Hepatic-specific Pgc-1α ablation drives fibrosis in a MASH model.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is a growing cause of chronic liver disease, characterized by fat accumulation, inflammation and fibrosis, which development depends on mitochondrial dysfunction and oxidative stress. Highly expressed in the liver during fasting, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) regulates mitochondrial and oxidative metabolism. Given the relevant role of mitochondrial function in MASH, we investigated the relationship between PGC-1α and steatohepatitis. METHODS: We measured the hepatic expression of Pgc-1α in both MASH patients and wild-type mice fed a western diet (WD) inducing steatosis and fibrosis. We then generated a pure C57BL6/J strain loss of function mouse model in which Pgc-1α is selectively deleted in the liver and we fed these mice with a WD supplemented with sugar water that accurately mimics human MASH. RESULTS: We observed that the hepatic expression of Pgc-1α is strongly reduced in MASH, in both humans and mice. Moreover, the hepatic ablation of Pgc-1α promotes a considerable reduction of the hepatic mitochondrial respiratory capacity, setting up a bioenergetic harmful environment for liver diseases. Indeed, the lack of Pgc-1α decreases mitochondrial function and increases inflammation, fibrosis and oxidative stress in the scenario of MASH. Intriguingly, this profibrotic phenotype is not linked with obesity, insulin resistance and lipid disbalance. CONCLUSIONS: In a MASH model the hepatic ablation of Pgc-1α drives fibrosis independently from lipid and glucose metabolism. These results add a novel mechanistic piece to the puzzle of the specific and crucial role of mitochondrial function in MASH development.

Fasting hyperglycaemia and fatty liver drive colorectal cancer: a retrospective analysis in 1145 patients.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents the hepatic manifestation of increased adiposopathy, whose pathogenetic features have been proposed as tumourigenic triggers for colorectal cancer (CRC). We aim to identify specific metabolic signatures involved in CRC development that may be used as non-invasive biomarkers, paving the way for specific and personalized strategies of CRC prevention and early detection. METHODS: We retrospectively assessed CRC onset during a time frame of 8 years in a cohort of 1145 out-patients individuals who had previously been evaluated for Metabolic Syndrome. RESULTS: 28 patients developed CRC. No association between CRC development and visceral and general obesity was detected, while baseline fasting plasma glucose (FPG) and non-invasive liver fibrosis scores were significantly higher in patients with CRC, compared to those who did not develop cancer. Liver steatosis and MASLD were more frequently diagnosed in patients who developed CRC compared to no cancer developers. Canonical correlations among metabolic biomarkers were not present in CRC developers, differently from no cancer group. In ROC analysis, FPG and non-invasive scores also showed good sensitivity and specificity in predicting colon cancer. We then calculated ORs for metabolic biomarkers, finding that higher FPG and non-invasive scores were associated with an increased risk of developing CRC. CONCLUSION: MASLD and increased FPG may play a role in the clinical background of CRC, bringing to light the fascinating possibility of a reversed gut-liver axis communication in the pathogenesis of CRC. Thus, the use of non-invasive scores of fatty liver may be helpful to predict the risk of CRC and serve as novel prognostic factors for prevention and therapeutic strategies.

Low Adherence to Mediterranean Diet Characterizes Metabolic Patients with Gastrointestinal Cancer.

Background. Gastrointestinal (GI) cancers are one of the most relevant causes of death globally, frequently associated with poor dietary patterns. The Mediterranean Diet (MedDiet) contributes to cancer prevention. To assess adherence to MedDiet, our research group validated a new score, the Chrono Med Diet Score (CMDS), that captures increased visceral adiposity. Methods. We enrolled 401 subjects who underwent an evaluation for metabolic diseases and specific screening procedures according to current guidelines and were asked to answer CMDS. A total of 71 new cancer cases were recorded, including 40 GI and 31 non-gastrointestinal (NON-GI) cancers. Results. We found that CMDS was reduced in subjects who were diagnosed with cancers. Patients who reported a CMDS score of 12 or less had an over three times increased risk of being diagnosed with GI cancers and presented increased waist circumference and triglycerides and reduced HDL cholesterol compared to adherent subjects. Conclusions. Low CMDS values capture the risk for cancer diagnosis, especially for GI cancers. Thus, CMDS, along with waist circumference, can be considered as a bona fide marker for increased risk of cancer, requiring anticipated screening procedures for the detection of premalignant and early stage GI cancers in patients with low adherence to MedDiet.

