HDAC-inhibitor (S)-8 disrupts HDAC6-PP1 complex prompting A375 melanoma cell growth arrest and apoptosis.

Histone deacetylase inhibitors (HDACi) are agents capable of inducing growth arrest and apoptosis in different tumour cell types. Previously, we reported a series of novel HDACi obtained by hybridizing SAHA or oxamflatin with 1,4-benzodiazepines. Some of these hybrids proved effective against haematological and solid cancer cells and, above all, compound (S)-8 has emerged for its activities in various biological systems. Here, we describe the effectiveness of (S)-8 against highly metastatic human A375 melanoma cells by using normal PIG1 melanocytes as control. (S)-8 prompted: acetylation of histones H3/H4 and α-tubulin; G(0)/G(1) and G(2)/M cell cycle arrest by rising p21 and hypophos-phorylated RB levels; apoptosis involving the cleavage of PARP and caspase 9, BAD protein augmentation and cytochrome c release; decrease in cell motility, invasiveness and pro-angiogenic potential as shown by results of wound-healing assay, down-regulation of MMP-2 and VEGF-A/VEGF-R2, besides TIMP-1/TIMP-2 up-regulation; and also intracellular accumulation of melanin and neutral lipids. The pan-caspase inhibitor Z-VAD-fmk, but not the antioxidant N-acetyl-cysteine, contrasted these events. Mechanistically, (S)-8 allows the disruption of cytoplasmic HDAC6-protein phosphatase 1 (PP1) complex in A375 cells thus releasing the active PP1 that dephosphorylates AKT and blocks its downstream pro-survival signalling. This view is consistent with results obtained by: inhibiting PP1 with Calyculin A; using PPP1R2-transfected cells with impaired PP1 activity; monitoring drug-induced HDAC6-PP1 complex re-shuffling; and, abrogating HDAC6 expression with specific siRNA. Altogether, (S)-8 proved very effective against melanoma A375 cells, but not normal melanocytes, and safe to normal mice thus offering attractive clinical prospects for treating this aggressive malignancy

The new low-toxic histone deacetylase inhibitor S-(2) induces apoptosis in various acute myeloid leukemia cells

Histone deacetylase inhibitors (HDACi) induce tumour cell cycle arrest and/or apoptosis, and some of them are currently used in cancer therapy. Recently, we described a series of powerful HDACi characterized by a 1,4-benzodiazepine (BDZ) ring hybridized with a linear alkyl chain bearing a hydroxamate function as Zn(++)-chelating group. Here, we explored the anti-leukaemic properties of three novel hybrids, namely the chiral compounds (S)-2 and (R)-2, and their non-chiral analogue 4, which were first comparatively tested in promyelocytic NB4 cells. (S)-2 and partially 4– but not (R)-2 – caused G0/G1 cell-cycle arrest by up-regulating cyclin G2 and p21 expression and down-regulating cyclin D2 expression, and also apoptosis as assessed by cell morphology and cytofluorimetric assay, histone H2AX phosphorylation and PARP cleavage. Notably, these events were partly prevented by an anti-oxidant. Moreover, novel HDACi prompted p53 and α-tubulin acetylation and, consistently, inhibited HDAC1 and 6 activity. The rank order of potency was (S)-2 > 4 > (R)-2, reflecting that of other biological assays and addressing (S)-2 as the most effective compound capable of triggering apoptosis in various acute myeloid leukaemia (AML) cell lines and blasts from patients with different AML subtypes. Importantly, (S)-2 was safe in mice (up to 150 mg/kg/week) as determined by liver, spleen, kidney and bone marrow histopathology; and displayed negligible affinity for peripheral/central BDZ-receptors. Overall, the BDZ-hydroxamate (S)-2 showed to be a low-toxic HDACi with powerful anti-proliferative and pro-apototic activities towards different cultured and primary AML cells, and therefore of clinical interest to support conventional anti-leukaemic therapy

An empirical assessment of human development through remote sensing: Evidences from Italy

The Human Development Index (HDI) based on life expectancy, education and per-capita income, is one of the most used indicators of human development. However, undeniable problems in data collection limit between-countries comparisons reducing the practical applicability of the HDI in official statistics. Elvidge et al. (2012) proposed an alternative index of human development (the so called Night Light Development Index, NLDI) derived from nighttime satellite imagery and population density, with improved comparability over time and space. The NLDI assesses inequality in the spatial distribution of night light among resident inhabitants and has proven to correlate with the HDI at the country scale. However, the NLDI presents some drawbacks, since similar NLDI values may indicate very different levels of human development. A modified NLDI overcoming such a drawback is proposed and applied to assessment of human development at 3 spatial scales (the entire country, 5 geographical divisions and 20 administrative regions) in Italy, a country with relevant territorial disparities in various socioeconomic dimensions. The original and modified NLDI were correlated with 5 independent indicators of economic growth, sustainable development and environmental quality. The spatial distribution of the original and modified NLDI is not coherent with the level of human development in Italy being indeed associated with various indexes of environmental quality. Further investigation is required to identify in which socioeconomic context (and at which spatial scale) the NDLI approach correctly estimates the level of human development in affluent countries

Sizing and operation of energy storage by Power-to-Gas and Underwater Compressed Air systems applied to offshore wind power generation

Among the possible solutions for large-scale renewable energy storage, Power-to-Gas (P2G) and Compressed Air Energy Storage (CAES) appear very promising. In this work, P2G and an innovative type of CAES based on underwater storage volumes (UW-CAES) are compared from a techno-economic point of view, when applied in combination with a 48 MWe offshore wind power plant, selecting an appropriate location for both high productivity and favorable seabed depth. An optimization model is employed to study the system design and operation, maximizing the lifetime plant profitability, while considering differential installation and operation costs, market values of the products (i.e., hydrogen and electricity), and technological constraints. In the current economic and technological scenario, the resulting P2G system has a nominal power equivalent to about 10% of the wind park capacity, with a small hydrogen storage buffer. On the other hand, the compressor and the turbine of the UWCAES have a nominal power close to the full wind farm capacity, and large underwater compressed air tanks are required. Both options significantly impact the wind plant management but the most beneficial applications of the two systems are different: the P2G results in a compact and flexible unit, whereas the UW-CAES is able to exploit a higher average conversion efficiency (about 80% round-trip) against a much higher installed power and investment cost. Anyway, considering the current framework, the resulting economics are still inadequate, but their competitiveness can improve compatible with the expected evolution of energy markets in the next future