioelectrical impedance analysis (BIA) serves as a method to estimate body composition. Parameters such as phase angle (PA), standardized phase angle (SPA), body mass cell (BCM), BCM index (BCMI), and fat-free mass (FFM) might significantly impact the prognosis of head and neck cancer (HNC) patients. The present study aimed to investigate whether bioelectrical parameters can be used to predict survival in the HNC population and establish the optimal cutoff points for predictive accuracy., Methods: A multicenter observational study was performed across 12 tertiary hospitals in Andalusia (a region from the south of Spain). A total of 494 patients diagnosed with HNC between 2020 and 2022 at different stages were included in this study, with a minimum follow-up period of 12 months. The BIA assessment was carried out during the first 2 weeks of radical radiotherapy treatment with chemotherapy or other systemic treatments. A multivariate logistic regression analysis of overall survival, complications, hospital admission, and palliative care and its relationship with BIA nutritional assessment was performed., Results: Significant prognostic factors identified in the multivariable analysis encompassed phase angle (PA), standardized phase angle (SPA), body cell mass (BCM), and BCM index (BCMI). Lower PA and BCM values were significantly associated with adverse clinical outcomes. A BCM threshold above 17 kg/m 2 was the most significant predictor for predicting survival within the overall HNC population. The PA values of <5.1° in male and <4.8° in female patients showed the best predictive potential for mortality. Increased PA (as a continuous variable) demonstrated a significantly reduced risk for mortality (OR, 0.64; 95% CI, 0.43-0.94; p  < 0.05) and a decreased likelihood of hospital admission (OR, 0.75; 95% CI, 0.52-1.07; p  < 0.05). Higher BCM correlated with a lower risk of mortality (OR, 0.88; 95% CI, 0.80-0.96; p  < 0.01) and a diminished probability of hospital admission (OR, 0.91; 95% CI, 0.83-0.99; p  < 0.05)., Conclusion: BIA is a crucial tool in the nutritional assessment of HNC patients. BCM and PA are the main bioelectrical parameters used to predict clinical outcomes in this population. Future studies are needed to validate BIA variables in a large cohort to ensure whether early intensification of nutritional treatment would improve survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Prior-Sánchez, Herrera-Martínez, Zarco-Martín, Fernández-Jiménez, Gonzalo-Marín, Muñoz-Garach, Vilchez-López, Cayón-Blanco, Villarubia-Pozo, Muñoz-Jiménez, Zarco-Rodríguez, Rabat-Restrepo, Luengo-Pérez, Boughanem, Martínez-Ramírez and García-Almeida.)

Head and neck cancer (HNC) is a prevalent and aggressive form of cancer with high mortality rates and significant implications for nutritional status. Accurate assessment of malnutrition in patients with HNC is crucial for optimizing treatment outcomes and improving survival rates. This study aimed to evaluate the use of ultrasound techniques for predicting nutritional status, malnutrition, and cancer outcomes in patients with HNC. A total of 494 patients with HNC were included in this cross-sectional observational study. Various tools and body composition measurements, including muscle mass and adipose tissue ultrasound evaluations, were implemented. Using regression models, we mainly found that high levels of RF-CSA (rectus femoris cross-sectional area) were associated with a decreased risk of malnutrition (as defined with GLIM criteria (OR = 0.81, 95% CI: 0.68-0.98); as defined with PG-SGA (OR = 0.78, 95% CI: 0.62-0.98)) and sarcopenia (OR = 0.64, 95% CI: 0.49-0.82) after being adjusted for age, sex, and BMI. To predict the importance of muscle mass ultrasound variables on the risk of mortality, a nomogram, a random forest, and decision tree models were conducted. RF-CSA was the most important variable under the random forest model. The obtained C-index for the nomogram was 0.704, and the Brier score was 16.8. With an RF-CSA < 2.7 (AUC of 0.653 (0.59-0.77)) as a split, the decision tree model classified up to 68% of patients as possessing a high probability of survival. According to the cut-off value of 2.7 cm 2 , patients with a low RF-CSA value lower than 2.7 cm 2 had worse survival rates ( p < 0.001). The findings of this study highlight the importance of implementing ultrasound tools, for accurate diagnoses and monitoring of malnutrition in patients with HNC. Adipose tissue ultrasound measurements were only weakly associated with malnutrition and not with sarcopenia, indicating that muscle mass is a more important indicator of overall health and nutritional status. These results have the potential to improve survival rates and quality of life by enabling early intervention and personalized nutritional management.