Gut microbiota in the pathogenesis and therapeutic approaches of diabetes.

The gut-liver axis plays a prominent role in the pathogenesis and therapy of metabolic diseases such as diabetes. The intestinal specific origin of several hormones that guide both inter- and post-prandial metabolism of carbohydrates and lipids, drives the attention of scientists and clinicians on the gut as a major site to intervene with novel diagnostic or prognostic markers. The role of intestinal ecology in the metabolic syndrome was postulated when gut microbiota was directly connected with inflammation, hyperinsulinemia, and diabetes. There have been several discoveries with the role of gut microbiota and gut-liver axis in diabetes. Also, there are several trials ongoing on the therapeutic efficacy of probiotic administration in diabetes and its complications. Here we point to the metabolic action of microbiota and discuss the actual state of the art on gut microbiota as a novel prognostic biomarker with a putative therapeutic role in diabetes.

AST/ALT-to-platelet ratio (AARPRI) predicts gynaecological cancers: a 8-years follow-up study in 653 women.

Non-alcoholic fatty liver disease (NAFLD), specifically liver steatosis and fibrosis with steatohepatitis (NASH), is often associated with visceral adiposopathy, whose pathogenetic features have been proposed as tumorigenic triggers. We performed a prospective analysis in 653 metabolic women to reveal any conditions that may predict and concur to cancer development during a 8-years period of follow-up. Among clinical and biochemical variables, only AST and non-invasive liver fibrosis scores (AARPRI, APRI, FIB-4, mFIB4) significantly distinguished cancer-developer women (n = 62, 9.5%) from those who did not develop cancer (p < 0.001). In ROC analysis, these scores also showed good sensitivity and specificity in differentiating women who developed cancer (all p < 0.001). We then calculated OR for these indexes finding that increased AARPRI was associated with the highest risk (OR = 6, p < 0.001) of gynaecological cancers development. We further validated these cut-off values in women who had developed other types of cancer, confirming that AARPRI is able to identify the risk for cancer development (OR = 5, p < 0.001). Our findings support the hypothesis that NAFLD, more than obesity per se, is directly associated with the clinical and pathogenic metabolic scenario of gynaecological cancers and encourage the use of liver fibrosis indexes to detect risk of cancer onset in women. Preventing adiposopathy and NAFLD through lifestyle and therapies may represent an instrumental strategy for cancer prevention and/or co-treatment in oncology.

Intestinal Pgc1α ablation protects from liver steatosis and fibrosis.

Background & Aims: The gut-liver axis modulates the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), a spectrum of conditions characterised by hepatic steatosis and a progressive increase of inflammation and fibrosis, culminating in metabolic dysfunction-associated steatohepatitis. Peroxisome proliferator-activated receptor-gamma coactivator 1α (Pgc1α) is a transcriptional co-regulator of mitochondrial activity and lipid metabolism. Here, the intestinal-specific role of Pgc1α was analysed in liver steatosis and fibrosis. Methods: We used a mouse model in which Pgc1α was selectively deleted from the intestinal epithelium. We fed these mice and their wild-type littermates a Western diet to recapitulate the major features of liver steatosis (after 2 months of diet) and metabolic dysfunction-associated steatohepatitis (after 4 months of diet). The chow diet was administered as a control diet. Results: In humans and mice, low expression of intestinal Pgc1α is inversely associated with liver steatosis, inflammation, and fibrosis. Intestinal disruption of Pgc1α impairs the transcription of a wide number of genes, including the cholesterol transporter Niemann-Pick C1-like 1 (Npc1l1), thus limiting the uptake of cholesterol from the gut. This results in a lower cholesterol accretion in the liver and a decreased production of new fatty acids, which protect the liver from lipotoxic lipid species accumulation, inflammation, and related fibrotic processes. Conclusions: In humans and mice, intestinal Pgc1α induction during Western diet may be another culprit driving hepatic steatosis and fibrosis. Here, we show that enterocyte-specific Pgc1α ablation protects the liver from steatosis and fibrosis by reducing intestinal cholesterol absorption, with subsequent decrease of cholesterol and de novo fatty acid accumulation in the liver. Impact and implications: Liver diseases result from several insults, including signals from the gut. Although the incidence of liver diseases is continuously increasing worldwide, effective drug therapy is still lacking. Here, we showed that the modulation of an intestinal coactivator regulates the liver response to a Western diet, by limiting the uptake of dietary cholesterol. This results in a lower accumulation of hepatic lipids together with decreased inflammation and fibrosis, thus limiting the progression of liver steatosis and fibrosis towards severe end-stage diseases.

