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Background. Very low-calorie ketogenic diets (VLCKD) are an effective weight-loss strategy for obese individuals, reducing risks of liver conditions such as non-alcoholic steatohepatitis and fibrosis. Small extracellular vesicles (sEVs) are implicated in liver fibrosis by influencing hepatic cell phenotypes and contributing to liver damage. This study investigates sEVs derived from serum of 60 obese adults categorized into low fibrosis risk (LR) and intermediate/high fibrosis risk (IHR) groups based on FibroScan elastography (FIB E scores, limit value 8 kPa) and all participants underwent an 8-week VLCKD intervention. Methods. The study examines the impact of these sEVs on fibrosis markers, inflammation, and autophagy in a hepatocyte cell line (HEPA-RG) using bioinformatics, RNA sequencing, lipidomics, RT-PCR, and Western blotting before (T0) and after (T1) VLCKD. Results. sEVs from LR patients post-VLCKD reduced fibrosis related gene expression (e.g., ACTA2) and enhanced proteins associated with regeneration and inflammation (e.g., HDAC6). Conversely, sEVs from IHR patients increased fibrosis and inflammation related gene expression (PIK3CB, AKT1, ACTA2) in hepatocytes, raising concerns about VLCKD suitability for IHR patients. IHR sEVs also decreased expression of HDAC10, HDAC6, HDAC3, MMP19, and MMP2, while increasing modulation of p-AKT, α-SMA, and VIM. Conclusion. These findings underscore the critical role of sEVs in regulating inflammation, remodeling, and hepatic stress responses, particularly in IHR patients, and suggest sEVs could complement instrumental evaluations like FibroScan in fibrosis assessment. [ABSTRACT FROM AUTHOR]

Background/Objectives: Metabolic dysfunction-associated fatty liver disease (MAFLD) is currently the most common cause of chronic liver disease. Systemic inflammatory status and peripheral metabolic symptoms in the clinical picture have an impact on gut commensal bacteria. Methods: Our designed clinical trial was based on a cohort of patients with MAFLD whose diet included the daily consumption of 400 g of "Navelina" oranges for 28 days, compared with a control group of patients with the same pathologic conditions whose diet did not include the consumption of oranges and other foods containing similar nutrients/micronutrients. We used 16S metataxonomics and GC/MS analyses to identify taxa and urine/fecal VOCs, respectively. Results: A set of micronutrients from the diet were inspected, and some specific fatty acids were identified as the main contributors in terms of cluster sample separation. Metataxonomics and metabolomics profiles were obtained, and a stringent statistical approach allowed for the identification of significant taxa/VOCs, which emerged from pairwise group comparisons in both fecal and urine samples. Conclusions: In conclusion, a set of taxa/VOCs can be directly referred to as a marker of dysbiosis status and other comorbidities that, together, make up the pathologic burden associated with MAFLD. The investigated variables can be a target of therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Consumption of flavonoid-rich orange juice has been shown to reduce adiposity and liver steatosis in murine models of diet-induced obesity. However, little is known about the effects of whole orange intake, independent of body weight changes, on liver function and steatosis in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD). The goal is to understand the direct impact of orange consumption on metabolic health. Methods: Sixty-two men and women aged 30–65 with MASLD (Controlled Attenuation Parameter, (CAP) > 275 dB/m) were randomly assigned to consume either 400 g of whole oranges or non-citrus fruits daily for 4 weeks. Baseline evaluations included medical assessments, blood tests, and body composition. Liver health was assessed using transient elastography (FibroScan®) for steatosis and fibrosis, conducted by blinded personnel. This clinical trial was registered at ClinicalTrials.gov (NCT05558592). Results: After 4 weeks of orange supplementation, liver steatosis decreased in the treatment group, with 70.9% showing steatosis compared to 100% in controls (p < 0.004), indicating a 30% reduction in liver disease prevalence. There were no significant changes in fibrosis or plasma liver enzymes, though plasma gamma glutaril transferase (GGT) levels decreased significantly. Body weight, waist circumference, body composition, lipid profile, fasting glucose, insulin, and C-reactive protein levels remained unchanged. Dietary analysis revealed no change in caloric intake, but vitamins C, A, thiamine, and riboflavin increased in the orange group. Conclusions: Our findings suggest that phytochemical-rich foods, especially whole fruits like oranges, may enhance liver function as an adjunct treatment for MASLD. The notable reduction in liver steatosis prevalence occurred independently of body weight changes. Further studies are needed to investigate the long-term effects of orange supplementation on steatosis and fibrosis progression and to identify the specific bioactive compounds and mechanisms involved. [ABSTRACT FROM AUTHOR]

