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In our ageing global population, the cognitive decline associated with dementia and neurodegenerative diseases represents a major healthcare problem. To date, there are no effective treatments for age-related cognitive impairment, thus preventative strategies are urgently required. Physical exercise is gaining traction as a non-pharmacological approach to promote brain health. Adult hippocampal neurogenesis (AHN), a unique form of brain plasticity which is necessary for certain cognitive functions declines with age and is enhanced in response to exercise. Accumulating evidence from research in rodents suggests that physical exercise has beneficial effects on cognition through its proneurogenic capabilities. Given ethical and technical limitations in human studies, preclinical research in rodents is crucial for a better understanding of such exercise-induced brain and behavioural changes. In this review, exercise paradigms used in preclinical research are compared. We provide an overview of the effects of different exercise paradigms on age-related cognitive decline from middle-age until older-age. We discuss the relationship between the age-related decrease in AHN and the potential impact of exercise on mitigating this decline. We highlight the emerging literature on the impact of exercise on gut microbiota during ageing and consider the role of the gut-brain axis as a future possible strategy to optimize exercise-enhanced cognitive function. Finally, we propose a guideline for designing optimal exercise protocols in rodent studies, which would inform clinical research and contribute to developing preventative strategies for age-related cognitive decline., Competing Interests: None., (© 2024 – The authors. Published by IOS Press.)

Although significant portion of women experience depressive symptoms during or after menopausal transition, there has been considerable controversy over the benefits of hormone replacement therapy (HRT) and antidepressants due to insufficient evidence supporting the superiority of either treatment. This frequentist model based network meta-analysis (NMA) included randomized controlled trials (RCTs) of menopausal depression symptoms management in menopausal women. Seventy RCTs involving a total of 18,530 women (mean age 62.5) were analyzed. The results demonstrated that fluoxetine plus oral HRT [standardized mean difference (SMD)=-1.59, 95% confidence interval (95%CIs)=-2.69 to -0.50] were associated with the largest improvement in depressive symptoms than placebos in overall menopausal women. Similar findings were also noted in the subgroup of participants with a definite diagnosis of depression, while no pharmacological or hormone replacement therapy was better than placebo in the subgroup of post-menopausal women (amenorrhea > 1 year) or in patients without diagnosis of depression. This NMA presented evidence that fluoxetine plus HRT may be beneficial to menopausal women with a definite diagnosis of depression but not to those without depression or post-menopausal women. Trial registration: PROSPERO (CRD42020167459)., Competing Interests: Declaration of Competing Interest The authors report no financial interests or potential conflicts of interest. The authors of this work were supported by the following grants: Brendon Stubbs was supported by a Clinical Lectureship (ICA-CL-2017-03-001) jointly funded by Health Education England (HEE) and the National Institute for Health Research (NIHR). Brendon Stubbs was partly funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust. Brendon Stubbs was also supported by the Maudsley Charity, King's College London and the NIHR South London Collaboration for Leadership in Applied Health Research and Care (CLAHRC) funding., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Acrylamide, a component of fried foods, has been associated with several negative health outcomes. However, the relationship between dietary acrylamide and osteoporotic fractures has been explored by a few cross-sectional studies., Aims: To investigate if dietary acrylamide is associated with the onset of fractures in North American participants at high risk/having knee osteoarthritis (OA), over 8 years of follow-up., Methods: A Cox's regression analysis, adjusted for baseline confounders was run and the data were reported as hazard ratios (HRs) and 95% confidence intervals (CIs). Dietary acrylamide intake was assessed at the baseline using a food frequency questionnaire and categorized in tertiles (T), whilst fractures' history was recorded using self-reported information., Results: Altogether, 4,436 participants were included. Compared to participants with lower acrylamide intake (T1; < 3,313 μg), those with a higher acrylamide intake (T3; > 10,180 μg) reported a significantly higher risk of any fracture (HR = 1.37; 95% CI 1.12-1.68; p for trend = 0.009), forearm (HR = 1.73; 95% CI 1.09-2.77; p for trend = 0.04), spine (HR = 2.21; 95% CI 1.14-4.31; p for trend = 0.04), and hip fracture (HR = 4.09; 95% CI 1.29-12.96; p for trend = 0.046)., Conclusions: Our study is the first to report that high dietary acrylamide may be associated with an increased risk of osteoporotic fractures., (© 2022. The Author(s).)

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.

