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Lineage-specific differentiation of human induced pluripotent stem cells (hiPSCs) relies on complex interactions between biochemical and physical cues. Here we investigated the ability of hiPSCs to undergo lineage commitment in response to inductive signals and assessed how this competence is modulated by substrate stiffness. We showed that Activin A-induced hiPSC differentiation into mesendoderm and its derivative, definitive endoderm, is enhanced on gel-based substrates softer than glass. This correlated with changes in tight junction formation and extensive cytoskeletal remodeling. Further, live imaging and biophysical studies suggested changes in cell motility and interfacial contacts underlie hiPSC layer reshaping on soft substrates. Finally, we repurposed an ultra-soft silicone gel, which may provide a suitable substrate for culturing hiPSCs at physiological stiffnesses. Our results provide mechanistic insight into how epithelial mechanics dictate the hiPSC response to chemical signals and provide a tool for their efficient differentiation in emerging stem cell therapies., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Due to the progressive ageing of the human population, the number of cancer cases is increasing. For this reason, there is an urgent need for new treatments that can prolong the lives of cancer patients or ensure them a good quality of life. Although significant progress has been made in the treatment of cancer in recent years and the survival rate of patients is increasing, limitations in the use of conventional therapies include the frequent occurrence of side effects and the development of resistance to chemotherapeutic agents. These limitations are prompting researchers to investigate whether combining natural agents with conventional drugs could have a positive therapeutic effect in cancer treatment. Several natural bioactive compounds, especially polyphenols, have been shown to be effective against cancer progression and do not exert toxic effects on healthy tissues. Many studies have investigated the possibility of combining polyphenols with conventional drugs as a novel anticancer strategy. Indeed, this combination often has synergistic benefits that increase drug efficacy and reduce adverse side effects. In this review, we provide an overview of the studies describing the synergistic effects of curcumin, a polyphenol that has been shown to have extensive cytotoxic functions against cancer cells, including combined treatment. In particular, we have described the results of recent preclinical and clinical studies exploring the pleiotropic effects of curcumin in combination with standard drugs and the potential to consider it as a promising new tool for cancer therapy.

The maintenance of redox homeostasis is associated with a healthy status while the disruption of this mechanism leads to the development of various pathological conditions. Bioactive molecules such as carbohydrates accessible to the microbiota (MACs), polyphenols, and polyunsaturated fatty acids (PUFAs) are food components best characterized for their beneficial effect on human health. In particular, increasing evidence suggests that their antioxidant ability is involved in the prevention of several human diseases. Some experimental data indicate that the activation of the nuclear factor 2-related erythroid 2 (Nrf2) pathway-the key mechanism in the maintenance of redox homeostasis-is involved in the beneficial effects exerted by the intake of PUFAs and polyphenols. However, it is known that the latter must be metabolized before becoming active and that the intestinal microbiota play a key role in the biotransformation of some ingested food components. In addition, recent studies, indicating the efficacy of the MACs, polyphenols, and PUFAs in increasing the microbial population with the ability to yield biologically active metabolites (e.g., polyphenol metabolites, short-chain fatty acids (SCFAs)), support the hypothesis that these factors are responsible for the antioxidant action on the physiology of the host. The underlying mechanisms through which MACs, polyphenols, and PUFAs might influence the redox status have not been fully elucidated, but based on the efficacy of SCFAs as Nrf2 activators, their contribution to the antioxidant efficacy of dietary bioactives cannot be excluded. In this review, we aimed to summarize the main mechanisms through which MACs, polyphenols, and PUFAs can modulate the host's redox homeostasis through their ability to directly or indirectly activate the Nrf2 pathway. We discuss their probiotic effects and the role played by the alteration of the metabolism/composition of the gut microbiota in the generation of potential Nrf2-ligands (e.g., SCFAs) in the host's redox homeostasis.

Grapevine ( Vitis vinifera L.) seeds are rich in polyphenols including proanthocyanidins, molecules with a variety of biological effects including anticancer action. We have previously reported that the grape seed semi-polar extract of Aglianico cultivar (AGS) was able to induce apoptosis and decrease cancer properties in different mesothelioma cell lines. Concomitantly, this extract resulted in enriched oligomeric proanthocyanidins which might be involved in determining the anticancer activity. Through transcriptomic and metabolomic analyses, we investigated in detail the anticancer pathway induced by AGS. Transcriptomics analysis and functional annotation allowed the identification of the relevant causative genes involved in the apoptotic induction following AGS treatment. Subsequent biological validation strengthened the hypothesis that MDM2 could be the molecular target of AGS and that it could act in both a p53-dependent and independent manner. Finally, AGS significantly inhibited tumor progression in a xenograft mouse model of mesothelioma, confirming also in vivo that MDM2 could act as molecular player responsible for the AGS antitumor effect. Our findings indicated that AGS, exerting a pro-apoptotic effect by hindering MDM2 pathway, could represent a novel source of anticancer molecules.