Many patients with irritable bowel syndrome (IBS) have a compromised intestinal barrier associated with low-grade inflammation. Polyunsaturated fatty acids (PUFAs) are potential mediators of inflammation: omega-6 PUFAs are pro-inflammatory, while omega-3 PUFAs are antioxidant and anti-inflammatory. Zonulin is a potential biomarker for small intestinal permeability (s-IP). This study investigated the relationship between PUFAs and gastrointestinal (GI) barrier integrity in IBS patients with predominant diarrhea (IBS-D). We evaluated GI barrier function indicators in the urine and bloodstream and erythrocyte membrane PUFA composition in 38 IBS-D patients (5 men, 33 women, 44.11 ± 1.64 years), categorized at baseline by fecal zonulin levels into high (≥107 ng/mL, H-FZ) and normal (<107 ng/mL N-FZ) groups. Evaluations were conducted prior to and following a 12-week diet low in FODMAPs (LFD). At baseline, H-FZ patients had s-IP significantly higher than the reference value, lower n-3 PUFAs levels, and higher n-6/n-3 PUFAs and arachidonic acid (AA) to eicosapentaenoic acid (EPA) ratios than N-FZ. After LFD, H-FZ patients showed significant increases in n-3 PUFAs levels; decreases in n-6 PUFAs, n-6/n-3 PUFAs and AA/EPA ratios; and improved s-IP. The n-6/n-3 PUFAs ratio positively correlated with fecal zonulin levels in all subjects. These findings highlight the relationship between PUFAs and the intestinal barrier, suggesting their role in IBS-D pathophysiology and confirming the positive effects of LFD in managing IBS-D. [ABSTRACT FROM AUTHOR]

Grape (Vitis vinifera L.) is a fruit rich in polyphenols, bioactive compounds able to prevent cancer, reduce tumorigenesis, and influence critical cancer-related pathways. This research shows the main results obtained in our previous works: 1) the characterization of the polyphenolic content and antioxidant activity of two table grape skin extracts (GSEs), Autumn Royal, and Egnatia; 2) the GSEs effects on Caco2 colon cancer cell; 3) the effects of GSEs on the lipid composition and the fluidity of the cell membrane. These in vitro studies suggested that Autumn Royal and Egnatia contain high levels of polyphenols, possess antiproliferative activity on the Caco2 human colon carcinoma cell line and inhibit cell migration by acting on membrane fatty acids composition. Moreover, these results highlighted that the new grape variety Egnatia is an exciting source of phenolic compounds that could interest the food and pharmaceutical industries.

