The Strange Case: The Unsymmetric Cisplatin-Based Pt(IV) Prodrug [Pt(CH3COO)Cl2(NH3)2(OH)] Exhibits Higher Cytotoxic Activity with respect to Its Symmetric Congeners due to Carrier-Mediated Cellular Uptake

The biological behavior of the axially unsymmetric antitumor prodrug (OC-6-44)-acetatodiamminedichloridohydroxidoplatinum(IV), 2, was deeply investigated and compared with that of analogous symmetric Pt(IV) complexes, namely, dihydroxido 1 and diacetato 3, which have a similar structure. The complexes were tested on a panel of human tumor cell lines. Complex 2 showed an anomalous higher cytotoxicity (similar to that of cisplatin) with respect to their analogues 1 and 3. Their reduction potentials, reduction kinetics, lipophilicity, and membrane affinity are compared. Cellular uptake and DNA platination of Pt(IV) complexes were deeply investigated in the sensitive A2780 human ovarian cancer cell line and in the corresponding resistant A2780cisR subline. The unexpected activity of 2 appears to be related to its peculiar cellular accumulation and not to a different rate of reduction or a different efficacy in DNA platination and/or efficiency in apoptosis induction. Although the exact mechanism of cell uptake is not fully deciphered, a series of naive experiments indicates an energy-dependent, carrier-mediated transport: the organic cation transporters (OCTs) are the likely proteins involved

Pt(IV)Ac-POA: new platinum compound Induced caspase independent apoptosis In B50 neuroblastoma stem cells

Neuroblastoma is a tumour that affects adults and children, characterized by a stem cells component. To date, cisplatin is the main antitumor agent used in the clinical treatment of this tumour; however, it induces side effects such as neurotoxicity in healthy cells and induces chemo resistance to therapy in cancer cells. New platinum-based compounds, platinum (II) have recently been synthesized, and due to their chemical characteristics, they are able to identify new cellular targets. These complexes act as prodrugs and performing their cytotoxic effect as platinum (II) after a reduction reaction within the hypoxic tumour cells. Among these prodrugs, Pt(IV)Ac-POA appears to be very promising, thanks to the presence of ligand (2 propinyl)octanoic acid (POA), which acts as an inhibitor of histone deacetylase (HDACi) and leads to the increase of histone acetylation, decreasing the interactions between histone and DNA, so as to produce chemo-sensitization to DNA-damaging agents. The greater cytotoxic effect of Pt(IV)Ac-POA on tumour cells, would therefore be mainly due to the mechanism of inhibition of histone deacetylase, which would increase the accessibility of DNA to platination mechanisms that induce cell death. In this study the results show that Pt(IV)Ac-POA, used at a concentration ten times lower than cisplatin, can induce apoptosis in B50 cells in culture both through the intrinsic pathway and through the independent caspase pathway. The data, obtained by immunohistochemical techniques in fluorescence microscopy, show that treatment with Pt(IV)Ac-POA has a greater proapoptotic effect on stem cells compared to the cisplatin standard treatment

Evidence for Strong and Weak Phenyl-C61-Butyric Acid Methyl Ester Photodimer Populations in Organic Solar Cells

In polymer/fullerene organic solar cells, the photochemical dimerization of phenyl-C61-butyric acid methyl ester (PCBM) was reported to have either a beneficial or a detrimental effect on device performance and stability. In this work, we investigate the behavior of such dimers by measuring the temperature dependence of the kinetics of PCBM de-dimerization as a function of prior light intensity and duration. Our data reveal the presence of both “weakly” and “strongly” bound dimers, with higher light intensities preferentially generating the latter. DFT simulations corroborate our experimental findings and suggest a distribution of dimer binding energies, correlated with the orientation of the fullerene tail with respect to the dimer bonds on the cage. These results provide a framework to rationalize the double-edged effects of PCBM dimerization on the stability of organic solar cells