The serious side effects caused by chemotherapeutics and the development of cancer chemoresistance represent the most significant limitations in the treatment of cancer. Some alternative approaches have been developed in recent years, which are based on natural compounds, and have allowed important advances in cancer therapeutics. During the last 50 years, sponges have been considered a promising source of natural products from the marine environment, representing ~30% of all marine natural products. Among sponges, the Mediterranean species Geodia cydonium represents a potential source of these type of products with considerable biotechnological interest as pharmaceutical agents. The present study demonstrated the antiproliferative effect of an organic G. cydonium extract (GEOCYDO) against three human mesothelioma cell lines, MSTO-211H (MSTO), NCI-H2452 (NCI) and Ist-Mes2 (Mes2), which differ in their sensitivity (MSTO and NCI) and resistance (Mes2) to standard combined treatment with cisplatin and piroxicam. To this aim, the activity of the extract was evaluated by analyzing its effects on cell viability, cancer properties and cell cycle progression by means of colony formation assay, cell cycle analysis and protein expression analysis. The results revealed, in mesothelioma, this extract was able to reduce self-renewal, cell migration and it could induce cell cycle arrest in G 0 /G 1 stage, thus blocking cell proliferation. In conclusion, to the best of our knowledge, the present results indicated for the first time that GEOCYDO can contain active compounds able to affect cell proliferation in mesothelioma, suggesting that it could be considered as a potential novel drug source for cancer treatment., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Di Meo et al.)

Short or small interfering RNAs (siRNAs) and microRNA (miRNAs) are molecules similar in size and function able to inhibit gene expression based on their complementarity with mRNA sequences, inducing the degradation of the transcript or the inhibition of their translation.siRNAs bind specifically to a single gene location by sequence complementarity and regulate gene expression by specifically targeting transcription units via posttranscriptional gene silencing. miRNAs can regulate the expression of different gene targets through their imperfect base pairing.This process - known as RNA interference (RNAi) - modulates transcription in order to maintain a correct physiological environment, playing a role in almost the totality of the cellular pathways.siRNAs have been evolutionary evolved for the protection of genome integrity in response to exogenous and invasive nucleic acids such as transgenes or transposons. Artificial siRNAs are widely used in molecular biology for transient silencing of genes of interest. This strategy allows to inhibit the expression of any target protein of known sequence and is currently used for the treatment of different human diseases including cancer.Modifications and rearrangements in gene regions encoding for miRNAs have been found in cancer cells, and specific miRNA expression profiles characterize the developmental lineage and the differentiation state of the tumor. miRNAs with different expression patterns in tumors have been reported as oncogenes (oncomirs) or tumor-suppressors (anti-oncomirs). RNA modulation has become important in cancer research not only for development of early and easy diagnosis tools but also as a promising novel therapeutic approach.Despite the emerging discoveries supporting the role of miRNAs in carcinogenesis and their and siRNAs possible use in therapy, a series of concerns regarding their development, delivery and side effects have arisen.In this review we report the biology of miRNAs and siRNAs in relation to cancer summarizing the recent methods described to use them as novel therapeutic drugs and methods to specifically deliver them to cancer cells and overcome the limitations in the use of these molecules., (© 2021. The Author(s).)

Oxidative stress has been associated to neuronal cell loss in neurodegenerative diseases. Neurons are post-mitotic cells that are very sensitive to oxidative stress-especially considering their limited capacity to be replaced. Therefore, reduction of oxidative stress, and inhibiting apoptosis, will potentially prevent neurodegeneration. In this study, we investigated the neuroprotective effect of Ginkgo biloba extract (EGb 761) against H 2 O 2 induced apoptosis in SK-N-BE neuroblastoma cells. We analysed the molecular signalling pathway involved in the apoptotic cell death. H 2 O 2 induced an increased acetylation of p53 lysine 382, a reduction in mitochondrial membrane potential, an increased BAX/Bcl-2 ratio and consequently increased Poly (ADP-ribose) polymerase (PARP) cleavage. All these effects were blocked by EGb 761 treatment. Thus, EGb 761, acting as intracellular antioxidant, protects neuroblastoma cells against activation of p53 mediated pathway and intrinsic mitochondrial apoptosis. Our results suggest that EGb 761, protecting against oxidative-stress induced apoptotic cell death, could potentially be used as nutraceutical for the prevention and treatment of neurodegenerative diseases., Competing Interests: The authors confirm that there are no conflicts of interest.