Identification of epigenetic silencing of the SFRP2 gene in colorectal cancer as a clinical biomarker and molecular significance.

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.

Adipose tissue and blood leukocytes ACE2 DNA methylation in obesity and after weight loss.

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.

Gender Dimorphism in Hepatic Carcinogenesis-Related Gene Expression Associated with Obesity as a Low-Grade Chronic Inflammatory Disease.

Non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) show clear evidence of sexual dimorphism, with a significantly higher incidence in males. Among the determining factors that could explain this sex-based difference, the specific distribution of fat by sex has been suggested as a primary candidate, since obesity is a relevant risk factor. In this context, obesity, considered a low-grade chronic inflammatory pathology and responsible for the promotion of liver disease, could lead to sexual dimorphism in the expression profile of genes related to tumor development. When we compared the expression levels of genes associated with the early stages of carcinogenesis in the liver between male and female diet-induced obesity (DIO) rats, we observed that the expression pattern was similar in obese male and female animals. Interestingly, the SURVIVIN/BIRC5 oncogene showed a higher expression in male DIO rats than in female DIO and lean rats. This trend related to sexual dimorphism was observed in leukocytes from patients with obesity, although the difference was not statistically significant. In conclusion, this study evidenced a similar pattern in the expression of most carcinogenesis-related genes in the liver, except SUVIVIN/BIRC5, which could be a predictive biomarker of liver carcinogenesis predisposition in male patients with obesity.

Weight loss normalizes enhanced expression of the oncogene survivin in visceral adipose tissue and blood leukocytes from individuals with obesity.

BACKGROUND/OBJECTIVES: Survivin is an oncogene associated with a decrease in apoptosis, an increase in tumor growth, and poor clinical outcome of diverse malignancies. A correlation between obesity, cancer, and survivin is reported in the literature. To date, the impact of weight loss on change in survivin levels is understudied. This study was aimed at: (1) comparing survivin levels in adipose tissue (AT) from lean and obese animal models and evaluating changes after weight loss induced by energy restriction and/or exercise; (2) comparing survivin levels in normal weighted and obese humans and evaluating changes in survivin levels after weight loss induced by a very-low-calorie ketogenic diet (VLCKD) or bariatric surgery in AT and/or blood leukocytes (PBL/PBMCs). SUBJECTS/METHODS: Survivin expression was evaluated in subcutaneous (SAT) and visceral (VAT) AT derived from animal models of monogenic (Zucker rats) and diet-induced obesity (Sprague Dawley rats and C57BL/6J mice) and after a 4-week weight-loss protocol of energy restriction and/or exercise. Plasma was used to measure the inflammatory status. Survivin expression was also evaluated in PBMCs from patients with obesity and compared with normal weight, in PBLs after VLCKD, and in SAT and/or PBLs after bariatric surgery. RESULTS: Survivin expression was specifically higher in VAT from obese that lean animals, without differences in SAT. It decreased after weight loss induced by energy restriction and correlated with adiposity and inflammatory markers. In humans, the correlation between being obese and higher levels of survivin was confirmed. In obese subjects, survivin levels were reduced following weight loss after either VLCKD or bariatric surgery. Particularly, a decrease in PBMCs expression (not in SAT one) was found after surgery. CONCLUSIONS: Weight loss is effective in decreasing survivin levels. Also, PBL/PBMC should be regarded as appropriate mirror of survivin levels in VAT for the identification of an obesity-related protumoral microenvironment.

An energy restriction-based weight loss intervention is able to reverse the effects of obesity on the expression of liver tumor-promoting genes.

