Inorganic Polyphosphate Promotes Colorectal Cancer Growth via TRPM8 Receptor Signaling Pathway.

BACKGROUND: Colorectal cancer (CRC) is characterized by a pro-inflammatory microenvironment and features high-energy-supply molecules that assure tumor growth. A still less studied macromolecule is inorganic polyphosphate (iPolyP), a high-energy linear polymer that is ubiquitous in all forms of life. Made up of hundreds of repeated orthophosphate units, iPolyP is essential for a wide variety of functions in mammalian cells, including the regulation of proliferative signaling pathways. Some evidence has suggested its involvement in carcinogenesis, although more studies need to be pursued. Moreover, iPolyP regulates several homeostatic processes in animals, spanning from energy metabolism to blood coagulation and tissue regeneration. RESULTS: In this study, we tested the role of iPolyP on CRC proliferation, using in vitro and ex vivo approaches, in order to evaluate its effect on tumor growth. We found that iPolyP is significantly increased in tumor tissues, derived from affected individuals enrolled in this study, compared to the corresponding peritumoral counterparts. In addition, iPolyP signaling occurs through the TRPM8 receptor, a well-characterized Na+ and Ca2+ ion channel often overexpressed in CRC and linked with poor prognosis, thus promoting CRC cell proliferation. The pharmacological inhibition of TRPM8 or RNA interference experiments performed in established CRC cell lines, such as Caco-2 and SW620, showed that the involvement of TRPM8 is essential, greater than that of the other two known iPolyP receptors, P2Y1 and RAGE. The presence of iPolyP drives cancer cells towards the mitotic phase of the cell cycle by enhancing the expression of ccnb1, which encodes the Cyclin B protein. In vitro 2D and 3D data reflected the ex vivo results, obtained by the generation of CRC-derived organoids, which increased in size. CONCLUSIONS: These results indicate that iPolyP may be considered a novel and unexpected early biomarker supporting colorectal cancer cell proliferation.

Role of Extracellular Vesicles in Crohn's Patients on Adalimumab Who Received COVID-19 Vaccination.

Crohn's disease (CD) is a type of inflammatory bowel disease (IBD) affecting the gastrointestinal tract that can also cause extra-intestinal complications. Following exposure to the mRNA vaccine BNT162b2 (Pfizer-BioNTech) encoding the SARS-CoV-2 Spike (S) protein, some patients experienced a lack of response to the biological drug Adalimumab and a recrudescence of the disease. In CD patients in progression, resistant to considered biological therapy, an abnormal increase in intestinal permeability was observed, more often with a modulated expression of different proteins such as Aquaporin 8 (AQP8) and in tight junctions (e.g., ZO-1, Claudin1, Claudin2, Occludin), especially during disease flares. The aim of this study is to investigate how the SARS-CoV-2 vaccine could interfere with IBD therapy and contribute to disease exacerbation. We investigated the role of the SARS-CoV-2 Spike protein, transported by extracellular vesicles (EVs), and the impact of various EVs components, namely, exosomes (EXOs) and microvesicles (MVs), in modulating the expression of molecules involved in the exacerbation of CD, which remains unknown.

Extracellular Vesicles Modulate Liver Cells Viability and Reactive Oxygen Species in Patients Following a Very Low-Calorie Ketogenic Diet.