Background: Modifiable risk factors for Parkinson's disease (PD) are poorly known. Objectives: The aim is to evaluate independent associations of different nutritional components, physical activity, and sedentary behavior and metabolic factors with the risk of PD. Methods: In this population‐based prospective cohort study using the data of the United Kingdom Biobank (from 2006–2010), 502,017 men and women who were free from PD (International Classification of Diseases 10th edition; "G20") at baseline were included. We implemented a Cox proportion hazard's model to evaluate the associations of different levels of physical activity, sitting time, sleep habits, diet quality, alcohol and coffee consumption, smoking, and body mass index with PD risk, adjusting for several confounding variables. Results: During a median follow‐up of 12.8 years, lifestyle factors including vigorous physical activity (hazard ration [HR] = 0.84; 95% confidence interval [CI], 0.75–0.94), low‐to‐moderate sitting time (HR = 0.89; 95% CI, 0.81–0.97), and high sleep quality (HR = 0.89; 95% CI, 0.80–0.99) were associated with a reduced risk of PD. Small amounts of coffee (HR = 0.88; 95% CI, 0.82–0.95), red meat (HR = 0.86; 95% CI, 0.76–0.97), and current smoking (HR = 0.65; 95% CI, 0.56–0.75) were also associated with a lower risk of PD, whereas alcohol intake (HR = 1.29; 95% CI, 1.06–1.56) with higher PD risk. Secondary analysis, including metabolic risk factors, confirmed these findings and highlighted the potential protective effect of plasma vitamin D and uric acid, but of low‐density lipoprotein‐cholesterol, triglycerides, and C‐reactive protein as well. Conclusions: Vigorous physical activity, reduced sitting time, good sleep quality together with small coffee intake and vitamin D supplementation are potentially neuroprotective lifestyle interventions for the prevention of PD. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated hepatic steatosis (MAFLD) indicates the metabolic risk associated with hepatic steatosis, overweight and obesity, and clinical evidence of metabolic dysregulation. Since MAFLD is one of the diseases that show a high frequency of alterations in the lipid content of cell membranes, the aim of this study was to evaluate the indices of oxidative damage of erythrocyte membranes in overweight and obese MAFLD subjects. The study was conducted on serum samples and red blood cell membranes of overweight and obese MAFLD subjects. For each patient, biochemical measurements and lipidomic analyses of erythrocytes membranes were performed. Significant differences in fatty acid profiles of RBC membranes were found between overweight and obese patients. In particular, the Peroxidation Index (PI) was higher in the erythrocyte membranes of obese subjects than in overweight subjects. The same behavior was observed for Unsaturation Index (UI) and Free Radical Stress Index (Free RSI), supporting the fact that the systemic increase in oxidative stress was associated with obesity. The study shows that there is a different susceptibility to erythrocyte membrane peroxidation for overweight and obese subjects, and the increased values of oxidative stress indices observed in the erythrocyte membranes of obese patients with MAFLD may be a possible indicator of pro-oxidative events occurring in obesity-related diseases. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely related to some metabolic disorders, such as central obesity and type 2 diabetes (T2D). Glucagon-like peptide 1 receptor agonists (GLP-1RAs), such as semaglutide, may have therapeutic roles in MASLD associated with T2D. This study aims to investigate the molecular mechanisms underlying the effectiveness of semaglutide on MASLD in terms of progression from liver steatosis to fibrosis. We characterized exosomes from ten patients with type 2 diabetes (T2D) before (T0) and after 12 months (T12) of treatment with once-weekly subcutaneous semaglutide. Six of ten patients were considered responders to therapy (R) based on MASLD severity downgrading by at least one class according to a validated ultrasonographic (US) score. Normal hepatocytes (HEPA-RG) and stellate (LX-2) cells were challenged with exosomes from R and NR patients, isolated before and after 12 months of therapy. Exosomes from both R and NR patients isolated at T0 significantly affected LX-2 viability. After 12 months of treatment, only those isolated from R patients restored cell viability, whereas those from NR patients did not. No effects were observed on HEPA-RG cells. Exosomes at T12 from R but not from NR patients significantly decreased the production of α-SMA, a marker of LX-2 activation, a liver stellate cell model, and ph-SMAD2 and CTGF, involved in fibrosis processes. TGF-β1 was not modulated by the exosomes of R and NR patients. As a downstream effect, Vimentin, Collagen 1A1, and Fibronectin extracellular matrix components were also downregulated, as measured by droplets digital PCR. In conclusion, these results shed light on the potential effectiveness of semaglutide in improving liver fibrosis in MASLD. [ABSTRACT FROM AUTHOR]

Extra virgin olive oil (EVOO) has healthy benefits for noncommunicable diseases (NCDs). However, limited evidence is available about the effects of liver disease and non-alcoholic fatty liver disease (NAFLD). We evaluate whether dose-increased consumption of EVOO is associated with a lower prevalence of NAFLD and if these effects vary based on body weight. The study included 2436 subjects with a 33% NAFLD prevalence. Daily EVOO was categorized into tertiles: low (0–24 g/day), moderate (25–37 g/day), and high consumption (>37 g/day). Subjects were also classified by body mass index (BMI) as normo-weight (18.5–24.9), overweight (25–29.9), and obese (≥30). Logistic regression analysis was applied to calculate odds ratios (ORs) for NAFLD, considering a 20-gram increment in EVOO intake and accounting for EVOO categories combined with BMI classes. The ORs were 0.83 (0.74;0.93) C.I. p = 0.0018 for continuous EVOO, 0.89 (0.69;1.15) C.I. p = 0.37, and 0.73 (0.55;0.97) C.I. p = 0.03 for moderate and high consumption, respectively, when compared to low consumption. Overall, the percent relative risk reductions (RRR) for NAFLD from low to high EVOO consumption were 18% (16.4%;19.2%) C.I. and 26% (25%;27.4%) C.I. in overweight and obese subjects. High EVOO consumption is associated with a reduced risk of NAFLD. This effect is amplified in overweight subjects and even more in obese subjects. [ABSTRACT FROM AUTHOR]