Background: Multiple sclerosis (MS) is a common and disabling condition. The importance of healthy lifestyle for this disease is poorly explored., Objective: To test whether adherence to healthier lifestyle patterns is associated with a lower presence of multiple sclerosis (MS)., Methods: 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/m 2 ) 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)., Results: 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., Conclusion: Following a healthy lifestyle is associated with a lower prevalence of MS. This association should be explored further in cohort studies.

Background: the possible relationship between dietary habits and the incidence of late-onset depression (LOD), defined as first depression onset at later age, is unclear., Objective: to investigate the relationship between consumption of different food groups and incident LOD., Design: longitudinal population-based study with a 12-year follow-up., Setting: Castellana Grotte, Bari, Italy., Subjects: five hundred and forty-six older subjects from the Salus in Apulia Study., Methods: baseline data were recorded in 2003-06, and diagnostic data were recorded in 2013-18 at follow-up. Dietary intake was assessed with a food frequency questionnaire. Depressive disorders were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders. Subjects who already suffered from depression or other psychiatric disorders at baseline were excluded from the analysis. The association between LOD and single dietary determinants was examined by Cox regression analysis and then applying the hazard ratio (HR)., Results: subjects with incident LOD (n = 34) had lower global cognition and total cholesterol levels and a higher body mass index (BMI) at baseline. Only processed meat significantly increased the risk of incident LOD of about 10% by 5 g/day intake (HR adjusted for age, sex, education, multimorbidity and BMI: 1.13, 95% confidence intervals: 1.04-1.22). A similar relationship was found for single foods in the processed meat food group such as sausages, salami and mortadella and baked ham, but not for raw ham., Conclusions: in midlife, a higher intake of processed meat was not only associated with an increased risk of cardiovascular- and metabolic-related chronic diseases in older age but also with an increased risk of developing LOD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Weight change is associated with all causes of death, cardiovascular, and cancer mortality and a heterogeneous group of other causes of death. We aimed to estimate the effect of weight change on all causes and cause-specific mortality in a cohort with a high prevalence of deaths due to diseases of the digestive system.MethodsIn this prospective cohort study, 2230 subjects aged 30 to 50 years were examined. The study consisted of a 32-year longitudinal study period (January 1985 to December 2017) and mortality follow-up. Outcomes were mortality from all causes and deaths from gastrointestinal disease. Root Mean Squared Error (RMSE) was evaluated to capture individual residual variation in Body Mass Index (BMI) after adjustment for baseline BMI, and the relationship of residual variation with mortality was calculated as cumulative incidence function and cause-specific hazard (CSH) rate.ResultsIn total, 793 participants died during the follow-up, 96 of them due to Digestive system causes. Magnitude of residual variation weight in the last quintile was associated with all-cause mortality (relative risk, 2.00; 95% CI, 1.54-2.59) and Digestive system causes (relative risk, 3.82; 95% CI, 1.86-7.81).ConclusionThe findings suggest an association between weight change and gastrointestinal disease mortality. Epidemiological works studying the correlation between weight change and mortality should consider this aspect., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: In real life, nutrition goes beyond purely biological domains. Primary prevention is the most efficient approach for reducing the risk of mortality. We aimed to study the association of lifestyle, as measured by a modified World Cancer Research Fund/American Institute for Cancer Research (mWCRF/AICR) scoring system with all-cause, digestive system disease-related (DSD-related), cardiovascular disease-related (CVD-related), cancer-related and other cause-related mortality using data from two population-based cohort studies conducted in Southern Italy., Methods: A random sample of 5271 subjects aged 18 years or older was enrolled in 2005-2006 and followed up until 2020. Usual food intakes were estimated using a validated dietary questionnaire. Competing risks survival models were applied., Results: High adherence to the mWCRF/AICR score was found to be statistically significant and negatively associated with all-cause mortality (HR 0.56, 95%CI 0.39; 0.82), DSD-related mortality (SHR 0.38, 95%CI 0.15; 0.97) and cancer-related mortality (SHR 0.43, 95%CI 0.19; 0.97) in the male sub-cohort and other-cause mortality (SHR 0.43, 95%CI 0.21; 0.88) only in the female group., Conclusions: This mWCRF/AICR score can be seen as a simple, easy tool for use in clinical practice to evaluate both qualitative and quantitative aspects of the diet.