The epidemiological evidence regarding the association of obesity with liver disease and possibly hepatocellular carcinoma highlights the need for investigations of whether obesity itself could induce the differential expression of genes commonly associated with the initial phase of liver tumorigenesis, and whether such phenomenon could be reversed after a weight loss intervention. In this study, obese Zucker rats were found to have dysregulated cell proliferation, antioxidative defenses, and tumor suppressor gene expression in association with liver dysfunction parameters, as well as oxidative stress and inflammation. Importantly, after a 4-week weight loss protocol of energy restriction and/or exercise, this effect on the liver carcinogenesis-related genes was reversed concomitantly with reductions in the fat mass, hepatic lipid content, oxidative stress, and inflammation. The findings indicate that the oxidative stress and inflammation associated with excess adiposity promote dysregulation of the genes involved in liver tumorigenesis. This is clinically relevant because these effects were detectable in the liver without evidence of a tumoral mass and were reversed after weight loss. Consequently, this study reveals the susceptibility of obese individuals to the initiation of a hepatocarcinogenic process, and how this can be prevented by achieving a healthy body weight.

Ketotherapy as an epigenetic modifier in cancer.

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.

Ketogenic diets as treatment of obesity and type 2 diabetes mellitus.

During the last decades, several interventions for the management of overweight and obesity have been proposed. Among diets, the first studies focused on the effect of water only and total fasting diets with or without proteins. Unfortunately, they were found to be associated with adverse events which lead to the abandon of these strategies. Interestingly, despite the radical approach, total fasting was effective and generally well tolerated. A strict connection between protein-calorie malnutrition and increased in morbidity and mortality in hospitalized patients was found at that time. Then, the seminal works of Blackburn and his collaborators lead to the introduction of the protein-sparing modified fast. Encouraged by the early results using this intervention, diets evolved to the current very-low-calorie ketogenic diets (VLCKD). In the present review, results of studies on the VLCKDs are presented and discussed, with a particular reference to the protocolled VLCKD. Also, a recent proposal on the nomenclature on the ketogenic diets is reported. Available evidence suggests VLCKDs to be effective in achieving a rapid and significant weight loss by means of an easily reversible intervention which could be repeated, if needed. Muscle mass and strength are preserved, resting metabolic rate is not impaired, hunger, appetite and mood are not worsened. Symptoms and abnormal laboratory findings can be there, but they have generally been reported as of mild intensity and transient. Preliminary studies suggest VLCKDs to be a potential game-changer in the management of type 2 diabetes too. Therefore, VLCKDs should be considered as an excellent initial step in properly selected and motivated patients with obesity or type 2 diabetes, to be delivered as a part of a multicomponent strategy and under strict medical supervision.

Epigenetic silencing of TGFBI confers resistance to trastuzumab in human breast cancer.

BACKGROUND: Acquired resistance to trastuzumab is a major clinical problem in the treatment of HER2-positive (HER2+) breast cancer patients. The selection of trastuzumab-resistant patients is a great challenge of precision oncology. The aim of this study was to identify novel epigenetic biomarkers associated to trastuzumab resistance in HER2+ BC patients. METHODS: We performed a genome-wide DNA methylation (450K array) and a transcriptomic analysis (RNA-Seq) comparing trastuzumab-sensitive (SK) and trastuzumab-resistant (SKTR) HER2+ human breast cancer cell models. The methylation and expression levels of candidate genes were validated by bisulfite pyrosequencing and qRT-PCR, respectively. Functional assays were conducted in the SK and SKTR models by gene silencing and overexpression. Methylation analysis in 24 HER2+ human BC samples with complete response or non-response to trastuzumab-based treatment was conducted by bisulfite pyrosequencing. RESULTS: Epigenomic and transcriptomic analysis revealed the consistent hypermethylation and downregulation of TGFBI, CXCL2, and SLC38A1 genes in association with trastuzumab resistance. The DNA methylation and expression levels of these genes were validated in both sensitive and resistant models analyzed. Of the genes, TGFBI presented the highest hypermethylation-associated silencing both at the transcriptional and protein level. Ectopic expression of TGFBI in the SKTR model suggest an increased sensitivity to trastuzumab treatment. In primary tumors, TGFBI hypermethylation was significantly associated with trastuzumab resistance in HER2+ breast cancer patients. CONCLUSIONS: Our results suggest for the first time an association between the epigenetic silencing of TGFBI by DNA methylation and trastuzumab resistance in HER2+ cell models. These results provide the basis for further clinical studies to validate the hypermethylation of TGFBI promoter as a biomarker of trastuzumab resistance in HER2+ breast cancer patients.