The tumor location in colorectal cancer (right- or left-sided colon cancer) is a key factor in determining disease progression. Right- and left-sided colon tumors are different in their clinical and molecular characteristics. Dysregulation of serum levels of proinflammatory cytokines, such as Transforming Growth Factor β (TGF-β) and Tumor Necrosis Factor-α (TNF-α), and Peroxisome Proliferator Activated Receptor-γ (PPAR-γ), known to be a growth-limiting and differentiation-promoting factor, as well as changes in miRNAs expression, are the major signaling pathways involved in the pathogenesis of this neoplasia. In the serum from 60 colorectal cancer (CRC) patients, we compared the differences in the expression of the levels of TGF-β, TNF-α, and PPAR-γ and in the expression of the main human miRNAs between right and left CRC. A significant over-expression in the TGF-β and TNF-α levels was observed in the serum from right-sided colon cancer patients. For the PPAR-γ, the patients with CRC located on the right-side showed lower levels than those detected in the serum from left-sided CRC subjects. Furthermore, significant differences also existed in the expression of specific circulating miRNAs between right- and left-sided CRC. In particular, the right upregulated miRNAs were all involved in the cell growth and proliferation related pathways. These findings confirm that the analysis of circulating levels of TGF-β, TNF-α, and PPAR-γ, as well as the study of the specific miRNAs in the serum, are able to identify specific characteristics of CRC patients, useful for choosing a personalized treatment protocol. [ABSTRACT FROM AUTHOR]

The gut microbiota has gained increasing attention in recent years due to its significant impact on colorectal cancer (CRC) development and progression. The recent detection of bacterial DNA load in plasma holds promise as a potential non-invasive approach for early cancer detection. The aim of this study was to examine the quantity of bacterial DNA present in the plasma of 50 patients who have CRC in comparison to 40 neoplastic disease-free patients, as well as to determine if there is a correlation between the amount of plasma bacterial DNA and various clinical parameters. Plasma bacterial DNA levels were found to be elevated in the CRC group compared to the control group. As it emerged from the logistic analysis (adjusted for age and gender), these levels were strongly associated with the risk of CRC (OR = 1.02, p < 0.001, 95% C.I.: 1.01–1.03). Moreover, an association was identified between a reduction in tumor mass and the highest tertile of plasma bacterial DNA. Our findings indicate that individuals with CRC displayed a higher plasma bacterial DNA load compared to healthy controls. This observation lends support to the theory of heightened bacterial migration from the gastrointestinal tract to the bloodstream in CRC. Furthermore, our results establish a link between this phenomenon and the size of the tumor mass. [ABSTRACT FROM AUTHOR]

Exosomes produced by hepatocytes upon lipotoxic insult play a relevant role in pathogenesis of nonalcoholic fatty liver disease (NAFLD), suggesting an inflammatory response by the activation of monocytes and macrophages and accelerating the disease progression. In the pathogenesis of NAFLD and liver fibrosis, the endogenous cannabinoids and their major receptors CB1 and CB2 appear to be highly involved. This study aimed at evaluating the expression of cannabinoids receptors (CB1R and CB2R) in plasma-derived exosomes extracted from patients with NAFLD, as well as investigating the in vitro effects of the circulating exosomes in cultured human HepaRG cells following their introduction into the culture medium. The results demonstrated that plasma-derived exosomes from NAFLD patients are vehicles for the transport of CB1R and are able to modulate CB receptors' expression in HepaRG cells. In particular, circulating exosomes from NAFLD patients are inflammatory drivers for HepaRG cells, acting through CB1R activation and the downregulation of CB2R. Moreover, CB1R upregulation was associated with increased expression levels of PPAR-γ, a well-known mediator of liver tissue injury. In conclusion, this study provides evidence for CB1R transport by exosomes and suggests that the in vitro effects of circulating exosomes from NAFLD patients are mediated by the expression of cannabinoid receptors. [ABSTRACT FROM AUTHOR]

Grapes represent a significant source of phenolic compounds known for their health-promoting properties, such as antioxidant capacity on normal cells and prooxidant activity on tumor cells. The genotype highly affects the polyphenolic composition in grapes and, consequently, the nutritional quality of berries. This work aimed to characterize the phenolic composition, the antioxidant, and anticancer activity of grape skin extracts (GSEs) of nine new table grape genotypes selected from a breeding program to obtain new cultivars of seedless table grapes, well adapted to the climatic change and with higher nutraceutical properties. The grape polyphenolic profile was characterized by Ultra-High-Performance Liquid Chromatography/ Quadrupole-Time of Flight mass spectrometry analysis. GSE antioxidant activity was determined by the ABTS, DPPH, and ORAC assays; GSE cell growth inhibition test was carried out in the Caco2 human cancer cell line. The nine GSEs showed different flavonoid and non-flavonoid profiles, and all possessed antioxidant activity, with the 'Aika N.', 'Turese N.', and 'Egnatia N.' the most active. As anticancer activity against the tested cancer cell line, 'Daunia N.' and 'Apenestae N.' showed the EC50 after 24 h of 35.60 µg/mL and 150.91 µg/mL, respectively. The relationship between polyphenolic profile and the antioxidant and anticancer activity of GSE was also investigated. Interestingly, among the different classes of polyphenolics, flavan-3-ols e proanthocyanidins showed the highest positive correlation with the anticancer activity of extracts. These findings can be helpful for the preparation of new extracts for the pharmaceutical and nutraceutical industry and geneticists working in vine breeding programs. [ABSTRACT FROM AUTHOR]