The VLCKD is a diet recognized to promote rapid fat mobilization and reduce inflammation, hepatic steatosis, and liver fibrosis. Extracellular vesicles (EVs) mediate cell-to-cell communication. The aim of the study is to investigate the role of circulating EVs in cell proliferation, ketone bodies, and ROS production in patients on an 8-week VLCKD regimen. Participants were classified as responders (R) or non-responders (NR) to VLCKD treatment based on their fibroscan results. In vitro experiments with the hepatic cell lines HEPA-RG (normal hepatocytes) and LX-2 (stellate cells) were conducted to investigate the effects of circulating EVs on cell viability, ROS production, and ketone body presence. The findings reveal a notable reduction in cell viability in both cell lines when treated with exosomes (EXOs). In contrast, treatment with microvesicles (MVs) did not appear to affect cell viability, which remained unchanged. Additionally, the levels of ketone bodies measured in urine were not consistently correlated with the reduction of fibrosis in responders (R). Similarly, an increase in ketone bodies was observed in non-responders (NR), which was also not aligned with the expected reduction in fibrosis. This inconsistency stands in stark contrast to the levels of Reactive Oxygen Species (ROS), which exhibited a clear and consistent pattern in accordance with the dietary intervention. Finally, in this preliminary study, ROS has been identified as a potential diet adherence marker for VLCKD patients; the ROS levels reliably follow the progression of the fibrosis response, providing a more accurate reflection of the therapeutic effects.

Unveiling the Potential of Extracellular Vesicles as Biomarkers and Therapeutic Nanotools for Gastrointestinal Diseases.

Extracellular vesicles (EVs), acting as inherent nanocarriers adept at transporting a range of different biological molecules such as proteins, lipids, and genetic material, exhibit diverse functions within the gastroenteric tract. In states of normal health, they participate in the upkeep of systemic and organ homeostasis. Conversely, in pathological conditions, they significantly contribute to the pathogenesis of gastrointestinal diseases (GIDs). Isolating EVs from patients' biofluids facilitates the discovery of new biomarkers that have the potential to offer a rapid, cost-effective, and non-invasive method for diagnosing and prognosing specific GIDs. Furthermore, EVs demonstrate considerable therapeutic potential as naturally targeted physiological carriers for the intercellular delivery of therapeutic cargo molecules or as nanoscale tools engineered specifically to regulate physio-pathological conditions or disease progression. Their attributes including safety, high permeability, stability, biocompatibility, low immunogenicity, and homing/tropism capabilities contribute to their promising clinical therapeutic applications. This review will delve into various examples of EVs serving as biomarkers or nanocarriers for therapeutic cargo in the context of GIDs, highlighting their clinical potential for both functional and structural gastrointestinal conditions. The versatile and advantageous properties of EVs position them as promising candidates for innovative therapeutic strategies in advancing personalized medicine approaches tailored to the gastroenteric tract, addressing both functional and structural GIDs.

Targeting the Gut: A Systematic Review of Specific Drug Nanocarriers.

The intestine is essential for the modulation of nutrient absorption and the removal of waste. Gut pathologies, such as cancer, inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), and celiac disease, which extensively impact gut functions, are thus critical for human health. Targeted drug delivery is essential to tackle these diseases, improve therapy efficacy, and minimize side effects. Recent strategies have taken advantage of both active and passive nanocarriers, which are designed to protect the drug until it reaches the correct delivery site and to modulate drug release via the use of different physical-chemical strategies. In this systematic review, we present a literature overview of the different nanocarriers used for drug delivery in a set of chronic intestinal pathologies, highlighting the rationale behind the controlled release of intestinal therapies. The overall aim is to provide the reader with useful information on the current approaches for gut targeting in novel therapeutic strategies.

Semaglutide Modulates Extracellular Matrix Production of LX-2 Cells via Exosomes and Improves Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

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-ß1 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.

The 'speck'-tacular oversight of the NLRP3-pyroptosis pathway on gastrointestinal inflammatory diseases and tumorigenesis.