Total serum FGF-21 levels positively relate to visceral adiposity differently from its functional intact form.

Objective: Increased Fibroblast Growth Factor-21 (FGF-21) circulating levels have been described in obesity. In this observational study, we analysed a group of subjects with metabolic disorders to unravel the putative link between visceral adiposity and FGF-21 serum levels. Methods: Total and intact serum FGF-21 concentration was measured with an ELISA assay respectively in 51 and 46 subjects, comparing FGF-21 levels in dysmetabolic conditions. We also tested Spearman's correlations between FGF-21 serum levels and biochemical and clinical metabolic parameters. Results: FGF-21 was not significantly increased in high-risk conditions such as visceral obesity, Metabolic Syndrome, diabetes, smoking, and atherosclerosis. Waist Circumference (WC), but not BMI, positively correlated with total FGF-21 levels (r=0.31, p <0.05), while HDL-cholesterol (r=-0.29, p <0.05) and 25-OH Vitamin D (r=-0.32, p <0.05) showed a significant negative correlation with total FGF-21. ROC analysis of FGF-21 in prediction of increased WC, showed that patients with total FGF-21 level over cut-off value of 161.47 pg/mL presented with impaired FPG. Conversely, serum levels of the intact form of FGF-21 did not correlate with WC and other metabolic biomarkers. Conclusion: Our newly calculated cut-off for total FGF-21 according to visceral adiposity identified subjects with fasting hyperglycemia. However, waist circumference correlates with total FGF-21 serum levels but does not correlate with intact FGF-21, suggesting that functional FGF-21 does not necessarily relate with obesity and metabolic features.

Identification of a Novel Score for Adherence to the Mediterranean Diet That Is Inversely Associated with Visceral Adiposity and Cardiovascular Risk: The Chrono Med Diet Score (CMDS).

Adherence to the Mediterranean diet (MedDiet) leads to reduction of mortality from all causes, especially in subjects with cardiovascular disease, obesity, and diabetes. Numerous scores have been proposed to evaluate the adherence to MedDiet, mainly focused on eating habits. In this study, we verified whether existing validated MedDiet scores, namely, MEDI-LITE and the Mediterranean Diet Score (MDS), could be associated with visceral adiposity. Failing to find a significant association with adiposity, we proposed the validation of a new, easy-to-use adherence questionnaire, the Chrono Med-Diet score (CMDS). CMDS contains eleven food categories, including chronobiology of dietary habits and physical activity. Compared to the MEDI-LITE score and MDS, low values of CMDS are linked to increased waist circumference (WC) and dysmetabolic conditions. CMDS was also inversely correlated with cardiovascular risk (CVR), as well as Fatty Liver Index (FLI). In conclusion, the CMDS is a novel questionnaire to study the adherence to the MedDiet that, focusing on type and timing of carbohydrates intake, has the peculiar capability of capturing subjects with abdominal obesity, thus being an easy-to-use instrument of personalized medicine.