Grape pomace (GP)—the major by-product of winemaking processes—still contains bioactive molecules with known beneficial properties for human health, such as an antiradical scavenging activity or an antiproliferative activity of tumors. In vitro studies have demonstrated that GP polyphenols specifically influence colon cancer cell proliferation. In addition to previously published work, we tested the phenolic compounds of Aglianico GP following an in vitro simulated gastrointestinal digestion on colorectal cancer cell lines at different degrees of differentiation. Our experiments, using HT29 and SW480 cells, confirmed the anti-proliferative effect of GP gastrointestinal digested extract and provided intriguing insights on the way it influences the cancer cell features (i.e., viability, proliferation, and apoptosis). We observed that Aglianico GP extract showed a great ability to affect cell proliferation and apoptosis. Interestingly, both HT29 and SW480 cells produced a significant increase in Bax, and a significant increase in the Bax/Bcl-2 ratio and caspase-3. The gastrointestinal digested GP extract was previously characterized both for antioxidant activity and phenolic composition. As a result, the TPC and the antioxidant activity reached high values in the Aglianico GP digested extract, and the main compounds assessed by UHPLC-DAD were anthocyanins, phenolic acids, and flavonoids. This work shed light on the use of digested GP extract as a dietary ingredient, a very sustainable source of nutritional compounds with potential health benefits for colon cancer cell proliferation. [ABSTRACT FROM AUTHOR]

This clinical trial was aimed to investigate the effects of fresh table grape intake on the serum levels of the Omega-3 index, defined as the sum of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) levels. Forty consecutive healthy subjects were randomly assigned to the control group, receiving only dietary recommendations, and the grape group receiving a daily dose of 5 g of fresh table grape per kg of body weight, for 21 days. Compared with baseline, the grape treatment produced no significant difference in the serum levels of glucose, liver transaminase, and triglycerides, with the exception of cholesterol value, which was significantly reduced in both control and grape group (180.5 ± 20.32 vs. 196.1 ± 30.0 and 181.4 ± 21.9 vs. 194.3 ± 37.5, respectively). After 4 weeks from the end of grape treatment, the analysis of single fatty acids showed a significant increase in oleic acid content (14.15 ± 1.8 vs. 12.85 ± 1.6, p < 0.05) and a significant induction of the Omega-3 index (8.23 ± 1.9 vs. 6.09 ± 1.2, p < 0.05), associated with increased serum levels of adiponectin (24.09 ± 1.08 vs. 8.8 ± 0.7, p < 0.001). In contrast, the expression of fibroblast growth factor 21 (FGF21), a molecule associated with metabolic syndrome and liver disease, was significantly reduced (37.9 ± 6.8 vs. 107.8 ± 10.1, p < 0.001). The data suggest that the intake of fresh grape improves the Omega-3 index in the serum and exerts beneficial effects on liver function through the overexpression of adiponectin and the reduction in FGF21 levels. [ABSTRACT FROM AUTHOR]