The NLRP3 inflammasome is an intracellular sensor and an essential component of the innate immune system involved in danger recognition. An important hallmark of inflammasome activation is the formation of a single supramolecular punctum, known as a speck, per cell, which is the site where the pro-inflammatory cytokines IL-1ß and IL-18 are converted into their bioactive form. Speck also provides the platform for gasdermin D protein activation, whose N-terminus domain perforates the plasma membrane, allowing the release of mature cytokines alongside with a highly inflammatory form of cell death, namely pyroptosis. Although controlled NLRP3 inflammasome-pyroptosis pathway activation preserves mucosal immunity homeostasis and contributes to host defense, a prolonged trigger is deleterious and could lead, in genetically predisposed subjects, to the onset of inflammatory bowel disease, including Crohn's disease and ulcerative colitis, as well as to gastrointestinal cancer. Experimental evidence shows that the NLRP3 inflammasome has both protective and pathogenic abilities. In this review we highlight the impact of the NLRP3-pyroptosis axis on the pathophysiology of the gastrointestinal tract at molecular level, focusing on newly discovered features bearing pro- and anti-inflammatory and neoplastic activity, and on targeted therapies tested in preclinical and clinical trials.

The oleic/palmitic acid imbalance in exosomes isolated from NAFLD patients induces necroptosis of liver cells via the elongase-6/RIP-1 pathway.

Excessive toxic lipid accumulation in hepatocytes underlies the development of non-alcoholic fatty liver disease (NAFLD), phenotypically characterized by necrosis and steato-fibrosis, whose molecular mechanism is not yet fully understood. Patients with NAFLD display an imbalanced palmitic (PA) to oleic acid (OA) ratio. Moreover, increasing experimental evidence points out a relevant involvement of the exosomal content in disease progression. Aim of the study was to highlight the PA/OA imbalance within circulating exosomes, the subsequent intracellular alterations, and the impact on NALFD. Liver cells were challenged with exosomes isolated from both healthy subjects and NAFLD patients. The exosomal PA/OA ratio was artificially modified, and biological effects were evaluated. A NAFLD-derived exosomal PA/OA imbalance impacts liver cell cycle and cell viability. OA-modified NAFLD-derived exosomes restored cellular viability and proliferation, whereas the inclusion of PA into healthy subjects-derived exosomes negatively affected cell viability. Moreover, while OA reduced the phosphorylation and activation of the necroptosis marker, Receptor-interacting protein 1 (phospho-RIP-1), PA induced the opposite outcome, alongside increased levels of stress fibers, such as vimentin and fibronectin. Administration of NAFLD-derived exosomes led to increased expression of Elongase 6 (ELOVL6), Stearoyl-CoA desaturase 1 (SCD1), Tumor necrosis factor α (TNF-α), Mixed-lineage-kinase-domain-like-protein (MLKL) and RIP-1 in the hepatocytes, comparable to mRNA levels in the hepatocytes of NAFLD patients reported in the Gene Expression Omnibus (GEO) database. Genetic and pharmacological abrogation of ELOVL6 elicited a reduced expression of downstream molecules TNF-α, phospho-RIP-1, and phospho-MLKL upon administration of NAFLD-derived exosomes. Lastly, mice fed with high-fat diet exhibited higher phospho-RIP-1 than mice fed with control diet. Targeting the Elongase 6-RIP-1 signaling pathway offers a novel therapeutic approach for the treatment of the NALFD-induced exosomal PA/OA imbalance.

Encapsulation of MCC950 in Liposomes Decorated with Anti-Frizzled 1 Improves Drug Bioavailability and Effectiveness in Fatty Liver Disease.

Inflammasome activation plays a crucial role in the progression to more severe stages of non-alcoholic fatty liver disease (NAFLD), representing a promising therapeutic target. MCC950 is a small molecule acting as a potent and specific inhibitor of the canonical and non-canonical activation of the NLRP3 inflammasome, but its short plasmatic half-life limits its use. Herein, we report, for the first time, the encapsulation of MCC950 in poly(ethylene glycol) (PEG) liposomes (LPs) that are specifically functionalized with an antibody against Frizzled 1 (FZD1), a g-coupled protein involved in the WNT pathway and overexpressed on inflammasome-activated macrophages. MCC950, encapsulated into PEG-LP formulations conjugated with an anti-FZD1 antibody, inhibits the NLRP3 inflammasome activation at concentrations 10 times lower than that of the free drug in THP-1 cells. Luminescent carbon dots (CDs) were also co-encapsulated with MCC950 in LPs to obtain optically traceable nanoformulations that have proved the enhanced ability of the targeted LPs to be internalized into THP-1 cells with respect to their nontargeted counterparts. Our results suggest that MCC950 encapsulation into targeted LPs represents a valuable strategy to achieve reformulation of the NLRP3 inhibitor, able to significantly curtail the threshold of MCC950 doses for inhibiting inflammasome activation, thus offering a new therapeutic approach.