Identification of an episignature of human colorectal cancer associated with obesity by genome-wide DNA methylation analysis.

BACKGROUND: Obesity was established as a relevant modifiable risk factor in the onset and progression of colorectal cancer (CRC). This relationship could be mediated by an epigenetic regulation. OBJECTIVES: The current work aimed to explore the effects of excess body weight on the DNA methylation profile of CRC using a genome-wide DNA methylation approach and to identify an epigenetic signature of obesity-related CRC. METHODS: Fifty-six CRC-diagnosed patients (50 years) were included in the study and categorized according to their body mass index (BMI) as non-obese (BMI ≤ 25 kg/m2) or overweight/obese (BMI > 25 kg/m2). Data from Infinium 450k array-based methylomes of 28 CRC tumor samples were coupled with information on BMI categories. Additionally, DNA methylation results were validated in 28 CRC tumor samples. RESULTS: The analysis revealed statistically significant differences at 299 CpG sites, and they were mostly characterized as changes towards CpG hypermethylation occurring in the obese group. The 152 identified genes were involved in inflammatory and metabolic functional processes. Among these genes, novel genes were identified as epigenetically regulated in CRC depending on adiposity. ZNF397OS and ZNF543 represented the top scoring associated events that were further validated in an independent cohort and exhibited strong correlation with BMI and excellent and statistically significant efficiency in the discrimination of obese from non-obese CRC patients (area under the curve >0.80; p < 0.05). CONCLUSIONS: The present study identifies a potential epigenome mark of obesity-related CRC that could be useful for precision medicine in the management of this disease taking into account adiposity as a relevant risk factor.

Role of epigenomic mechanisms in the onset and management of insulin resistance.

The prevalence of insulin resistance (IR) is increasing rapidly worldwide and it is a relevant health problem because it is associated with several diseases, such as type 2 diabetes, cardiovascular disorders and cancer. Understanding the mechanisms involved in IR onset and progression will open new avenues for identifying biomarkers for preventing and treating IR and its co-diseases. Epigenetic mechanisms such as DNA methylation are important factors that mediate the environmental effect in the genome by regulating gene expression and consequently its effect on the phenotype and the development of disease. Taking into account that IR results from a complex interplay between genes and the environment and that epigenetic marks are reversible, disentangling the relationship between IR and epigenetics will provide new tools to improve the management and prevention of IR. Here, we review the current scientific evidence regarding the association between IR and epigenetic markers as mechanisms involved in IR development and potential management.

Association between serum 25-hydroxyvitamin D and global DNA methylation in visceral adipose tissue from colorectal cancer patients.

BACKGROUND: Visceral adipose tissue (VAT) has been identified as the essential fat depot for pathogenetic theories that associateobesity and colon cancer. LINE-1 hypomethylation has been mostly detected in tumor colon tissue, but less is known about the epigenetic pattern in surrounding tissues. The aim was to analyze for the first time the potential relationship between serum vitamin D, obesity and global methylation (LINE-1) in the visceral adipose tissue (VAT) from patients with and without colorectal cancer. METHODS: A total of 55 patients with colorectal cancer and 35 control subjects participated in the study. LINE-1 DNA methylation in VAT was measured by pyrosequencing. Serum 25(OH)D levels were determined by ELISA. RESULTS: Cancer patients had lower levels of LINE-1 methylation in VAT compared with the control group. In the subjects with colorectal cancer, LINE-1 DNA methylation levels were associated positively with vitamin D levels (r = 0,463; p < 0.001) and negatively with BMI (r = - 0.334, p = 0.01) and HOMA insulin resistance index (r = - 0.348, p = 0.01). Serum vitamin D was the main variable explaining the LINE-1% variance in the cancer group (ß = 0.460, p < 0.001). In a multivariate analysis, subjects with higher LINE-1 methylation values had lower risk of developing colorectal cancer (OR = 0.53; IC95% =0.28-0.99) compared with the control group. CONCLUSIONS: We showed for the first time an association between LINE-1 DNA methylation in VAT and vitamin D levels in subjects with colorectal cancer, highlighting the importance of VAT from cancer patients, which could be modified epigenetically compared to healthy subjects.

Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer.

Long noncoding RNAs (lncRNAs) are important regulators of cellular homeostasis. However, their contribution to the cancer phenotype still needs to be established. Herein, we have identified a p53-induced lncRNA, TP53TG1, that undergoes cancer-specific promoter hypermethylation-associated silencing. In vitro and in vivo assays identify a tumor-suppressor activity for TP53TG1 and a role in the p53 response to DNA damage. Importantly, we show that TP53TG1 binds to the multifaceted DNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. TP53TG1 epigenetic inactivation in cancer cells releases the transcriptional repression of YBX1-targeted growth-promoting genes and creates a chemoresistant tumor. TP53TG1 hypermethylation in primary tumors is shown to be associated with poor outcome. The epigenetic loss of TP53TG1 therefore represents an altered event in an lncRNA that is linked to classical tumoral pathways, such as p53 signaling, but is also connected to regulatory networks of the cancer cell.

Food Addiction in Bulimia Nervosa: Clinical Correlates and Association with Response to a Brief Psychoeducational Intervention.

Food addiction (FA) has been examined in different populations. Although high FA levels are associated with greater eating disorder severity, few studies have addressed how FA relates to treatment outcome. GOALS: The study aims (1) to determine whether a brief intervention for bulimia nervosa (BN) reduces FA diagnosis or severity compared with baseline and (2) to determine if FA is predictive of treatment outcome. METHOD: Sixty-six female BN patients participated in the study. The Yale Food Addiction Scale was administered at two time points: prior to and following a 6-week intervention. The number of weekly binging/purging episodes, dropout and abstinence from bulimic behaviour were used as primary outcome measures. RESULTS: This brief intervention reduced FA severity and FA diagnosis in the 55 patients who completed treatment. FA severity was a short-term predictor of abstinence from binging/purging episodes after treatment (p = .018). CONCLUSIONS: Food addiction appears to be prevalent in BN although FA severity can improve following a short-term intervention. Copyright © 2016 John Wiley & Sons, Ltd and Eating Disorders Association.

Interaction Between Orexin-A and Sleep Quality in Females in Extreme Weight Conditions.

The current study examined the relationship between plasma orexin-A and sleep in obesity. Concentrations of orexin-A and sleep were evaluated in 26 obese, 40 morbid obese and 32 healthy-weight participants. The sleep monitor Actiwatch AW7 and the Pittsburgh Sleep Quality Index were used to evaluate sleep. The Symptom Checklist-90-Revised was administered to assess symptoms of psychopathology. A higher weight status was associated with elevated orexin-A levels (p = .050), greater depression, anxiety and somatization symptoms (all: p < .001), and impoverished self-reported sleep quality (p < .001). A quadratic trend was found in objective sleep time, being longest in the obese group (p = .031). Structural equation modelling showed plasma orexin-A to be related to poor total sleep quality, which in turn was associated with elevated body mass index. Our data confirm an interaction between elevated plasma orexin-A concentrations and poor sleep that contributes to fluctuations in body mass index. Copyright © 2016 John Wiley & Sons, Ltd and Eating Disorders Association.

Enduring Changes in Decision Making in Patients with Full Remission from Anorexia Nervosa.