Low HDL-cholesterol levels predict hepatocellular carcinoma development in individuals with liver fibrosis.

Background & Aims: Dysmetabolic conditions could drive liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), increasing susceptibility to hepatocellular carcinoma (HCC). We therefore aimed to identify novel predictive biomarkers of HCC in patients with and without liver fibrosis. Methods: A total of 1,234 patients with putative metabolic conditions and NAFLD were consecutively assessed in our outpatient clinic. Clinical and biochemical data were recorded, and then liver ultrasonography was performed annually for 5 years to detect HCC onset. For the analysis, the population was first divided according to HCC diagnosis; then a further subdivision of those who did not develop HCC was performed based on the presence or absence of liver fibrosis at time 0. Results: Sixteen HCC cases were recorded in 5 years. None of our patients had been diagnosed with cirrhosis before HCC was detected. Compared to patients who did not develop HCC, those who did had higher liver transaminases and fibrosis scores at time 0 (p <0.001). In addition, they presented with increased glycated haemoglobin levels and lower 25-OH vitamin D levels (p <0.05). Intriguingly, patients with higher liver fibrosis scores who subsequently developed HCC had lower HDL-cholesterol (HDL-c) levels at time 0 (p <0.001). Furthermore, in the 484 patients presenting with lower HDL-c at baseline, we found that waist circumference, and then vitamin D and glycated haemoglobin levels, were significantly different in those who developed HCC, regardless of liver fibrosis (p <0.05). Conclusions: This study identifies HDL-c as a bona fide novel marker to predict HCC in patients with NAFLD. Increased waist circumference and deranged metabolic pathways represent additional predisposing factors among patients with low HDL-c, highlighting the importance of studying cholesterol metabolism and integrating clinical approaches with dietary regimens and a healthy lifestyle to prevent HCC. Impact and implications: Visceral adiposity and its associated conditions, such as chronic inflammation and insulin resistance, may play a pivotal role in hepatocellular carcinoma development in patients with non-alcoholic fatty liver disease. We provide new insights on the underlying mechanisms of its pathogenesis, shedding light on the involvement of low levels of "good" HDL-cholesterol. We recommend integrating dietary regimens and advice on healthy lifestyles into the clinical management of non-alcoholic fatty liver disease, with the goal of reducing the incidence of hepatocellular carcinoma.

Bile Salt Hydrolase-Competent Probiotics in the Management of IBD: Unlocking the "Bile Acid Code".

Bile acid (BA) species and the gut microbiota (GM) contribute to intestinal mucosa homeostasis. BAs shape the GM and, conversely, intestinal bacteria with bile salt hydrolase (BSH) activity modulate the BA pool composition. The mutual interaction between BAs and intestinal microorganisms also influences mucosal barrier integrity, which is important for inflammatory bowel disease (IBD) pathogenesis, prevention and therapy. High levels of secondary BAs are detrimental for the intestinal barrier and increase the intestinal inflammatory response and dysbiosis. Additionally, a lack of BSH-active bacteria plays a role in intestinal inflammation and BA dysmetabolism. Thus, BSH-competent bacteria in probiotic formulations are being actively studied in IBD. At the same time, studies exploring the modulation of the master regulator of BA homeostasis, the Farnesoid X Receptor (FXR), in intestinal inflammation and how this impacts the GM are gaining significant momentum. Overall, the choice of probiotic supplementation should be a peculiar issue of personalized medicine, considering not only the disease but also the specific BA and metabolic signatures of a given patient.

Intestinal FXR Activation via Transgenic Chimera or Chemical Agonism Prevents Colitis-Associated and Genetically-Induced Colon Cancer.