The multiple combination of Paclitaxel, Ramucirumab and Elacridar reverses the paclitaxel-mediated resistance in gastric cancer cell lines.

Introduction: Paclitaxel (PTX) interferes with microtubule architecture by binding to ß-tubulin, thereby blocking progression at the G2/M phase and inducing apoptosis. This study aimed to investigate molecular processes underlying PTX-mediated resistance in gastric cancer (GC) cells. Methods: PTX-mediated resistance involves many processes, and in this work some of the factors involved in the resistance mechanism were identified by comparing two GC lines with PTX induced resistance to their sensitive counterparts. Results: Thus, the key feature of PTX-resistant cells was the overexpression of pro-angiogenic factors such as VEGFA, VEGFC, and Ang2, known to support tumor cell growth. A second relevant change detected in PTX-resistant lines was the elevated level of TUBßIII, a tubulin isoform that opposes microtubule stabilization. A third identified factor contributing to PTX-resistance was P-glycoprotein (P-gp), a transporter responsible for chemotherapy efflux from the cells, highly expressed in PTX-resistant lines. Discussion: These findings were in line with a greater sensitivity of resistant cells to treatment with both Ramucirumab and Elacridar. Ramucirumab significantly reduced the expression of angiogenic molecules and TUBßIII, while Elacridar restored the access of chemotherapy, recovering its anti-mitotic and pro-apoptotic effects. Finally, this study highlighted the role played by exosomes in spreading factors responsible for resistance in the tumor microenvironment.

Plasma-Derived Exosomes from NAFLD Patients Modulate the Cannabinoid Receptors' Expression in Cultured HepaRG Cells.

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.

Au nanoparticles decorated nanographene oxide-based platform: Synthesis, functionalization and assessment of photothermal activity.

A novel hybrid nanocomposite formed of carboxylated Nano Graphene Oxide (c-NGO), highly densely decorated by monodisperse citrate-coated Au nanoparticles (c-NGO/Au NPs), is synthesized and thoroughly characterized for photothermal applications. A systematic investigation of the role played by the synthetic parameters on the Au NPs decoration of the c-NGO platform is performed, comprehensively studying spectroscopic and morphological characteristics of the achieved nanostructures, thus elucidating their still not univocally explained synthesis mechanism. Remarkably, the Au NPs coating density of the c-NGO sheets is much higher than state-of-the-art systems with analogous composition prepared with different approaches, along with a higher NPs size dispersion. A novel theoretical approach for estimating the average number of NPs per sheet, combining DLS and TEM results, is developed. The assessment of the c-NGO/Au NPs photothermal activity is performed under continuous wave (CW) laser irradiation, at 532 nm and 800 nm, before and after functionalization with PEG-SH. c-NGO/Au NPs composite behaves as efficient photothermal agent, with a light into heat conversion ability higher than that of the single components. The c-NGO/Au NPs compatibility for photothermal therapy is assessed by in vitro cell viability tests, which show no significant effects of c-NGO/Au NPs, as neat and PEGylated, on cell metabolic activity under the investigated conditions. These results demonstrate the great potential held by the prepared hybrid nanocomposite for photothermal conversion technologies, indicating it as particularly promising platform for photothermal ablation of cancer cells.

NIR-Absorbing Mesoporous Silica-Coated Copper Sulphide Nanostructures for Light-to-Thermal Energy Conversion.