BACKGROUND: Deficits in neuropsychological functioning have consistently been identified in patients with anorexia nervosa (AN). However, little is known on how decision making in AN patients evolves in response to treatment or whether impairments are reversible. METHOD: AN patients (n = 42) completed the Iowa Gambling Task (IGT) upon admission to a 3-month day-hospital treatment programme and at a 1-year follow-up. Patient IGT performance was compared to age-matched controls (n = 46). RESULTS: AN patients displayed poorer performance on the IGT at admission compared to controls (p < .001). Patients with full remission (n = 31; 73.9%) at the 1-year follow-up improved IGT performance (p = 0.007), and scores were similar compared to controls (p = 0.557). AN patients with partial/no remission at follow-up (n = 11; 26.1%) did not improve IGT scores (p = 0.867). CONCLUSIONS: These findings uphold that enduring remission from AN can reverse decision-making impairments, and they might be most likely explained by clinical state rather than a trait vulnerability. Copyright © 2016 John Wiley & Sons, Ltd and Eating Disorders Association.

Plasma irisin depletion under energy restriction is associated with improvements in lipid profile in metabolic syndrome patients.

OBJECTIVE: A recently discovered myokine, irisin, may have an important role in energy metabolism. This study aimed to evaluate the relationship between this hormone and the lipid profile of patients with metabolic syndrome (MetS) following a hypocaloric diet. DESIGN: Ninety-three Caucasian adults (52 men/41 women) diagnosed with MetS followed an 8-week-long energy-restricted programme (-30% of the energy requirements). Anthropometric measurements, biochemical markers and plasma irisin levels were analysed before and after the nutritional intervention. RESULTS: Global plasma irisin levels were significantly reduced at the end of the study (-72.0 ± 100.9 ng/ml, P < 0.001) accompanying the weight loss (-6.9%). The depletion of irisin significantly correlated with changes in some atherogenic-related variables: total cholesterol (B = 0.106, P = 0.018), total cholesterol/high-density lipoprotein cholesterol ratio (B = 0.002, P = 0.036), low-density lipoprotein cholesterol (B = 0.085, P = 0.037) and apolipoprotein B (B = 0.052, P = 0.002), independently of changes in body weight. CONCLUSIONS: An association between the reduction in plasma irisin levels and the depletion of important lipid metabolism biomarkers was observed in patients with MetS undergoing an energy-restricted programme.

Longitudinal variation of circulating irisin after an energy restriction-induced weight loss and following weight regain in obese men and women.

OBJECTIVE: The recently discovered peptide irisin has been hypothesized to be a regulator of body metabolism. The objective of this work was to evaluate whether circulating human irisin levels are modulated by body size and changes in adiposity during an energy restriction treatment and the subsequent weight regain. METHODS: A group of 94 obese patients (50 men, 44 women; 49.4 ± 9.4 years; BMI 35.6 ± 4.5 kg/m(2) ) participated in a weight loss program following an 8-week hypocaloric diet (-30% energy expenditure) with a weight maintenance follow-up. The patients were evaluated at 0, 8, and 24 weeks after starting treatment. In addition, 48 normal-weight subjects (16 men, 32 women; 35.71 ± 8.8 years; BMI 22.9 ± 2.2 kg/m(2) ) participated as controls. Plasma irisin, body weight, body composition, and hormones controlling energy homeostasis were measured. RESULTS: Irisin levels were higher in obese subjects (353.1 ± 18.6 ng/mL) than in those of normal-weight (198.4 ± 7.8 ng/mL; P ≤ 0.001) and were also higher in men (340.9 ± 20 ng/mL) than in women (267.6 ± 12 ng/mL; P < 0.05). Moreover, irisin plasma levels were significantly correlated with high levels of direct and indirect adiposity markers, such as weight, BMI, waist circumference, and fat mass, as measured by bioimpedance, but not with height or leptin levels. Interestingly, irisin levels paralleled body weight reduction after the dietary treatment (week 8) and again returned to the baseline levels at 24 weeks in those patients regaining the lost weight. CONCLUSIONS: Irisin strongly reflects body fat mass, suggesting that the irisin circulating levels are conditioned by adiposity level.

Efficacy of a new immunonutrition formula with extra virgin olive oil in the reduction of complications in surgeries of upper digestive tract tumors.