Scope: The study aims to investigate the effects of fresh table grape consumption in healthy subjects on circulating levels of the most common human microRNAs (miRNAs). The regulatory network governed by these modulated miRNAs is also investigated., Methods and Results: Autumn Royal table grape, used in this study, is chosen for its high polyphenolic content and antioxidant properties. The study is a randomized controlled trial, in which 40 consecutive subjects are recruited on a voluntary basis and randomly assigned to two groups of the study, the control group, receiving only dietary recommendations and a grape group receiving a daily dose of 5 g of fresh table grape per kg of body weight for 21 days. All analyses are performed at baseline and after 21 days of dietary treatment. Circulating miRNAs levels are detected by Real-Time quantitative PCR (RT-qPCR) followed by bioinformatic functional analysis. The study identifies 20 circulating miRNAs differentially expressed in healthy subjects after grape intake, and in particular, 18 of 20 are down-regulated and 2 are up-regulated., Conclusion: The dietary intake of table grape affects circulating miRNAs levels in healthy subjects, particularly the miRNAs related to pathways involved in counteracting cancer development, including gastrointestinal cancers., (© 2021 Wiley-VCH GmbH.)

Non-Alcoholic Fatty Liver Disease (NAFLD) affects about 20-30% of the adult population in developed countries and is an increasingly important cause of hepatocellular carcinoma. Liver ultrasound (US) is widely used as a noninvasive method to diagnose NAFLD. However, the intensive use of US is not cost-effective and increases the burden on the healthcare system. Electronic medical records facilitate large-scale epidemiological studies and, existing NAFLD scores often require clinical and anthropometric parameters that may not be captured in those databases. Our goal was to develop and validate a simple Neural Network (NN)-based web app that could be used to predict NAFLD particularly its absence. The study included 2970 subjects; training and testing of the neural network using a train-test-split approach was done on 2869 of them. From another population consisting of 2301 subjects, a further 100 subjects were randomly extracted to test the web app. A search was made to find the best parameters for the NN and then this NN was exported for incorporation into a local web app. The percentage of accuracy, area under the ROC curve, confusion matrix, Positive (PPV) and Negative Predicted Value (NPV) values, precision, recall and f1-score were verified. After that, Explainability (XAI) was analyzed to understand the diagnostic reasoning of the NN. Finally, in the local web app, the specificity and sensitivity values were checked. The NN achieved a percentage of accuracy during testing of 77.0%, with an area under the ROC curve value of 0.82. Thus, in the web app the NN evidenced to achieve good results, with a specificity of 1.00 and sensitivity of 0.73. The described approach can be used to support NAFLD diagnosis, reducing healthcare costs. The NN-based web app is easy to apply and the required parameters are easily found in healthcare databases., (© 2021. The Author(s).)

COVID-19 (Coronavirus disease-19) may present with neurological signs, but whether people already affected by neurological conditions are at a higher risk of contracting COVID-19 is still not known. We, therefore, aimed to investigate the association of previously diagnosed neurological conditions with COVID-19. 502,536 community-dwelling UK Biobank participants (54.4% male, mean age 56.6 ± 10.3 years) were included. Among these, 57,463 participants had a diagnosis of neurological conditions (11.43%) and a total of 1326 COVID-19-positive cases were identified (0.26%). Neurological conditions were identified through medical history and linkage to data on hospital admissions (ICD-10 code G00-G99). COVID-19 presence was diagnosed using the data provided by Public Health England. The association of previous diagnosis of neurological conditions with COVID-19 was evaluated through logistic regressions, adjusted for potential confounders, reported as odds ratios (ORs) with their 95% confidence intervals (CIs). Nerve, nerve root and plexus disorders (G50-G59) were the most common conditions identified. The presence of COVID-19 was almost doubled in neurological conditions compared to the general population (0.45 vs. 0.24%, p < 0.0001). Previously diagnosed neurological conditions were associated with 60% higher odds of COVID-19 positive in the multivariable-adjusted model (OR = 1.6, 95% CI 1.4-1.8). Other degenerative diseases of the nervous system, extrapyramidal and movement disorders, polyneuropathies and other disorders of the peripheral nervous system, cerebral palsy and other paralytic syndromes were significantly associated with a higher odds of COVID-19. The presence of neurological conditions was associated with a significantly higher likelihood of COVID-19 compared to the general population., (© 2021. The Author(s).)