In recent years, nutraceuticals have gained great popularity, owing to their physiological and potential health effects, such as anti-inflammatory, anti-cancer, antioxidant, and prebiotic effects, and their regulation of lipid metabolism. Since the Mediterranean diet is a nutritionally recommended dietary pattern including high-level consumption of nutraceuticals, this review aimed to summarize the main results obtained by our in vitro and in vivo studies on the effects of the major constituents of the Mediterranean diet (i.e., extra virgin olive oil compounds, polyunsaturated fatty acids, and fruit components). Based on experimental studies, the therapeutic purpose of nutraceuticals depends on their bioavailability, solubility, toxicity, and delivery system. This review provides more in-depth knowledge on the effects linked to nutraceuticals administration on human health, focusing the gastrointestinal tract and suggesting specific dietary components for personalized adjuvant therapies. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a common and disabling condition. The importance of healthy lifestyle for this disease is poorly explored. To test whether adherence to healthier lifestyle patterns is associated with a lower presence of multiple sclerosis (MS). By using a case–control design, we investigated the combined association of four healthy lifestyle-related factors (no current smoking, healthy diet, exercising regularly, body mass index <30 kg/m2) and the prevalence of MS. A logistic regression analysis, adjusted for potential confounders, was used and data reported as odds ratios (ORs) with their 95% confidence intervals (CIs). 728 participants with MS were matched with healthy controls (n = 2,912) using a propensity score approach. In a multivariable analysis, compared to those who scored low in the composite lifestyle score (0–1 healthy lifestyle factors), people who adopted all four low risk lifestyle factors showed a 71% lower odds of having MS (OR = 0.29; 95% CI: 0.15–0.56). Moreover, there was a strong linear trend, suggesting that the higher number of healthy lifestyle behaviors was associated with lower odds of having MS. Following a healthy lifestyle is associated with a lower prevalence of MS. This association should be explored further in cohort studies. [ABSTRACT FROM AUTHOR]

Abstract Background Lipid metabolism is altered in subjects with liver steatosis. FAS is a key enzyme in de novo lipogenesis and both FAS gene expression and enzymatic activity are primarily regulated by metabolic signals in the liver. Lipoprotein lipase (LPL), the rate-limiting enzyme for the hydrolysis of core triglycerides, plays a pivotal role in lipid metabolism. This study aims to investigate if circulating levels of FAS and LPL could be clinically associated with liver steatosis. Methods In this work, we present data obtained from a subsample of 94 subjects with liver steatosis enrolled by NUTRIEPA study, a nutritional trial in subjects with liver steatosis. Serum levels of FAS protein and LPL activity were evaluated by ELISA test and by a fluorescent method, respectively. The diagnosis and the degree of liver steatosis were based on laboratory and ecographic measurements. Statistical methods included Kruskal-Wallis analysis of variance and Wilcoxon signed-rank test, where appropriate. The χ2 test has been performed to analyse categorical variables. Results The subjects with severe steatosis had significantly higher serum levels of FAS protein and LPL activity compared to subjects with mild and moderate liver steatosis. Moreover, a positive trend in serum levels of FAS expression from lower to higher degree of steatosis was also detected. Conclusions We describe a relationship between human liver steatosis and elevated levels of circulating lipogenic enzymes. Increased serum levels of FAS expression and LPL activity could be considered a marker of severe liver steatosis.

Abstract Background n-3 and n-6 polyunsaturated fatty acids (PUFAs) are the two major classes of PUFAs encountered in the diet, and both classes of fatty acids are required for normal human health. Moreover, PUFAs have effects on diverse pathological processes impacting chronic disease, such as cardiovascular and immune disease, neurological disease, and cancer. Aim To investigate the effects of eicosapentaenoic acid (EPA) and arachidonic acid (ARA) on the proliferation and apoptosis of human hepatoma cell line HepG2 after exposure to increasing concentrations of EPA or ARA for 48 h. Moreover, in the same cells the gene expression of Fatty Acid Synthase (FAS) and 3-Hydroxy-3-Methyl-Glutaryl Coenzyme A Reductase (HMG-CoAR) was also investigated. Method Cell growth and apoptosis were assayed by MTT and ELISA test, respectively after cell exposure to increasing concentrations of EPA and ARA. Reverse-transcription and real-time PCR was used to detect FAS and HMG-CoAR mRNA levels in treated cells. Results Our findings show that EPA inhibits HepG2 cell growth in a dose-dependent manner, starting from 25 μM (P < 0.01, one-way ANOVA test and Dunnett's post test) and exerts a statistically significant pro-apoptotic effect already at 1 μM of EPA. Higher doses of ARA were need to obtain a statistically significant inhibition of cell proliferation and a pro-apoptotic effect in these cells (100 μM, P < 0.01, one-way ANOVA test and Dunnett's post test). Moreover, a down-regulation of FAS and HMG-CoAR gene expression was observed after EPA and ARA treatment in HepG2 cells, starting at 10 μM (P < 0.05, one-way ANOVA test and Dunnett's post test). Conclusion Our results demonstrate that EPA and ARA inhibit HepG2 cell proliferation and induce apoptosis. The down-regulation of FAS and HMG-CoAR gene expression by EPA and ARA might be one of the mechanisms for the anti-proliferative properties of PUFAs in an in vitro model of hepatocellular carcinoma.