Background: To demonstrate whether a nutritional supplement enriched with arginine, nucleotides, omega-3 fatty acids, and extra virgin olive oil reduces postoperative complications in patients with tumors in the upper digestive tract. Methods: A randomized, controlled, double-blind, multicenter clinical trial, in which a new immunomodulatory formula with extra virgin olive oil was compared with a standard isoprotein and isoenergetic formula. Patients with gastric, esophageal or biliopancreatic tumors were recruited to receive two units of immunomodulatory formula or control, 5 days before the surgical intervention. Results: A total of 119 patients were recruited. There was a significant reduction in the number of reinterventions (7.7 vs. 20.4%; p = 0.044) in the intervention group. There was a significant reduction in the development of fistulas in patients with phase angles >5.7°. Also, there were fewer readmissions after biliopancreatic surgeries (0.0 vs. 100%; p = 0.014). The length of hospital stay was similar between groups; however, with the immunomodulatory formula, the patients exhibited greater phase angle at the end of follow-up. Conclusion: The immunomodulatory formula with extra virgin olive oil administered 5 days before surgery for stomach, esophageal and biliopancreatic tumors improved cellular health and reduced postoperative complications.Clinical trial registration: [https://clinicaltrials.gov/], identifier [NCT04027088].

The obestatin/GPR39 system is up-regulated by muscle injury and functions as an autocrine regenerative system.

The maintenance and repair of skeletal muscle are attributable to an elaborate interaction between extrinsic and intrinsic regulatory signals that regulate the myogenic process. In the present work, we showed that obestatin, a 23-amino acid peptide encoded by the ghrelin gene, and the GPR39 receptor are expressed in rat skeletal muscle and are up-regulated upon experimental injury. To define their roles in muscle regeneration, L6E9 cells were used to perform in vitro assays. For the in vivo assays, skeletal muscle tissue was obtained from male rats and maintained under continuous subcutaneous infusion of obestatin. In differentiating L6E9 cells, preproghrelin expression and correspondingly obestatin increased during myogenesis being sustained throughout terminal differentiation. Autocrine action was demonstrated by neutralization of the endogenous obestatin secreted by differentiating L6E9 cells using a specific anti-obestatin antibody. Knockdown experiments by preproghrelin siRNA confirmed the contribution of obestatin to the myogenic program. Furthermore, GPR39 siRNA reduced obestatin action and myogenic differentiation. Exogenous obestatin stimulation was also shown to regulate myoblast migration and proliferation. Furthermore, the addition of obestatin to the differentiation medium increased myogenic differentiation of L6E9 cells. The relevance of the actions of obestatin was confirmed in vivo by the up-regulation of Pax-7, MyoD, Myf5, Myf6, myogenin, and myosin heavy chain (MHC) in obestatin-infused rats when compared with saline-infused rats. These data elucidate a novel mechanism whereby the obestatin/GPR39 system is coordinately regulated as part of the myogenic program and operates as an autocrine signal regulating skeletal myogenesis.

Exercise training and DNA methylation profile in post-bariatric women: Results from an exploratory study.

Exercise training and bariatric surgery have been shown to independently modulate DNA methylation profile in clusters of genes related to metabolic and inflammatory pathways. This study aimed to investigate the effects of a 6-month exercise training program on DNA methylation profile in women who underwent bariatric surgery. In this exploratory, quasi-experimental study, we analyzed DNA methylation levels by array technology in eleven women who underwent Roux-en-Y Gastric Bypass and a 6-month, three-times-a-week, supervised exercise training program. Epigenome Wide Association Analysis showed 722 CpG sites with different methylation level equal to or greater than 5% (P < 0.01) after exercise training. Some of these CpGs sites were related to pathophysiological mechanisms of inflammation, specially Th17 cell differentiation (FDR value < 0.05 and P < 0.001). Our data showed epigenetic modification in specific CpG sites related to Th17 cell differentiation pathway in post-bariatric women following a 6-months exercise training program.