Vitamin D, microbiota, and the Mediterranean diet (MedDiet) have been the focus of recent research due to their potential role in maintaining overall health. We hypothesize that MedDiet may alter the gut microbiota profile through changes in vitamin D levels. We aimed to investigate changes in gut microbiota and serum vitamin D levels after a MedDiet within a lifestyle intervention. The study included 91 patients with obesity and metabolic syndrome, who were categorized based on their serum vitamin D levels as having either optimal or low 25-hydroxyvitamin D [25(OH)D levels]. The profile of the gut microbiota was analyzed by the 16S rRNA sequencing, inferring its functionality through PICRUsT. Participants underwent a hypocaloric MedDiet and change in their lifestyle for 1 year, and the profile and functionality of their gut microbiota were evaluated by analyzing inter-individual differences in time. At baseline, gut microbiota profiles qualitatively differed between participants with Optimal or Low 25(OH)D levels [Unweighted ( p  = 0.016)]. Moreover, participants with Optimal 25(OH)D levels showed a higher gut microbiota diversity than those with Low 25(OH)D levels ( p  < 0.05). The differential analysis of abundance between the Low and Optimal 25(OH)D groups revealed differences in the levels of Bacteroides , Prevotella , and two Clostridiales features. After 1-year dietary intervention, both groups increased their 25(OH)D levels. Furthermore, both groups did not show significant differences in gut microbiota diversity, although the Low 25(OH)D group showed greater improvement in gut microbiota diversity by comparing at baseline and after dietary intervention ( p  < 0.05). Changes in specific bacterial taxa were observed within each group but did not differ significantly between the groups. Metabolic pathway analysis indicated differences in microbial functions between the groups ( p  < 0.05). These findings suggest that 25(OH)D status is associated with gut microbiota composition, diversity, and functionality, and lifestyle intervention can modulate both gut microbiota and 25(OH)D levels, potentially influencing metabolic pathways.

DNA damage has been extensively studied as a potentially helpful tool in assessing and preventing cancer, having been widely associated with the deregulation of DNA damage repair (DDR) genes and with an increased risk of cancer. Adipose tissue and tumoral cells engage in a reciprocal interaction to establish an inflammatory microenvironment that enhances cancer growth by modifying epigenetic and gene expression patterns. Here, we hypothesize that 8-oxoguanine DNA glycosylase 1 (OGG1)-a DNA repair enzyme-may represent an attractive target that connects colorectal cancer (CRC) and obesity. In order to understand the mechanisms underlying the development of CRC and obesity, the expression and methylation of DDR genes were analyzed in visceral adipose tissue from CRC and healthy participants. Gene expression analysis revealed an upregulation of OGG1 expression in CRC participants ( p < 0.005) and a downregulation of OGG1 in normal-weight healthy patients ( p < 0.05). Interestingly, the methylation analysis showed the hypermethylation of OGG1 in CRC patients ( p < 0.05). Moreover, expression patterns of OGG1 were found to be regulated by vitamin D and inflammatory genes. In general, our results showed evidence that OGG1 can regulate CRC risk through obesity and may act as a biomarker for CRC.

Gene expression altering epigenomic modifications such as DNA methylation, histone modification, and chromosome remodeling is crucial to regulating many biological processes. Several lifestyle factors, such as diet and natural, bioactive food compounds, such as vitamins, modify epigenetic patterns. However, epigenetic dysregulation can increase the risk of many diseases, including cancer. Various studies have provided supporting and contrasting evidence on the relationship between vitamins and cancer risk. Though there is a gap in knowledge about whether dietary vitamins can induce epigenetic modifications in the context of colorectal cancer (CRC), the possibility of using them as epidrugs for CRC treatment is being explored. This is promising because such studies might be informative about the most effective way to use vitamins in combination with DNA methyltransferase inhibitors and other approved therapies to prevent and treat CRC. This review summarizes the available epidemiological and observational studies involving dietary, circulating levels, and supplementation of vitamins and their relationship with CRC risk. Additionally, using available in vitro, in vivo, and human observational studies, the role of vitamins as potential epigenetic modifiers in CRC is discussed. This review is focused on the action of vitamins as modifiers of DNA methylation because aberrant DNA methylation, together with genetic alterations, can induce the initiation and progression of CRC. Although this review presents some studies with promising results, studies with better study designs are necessary. A thorough understanding of the underlying molecular mechanisms of vitamin-mediated epigenetic regulation of CRC genes can help identify effective therapeutic targets for CRC prevention and treatment., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Mitochondrial epitranscriptomics refers to the modifications occurring in all the different RNA types of mitochondria. Although the number of mitochondrial RNA modifications is less than those in cytoplasm, substantial evidence indicates that they play a critical role in accurate protein synthesis. Recent evidence supported those modifications in mitochondrial RNAs also have crucial implications in mitochondrial-related diseases. In the light of current knowledge about the involvement, the association between mitochondrial RNA modifications and diseases arises from studies focusing on mutations in both mitochondrial and nuclear DNA genes encoding enzymes involved in such modifications. Here, we review the current evidence available for mitochondrial RNA modifications and their role in metabolic disorders, and we also explore the possibility of using them as promising targets for prevention and early detection. Finally, we discuss future directions of mitochondrial epitranscriptomics in these metabolic alterations, and how these RNA modifications may offer a new diagnostic and theragnostic avenue for preventive purposes. This article is categorized under: RNA Processing > RNA Editing and Modification., (© 2022 The Authors. WIREs RNA published by Wiley Periodicals LLC.)