The Farnesoid X Receptor (FXR) is the master regulator of Bile Acids (BA) homeostasis orchestrating their synthesis, transport and metabolism. Disruption of BA regulation has been linked to gut-liver axis diseases such as colorectal cancer (CRC). In this study, firstly we examined the role of constitutive activation of intestinal FXR in CRC; then we pre-clinically investigated the therapeutic potential of a diet enriched with a synthetic FXR agonist in two models of CRC (chemically-induced and genetic models). We demonstrated that mice with intestinal constitutive FXR activation are protected from AOM/DSS-induced CRC with a significant reduction of tumor number compared to controls. Furthermore, we evaluated the role of chemical FXR agonism in a DSS model of colitis in wild type (WT) and FXRnull mice. WT mice administered with the FXR activating diet showed less morphological alterations and decreased inflammatory infiltrates compared to controls. The FXR activating diet also protected WT mice from AOM/DSS-induced CRC by reducing tumors' number and size. Finally, we proved that the FXR activating diet prevented spontaneous CRC in APCMin/+ mice via an FXR-dependent modulation of BA homeostasis. Our results demonstrate that intestinal FXR activation prevented both inflammation- and genetically-driven colorectal tumorigenesis by modulating BA pool size and composition. This could open new avenues for the therapeutic management of intestinal inflammation and tumorigenesis.

Reduction in gut-derived MUFAs via intestinal stearoyl-CoA desaturase 1 deletion drives susceptibility to NAFLD and hepatocarcinoma.

Nonalcoholic fatty liver disease (NAFLD) is defined by a set of hepatic conditions ranging from steatosis to steatohepatitis (NASH), characterized by inflammation and fibrosis, eventually predisposing to hepatocellular carcinoma (HCC). Together with fatty acids (FAs) originated from adipose lipolysis and hepatic lipogenesis, intestinal-derived FAs are major contributors of steatosis. However, the role of mono-unsaturated FAs (MUFAs) in NAFLD development is still debated. We previously established the intestinal capacity to produce MUFAs, but its consequences in hepatic functions are still unknown. Here, we aimed to determine the role of the intestinal MUFA-synthetizing enzyme stearoyl-CoA desaturase 1 (SCD1) in NAFLD. We used intestinal-specific Scd1-KO (iScd1-/- ) mice and studied hepatic dysfunction in different models of steatosis, NASH, and HCC. Intestinal-specific Scd1 deletion decreased hepatic MUFA proportion. Compared with controls, iScd1-/- mice displayed increased hepatic triglyceride accumulation and derangement in cholesterol homeostasis when fed a MUFA-deprived diet. Then, on Western diet feeding, iScd1-/- mice triggered inflammation and fibrosis compared with their wild-type littermates. Finally, intestinal-Scd1 deletion predisposed mice to liver cancer. Conclusions: Collectively, these results highlight the major importance of intestinal MUFA metabolism in maintaining hepatic functions and show that gut-derived MUFAs are protective from NASH and HCC.

Platelets from patients with visceral obesity promote colon cancer growth.

Several studies highlighted the importance of platelets in the tumor microenvironment due to their ability to interact with other cell types such as leukocytes, endothelial, stromal and cancer cells. Platelets can influence tumor development and metastasis formation through several processes consisting of the secretion of growth factors and cytokines and/or via direct interaction with cancer cells and endothelium. Patients with visceral obesity (VO) are susceptible to pro-thrombotic and pro-inflammatory states and to development of cancer, especially colon cancer. These findings provide us with the impetus to analyze the role of platelets isolated from VO patients in tumor growth and progression with the aim to explore a possible link between platelet activation, obesity and colon cancer. Here, using xenograft colon cancer models, we prove that platelets from patients with visceral obesity are able to strongly promote colon cancer growth. Then, sequencing platelet miRNome, we identify miR-19a as the highest expressed miRNA in obese subjects and prove that miR-19a is induced in colon cancer. Last, administration of miR-19a per se in the xenograft colon cancer model is able to promote colon cancer growth. We thus elect platelets with their specific miRNA abundance as important factors in the tumor promoting microenvironment of patients with visceral obesity.

Monocyte-to-HDL Ratio (MHR) Predicts Vitamin D Deficiency in Healthy and Metabolic Women: A Cross-Sectional Study in 1048 Subjects.