Alpha B-crystallin (CRYAB, HSPB5) belongs to the small heat shock protein (HSP) family and is highly expressed in various human cancers, suggesting a crucial role in tumor progression. However, few studies have examined CRYAB expression in colorectal cancer (CRC). In the present study, we investigated the relationship between CRYAB expression and the clinicopathological features of CRC samples. We comparatively analyzed CRYAB protein expression in 111 CRC tissues and normal adjacent colonic tissue, observing that it was significantly lower in CRC tissues than in corresponding non-cancerous tissues. Moreover, immunohistochemical analysis showed a significant correlation between CRYAB expression and high histological grade G3 ( p = 0.033). In summary, our results point to its possible application as a prognostic biomarker in CRC patients.

Nonalcoholic fatty liver disease (NAFLD) is considered a hepatic manifestation of metabolic syndrome, characterized from pathological changes in lipid and carbohydrate metabolism. Its main characteristics are excessive lipid accumulation and oxidative stress, which create a lipotoxic environment in hepatocytes leading to liver injury. Recently, many studies have focused on the identification of the genetic and epigenetic modifications that also contribute to NAFLD pathogenesis and their prognostic implications. The present review is aimed to discuss on cellular and metabolic alterations associated with NAFLD, which can be helpful to identify new noninvasive biomarkers. The identification of accumulated lipids in the cell membranes, as well as circulating cytokeratins and exosomes, provides new insights in understanding of NAFLD. This review also suggests that lifestyle modifications remain the main prevention and/or treatment for NAFLD.

The administration of a ketogenic diet (KD) has been considered therapeutic in subjects with irritable bowel syndrome (IBS). This study aimed to investigate the molecular mechanisms by which a low-carbohydrate diet, such as KD, can improve gastrointestinal symptoms and functions in an animal model of IBS by evaluating possible changes in intestinal tissue expression of endocannabinoid receptors. In rats fed a KD, we detected a significant restoration of cell damage to the intestinal crypt base, a histological feature of IBS condition, and upregulation of CB1 and CB2 receptors. The diet also affected glucose metabolism and intestinal membrane permeability, with an overexpression of the glucose transporter GLUT1 and tight junction proteins in treated rats. The present data suggest that CB receptors represent one of the molecular pathways through which the KD works and support possible cannabinoid-mediated protection at the intestinal level in the IBS rats after dietary treatment.

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., (© The Author(s) 2020; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Growing evidence reports that obesity might play a role in erectile dysfunction (ED), but limited knowledge is available. We conducted a meta-analysis to estimate the prevalence of ED in overweight men and men with obesity. We performed a systematic review up to 01/04/2019 to investigate the associations between obesity and ED. Applying a random-effect model, we calculated the prevalence of ED, the odds ratio (OR) for the presence of ED by Body Mass Index (BMI) categories and the mean differences between ED and controls in BMI and Waist Circumference (WC). Among 3409 studies, we included 45 articles with 42,489 men (mean age = 55 years). Taking normal weight men as reference, the prevalence of ED was significantly higher in overweight (OR = 1.31; 95%CI: 1.13-1.51; I 2  = 72%) and in men with obesity (OR = 1.60; 95%CI: 1.29-1.98; I 2  = 79%). Adjusting our analyses for potential confounders, the results were confirmed in men with obesity (OR = 1.46; 95%CI: 1.24-1.72; I 2  = 72%). ED was associated with significant higher values of BMI (MD = 0.769; 95%CI: 0.565-0.973 Kg/m 2 ; I 2  = 78%) and WC (MD = 5.251 cm; 95%CI: 1.295-9.208; I 2  = 96%). Considering the high prevalence of ED among men with obesity, clinicians should screen for this clinical condition in this population. Findings from the present study suggest that reducing adiposity is a crucial approach in patients with ED who are affected by obesity.

Background and Aims: Cardiovascular diseases (CVDis) are leading causes of morbidity and mortality. Even after the introduction of pharmacological therapy to lower Cholesterol, there is still a residual risk that may be ascribed to remnant cholesterol (RC). We aimed, by analyzing two prospective cohort studies, to estimate the effect of RC on risk and hazard of cardiovascular deaths (CVDs), while accounting for competing risks such as cancer (CDs) and other-causes deaths (OCDs)., Methods and Results: Cohorts were enrolled in 1992 and 2005. Personal data history was recorded. A fasting venous blood sample was obtained, and RC was calculated at baseline. Cause of Death was coded by using ICD-10th version. Follow-up ended on December 31, 2017. Flexible parametric competing-risks models were applied, with age at death as time-axis. In total, 5729 subjects were enrolled. There were 861 (15.1%) deaths: 234 CVDs (27.2%), 245 CDs (28.5%), 271 OCDs (31.5%) and 111 unknown causes of death (12.8%). RC exposure was a strong risk factor only for CVDs (Risk 2.54, 95% Confidence Interval 1.21; 5.34; Trend 1.26 (1.00; 1.58) for ≥1.29 mmol/L)., Conclusions: RC is a strong independent risk factor for cardiovascular mortality. Competing risk analysis is demonstrably a useful tool to disentangle associations among different competing events with a common risk factor., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: The authors have declared that no competing interests exist.