Background: Patients with colorectal cancer (CRC) are largely malnourished, which decreases overall survival and treatment efficacy and increases mortality rates. We hypothesize that angle phase might be associated with the risk of sarcopenia as well as cancer complications in patients with CRC. The inclusion of various nutritional status indicators and clinical cancer outcomes can result in significant variability. Therefore, the objective of this study was to perform an exploratory analysis of nutritional evaluation tools used to assess body composition and muscle quality in patients with CRC, in order to predict cancer complications and survival rate., Methods: A total of 127 patients with CRC were included in this study. Bioelectrical impedance analysis and body composition were performed, which we used to obtain phase angle (PhA) values. Muscle function was assessed by hand-grip strength (HGS) and muscle quality and adipose tissue depot were performed using ultrasound techniques., Results: This study showed that there were significant differences in body composition between females and males, as well as in muscle quantity and quality. PhA was highly correlated with quadriceps rectus femoris of cross-sectional area (RF-CSA), circumference of quadriceps rectus femoris (RF-CIR), superficial subcutaneous abdominal fat (S-SAT), as well as HGS ( p < 0.05). PhA was also correlated with water content in females, and with muscle mass and quality in males ( p < 0.05). Specifically, we found that PhA was a good predictor for cancer complications in women and the risk of sarcopenia in men. In the linear model controlled for age and body mass index (BMI), high PhA value was associated with a decreased risk of complications in females (Odds Ratio (OR) = 0.15, 95% CI: 0.03-0.81, p < 0.05). High PhA value was associated with a decreased risk of sarcopenia in males (OR = 0.42, 95% CI: 0.19-0.95, p < 0.05). In addition, Receiving Operating Characteristics (ROC) curve analysis showed that PhA had a good diagnostic accuracy for detecting cancer complications in females (Area under curve (AUC) = 0.894, 95% CI: 0.88-0.89, p < 0.05) and the risk of sarcopenia in males (AUC = 0.959, 95% CI: 0.91-0.92, p < 0.05)., Conclusions: PhA can accurately predict oncological complications in women and sarcopenia in men. These differences are relevant to understanding the nutritional status of patients with CRC and their personalized nutritional treatment.

The associations between circulating vitamin D concentrations and total and site-specific colorectal cancer (CRC) incidence have been examined in several epidemiological studies with overall inconclusive findings. The aim of this systematic review and meta-analysis of both case-control and prospective cohort studies was to evaluate the association between CRC and circulating levels of vitamin D. The main exposure and outcome were circulating total 25(OH)D and CRC, respectively, in the overall population (i.e., all subjects). Two reviewers, working independently, screened all the literature available to identify studies that met the inclusion criteria (e.g., case-control or prospective cohort studies, published in English, and excluding non-original papers). Data were pooled by the generic inverse variance method using a random or fixed effect model, as approriate. Heterogeneity was identified using the Cochran's Q-test and quantified by the I 2 statistic. Results were stratified by study design, sex, and metabolite of vitamin D. Sensitivity and subgroup analyses were also performed. A total of 28 original studies were included for the quantitative meta-analysis. Meta-analyses comparing the highest vs lowest categories, showed a 39% lower risk between levels of total 25(OH)D and CRC risk (OR (95% CI): 0.61 (0.52; 0.71); 11 studies) in case-control studies; whereas a 20% reduced CRC risk in prospective cohort studies (HR (95% CI): 0.80 (0.66; 0.97); 6 studies). Results in women mirrored main results, whereas results in men were non-significant in both analyses. Our findings support an inverse association between circulating vitamin D levels and CRC risk.

The Mediterranean diet (MD) is one of the healthiest ones and is associated with a lower incidence of cardiovascular and cerebrovascular diseases as well as cancer. Extra virgin olive oil (EVOO) is probably the most idiosyncratic component of this diet. EVOO has been attributed with many healthful effects, which may be due to its phenolic components, e.g. including hydroxytyrosol (HT). Recent studies suggest that EVOO and HT have molecular targets in human tissues and modulate epigenetic mechanisms. DNA methylation is one of the most studied epigenetic mechanisms and consists of the addition of a methyl group to the cytosines of the DNA chain. Given the purported health effects of EVOO (poly)phenols, we analyzed the changes induced by HT in DNA methylation, in a colorectal cancer cell line. Caco-2 cells were treated with HT for one week or with the demethylating agent 5'-azacytidine for 48 h. Global DNA methylation was assessed by ELISA. DNA bisulfitation was performed and Infinium Methylation EPIC BeadChips were used to analyze the specific methylation of CpG sites. We show an increase in global DNA methylation in Caco-2 cells after HT treatment, with a total of 32,141 differentially methylated (CpGs DMCpGs). Interestingly, our analyses revealed the endothelin receptor type A gene (EDNRA) as a possible molecular target of HT. In summary, we demonstrate that cellular supplementation with HT results in a specific methylome map and propose a potential gene target for HT., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest associated with this work., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Backgrounds: Vitamin D and testosterone deficiency have been widely related to obesity. However, only a few studies have investigated the effect of vitamin D on testosterone in the context of obesity, in which controversial results have been raised., Objectives: The purpose of this study was to determine the relationship between serum 25-hydroxyvitamin D (25(OH)D) and testosterone levels in young men with different grade of obesity., Design and Methods: This cross-sectional study included 269 healthy young men with obesity (body mass index (BMI) ≥ 30 kg/m 2 ). Participants were divided into two groups based on their serum 25(OH)D levels (134 subjects with vitamin D sufficiency and 135 participants with vitamin D deficiency, according to the 50 th percentile of 25(OH)D). Serum 25(OH)D and sex hormones have been measured. The relationships between 25(OH)D, sex hormones, and obesity grades were investigated with linear and binary logistic regression analyses, as well as mediation analysis., Results: Compared to the 25(OH)D sufficiency group, total and free testosterone levels were found to be decreased, whereas serum androstenedione levels were increased in the 25(OH)D deficiency group ( p <0.05). Using multivariable lineal regression analyses, 25(OH)D was correlated with the majority of sex hormones ( p <0.05). When mediation with BMI was performed, the direct effect between 25(OH)D and sex hormones disappeared, and only the indirect effect via BMI remained (demonstrating the importance of BMI). Furthermore, after controlling for age and smoking status, we discovered that total testosterone and SHBG were both significantly associated with 25(OH)D ( p <0.05) in subjects with obesity type III. Using a mediation analysis, we discovered that BMI had a partial effect on the association between 25(OH)D and total testosterone levels in morbidly obese participants, indicating that a direct association between 25(OH)D and total testosterone levels, and that BMI partially mediated this association., Conclusions: Serum 25(OH)D is associated with total testosterone levels in only those subjects with morbid obesity, suggesting a specific benefit in severe cases of obesity. Additional research is needed to elucidate possible common mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Damas-Fuentes, Boughanem, Molina-Vega, Tinahones, Fernández-García and Macías-González.)

