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

Background: Irritable Bowel Syndrome (IBS) is a chronic functional gastrointestinal (GI) disorder characterized by abdominal pain, altered bowel habits, and bloating, affecting approximately 10.1% of the global population. While current treatments emphasize dietary modifications and symptom management, emerging evidence suggests that physical activity (PA) may help alleviate IBS symptoms. This study evaluated the effects of a structured walking program, "StepFit-18K", on IBS symptom relief. Methods: A total of 106 participants (68 females and 38 males) completed the 12-week intervention, which consisted of 18,000 additional steps per week (6000 extra steps on three days per week) tracked via fitness devices. The program emphasized step count, ease of adoption, and social support through walking groups. Results: As assessed by validated questionnaires, significant reductions in GI symptoms were observed. The IBS Symptom Severity Score (IBS-SSS) decreased from 118.30 ± 98.73 to 74.46 ± 74.93, with a delta score of −43.84%, highlighting bloating as the most improved symptom. No clinically significant changes were observed in anthropometric or biochemical markers. Conclusions: StepFit-18K is a simple, accessible, and effective form of physical activity that has demonstrated therapeutic benefits for IBS symptoms. This offers an additional application beyond its well-established role in preventing cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: Inorganic polyphosphate, a molecule composed of a few to several hundred orthophosphates, is involved in disparate pathological processes, including cancer development and progression. In this study, by analyzing biopsies derived from 50 subjects carrying colorectal cancer, collected by the Histopathology Unit of IRCCS "S. de Bellis," we showed a significant discrepancy in the level of inorganic polyphosphate between tumoral and peritumoral counterparts, with the former displaying a higher concentration. Moreover, by employing in vitro and ex vivo approaches, we revealed the involvement of inorganic polyphosphate in colorectal cancer cell proliferation. Additionally, we identified the calcium channel TRPM8 as the inorganic polyphosphate receptor responsible for propagating the signal downstream and, ultimately, enhancing the expression of proliferative markers. Thus, our results recognize inorganic polyphosphate as a novel pivotal biomarker linked with colorectal cancer growth. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Steatosis is the most common liver disease worldwide and the leading cause of liver-associated morbidity and mortality. The aim of this study was to explore the differences in blood parameters and dietary habits in non-obese patients with and without steatosis. Methods: The present study included 987 participants with BMI < 30, assessed in the fourth recall of the MICOL study. Patients were divided by steatosis grade, and a validated food frequency questionnaire (FFQ) with 28 food groups was administered. Results: The prevalence of non-obese participants with steatosis was 42.86%. Overall, the results indicated many statistically significant blood parameters and dietary habits. Analysis of dietary habits revealed that non-obese people with or without steatosis had similar dietary habits, although higher daily amounts of red meat, processed meat, ready meals, and alcohol were recorded in participants with liver disease (p < 0.05). Conclusions: Many differences were found in non-obese people with and without steatosis, but in light of a network analysis, the two groups demonstrated similar dietary habits, proving that pathophysiological, genetic, and hormonal patterns are probably the basis of their liver status, regardless of weight. Future genetic analyses will be performed to analyze the expression of genes involved in the development of steatosis in our cohort. [ABSTRACT FROM AUTHOR]