Publications

Inorganic polyphosphate (iPolyP) is a ubiquitous molecule composed of a variable number of orthophosphate units. Recent studies have highlighted its involvement in colorectal cancer (CRC) cell proliferation. However, further investigations are needed to elucidate its role in CRC cell progression and migration, as well as its influence on the tumor microenvironment. This study focuses on the inorganic polyphosphate (iPolyP)/transient receptor potential cation channel subfamily M member 8 (TRPM8) axis and its impact on CRC progression. To investigate these issues, western blotting, fixed and live cells immunofluorescence, 2D and 3D cell culture on CRC-patient derived tissues, ELISA, and wound healing assays were performed. Our results show that inorganic polyphosphate induces the expression of epithelial-to-mesenchymal transition (EMT) markers in CRC cells. Furthermore, the iPolyP/TRPM8 axis indirectly promotes tumor growth through activation of the Nucleotide-binding oligomerization domain, Leucine-rich Repeat and Pyrin domain-containing protein 3 (NLRP3) inflammasome in immune cells, leading to increased levels of the pro-inflammatory cytokine interleukin-1β (IL-1β) in the tumor microenvironment (TME), thereby advancing CRC. These findings suggest that targeting the iPolyP/TRPM8 pathway may be a promising strategy to inhibit CRC progression and metastasis.

A scoping review was conducted to systematically assess the current evidence and emerging applications of regenerative medicine in the treatment of End Stage Renal Disease (ERSD), aiming to map existing knowledge and identify key research gaps. ESRD represents a major global health burden, and despite being managed primarily through dialysis and kidney transplantation, both approaches are limited by morbidity, mortality, and organ donor shortages. Regenerative medicine emerged as a promising alternative, leveraging stem cells technologies and tissue engineering to develop functional renal tissues with the potential to restore or replace damaged kidney structures. Our review protocol was developed in accordance with the PRISMA-ScR guidelines and was prospectively registered on Figshare. Inclusion criteria comprised peer-reviewed articles published between 2004 and 2024, focusing on bioengineering strategies relevant to kidney regeneration and ESRD, with no restrictions on language or geographic origin. Editorials, letters, and non-peer-reviewed sources were excluded. A comprehensive literature search was performed in Medline, Scopus, and Web of Science using pre-defined search terms. Screening and selection were conducted independently by four reviewers working in pairs selected with discrepancies resolved through consensus. A standardized data extraction form was iteratively developed and piloted to collect relevant information on study characteristics and experimental models. Of the 5,869 records initially identified, 111 studies met the inclusion criteria. The findings underscore the therapeutic potential of regenerative medicine in ESRD, with kidney organoids and organ-on-a-chip platforms representing two of the most advanced and translationally relevant approaches currently under investigation. These technologies are increasingly recognized not only for their role in disease modeling and drug screening, but also as potential precursors to fully bioengineered renal replacement therapies.

Psychosomatic disorders are conditions in which physical (somatic) symptoms are triggered or aggravated by psychological distress. These disorders result from complex interactions among the endocrine, central nervous, and immune systems. Emerging evidence indicates that gut microbiota (GM) dysbiosis, epigenetic alterations, and immune system dysregulation play pivotal roles in the pathogenesis of psychosomatic disorders and may serve as potential biomarkers for disease states and therapeutic outcomes. This review first outlines how epigenetic dysregulation contributes to psychosomatic disorders through altered expression of genes such as GRM2, TRPA1, SLC6A4, NR3C1, leptin, BDNF, NAT15, HDAC4, PRKCA, RTN1, PRKG1, and HDAC7. We then examine current evidence linking psychosomatic disorders with changes in GM composition and GM-derived epigenetic metabolites, which influence immune function and neurobiological pathways. The core focus of this review is on therapeutic interventions-including probiotics, prebiotics, postbiotics, fecal microbiota transplantation, and targeted dietary approaches-that modulate the gut-brain axis through epigenetic mechanisms for the management of psychosomatic disorders. Finally, we highlight the current challenges and future directions in elucidating the interplay between epigenetics, the GM, and psychosomatic disease mechanisms. In this context, human iPSC-derived multicellular organoids may serve as powerful platforms to unravel mechanistic pathways underlying inter-organ interactions.

Eating disorders (EDs) are a heterogeneous class of increasing mental disorders that are characterized by disturbances in eating behaviors, body weight regulation, and associated psychological dysfunctions. These disorders create physiological imbalances that alter the diversity and composition of the gut microbiota. While evidence suggests that EDs can arise from epigenetic aberrations, alterations in gut microbial communities may also contribute to the development and/or persistence of EDs through epigenetic mechanisms. Understanding the interplay among gut microbial communities, epigenetic processes, and the risk of EDs provides opportunities for designing preventive and/or therapeutic interventions through gut microbiome modulation. This review highlights how microbiome-based therapeutics and specific dietary interventions can contribute to improving various subtypes of EDs by modulating gut microbial communities and mitigating epigenetic aberrations. First, we briefly review the literature on links between epigenetic aberrations and the pathophysiology of EDs. Second, we examine the potential role of the gut microbiome in the pathogenesis of EDs through epigenetic mechanisms. Next, we explore the associations between EDs and other psychiatric disorders, and examine the potential roles of the microbiome in their pathogenesis. Finally, we present evidence supporting the potential of microbiome-based therapeutics and specific dietary interventions to improve EDs through epigenetic modifications.