The production of plastic has dramatically increased in the last 50 y. Because of their stability and durability, plastics are ubiquitously incorporated in both marine and terrestrial ecosystems. Plastic is acted upon by biological, chemical, and physical agents, leading to fragmentation into small pieces [i.e., microplastics (MPs) or nanoplastics (NPs)], classified depending on their size. MPs range from 0.1 to 5000 μm and NPs are fragments between 0.001 to 0.1 μm. MPs and, especially NPs, are easily incorporated into living beings via ingestion. The penetration of MPs and NPs into the food system is an important issue, for both food security and health risk assessment. Ingestion of different MPs and NPs has been associated with different issues in the intestine, such as direct physical damage, increased intestinal permeability, diminished microbiota diversity, and increases in local inflammatory response. However, the potential harmful effects of low-dose dietary plastic are still unclear. Some evidence indicates that intestinal uptake of plastic particles is relatively low and is mostly dependent on the particle's size. However, other evidence highlights that NPs dysregulate key molecular signaling pathways, modify the gut microbiota composition, and may induce important epigenetic changes, including transgenerational effects that might be involved in the onset of many different metabolic disorders. Until now, experiments have been mostly performed on marine organisms, Caenorhabditis elegans, and mouse models, but some research indicates accidental plastic dietary consumption by humans, raising the issue of detrimental health effects of MPs and NPs. This review discusses the impact that MPs and NPs could have on the intestinal tract and the biodistribution and systemic, cellular, and molecular levels. Accumulated evidence of MPs' effects on the human gut suggests that large exposure to MPs and NPs may have phenotypical untoward effects in humans, calling for urgent research in this field., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Obesity was consistently associated with a poor prognosis in patients with COVID-19. Epigenetic mechanisms were proposed as the link between obesity and comorbidities risk., Aim: To evaluate the methylation levels of angiotensin-converting enzyme 2 (ACE2) gene, the main entry receptor of SARS-CoV-2, in different depots of adipose tissue (AT) and leukocytes (PBMCs) in obesity and after weight loss therapy based on a very-low-calorie ketogenic diet (VLCKD), a balanced hypocaloric diet (HCD) or bariatric surgery (BS)., Materials and Methods: DNA methylation levels of ACE2 were extracted from our data sets generated by the hybridization of subcutaneous (SAT) (n = 32) or visceral (VAT; n = 32) adipose tissue, and PBMCs (n = 34) samples in Infinium HumanMethylation450 BeadChips. Data were compared based on the degree of obesity and after 4-6 months of weight loss either by following a nutritional or surgical treatment and correlated with ACE2 transcript levels., Results: As compared with normal weight, VAT from patients with obesity showed higher ACE2 methylation levels. These differences were mirrored in PBMCs but not in SAT. The observed obesity-associated methylation of ACE2 was reversed after VLCKD and HCD but not after BS. Among the studied CpG sites, cg16734967 and cg21598868, located at the promoter, were the most affected and correlated with BMI. The observed DNA methylation pattern was inversely correlated with ACE2 expression., Conclusion: Obesity-related VAT shows hypermethylation and downregulation of the ACE2 gene that is mirrored in PBMCs and is restored after nutritional weight reduction therapy. The results warrant the necessity to further evaluate its implication for COVID-19 pathogenesis., (© 2021 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