Abstract Background PUFAs are potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme catalyzing the conversion of HMGCoA to mevalonate, the rate limiting step in cholesterol biosynthesis. Statins represent a class of drugs that are widely used to treat hypercholesterolemia for their ability to inhibit cholesterol biosynthesis and to up-regulate the synthesis of Low Density Lipoprotein (LDL) receptors in the liver. PUFAs mediate many, if not all, actions of statins and this could be one mechanism by which they lower cholesterol levels. The purpose of this study was to investigate whether combined treatment with Eicosapentaenoic acid (EPA) and lovastatin enhanced the regulatory effect on gene expression of HMGCoA reductase and LDL receptor in HepG2 cell line. Results The combined treatment with EPA and lovastatin enhanced the regulatory effect on gene expression of HMGCoA reductase and LDL receptor in HepG2 cell line. Moreover, we detected a synergistic effect on the inhibition of cancer cell proliferation obtained by combination of EPA and Lovastatin. Conclusions The use of EPA, in combination with low doses of Lovastatin may have potential value in treatment of neoplastic diseases.

Abstract Background The peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor that regulates adipogenic differentiation and glucose homeostasis. Spermidine/spermine N1-acetyltransferase (SSAT) and ornithine decarboxylase (ODC) are key enzymes involved in the metabolism of polyamines, compounds that play an important role in cell proliferation. While the PPARγ role in tumour growth has not been clearly defined, the involvement of the altered polyamine metabolism in colorectal carcinogenesis has been established. In this direction, we have evaluated the PPARγ expression and its relationship with polyamine metabolism in tissue samples from 40 patients operated because of colorectal carcinoma. Since it is known that the functional role of K-ras mutation in colorectal tumorigenesis is associated with cell growth and differentiation, polyamine metabolism and the PPARγ expression were also investigated in terms of K-ras mutation. Methods PPARγ, ODC and SSAT mRNA levels were evaluated by reverse transcriptase and real-time PCR. Polyamines were quantified by high performance liquid chromatography (HPLC). ODC and SSAT activity were measured by a radiometric technique. Results PPARγ expression, as well as SSAT and ODC mRNA levels were significantly higher in cancer as compared to normal mucosa. Tumour samples also showed significantly higher polyamine levels and ODC and SSAT activities in comparison to normal samples. A significant and positive correlation between PPARγ and the SSAT gene expression was observed in both normal and neoplastic tissue (r = 0.73, p < 0.0001; r = 0.65, p < 0.0001, respectively). Moreover, gene expression, polyamine levels and enzymatic activities were increased in colorectal carcinoma samples expressing K-ras mutation as compared to non mutated K-ras samples. Conclusion In conclusion, our data demonstrated a close relationship between PPARγ and SSAT in human colorectal cancer and this could represent an attempt to decrease polyamine levels and to reduce cell growth and tumour development. Therefore, pharmacological activation of PPARγ and/or induction of SSAT may represent a therapeutic or preventive strategy for treating colorectal cancer.

Background: The Mediterranean diet (MedDiet) is associated with good health. We aimed to estimate the effect of levels of adherence to the MedDiet on lifespan by performing treatment effects survival analysis.Methods: A sample of 5250 subjects aged ≥18 years were randomly selected from the electoral list of Castellana Grotte and Putignano (Apulian Region, Italy). Cohorts were enrolled in 2005-06 and followed-up until December 2018. The adherence to the MedDiet was measured by the relative Mediterranean score (rMED) and categorized as high, medium and low. Time-to-death (all-causes) as estimated by average treatment effect on the treated (ATET), potential outcome mean (POM) and relative efficiency of exposure were the outcomes.Results: A total of 4896 subjects were included. The median follow-up time was 12.82 (inter quartile range (IQR) 12.22-13.05), 12.91 (IQR 12.21-13.27) and 12.84 (IQR 12.19-13.03) years for high, medium and low rMED subjects respectively. By December 2018, 453 (9.25%) had died. There was a strong effect of medium and low rMED {ATET, -5.10 [95% confidence interval (CI) -9.39, -0.80] and -8.91 (95%CI -13.37, -4.45), respectively}. High rMED has an important effect on mean age at death [POM 90.16 (95% CI 86.06, 94.25)]. The relative effect size for medium and low rMED subjects was a lower lifespan of 5.62% (95% CI 1.01, 10.3) and 9.90% (95% CI 5.30, 5.30), respectively.Conclusions: We observed an important benefit in additional years of survival from adherence to MedDiet in this southern Italian cohort. Further investigation corroborating our findings in other population groups in other geographic regions will be an important contribution to promoting health and longevity. [ABSTRACT FROM AUTHOR]

