Description: Colorectal cancer (CRC) is one of the major causes of cancer death worldwide. The development of novel anti-CRC agents able to overcome drug resistance and/or off-target toxicity is of pivotal importance. The mammalian target of rapamycin (mTOR) plays a critical role in CRC, regulating protein translation and controlling cell growth, proliferation, metabolism and survival. The aim of this study was to explore the effect of a combination of three natural compounds, eicosapentaenoic acid-free fatty acid (EPA-FFA), epigallocatechin-3-gallate (EGCG) and proanthocyanidins (grape seed [GS] extract) at low cytotoxic concentrations on CRC cells and test their activity on mTOR and translational regulation. The CRC cell lines HCT116 and SW480 were treated for 24h with combinations of EPA-FFA (0–150 µM), EGCG (0–175 µM) and GS extract (0–15 µM) to evaluate the effect on cell viability. The low cytotoxic combination of EPA-FFA 150 µM, EGCG 175 µM and GS extract 15 µM completely inhibited the mTOR signaling in HCT116 and SW480 cells, reaching an effect stronger than or comparable to that of the mTOR inhibitor Rapamycin in HCT116 or SW480 cells, respectively. Moreover, the treatment led to changes of protein translation of ribosomal proteins, c-Myc and cyclin D1. In addition, we found a reduction of clonal capability in both cell lines, with block of cell cycle in G 0 G 1 and induction of apoptosis. Our data suggest that the low cytotoxic combination of EPA-FFA, EGCG and GS extract, tested for the first time here, inhibits mTOR signaling and thus could be considered for CRC treatment.

Description: Oscillatory patterns permeate the universe and are essential requisite in living cells. Circadian clocks exist at the subcellular and single-cell level. Chromatin is assembled into rhythmic oscillatory domains driving stem cell growth/differentiation up to higher hierarchical embryo development. The cytoskeleton is organized as rhythmically oscillating networks, producing radioelectric fields that may turn local events into non-local, long-ranging paths. For decades, scientists have used chemical tools to affect cell behaviour. However, this view is now deeply challenged. Consonant with a major role of physical forces in living processes is the use of physical energies to modulate cell dynamics. To explore cell biology in the light of physics, we have recently established the Stem Wave Institute for Tissue Healing, within the context of GVM Care & Research—E.S. Health Science Foundation, Lugo, Italy. Here, we will discuss our recent findings that proper delivery of radioelectric fields is able to (i) finely tune stem cell multipotency, (ii) directly reprogramme human skin fibroblasts into cardiac-, neuronal-, and skeletal muscle-like cells, and (iii) revert stem cell senescence. We are dissecting vibrational modes as inherent properties of living cells, entailing nanomechanical signatures that can be used to direct stem cell fate. Mild mechanical forces are deployed to obtain human fluid tissues harbouring stem cells within their stromal–vascular niche. Synthetic molecules are designed to afford stem cell pluripotency. These discoveries prompt a deeper understanding of the interconnections between the physical universe and the living world in the attempt to further approach the information of Life.

Description: Arsenic-induced health effects may be associated with critically shortened telomeres. However, few data are available on the effects of arsenic exposure on telomere length. The aim of this study was to investigate the effects of chronic arsenic exposure on leukocyte telomere length (LTL) as well as the contribution of common polymorphisms in genes implicated in arsenic metabolism (GSTT1 and GSTM1) and DNA repair (hOGG1 and XRCC1). A group of 241 healthy subjects was enrolled from four areas of Italy known to be affected by natural or anthropogenic arsenic pollution. Urine samples were tested for inorganic As (iAs), monomethylarsinic (MMA) and dimethylarsinic acid (DMA). LTL was evaluated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Genotyping was carried out by PCR-RFLP on leukocyte DNA. In multiple linear regression analysis, LTL was significantly and inversely correlated with age (β = –0.231, P = 0.006) and showed a certain trend toward significance with iAs urinary concentration (log 10 iAs, β = –0.106, P = 0.08). The genotype distribution showed significant associations between GSTT1 and the As concentration (log 10 iAs, P = 0.01) and metabolite patterns (log 10 DMA, P = 0.05) in the urine. However, GST genes did not interact with arsenic exposure in the modulation of LTL. Conversely, the combined presence of a higher level of iAs + MMA + DMA ≥ 19.3 μg/l ( F = 6.0, P interaction = 0.01), Asi ≥ 3.86 ( F = 3.9, P interaction = 0.04) μg/l, iAs + MMA + DMA ≥ 15 μg/l ( F = 4.2, P interaction = 0.04) and hOGG1 Cys allele was associated with a significantly lower LTL. An interaction between XRCC1 Arg399Gln and arsenic exposure was also observed (all P interaction = 0.04). These findings suggest that telomere shortening may represent a mechanism that contributes to arsenic-related disease. The interaction of hOGG1 and XRCC1 DNA repair polymorphisms and exposure enhances telomeric DNA damage. Future studies are warranted to understand better the epidemiologic impact of arsenic on telomere function as well as to identify the subgroups of exposed subjects who need better health surveillance.

Description: Mutations of FIG4 are responsible for Yunis-Varón syndrome, familial epilepsy with polymicrogyria, and Charcot-Marie-Tooth type 4J neuropathy (CMT4J). Although loss of the FIG4 phospholipid phosphatase consistently causes decreased PtdIns(3,5) P 2 levels, cell-specific sensitivity to partial loss of FIG4 function may differentiate FIG4-associated disorders. CMT4J is an autosomal recessive neuropathy characterized by severe demyelination and axonal loss in human, with both motor and sensory involvement. However, it is unclear whether FIG4 has cell autonomous roles in both motor neurons and Schwann cells, and how loss of FIG4/PtdIns(3,5) P 2 -mediated functions contribute to the pathogenesis of CMT4J. Here, we report that mice with conditional inactivation of Fig4 in motor neurons display neuronal and axonal degeneration. In contrast, conditional inactivation of Fig4 in Schwann cells causes demyelination and defects in autophagy-mediated degradation. Moreover, Fig4-regulated endolysosomal trafficking in Schwann cells is essential for myelin biogenesis during development and for proper regeneration/remyelination after injury. Our data suggest that impaired endolysosomal trafficking in both motor neurons and Schwann cells contributes to CMT4J neuropathy.