The field of epitranscriptomics is rapidly developing. Several modifications (e.g. methylations) have been identified for different RNA types. Current evidence shows that chemical RNA modifications can influence the whole molecule's secondary structure, translatability, functionality, stability, and degradation, and some are dynamically and reversibly modulated. miRNAs, in particular, are not only post-transcriptional modulators of gene expression but are themselves submitted to regulatory mechanisms. Understanding how these modifications are regulated and the resulting pathological consequences when dysregulation occurs is essential for the development of new therapeutic targets. In humans and other mammals, dietary components have been shown to affect miRNA expression and may also induce chemical modifications in miRNAs. The identification of chemical modifications in miRNAs (endogenous and exogenous) that can impact host gene expression opens up an alternative way to select new specific therapeutic targets.Hence, the aim of this review is to briefly address how RNA epitranscriptomic modifications can affect miRNA biogenesis and to summarize the existing evidence showing the connection between the (de)regulation of these processes and disease settings. In addition, we hypothesize on the potential effect certain chemical modifications could have on the potential cross-kingdom journey of dietary plant miRNAs.

A dysfunctional visceral adipose tissue (VAT) is characterized by increased production of proinflammatory cytokines, which may increase the risk of colorectal cancer (CRC). However, the epigenetic contribution to the inflammatory status is poorly understood. In our study, we hypothesized that a dysfunctional VAT may be a risk factor for CRC, through epigenetic modifications. Therefore, we aimed to study the transcriptional/methylation profile of proinflammatory cytokines and genes related to vitamin D metabolism in VAT from CRC patients, and evaluate their association with serum 25-hydroxyvitamin D (25(OH)D). We included 129 participants (68 healthy participants and 61 CRC patients). We found that the majority of the studied genes are upregulated and hypomethylated in CRC patients, when compared to the healthy subjects ( p < 0.05). In addition, serum 25(OH)D was associated with both mRNA gene expression and methylation of key genes, such as interleukin ( IL ) 6 , IL10 , vitamin D receptor ( VDR ) or cytochrome P450 subfamily 27 type B1 ( CYP27B1 ) ( p < 0.05). Interestingly, while high IL6 expression was related to poor survival in CRC ( p < 0.05), IL6 methylation was associated with an increased risk of CRC, in which 25(OH)D partially mediated this association ( p < 0.05). Our study suggests a potential association between epigenetic regulation of inflammatory mediators in VAT - such as IL6 - in the CRC context, in which 25(OH)D may mediate this risk. Therefore, vitamin D could affect the epigenetic status of IL6 , which can be considered for additional preventive strategies.

Introduction: Vitamin D has been widely associated with colorectal cancer (CRC) through different insights. This study aims to explore the association between serum 25-hydroxyvitamin D (25(OH)D) and the global DNA methylation in tumor from CRC patients., Methods and Results: A genome-wide DNA methylation analysis is conducted in 20 CRC patients under categorical (10 patients have 25(OH)D <30 ng mL -1 ; 10 patients with 25(OH)D ≥30 ng mL -1 ) and continuous models of 25(OH)D. A total of 95 differentially methylated CpGs (DMCpGs) are detected under the categorical model (false discovery rate (FDR) < 0.05), while 16 DMCpGs are found under the continuous model. Regional analysis showed eight vitamin D-associated differentially methylated regions (DMR). Between them, a DMR is the most significant at cAMP-Dependent Protein Kinase Inhibitor Alpha (PKIA) locus. Furthermore, seven genes, including PKIA gene, have more or equal than two significant DMCpGs. The protein networking analysis found pathways implicated in cell adhesion and extracellular matrix, as well as signaling transduction., Conclusions: This study identifies novel epigenetic loci associated with serum 25(OH)D status. Interestingly, also, a positive association between vitamin D and DNA methylation in the CRC context is found, suggesting a role in CRC. Further studies are warranted to clarify and replicate these results., (© 2021 Wiley-VCH GmbH.)

Obesity, a sedentary lifestyle, high red meat consumption and alcohol, and tobacco are considered the driving factors behind colorectal cancer (CRC) worldwide. Both diet and lifestyle are recognized to play an important role in the prevention of CRC. Forty years later, the vitamin D-cancer hypothesis is considered consistent. However, the relationship between low vitamin D intake and CRC is still controversial. The aim of this meta-analysis is to determine the associations between Vitamin D intake and CRC. MEDLINE-PubMed and Cochrane databases were searched up to May 2020 for studies evaluating the association between vitamin D intake (from foods and supplements) and CRC. Two reviewers, working independently, screened all titles and abstracts to identify the studies that met the inclusion criteria (case-control or prospective cohort (PC) studies published in English). Data were pooled by the generic inverse variance method using a random or fixed effect model. Heterogeneity was identified using the Cochran Q-test and quantified by the I 2 statistic. A total of 31 original studies were included for the quantitative meta-analysis, comprising a total 47.540 cases and 70.567 controls in case-control studies, and a total of 14.676 CRC-incident cases (out of 808.130 subjects in PC studies) from 17 countries. A significant 25% lower risk was reported comparing the highest vs. the lowest dietary vitamin D consumption and CRC risk (odds ratio (95% confidence interval): 0.75 (0.67; 0.85)) in case-control studies, whereas a non-significant association was reported in case of prospective studies (hazard ratio (95% confidence interval): 0.94 (0.79; 1.11). The present meta-analysis demonstrates that high dietary vitamin D is associated to CRC prevention. However, larger and high-quality prospective studies and clinical trials are warranted to confirm this association.