Vitamin D deficiency is often linked with Metabolic Syndrome, both being more frequent with ageing and associated with an increase inflammatory state. Recently, monocytes-to-high density lipoprotein (HDL) ratio (MHR) has emerged as a powerful index to predict systemic inflammation. In this cross-sectional study, we investigated the association between circulating vitamin D level (25-OH vitamin D) and inflammatory status in a population of 1048 adult individuals. Our study reveals an inverse association between 25-OH vitamin D levels and MHR in the overall population. When the population is stratified by gender, waist circumference, and body mass index (BMI), we observed that while in men this relation is strongly significative only in condition of central obesity, in women a lifelong negative correlation exists between circulating 25-OH vitamin D and MHR and it is independent of the metabolic status. These observations underscore the relevance of circulating biomarkers such as MHR in the prediction of systemic inflammatory conditions sustained by vitamin D deficiency also in healthy and young women.

The gut-liver axis in cholangiopathies: focus on bile acid based pharmacological treatment.

PURPOSE OF REVIEW: This review analyses the main features of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) and provides an overview of the currently available (bile acid) bile acid related treatments. RECENT FINDINGS: In PBC, biliary injury is the consequence of a dysregulated intrahepatic and systemic immune response. Given the close association between PSC and inflammatory bowel disease (IBD), the microbiota represents an important factor in the development of PSC. Bile acid based pharmacological treatments could represent promising therapeutic strategies in the management of cholangiopathies. SUMMARY: Cholangiopathies include a spectrum of diseases resulting in cholestasis, an impairment of bile flow in the biliary tree, leading to biliary obstruction and damage as well as liver inflammation and fibrosis. PSC and PBC are highly heterogeneous cholangiopathies and progressive disorders with defined pathophysiological mechanisms. Curative treatments have not been established, and although their prevalence is low, they are a frequent indication for liver transplantation in the advanced stages of cholangiopathies. These diseases still present with unmet therapeutic strategies, also taking into account that on average 30-40% of patients undergoing liver transplantation will have recurrence of the original illness.

Enterocyte superoxide dismutase 2 deletion drives obesity.

Compelling evidence support an involvement of oxidative stress and intestinal inflammation as early events in the predisposition and development of obesity and its related comorbidities. Here, we show that deficiency of the major mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2) in the gastrointestinal tract drives spontaneous obesity. Intestinal epithelium-specific Sod2 ablation in mice induced adiposity and inflammation via phospholipase A2 (PLA2) activation and increased release of omega-6 polyunsaturated fatty acid arachidonic acid. Remarkably, this obese phenotype was rescued when fed an essential fatty acid-deficient diet, which abrogates de novo biosynthesis of arachidonic acid. Data from clinical samples revealed that the negative correlation between intestinal Sod2 mRNA levels and obesity features appears to be conserved between mice and humans. Collectively, our findings suggest a role of intestinal Sod2 levels, PLA2 activity, and arachidonic acid in obesity presenting new potential targets of therapeutic interest in the context of this metabolic disorder.

Abdominal obesity negatively influences key metrics of reverse cholesterol transport.

Cardiometabolic risk factors increase the risk of atherosclerotic cardiovascular disease (ASCVD), but whether these metabolic anomalies affect the anti-atherogenic function of reverse cholesterol transport (RCT) is not yet clearly known. The present study aimed to delineate if the function and maturation of high density lipoprotein (HDL) particles cross-sectionally associate with surrogate markers of ASCVD in a population comprising of different degree of cardiometabolic risk. We enrolled 131 subjects and characterized cardiometabolic risk based on the IDF criteria's for metabolic syndrome (MS). In this population, cholesterol efflux capacity (CEC), Lecithin-cholesterol acyltransferase (LCAT) and ApoA-1 glycation was associated with waist circumference, abdominal visceral fat (VFA) and abdominal subcutaneous fat. In multivariate analyses, VFA was identified as a critical contributor for low CEC and LCAT. When stratified into groups based on the presence of cardiometabolic risk factors, we found a prominent reduction in CEC and LCAT as a function of the progressive increase of cardiometabolic risk from 0-2, 0-3 to 0-4/5, whereas an increase in Pre-ß-HDL and ApoA-1 glycation was observed between the lowest and highest risk groups. These findings confirm the connection between MS and its predisposing conditions to an impairment of atheroprotective efflux-promoting function of HDLs. Furthermore, we have identified the bona fide pathogenically contribution of abdominal obesity to profound alterations of key metrics of RCT.