Gastric cancer (GC) is characterized by extreme heterogeneity due to histopathological differences, molecular characteristics, and immune gene expression signature. Until recently, several targeted therapies failed due to this complexity. The recent immunotherapy resulted in more effective and safe approaches in several malignancies. All tumors could be considered potentially immunogenic and the new knowledge regarding the interactions among tumor cells, immune cells, and tumor microenvironment (TME) allowed to reverse possible immune resistance. The immune response is a complex multisteps process that finely regulates the balance between the recognition of non-self and the prevention of autoimmunity. Cancer cells can use these pathways to suppress tumor immunity as a major mechanism of immune resistance. The recent molecular classifications of GCs by The Cancer Genome Atlas (TCGA) and by the Asian Cancer Research (ACRG) networks, together with the identification of multiple biomarkers, open new perspectives for stratification of patients who might benefit from a long-term immune checkpoint therapy. One of the major processes that contribute to an immunosuppressive microenvironment is represented by tumor angiogenesis. The cellular mechanisms inducing both angiogenesis and immunosuppressive responses are often reached by the same cell types and soluble factors, such as vascular endothelial growth factor A (VEGFA). Recent studies point out that combinatorial strategies should be adapted as useful therapeutic approach to reverse the immunosuppressive status of microenvironment occurring in a relevant percentage of gastric tumors., (©2020 Society for Leukocyte Biology.)

Grapes contain many flavonoid and non-flavonoid compounds with anticancer effects. In this work we fully characterized the polyphenolic profile of two grape skin extracts (GSEs), Autumn Royal and Egnatia, and assessed their effects on Polyunsaturated Fatty Acid (PUFA) membrane levels of Caco2 and SW480 human colon cancer cell lines. Gene expression of 15-lipoxygenase-1 (15-LOX-1), and peroxisome proliferator-activated receptor gamma (PPAR-γ), as well as cell morphology, were evaluated. The polyphenolic composition was analyzed by Ultra-High-Performance Liquid Chromatography/Quadrupole-Time of Flight mass spectrometry (UHPLC/QTOF) analysis. PUFA levels were evaluated by gas chromatography, and gene expression levels of 15-LOX-1 and PPAR-γ were analyzed by real-time Polymerase Chain Reaction (PCR). Morphological cell changes caused by GSEs were identified by field emission scanning electron microscope (FE-SEM) and photomicrograph examination. We detected a different profile of flavonoid and non-flavonoid compounds in Autumn Royal and Egnatia GSEs. Cultured cells showed an increase of total PUFA levels mainly after treatment with Autumn Royal grape, and were richer in flavonoids when compared with the Egnatia variety. Both GSEs were able to affect 15-LOX-1 and PPAR-γ gene expression and cell morphology. Our results highlighted a new antitumor mechanism of GSEs that involves membrane PUFAs and their downstream pathways.

Background: Elevated fasting remnant cholesterol (REM-C) levels have been associated with an increased cardiovascular risk in patients with metabolic syndrome (Mets) and Non-Alcoholic Fatty Liver Disease (NAFLD). We aimed to estimate the effect of different diets on REM-C levels in patients with MetS, as well as the association between NAFLD and REM-C., Methods: This is a secondary analysis of the MEDIDIET study, a parallel-arm Randomized Clinical Trial (RCT). We examined 237 people with MetS who underwent Liver Ultrasound (LUS) to assess the NAFLD score at baseline, 3-, and 6-months follow-up. Subjects were randomly assigned to the Mediterranean diet (MD), Low Glycemic Index diet (LGID), or Low Glycemic Index Mediterranean diet (LGIMD). REM-C was calculated as [total cholesterol-low density lipoprotein cholesterol (LDL-C)-high density lipoprotein cholesterol (HDL-C)]., Results: REM-C levels were higher in subjects with moderate or severe NAFLD than in mild or absent ones. All diets had a direct effect in lowering the levels of REM-C after 3 and 6 months of intervention. In adherents subjects, this effect was stronger among LGIMD as compared to the control group. There was also a significant increase in REM-C levels among Severe NAFLD subjects at 3 months and a decrease at 6 months., Conclusions: fasting REM-C level is independently associated with the grade of severity of NAFLD. LGIMD adherence directly reduced the fasting REM-C in patients with MetS.