Evidence from observational and in vitro studies suggests that insulin growth-factor-binding protein type 2 (IGFBP2) is a promising protein in non-communicable diseases, such as obesity, insulin resistance, metabolic syndrome, or type 2 diabetes. Accordingly, great efforts have been carried out to explore the role of IGFBP2 in obesity state and insulin-related diseases, which it is typically found decreased. However, the physiological pathways have not been explored yet, and the relevance of IGFBP2 as an important pathway integrator of metabolic disorders is still unknown. Here, we review and discuss the molecular structure of IGFBP2 as the first element of regulating the expression of IGFBP2 . We highlight an update of the association between low serum IGFBP2 and an increased risk of obesity, type 2 diabetes, metabolic syndrome, and low insulin sensitivity. We hypothesize mechanisms of IGFBP2 on the development of obesity and insulin resistance in an insulin-independent manner, which meant that could be evaluated as a therapeutic target. Finally, we cover the most interesting lifestyle modifications that regulate IGFBP2, since lifestyle factors (diet and/or physical activity) are associated with important variations in serum IGFBP2.

Epigenetic alterations in cancer play a variety of roles. Aberrant DNA methylation, as one of the epigenetic mechanisms, has been widely studied in both tumor and liquid biopsies and provide a useful bench mark for treatment response in cancer. Recently, several studies have reported an association between the type of diet and epigenetic modifications. Whereby there is a growing interest in finding the "anti-cancer diet formula", if such a thing exists. In this sense, ketogenic diets (KD) have reported potentially beneficial effects, which were able to prevent malignancies and decrease tumor growth. Some studies have even shown increased survival in cancer patients, reduced side effects of cytotoxic treatments, and intensified efficacy of cancer therapies. Although the biological mechanisms of KD are not well understood, it has been reported that KD may affect DNA methylation by modulating the expression of crucial genes involved in tumor survival and proliferation. However, there are many considerations to take into account to use ketotherapy in cancer, such as epigenetic mark, type of cancer, immunological and metabolic state or microbiota profile. In this review, we argue about ketotherapy as a potential strategy to consider as coadjuvant of cancer therapy. We will focus on mainly epigenetic mechanisms and dietary approach that could be included in the current clinical practice guidelines.

Vitamin B12 has been widely related to methionine metabolism, which is an essential component for biological methylation reactions, including DNA methylation. However, the relationship between vitamin B12 and DNA methylation is still controversial. In addition, there is increasing evidence for the association between vitamin B12 and the risk of colorectal cancer (CRC), although results of this association need to be assessed with caution. For this purpose, we hypothesized that serum vitamin B12 could be associated with global DNA methylation in the CRC context. To test this hypothesis, we studied the association between global DNA methylation through long interspersed nuclear element-1 ( LINE1 ) in CRC patients under the 25th percentile of serum vitamin B12. We found that the high vitamin B12 group had low LINE1 methylation in both tumor area and peripheral blood mononuclear cells (PBMCs) than the low serum vitamin B12 group. LINE1 methylation levels were significantly lower in tumor area compared to the adjacent tumor-free area, only in the high vitamin B12 group. LINE1 methylation in visceral adipose tissue (VAT) and PBMCs were correlated with tumoral, inflammatory, and insulin metabolism markers. However, the interaction between LINE1 methylation and vitamin B12 levels was associated with neoadjuvant therapy in the regression analysis only in men, suggesting a beneficial relationship. In conclusion, our results reported an inverse association between DNA methylation and vitamin B12 in the CRC context, which suggests that vitamin B12 may be implicated in an epigenetic state or mediation in CRC.

Recent studies suggest that long-interspersed nucleotide element-1 ( LINE-1 ) hypomethylation is commonly found in colorectal cancer (CRC), and is associated with worse prognosis. However, the utility of LINE-1 methylation on the prognosis of CRC is still controversial, and may be due to the fact that some clinical and pathological features may affect LINE-1 methylation. Thus, the aim of this study was to assess the prognostic value of tumor LINE-1 methylation in CRC, through their association with the CRC clinical and pathological characteristics. Survival of sixty-seven CRC patients was evaluated according to the median of tumor LINE-1 methylation, as well as pathological and oncological variables. We also studied the association between LINE-1 methylation and pathological features, and finally, we assessed the overall and disease-free survival of LINE1 methylation, stratified by neoadjuvant treatment and further checked by multivariate Cox regression to assess the statistical interactions. LINE-1 was hypomethylated in the CRC tumor with respect to the tumor adjacent-free area ( p < 0.05), without association with any other clinical and oncological features, nor with overall and disease-free survival rates for CRC. Relevantly, in neoadjuvant treatment, LINE-1 methylation was associated with survival rates. Thus, disease-free and overall survival rates of treated CRC patients were worse in the hypomethylated LINE-1 tumors than those with normal LINE-1 methylation ( p = 0.004 and 0.0049, respectively). Indeed, LINE-1 was hypermethylated more in the treated patients than in the non-treated patients ( p < 0.05). The present study showed that tumor LINE-1 hypomethylation was associated with worse survival rates in only treated patients. Our data suggest an interactive effect of neoadjuvant treatment and tumor LINE-1 methylation, which could be a specific-tissue biomarker to predict survival of the treated patients, and help to personalize treatment in CRC.