Adhesion of Platelets to Colon Cancer Cells Is Necessary to Promote Tumor Development in Xenograft, Genetic and Inflammation Models.

Platelets represent the linkage between tissue damage and inflammatory response with a putative role in tumorigenesis. Given the importance of the microenvironment in colon cancer development, we elucidated the eventual role of platelets-cancer cells crosstalk in in vivo colon cancermodels. To evaluate the involvement of platelets in intestinal tumorigenesis, we first analyzed if the ablation of ß-integrin P-selectin that drives platelets-cell adhesion, would contribute to platelets-colon cancer cell interaction and drive cancer progression. In a xenograft tumor model, we observed that when tumors are inoculated with platelets, the ablation of P-selectin significantly reduced tumor growth compared to control platelets. Furthermore, in genetic models, as well as in chronic colitis-associated colorectal carcinogenesis, P-selectin ablated mice displayed a significant reduction in tumor number and size compared to control mice. Taken together, our data highlights the importance of platelets in the tumor microenvironment for intestinal tumorigenesis. These results support the hypothesis that a strategy aimed to inhibit platelets adhesion to tumor cells are able to block tumor growth and could represent a novel therapeutic approach to colon cancer treatment.

AST to Platelet Ratio Index (APRI) is an easy-to-use predictor score for cardiovascular risk in metabolic subjects.

Visceral obesity is characterized by a low-grade inflammatory systemic state that contributes to the genesis of non-alcoholic fatty liver disease (NAFLD), frequently associated with liver fibrosis. Non-invasive serum markers have recently emerged as reliable, easy-to-use scores to predict liver fibrosis. NAFLD is often linked to metabolic and cardiovascular risk. Thus, in this cross-sectional study, we investigated in a population of 1225 subjects if AST to Platelet Ratio Index (APRI), one of the non-invasive liver fibrosis serum markers, can predict cardiovascular risk (CVR). APRI has been previously validated as an efficient score to predict liver fibrosis in viral hepatitis patients with a cut-off of 0.5 for fibrosis and 1.5 for cirrhosis. Our study showed that APRI significantly correlates with CVR and determines, when elevated, a significant increase in CVR for both genders, especially females. This spike in CVR, observed when APRI is elevated, is relatively high in patients in the age of 51-65 years, but it is significantly higher in younger and premenopausal women, approaching risk values usually typical of men at the same age. Taken together, our data highlighted the role of APRI as a reliable predictor easy-to-use score for CVR in metabolic patients.

let-7e downregulation characterizes early phase colonic adenoma in APCMin/+ mice and human FAP subjects.

The crypt-villus axis represents the essential unit of the small intestine, which integrity and functions are fundamental to assure tissue and whole-body homeostasis. Disruption of pathways regulating the fine balance between proliferation and differentiation results in diseases development. Nowadays, it is well established that microRNAs (miRNAs) play a crucial role in the homeostasis maintenance and perturbation of their levels may promote tumor development. Here, by using microarray technology, we analysed the miRNAs differentially expressed between the crypt and the villus in mice ileum. The emerged miRNAs were further validated by Real Time qPCR in mouse model (ApcMin/+), human cell lines and human tissue samples (FAP) of colorectal cancer (CRC). Our results indicated that miRNAs more expressed in the villi compartment are negatively regulated in tumor specimens, thus suggesting a close association between these microRNAs and the differentiation process. Particularly, from our analysis let-7e appeared to be a promising target for possible future therapies and a valuable marker for tumor staging, being upregulated in differentiated cells and downregulated in early-stage colonic adenoma samples.