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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

The polyphenolic compounds present in grape extracts have chemopreventive and anticancer properties. Here, we studied the ability of two grape skin extracts (GSEs), Autumn Royal and Egnatia, to influence the cell motility and membrane fluidity regulated by the enzyme Stearoyl-CoA desaturase-1 (SCD1) which increases with the cancer aggressiveness. Caco2 and SW480 human colon cancer cell lines were treated with increasing concentrations of GSEs to evaluate cell proliferation and motility. SCD1 levels were evaluated in both treated cell lines, by membrane lipidomic analysis conducted by gas chromatography. The expression levels of SCD1 and other factors involved in the reorganization of the cytoskeleton and focal adhesions were assessed by Real-time PCR, Western Blotting, and Immunofluorescence staining. High-performance liquid chromatography (HPLC) analyses were performed to determine the phenolic composition in the GSEs, finding them more expressed in Autumn Royal than in Egnatia. Both treatments reduced the levels of SCD1, phospho-Rac1/Cdc42/Rac1/Cdc42 ratio, Cofilin, Vimentin, and phospho-Paxillin especially in Caco2 compared to SW480, showing a different behavior of the two cell lines to these natural compounds. Our findings show that GSEs block the cell migration and membrane fluidity through a new mechanism of action involving structural cellular components., Competing Interests: The authors declare no conflict of interest.

Background: Higher Dietary Inflammatory Index (DII®) scores are associated with increased morbidity and mortality. However, little is known about the effects of DII on mortality in Mediterranean countries. Therefore, in the present study, we aimed to investigate the potential association between DII scores and overall, cancer and cardiovascular disease (CVD) mortality in people living in a Mediterranean area., Methods: DII scores were calculated using a validated food-frequency questionnaire. DII scores were then categorised into tertiles. Mortality was ascertained via death certificates. The association between DII scores with overall and cause-specific mortality was assessed via a multivariable Cox's regression analysis and reported as hazard ratios (HRs) with their 95% confidence intervals (CIs)., Results: The study included 1565 participants (mean age 65.5 years; females 44.7%). After a median follow-up of 12 years (2005-2017), 366 (23.4%) participants died. After adjusting for 17 potential confounders, people with higher DII scores had an increased risk of death compared to those in the lowest (most anti-inflammatory) tertile (HR = 1.38; 95% CI = 1.04-1.82 for the second tertile; HR = 1.38; 95% CI = 1.03-1.86 for the third tertile). Each 1 SD increase in DII score increased the risk of death by 13%. No association was found between DII scores and cancer or CVD death when considered separately., Conclusions: Higher DII scores were associated with a significantly higher mortality risk, whereas the association with cause-specific mortality was less clear. These findings highlight the potential importance of diet in modulating inflammation and preventing death., (© 2019 The British Dietetic Association Ltd.)

Background: Unrecovered Bell palsy is difficult to treat, because until now in literature there is not a gold standard. This study aimed to evaluate the effectiveness of neuromuscular electrical stimulation (NMES) and shortwave diathermy (SWD) therapy for chronic Bell palsy., Methods: After 5 months of conventional therapy, this 2-arm randomized controlled trial enrolled and randomly allocated 20 patients to a treatment group with NMES+SWD and supervised exercises (n = 10) or a sham group with supervised exercise alone (n = 10). The administration of NMES or sham NMES, as intervention, was performed 30 min/session, 5 sessions/wk, for 4 weeks. The primary outcome was assessed by Sunnybrook scale. The secondary outcomes were evaluated by the Kinovea©, a movement analysis software. All primary and secondary outcomes were measured at baseline (T0), at the end of 4-week treatment (T1)., Results: At the end of 4-week treatment, the patients in the treatment group did not achieve better outcomes in resting symmetry, but we observed an increase of the perceived a significant improvement (P < .05) for symmetry of voluntary movements by the Sunnybrook subscale, with a score of 55.4 ± 9 compared to 46.4 ± 3.7 to control group and an increase in zygomatic muscle movement symmetry ratio (P < .05) by Kinovea©. No adverse events occurred in either group., Conclusion: The improvements in the symmetry of voluntary movements demonstrated that combining diathermy with neuromuscular electrostimulation is valid and reliable in the treatment of chronic Bell palsy.