Obesity (OB) has become a serious health issue owing to its ever-increasing prevalence over the past few decades due to its contribution to severe metabolic and inflammatory disorders such as cardiovascular disease, type 2 diabetes, and cancer. The unbalanced energy metabolism in OB is associated with substantial epigenetic changes mediated by the gut microbiome (GM) structure and composition alterations. Remarkably, experimental evidence also indicates that OB-induced epigenetic modifications in adipocytes can lead to cellular "memory" alterations, predisposing individuals to weight regain after caloric restriction and subsequently inducing inflammatory pathways in the liver. Various environmental factors, especially diet, play key roles in the progression or prevention of OB and OB-related disorders by modulating the GM structure and composition and affecting epigenetic mechanisms. Here, we will first focus on the key role of epigenetic aberrations in the development of OB. Then, we discuss the association between abnormal alterations in the composition of the microbiome and OB and the interplays between the microbiome and the epigenome in the development of OB. Finally, we review promising strategies, including prebiotics, probiotics, a methyl-rich diet, polyphenols, and herbal foods for the prevention and/or treatment of OB via modulating the GM and their metabolites influencing the epigenome.

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.

One of the main causes of post-transplant-associated morbidity and mortality is cancer. The aims of the project were to study the neoplastic risk within the kidney transplant population and identify the determinants of this risk. A cohort of 462 renal transplant patients from 2010 to 2020 was considered. The expected incidence rates of post-transplant cancer development in the referenced population, the standardized incidence ratios (SIR) taking the Italian population as a comparison, and the absolute risk and the attributable fraction were extrapolated from these cohorts of patients. Kidney transplant recipients had an overall cancer risk of approximately three times that of the local population (SIR 2.8). A significantly increased number of cases were observed for Kaposi's sarcoma (KS) (SIR 195) and hematological cancers (SIR 6.8). In the first 3 years post-transplant, the risk to develop either KS or hematological cancers was four times higher than in the following years; in all cases of KS, the diagnosis was within 2 years from the transplant. Post-transplant immunosuppression represents the cause of 99% of cases of KS and 85% of cases of lymphomas, while only 39% is represented by solid tumors. Data related to the incidence, the percentages attributable to post-transplant immunosuppression, and the time of onset of neoplasms, particularly for KS and hematological tumors could help improve the management for the follow-up in these patients.

Over 40,000 patients in the United States are estimated to suffer from end-stage liver disease and acute hepatic failure, for which liver transplantation is the only available therapy. Human primary hepatocytes (HPH) have not been employed as a therapeutic tool due to the difficulty in growing and expanding them in vitro, their sensitivity to cold temperatures, and tendency to dedifferentiate following two-dimensional culture. The differentiation of human-induced pluripotent stem cells (hiPSCs) into liver organoids (LO) has emerged as a potential alternative to orthotropic liver transplantation (OLT). However, several factors limit the efficiency of liver differentiation from hiPSCs, including a low proportion of differentiated cells capable of reaching a mature phenotype, the poor reproducibility of existing differentiation protocols, and insufficient long-term viability in vitro and in vivo. This review will analyze various methodologies being developed to improve hepatic differentiation from hiPSCs into liver organoids, paying particular attention to the use of endothelial cells as supportive cells for their further maturation. Here, we demonstrate why differentiated liver organoids can be used as a research tool for drug testing and disease modeling, or employed as a bridge for liver transplantation following liver failure.

Human induced pluripotent stem cells (hiPSCs) represent a powerful tool for the generation of specialized cells to be used in regenerative medicine as well as hepatocellular repopulation tool to treat liver metabolic diseases such as nonalcoholic steatohepatitis (NASH). Here we describe a strategy to obtain fully functional liver organoids from hiPSCs in a scalable manner. Our approach uses a two-step process, with a first step involving the scalable formation of homogeneous and uniform-sized human embryoid bodies (hEBs), followed by the application of a four-step liver differentiation protocol for the derivation of liver organoids that possess all the features of primary human hepatocytes. This chapter will also illustrate the characterization of the liver organoids by directed biomolecular techniques.

Human-induced pluripotent stem cells (hiPSCs) constitute a great source to generate specialized cells that can be employed in cell replacement therapy for a number of degenerative diseases. In this chapter, I describe a strategy to mass-produce fully functional hepatocyte organoids using hiPSCs interlaced with human adipose microvascular endothelial cells (HAMEC). Our unique technology employs a two-step strategy, consisting of the scalable generation of nearly spherical uniform-sized human embryoid bodies (hEBs), and the subsequent employment of a four-step hepatocyte differentiation approach for the generation of hepatocyte organoids that display all the characteristics of human primary hepatocytes. In this chapter, we also describe methodologies to characterize the hepatocyte organoids by using different biomolecular assays.