Plasmonic nanostructures, featuring near infrared (NIR)-absorption, are rising as efficient nanosystems for in vitro photothermal (PT) studies and in vivo PT treatment of cancer diseases. Among the different materials, new plasmonic nanostructures based on Cu2-xS nanocrystals (NCs) are emerging as valuable alternatives to Au nanorods, nanostars and nanoshells, largely exploited as NIR absorbing nanoheaters. Even though Cu2-xS plasmonic properties are not linked to geometry, the role played by their size, shape and surface chemistry is expected to be fundamental for an efficient PT process. Here, Cu2-xS NCs coated with a hydrophilic mesoporous silica shell (MSS) are synthesized by solution-phase strategies, tuning the core geometry, MSS thickness and texture. Besides their loading capability, the silica shell has been widely reported to provide a more robust plasmonic core protection than organic molecular/polymeric coatings, and improved heat flow from the NC to the environment due to a reduced interfacial thermal resistance and direct electron-phonon coupling through the interface. Systematic structural and morphological analysis of the core-shell nanoparticles and an in-depth thermoplasmonic characterization by using a pump beam 808 nm laser, are carried out. The results suggest that large triangular nanoplates (NPLs) coated by a few tens of nanometers thick MSS, show good photostability under laser light irradiation and provide a temperature increase above 38 °C and a 20% PT efficiency upon short irradiation time (60 s) at 6 W/cm2 power density.

Premenopausal Syndrome and NAFLD: A New Approach Based on Gender Medicine.

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition that affects 25% of the world's population. There is a clear difference in both geographical distribution and sex in childbearing age. These differences are reduced when women become older and senescence begins. The factors that affect the likelihood of developing NAFLD in a premenopausal woman are an imbalance of sex hormones (especially in estradiol and androgen), microbiome dysregulation, insulin resistance, early menarche, the length of time that the woman breastfeeds for and polycystic ovarian syndrome (PCOS). The aim of this review is to identify various physical ailments that may not appear to be serious to young women but that then affect the onset of NAFLD in perimenopause and can degenerate into NASH. These conditions should also be considered in future clinical management, as well as in research opportunities, in order to customize the monitoring and treatment of NAFLD, considering gender medicine for those women who had early metabolic symptoms that were not considered to be significant at the time.

Exosomal FZD-7 Expression Is Modulated by Different Lifestyle Interventions in Patients with NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition characterized from hypertriglyceridemia and hepatic fat accumulation, in the absence of alcohol intake. NAFLD starts as steatosis (NAFL), and the continued injury relative to the toxic fat induces inflammation, steatohepatitis (NASH), and HCC. One of the factors determining liver degeneration during the evolution of NAFLD is a modification of Wnt/Frizzled (FZD) signaling. In particular, an inhibition of Wnt signaling and an overexpression of a specific FZD receptor protein, namely, the FZD7, have been observed in NAFLD. Actually, the prognosis and the follow-up of NAFLD is not easy, and the liver biopsy is the gold standard for an accurate detection of liver fibrosis. In this study, the modulation of the FZD7 expression levels in plasma-derived exosomes of NAFLD-affected patients, before and after specific lifestyle interventions, were experimentally evaluated by Western blotting analysis. The experimental data were analyzed by an accurate statistical study that indicated, in the exosomes derived from plasma of NAFLD patients with moderate or severe steatosis, an average expression level of FZD7 that was significantly higher than healthy subjects at baseline; conversely, the values were normalized after 90 days of specific lifestyle interventions. The overall results suggested that the FZD7 delivered by exosomes represents a good candidate as a new and effective biomarker for diagnosis and prognosis of NAFLD.

Magnetic implants in vivo guiding sorafenib liver delivery by superparamagnetic solid lipid nanoparticles.