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.

Fatty Acid Synthase (FASN) is responsible for the de novo synthesis of fatty acids, which are involved in the preservation of biological membrane structure, energy storage and assembly of factors involved in signal transduction. FASN plays a critical role in supporting tumor cell growth, thus representing a potential target for anti-cancer therapies. Moreover, this enzyme has been recently associated with increased PD-L1 expression, suggesting a role for fatty acids in the impairment of the immune response in the tumor microenvironment. Orlistat, a tetrahydrolipstatin used for the treatment of obesity, has been reported to reduce FASN activity, while inducing a sensible reduction of the growth potential in different cancer models. We have analyzed the effect of orlistat on different features involved in the tumor cell biology of the T-ALL Jurkat cell line. In particular, we have observed that orlistat inhibits Jurkat cell growth and induces a perturbation of cell cycle along with a decline of FASN activity and protein levels. Moreover, the drug produces a remarkable impairment of PD-L1 expression. These findings suggest that orlistat interferes with different mechanisms involved in the control of tumor cell growth and can potentially contribute to decrease the tumor-associated immune-pathogenesis.

Objective: Polyphenols extracted by table grape have been demonstrated to decrease cell proliferation in vitro and to exert anti-atherosclerotic and antithrombotic activities, regulating cell functions. A grape polyphenolic profile is affected by climate as well as a grape cultivar. This study was aimed to characterize the berry skin polyphenolic composition, antioxidant activity and antiproliferative properties of two black grape cultivars, Autumn Royal and Egnatia., Methods: The phenolic composition of Grape Skin Extracts (GSEs) was determined by HPLC analyses. The antioxidant activity was determined using DPPH, ABTS and ORAC tests. Caco2, HT29 and SW480 human colon cancer cell lines were used to test the effects of GSEs in vitro. Cell proliferation and cell cycle were assessed with the MTT method and a Muse cell analyzer, respectively. qPCR and Western Blotting analysis were used to evaluate gene and protein expression, respectively., Results: The total polyphenolic content and the total antioxidant capacity were significantly higher in Autumn Royal than in Egnatia. However, table grape Egnatia showed greater ability to affect cell proliferation and apoptosis, as well as to exert a growth arrest in the S phase of the cell cycle, particularly in the Caco2 cell line., Conclusion: These data suggest that the new grape variety Egnatia is an interesting source of phenolic compounds that could be of interest in the food and pharmaceutical industries., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: Mediterranean diet has several beneficial effects on health, but data regarding the association between Mediterranean diet and knee osteoarthritis (OA) are limited mainly to cross-sectional studies. We investigated whether higher Mediterranean diet adherence is prospectively associated with lower risk of radiographic OA (ROA), radiographic symptomatic knee OA (SxOA) and pain worsening in North American people at high risk or having knee OA., Methods: Adherence to the Mediterranean diet was evaluated using a validated Mediterranean diet score (aMED), categorized in five categories (Q1 to Q5, higher values reflecting higher adherence to Mediterranean diet). Knee OA outcomes included incident (1) ROA, (2) SxOA, as the new onset of a combination of a painful knee and ROA, (3) knee pain worsening, i.e. a Western Ontario and McMaster Universities Osteoarthritis Index difference between baseline and each annual exam of ≥14%., Results: 4330 subjects (mean age: 61.1 years; 58.0% females) were included. Based on a multivariable Poisson regression analysis, during a mean follow-up period of 4 years, participants who were more highly adherent to a Mediterranean diet (Q5) reported lower risk of pain worsening (relative risk, RR = 0.96; 95% CI: 0.91-0.999) compared to those in Q1. In 2994 people free from SxOA at baseline, higher adherence to a Mediterranean diet was associated with a lower risk for SxOA during follow-up by 9% (Q5 vs. Q1; RR = 0.91; 95% CI: 0.82-0.998). No significant associations emerged between aMED and incident ROA., Conclusion: Higher adherence to Mediterranean diet is associated with a lower risk of pain worsening and symptomatic forms of knee OA., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background/aim: Low-density lipoproteins (LDL) are a heterogeneous class of particles that differ in size and density from each other. Small dense LDL (sdLDL) particles are considered more atherogenic than larger particles. The aim of the study was to evaluate serum levels of sdLDL in patients who died from cardiovascular diseases (CVD) or cancer in a cohort of patients followed up in the De Bellis Research Hospital for 20 years., Patients and Methods: A total of 75 participants who died of cancer and 87 who died of CVD were enrolled and they were matched for age and sex with 135 healthy controls, i.e. without CVD or cancer and are still alive., Results: Patients who died from cancer had the highest value of LDL IV subfraction (0.25±1.16), followed by those who died from CVD (0.17±0.96)., Conclusion: The integrated profile of sdLDL between CVD and cancer suggests that therapeutic modulation of sdLDL may be associated with a risk reduction for these diseases., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Liquid biopsy (LB) is a non-invasive approach representing a promising tool for new precision medicine strategies for cancer treatment. However, a comprehensive analysis of its reliability for pancreatic cancer (PC) is lacking. To this aim, we performed the first meta-analysis on this topic. We calculated the pooled sensitivity, specificity, positive (LR+) and negative (LR-) likelihood ratio, and diagnostic odds ratio (DOR). A summary receiver operating characteristic curve (SROC) and area under curve (AUC) were used to evaluate the overall accuracy. We finally assessed the concordance rate of all mutations detected by multi-genes panels. Fourteen eligible studies involving 369 patients were included. The overall pooled sensitivity and specificity were 0.70 and 0.86, respectively. The LR+ was 3.85, the LR- was 0.34 and DOR was 15.84. The SROC curve with an AUC of 0.88 indicated a relatively high accuracy of LB for molecular characterization of PC. The concordance rate of all mutations detected by multi-genes panels was 31.9%. LB can serve as surrogate for tissue in the molecular profiling of PC, because of its relatively high sensitivity, specificity and accuracy. It represents a unique opportunity to be further explored towards its introduction in clinical practice and for developing new precision medicine approaches against PC.