Backgrounds: Colorectal cancer (CRC) results from the accumulation of epigenetic and genetic changes in colon cells during neoplasic transformation, which the activation of Wingless (Wnt) signaling pathway is a common mechanism for CRC initiation. The Wnt pathway is mainly regulated by Wnt antagonists, as secreted frizzled-related protein (SFRP) family. Indeed, SFRP2 is proposed as a noninvasive biomarker for CRC diagnosis. Vitamin D also antagonizes Wnt signaling in colon cancers cells. Several studies showed that vitamin D was able to alter DNA methylation, although this mechanism is not yet clear. Therefore, the aim of this study was to find an association between circulating 25-OH vitamin D (30th percentile of vitamin D) and the SFRP2 methylation., Methods: A total of 67 CRC patients were included in the study. These patients were subdivided into two groups based on their 30th percentile vitamin D (20 patients were below, and 47 participants were above the 30th percentile of vitamin D). We investigated the SFRP2 methylation in peripheral blood mononuclear cells (PBMCs), visceral adipose tissue (VAT), CRC tumor tissue, and adjacent tumor-free area. We also determined the relationship between SFRP2 methylation and methylation of carcinogenic and adipogenic genes. Finally, we tested the effect of vitamin D on the SFRP2 methylation in human colorectal carcinoma cell lines 116 (HCT116) and studied the association of neoadjuvant therapy under the 30th percentile vitamin D with SFRP2 promoter methylation., Results: SFRP2 methylation in tumor area was decreased in patients who had higher levels of vitamin D. SFRP2 promoter methylation was positively correlated in tumor area with insulin and homeostasis model assessment of insulin resistance (HOMA-IR) but negatively correlated with HDL-c. SFRP2 methylation was also correlated with T cell lymphoma invasion and metastasis 1 (TIAM1) methylation in tumor area and CCAAT/enhancer-binding protein alpha (C/EBPα) in VAT. Treatment with vitamin D did not affect SFRP2 methylation in HCT116 cell line. Finally, neoadjuvant treatment was correlated with higher circulating 25-OH vitamin D and SFRP2 methylation under linear regression model., Conclusion: Our results showed that higher circulating vitamin D is associated with low SFRP2 promoter methylation. Therefore, our results could suggest that vitamin D may have an epigenetic effect on DNA methylation. Finally, higher vitamin D could contribute to an improvement response to neoadjuvant treatment.

Background: The interaction between obesity and genetic traits on high density lipoprotein (HDL) levels has been extensively studied. The variance of serum HDL has a strong genetic heritability, although the studied variant only explains a small part of this variation. The goal of this study was to investigate the associations between the apolipoprotein type 2 ( APOA2) rs3813627 single nucleotide polymorphism (SNP) and anthropometric and biochemical variables, though body mass index (BMI). Methods: This study included 153 subjects (91 overweight/obese (BMI³25 kg/m 2 ) and 62 non-obese individuals (BMI < 25 kg/m 2 )). The APOA2 rs3813627 SNP was selected and genotyped. Genotype analysis was performed to analyze the associations between APOA2 SNPs and anthropometric and biochemical variables through BMI. Results: The APOA2 rs3813627 TT genotype was associated with low HDL levels in comparison with the APOA2 rs3813627 GG and GT genotype in overweight/obese individuals, but not in the non-obese subjects ( p < 0.05). The same trend was observed in the apolipoprotein type 1 (APOA1) protein levels ( p < 0.05). Correlation analysis revealed a negative correlation between HDL and APOA1 levels and APOA2 rs3813627 SNP under recessive model ( p < 0.05). The odds ratio for low HDL levels was 3.76 and 3.94 for low APOA1 levels. The mediation analysis of APOA2 rs3813627 SNP through BMI showed a full mediation on HDL and partial mediation on APOA1 levels ( p < 0.05). Bioinformatic analysis showed that rs3813627 lies in the APOA2 promoter and overlaps motifs for several bound transcription factors. Conclusion : On the basis of these data, the APOA2 rs3813627 SNP is associated with low HDL and APOA1 levels susceptibility, and this effect was mediated by an increased BMI.