HYPOTHESIS: Solid lipid nanoparticles (SLNs), co-encapsulating superparamagnetic iron oxide nanoparticles and sorafenib, have been exploited for magnetic-guided drug delivery to the liver. Two different magnetic configurations, both comprising two small magnets, were under-skin implanted to investigate the effect of the magnetic field topology on the magnetic SLNP accumulation in liver tissues. A preliminary simulation analysis was performed to predict the magnetic field topography for each tested configuration. EXPERIMENTS: SLNs were prepared using a hot homogenization approach and characterized using complementary techniques. Their in vitro biological behavior was assessed in HepG-2 liver cancer cells; wild-type mice were used for the in vivo study. The magnet configuration that resulted in a higher magnetic targeting efficiency was investigated by evaluating the iron content in homogenated murine liver tissues. FINDINGS: SLNs, characterized by an average size smaller than 200 nm, retained their superparamagnetic behavior and relevant molecular resonance imaging properties as negative contrast agents. The evaluation of iron accumulation in the liver tissues was consistent with the magnetic induction profile of each magnet configuration, concurring with the results predicted by simulation analysis and obtained by measurements in living mice.

Exosome Released FZD10 Increases Ki-67 Expression via Phospho-ERK1/2 in Colorectal and Gastric Cancer.

Frizzled (FZD) proteins are primary receptors for Wnt signaling that activates the mitogen-activated protein kinase (MAPK) pathways. Dysfunction of Wnt signals with consequently abnormal activation of MAPK3 pathways was found in colorectal cancer (CRC) and gastric cancer (GC). Upregulation of FZD10 protein, localized in the exosomes isolated from plasma of CRC and GC patients, was associated with a poor prognosis. Herein, the expression levels of circulating FZD10 were found to be strongly correlated to their expression levels in the corresponding tissues in CRC and GC patients. Bioinformatic prediction revealed a link between FZD10 and Ki-67 through MAPK3. In both CRC and GC tissues, pERK1/2 levels were significantly increased at more advanced disease stages, and pERK1/2 and Ki-67 were correlated. Silencing of FZD10 in CRC and GC cells resulted in a significant reduction of pERK1/2 and Ki-67 expression, while subsequent treatment with exogenous exosomes partially restored their expression levels. The strong correlation between the expression of Ki-67 in tissues and of FZD10 in exosomes suggests that the exosome-delivered FZD10 may be a promising novel prognostic and diagnostic biomarker for CRC and GC.

Nonalcoholic Fatty Liver Disease: Focus on New Biomarkers and Lifestyle Interventions.

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.

A Possible Role of FZD10 Delivering Exosomes Derived from Colon Cancers Cell Lines in Inducing Activation of Epithelial-Mesenchymal Transition in Normal Colon Epithelial Cell Line.

Exosomes belong to the family of extracellular vesicles released by every type of cell both in normal and pathological conditions. Growing interest in studies indicates that extracellular vesicles, in particular, the fraction named exosomes containing lipids, proteins and nucleic acid, represent an efficient way to transfer functional cargoes between cells, thus combining all the other cell-cell interaction mechanisms known so far. Only a few decades ago, the involvement of exosomes in the carcinogenesis in different tissues was discovered, and very recently it was also observed how they carry and modulate the presence of Wnt pathway proteins, involved in the carcinogenesis of gastrointestinal tissues, such as Frizzled 10 protein (FZD10), a membrane receptor for Wnt. Here, we report the in vitro study on the capability of tumor-derived exosomes to induce neoplastic features in normal cells. Exosomes derived from two different colon cancer cell lines, namely the non-metastatic CaCo-2 and the metastatic SW620, were found to deliver, in both cases, FZD10, thus demonstrating the ability to reprogram normal colonic epithelial cell line (HCEC-1CT). Indeed, the acquisition of specific mesenchymal characteristics, such as migration capability and expression of FZD10 and markers of mesenchymal cells, was observed. The exosomes derived from the metastatic cell line, characterized by a level of FZD10 higher than the exosomes extracted from the non-metastatic cells, were also more efficient in stimulating EMT activation. The overall results suggest that FZD10, delivered by circulating tumor-derived exosomes, can play a relevant role in promoting the CRC carcinogenesis and propagation.