Non-alcoholic fatty liver disease (NAFLD) is a common condition in Western countries. However, their metabolic characteristics are poorly known even though they could be important. Therefore, the objective of this study was to measure resting metabolic parameters in overweight/obese adults with hepatic steatosis compared to controls, matched for age, sex, and obesity level. Hepatic steatosis was diagnosed with liver ultrasound. Energy metabolism was measured with indirect calorimetry: energy expenditure (REE), predicted REE, the ratio between REE and the predicted REE, and the respiratory quotient (RQ) were reported. We measured some anthropometric, body composition, and bio-humoral parameters; 301 participants with NAFLD were matched for age, sex, and obesity level with 301 participants without NAFLD. People with NAFLD showed significantly higher REE (1523 ± 238 vs. 1464 ± 212 kcal, p = 0.005), REE/REE predicted ratio (98.2 ± 9.4 vs. 95.7 ± 8.1, p = 0.002), and RQ (0.88 ± 0.08 vs. 0.85 ± 0.07, p = 0.03). Moreover, the NAFLD group had significantly higher inflammatory and insulin-resistance parameters compared to controls. In conclusion, NAFLD is associated with a significantly higher metabolic expenditure, as measured with indirect calorimetry, compared to a similar cohort of individuals without this condition. Higher inflammatory levels in patients with NAFLD can probably explain our findings, even if other research is needed on this issue., Competing Interests: The authors declare no conflict of interest.

Aberrant function of Smad2, a crucial member of transforming growth factor beta (TGF-β) signaling, is associated with the development of malignancies, particularly in the gastrointestinal district. However, little is known about its possible prognostic role in such tumor types. With the first meta-analysis on this topic, we demonstrated that the lack of the activated form of Smad2 (phosphor-Smad2 or pSmad2), which was meant to be the C-terminally phosphorylated form, showed a statistically significant association with an increased risk of all-cause mortality in patients with gastrointestinal cancers (RR, 1.58; 95% CI, 1.05-2.37, p = 0.029, I 2 = 84%), also after having adjusted for potential confounders (RR, 1.65; 95% CI, 1.24-2.18; p < 0.001; I 2 = 4%). This finding highlights the importance of the TGF-β signaling in this type of cancer. In this line, further studies are needed to explore more in depth this important molecular pathway, focusing also on potential therapeutic strategies based on its effectors or molecular targets.