Obesity is well accepted as crucial risk factor that plays a critical role in the initiation and progression of colorectal cancer (CRC). More specifically, visceral adipose tissue (VAT) in people with obesity could produce chronic inflammation and an altered profile expression of key transcription factors that promote a favorable microenvironment to colorectal carcinogenesis. For this, the aim of this study was to explore the relationship between adipogenic and inflammatory transcription factors in VAT from nonobese, obese, and/or CRC patients. To test this idea, we studied the expression and methylation of CCAAT-enhancer binding protein type alpha (C/EBP-α), peroxisome proliferator-activated receptor gamma (PPAR-γ), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) in VAT from non-obese control, non-obese CRC subjects, overweight/obese control, and overweight/obese CRC patients and their correlation with anthropometric and biochemical variables. We found decreased expression of C/EBP-α in overweight/obese CRC patients in comparison with overweight/obese control subjects. PGC-1α and NF-κB were overexpressed in CRC patients independently of the BMI. NF-κB promoter was hypomethylated in overweight/obese CRC patients when compared to overweight/obese control individuals. In addition, multiple significant correlations between expression, methylation, and biochemical parameters were found. Finally, linear regression analysis showed that the expression of C/EBP-α and NF-κB and that NF-κB methylation were associated with CRC and able to explain up to 55% of CRC variability. Our results suggest that visceral adipose tissue may be a key factor in tumor development and inflammatory state. We propose C/EBP-α, PGC-1α and NF-κB to be interesting candidates as potential biomarkers in adipose tissue for CRC patients.

Background: Obesity is associated with several comorbid disorders, ranging from cardiovascular diseases to insulin resistance. In this context, visceral adipose tissue (VAT) seems to have a close connection with insulin resistance. In our study, we hypothesized that the expression profile of key adipogenic genes, such as proliferator-activated receptor γ type 2 (PPAR-γ2), CCAAT/enhancer-binding protein type α (C/EBP-α), and forkhead box protein class O type 1 (FOXO1) in VAT should shed light on their association with obesity-related insulin resistance., Methods: To test this idea, we studied the expression profile of C/EBP-α, FOXO1 and PPAR-γ2 in VAT from non-obese individuals, and low insulin (LIR-MO) and high insulin morbidly obese (HIR-MO) subjects, through a combination of RT-qPCR, co-immunoprecipitation, ELISA, Western blot analysis and EMSA assays., Results: Our results show that C/EBP-α and PPAR-γ2 were down-expressed in HIR-MO individuals, while FOXO1 was overexpressed. In addition, the PPAR-γ2-RXR-α heterodimer showed weak activity and bound weakly to the putative IGFBP-2-PPRE promoter sequence in VAT from HIR-MO subjects when compared with LIR-MO individuals., Conclusions: These results show that PPAR-γ2, C/EBP-α, FOXO1 and IGFBP-2 have a close relationship with insulin resistance in VAT of morbidly obese individuals.

The World Health Organization (WHO) considers that obesity has reached proportions of pandemic. Experts also insist on the importance of considering obesity as a chronic disease and one of the main contributors to the worldwide burden of other nontransmissible chronic diseases, which have a great impact on health, lifestyle, and economic cost. One of the most current challenges of biomedical science faces is to understand the origin of the chronic nontransmissible diseases, such as obesity and cancer. There is a large evidence, both in epidemiological studies in humans and in animal models, of the association between obesity and an increased risk of cancer incidence. In the last years, the initial discovery of epigenetic mechanisms represents the most relevant finding to explain how the genome interacts with environmental factors and the ripple effects on disease pathogeneses. Since then, all epigenetic process has been investigated by the scientific communities for nearly two decades to determine which components are involved in this process. DNA/RNA methylation and miRNA are classified as two of the most important representative classes of such epigenetic mechanisms and dysregulated activity of such mechanism can certainly contribute to disease pathogenesis and/or progression especially in tumors. This review article serves to highlight the impact of DNA/RNA methylation and miRNA-based epigenetic mechanism activities in the interplay between obesity and the development and clinical significance of colorectal cancer.

Objectives: Obesity is a complex disease that has a strong association with diet and lifestyle. Dietary factors can influence the expression of key genes connected to insulin resistance, lipid metabolism, and adipose tissue composition. In this study, our objective was to determine gene expression and fatty acid (FA) profiles in visceral adipose tissue (VAT) from lean and morbidly obese individuals. We also aimed to study the agonist effect of dietary factors on glucose metabolism., Design and Methods: Lean and low and high insulin resistance morbidly obese subjects (LIR-MO and HIR-MO) were included in this study. The gene expression of liver X receptor type alpha (LXR-α) and glucose transporter type 4 (GLUT4) and the FA profiles in VAT were determined. Additionally, the in vivo and in vitro agonist effects of oleic acid (OA), linoleic acid (LA), and arachidonic acid (AA) by peroxisome proliferator-activated receptor type gamma 2 (PPAR-γ2) on the activity of GLUT4 were studied., Results: Our results showed a dysregulation of GLUT4 and LXR-α in VAT of morbidly obese subjects. In addition, a specific FA profile for morbidly obese individuals was found. Finally, AA was an PPAR-γ2 agonist that activates the expression of GLUT4., Conclusions: Our study suggests a dysregulation of LXR-α and GLUT4 expression in VAT of morbidly obese individuals. FA profiles in VAT could elucidate their possible role in lipolysis and adipogenesis. Finally, AA binds to PPAR-γ2 to activate the expression of GLUT4 in the HepG2 cell line, showing an alternative insulin-independent activation of GLUT4.