Background & aims Liver ultrasound scan (US) use in diagnosing Non-Alcoholic Fatty Liver Disease (NAFLD) causes costs and waiting lists overloads. We aimed to compare various Machine learning algorithms with a Meta learner approach to find the best of these as a predictor of NAFLD. Methods The study included 2970 subjects, 2920 constituting the training set and 50, randomly selected, used in the test phase, performing cross-validation. The best predictors were combined to create three models: 1) FLI plus GLUCOSE plus SEX plus AGE, 2) AVI plus GLUCOSE plus GGT plus SEX plus AGE, 3) BRI plus GLUCOSE plus GGT plus SEX plus AGE. Eight machine learning algorithms were trained with the predictors of each of the three models created. For these algorithms, the percent accuracy, variance and percent weight were compared. Results The SVM algorithm performed better with all models. Model 1 had 68% accuracy, with 1% variance and an algorithm weight of 27.35; Model 2 had 68% accuracy, with 1% variance and an algorithm weight of 33.62 and Model 3 had 77% accuracy, with 1% variance and an algorithm weight of 34.70. Model 2 was the most performing, composed of AVI plus GLUCOSE plus GGT plus SEX plus AGE, despite a lower percentage of accuracy. Conclusion A Machine Learning approach can support NAFLD diagnosis and reduce health costs. The SVM algorithm is easy to apply and the necessary parameters are easily retrieved in databases. [ABSTRACT FROM AUTHOR]

Background and Aims: Increasing literature data show that adherence to the Mediterranean diet is undergoing profound changes in recent years, albeit with marked differences across nations. In Italy, one of the cradles of the Mediterranean diet, the literature regarding the trend for Mediterranean diet adherence is conflicting. Thus, we aimed to explore the trends of adherence to the Mediterranean diet in a large cohort of participants living in South Italy, over 20 years from 1985-86 to 2005-06.Methods and Results: Cross-sectional study with two evaluations, one made in 1985-86 and another in 2005-06; all participants were adults aged 30-70 years of age. The adherence to the Mediterranean diet was evaluated using the score proposed by Panagiotakos et al. This score features values ranging from 0 to 55, higher scores reflecting a greater adherence. The data are reported by age (30-49 vs. 50-69 years). Overall, 2451 subjects were included in 1985-86 and 2375 in 2005-06. A significant reduction was observed in the adherence to the Mediterranean diet (age 30-49 years: 31.82 ± 4.18 in 1985-86 vs. 29.20 ± 4.48 in 2005-06, reduction by 8.2%, p < 0.0001; age 50-69: 32.20 ± 4.09 in 1985-86 vs.30.15 ± 4.27 in 2005-06, reduction by 6.3%, p < 0.0001). Among all these items, the most dramatic change was observed for olive oil consumption, that decreased by 2.35 points in younger and 0.89 in older people.Conclusion: The adherence to the Mediterranean diet decreased from 1985-86 to 2005-06 in South Italy, particularly in younger people, above all due to a decreased olive oil consumption. [ABSTRACT FROM AUTHOR]

Purpose: To map and grade all health outcomes associated with magnesium (Mg) intake and supplementation using an umbrella review. Methods: Umbrella review of systematic reviews with meta-analyses of observational studies and randomized controlled trials (RCTs) using placebo/no intervention as control group. We assessed meta-analyses of observational studies based on random-effect summary effect sizes and their p values, 95% prediction intervals, heterogeneity, small-study effects and excess significance. For meta-analyses of RCTs, outcomes with a random-effect p value < 0.005 and a high-GRADE assessment were classified as strong evidence. Results: From 2048 abstracts, 16 meta-analyses and 55 independent outcomes were included (36 in RCTs and 19 in observational studies). In RCTs of Mg versus placebo/no active treatment, 12 over 36 outcomes reported significant results (p < 0.05). A strong evidence for decreased need for hospitalization in pregnancy and for decreased risk of frequency and intensity of migraine relapses in people with migraine was observed using the GRADE assessment. In observational studies, 9/19 outcomes were significant (p < 0.05). However, only one outcome presented highly suggestive evidence (lower incidence of type 2 diabetes in people with higher Mg intake at baseline) and one suggestive (lower incidence of stroke associated with higher Mg intake at baseline). Conclusion: Strong evidence according to the GRADE suggests that Mg supplementation can decrease the risk of hospitalization in pregnant women and reduce the intensity/frequency of migraine. Higher Mg intake is associated with a decreased risk of type 2 diabetes and stroke with highly suggestive and suggestive evidence, respectively, in observational studies. [ABSTRACT FROM AUTHOR]