Experimental Observation of Strong Exciton Effects in Graphene Nanoribbons

Graphene nanoribbons (GNRs) with atomically precise width and edge structures are a promising class of nanomaterials for optoelectronics, thanks to their semiconducting nature and high mobility of charge carriers. Understanding the fundamental static optical properties and ultrafast dynamics of charge carrier generation in GNRs is essential for optoelectronic applications. Combining THz spectroscopy and theoretical calculations, we report a strong exciton effect with binding energy up to 700 meV in liquid-phase-dispersed GNRs with a width of 1.7 nm and an optical bandgap of 1.6 eV, illustrating the intrinsically strong Coulomb interactions between photogenerated electrons and holes. By tracking the exciton dynamics, we reveal an ultrafast formation of excitons in GNRs with a long lifetime over 100 ps. Our results not only reveal fundamental aspects of excitons in GNRs (gigantic binding energy and ultrafast exciton formation etc.), but also highlight promising properties of GNRs for optoelectronic devices.Comment: 26 pages, 4 figures, 5 pages Supplementary Informatio

Investigating the epi-miRNome: Identification of epi-miRNAs using transfection experiments

Aim: Growing evidence shows a strong interplay between post-transcriptional regulation, mediated by miRNAs (miRs) and epigenetic regulation. Nevertheless, the number of experimentally validated miRs (called epi-miRs) involved in these regulatory circuitries is still very small. Material & methods: We propose a pipeline to prioritize candidate epi-miRs and to identify potential epigenetic interactors of any given miR starting from miR transfection experiment datasets. Results & conclusion: We identified 34 candidate epi-miRs: 19 of them are known epi-miRs, while 15 are new. Moreover, using an in-house generated gene expression dataset, we experimentally proved that a component of the polycomb-repressive complex 2, the histone methyltransferase enhancer of zeste homolog 2 (EZH2), interacts with miR-214, a well-known prometastatic miR in melanoma and breast cancer, highlighting a miR-214-EZH2 regulatory axis potentially relevant in tumor progression

Coffee, tea, and caffeine consumption and prevention of late-life cognitive decline and dementia: A systematic review

A prolonged preclinical phase of more than two decades before the onset of dementia suggested that initial brain changes of Alzheimer’s disease (AD) and the symptoms of advanced AD may represent a unique continuum. Given the very limited therapeutic value of drugs currently used in the treatment of AD and dementia, preventing or postponing the onset of AD and delaying or slowing its progression are becoming mandatory. Among possible reversible risk factors of dementia and AD, vascular, metabolic, and lifestyle-related factors were associated with the development of dementia and late-life cognitive disorders, opening new avenues for the prevention of these diseases. Among diet-associated factors, coffee is regularly consumed by millions of people around the world and owing to its caffeine content, it is the best known psychoactive stimulant resulting in heightened alertness and arousal and improvement of cognitive performance. Besides its short-term effect, some case-control and cross-sectional and longitudinal population-based studies evaluated the long-term effects on brain function and provided some evidence that coffee, tea, and caffeine consumption or higher plasma caffeine levels may be protective against cognitive impairment/decline and dementia. In particular, several cross-sectional and longitudinal population-based studies suggested a protective effect of coffee, tea, and caffeine use against late-life cognitive impairment/decline, although the association was not found in all cognitive domains investigated and there was a lack of a distinct dose-response association, with a stronger effect among women than men. The findings on the association of coffee, tea, and caffeine consumption or plasma caffeine levels with incident mild cognitive impairment and its progression to dementia were too limited to draw any conclusion. Furthermore, for dementia and AD prevention, some studies with baseline examination in midlife pointed to a lack of association, although other case-control and longitudinal population-based studies with briefer follow-up periods supported favourable effects of coffee, tea, and caffeine consumption against AD. Larger studies with longer follow-up periods should be encouraged, addressing other potential bias and confounding sources, so hopefully opening new ways for diet-related prevention of dementia and AD

Actually existing Silk Roads

This article explores the relevance of the concept of Silk Road for understandings patterns of trade and exchange between China, Eurasia and the Middle East. It is based on ethnographic fieldwork in the city of Yiwu, in China’s Zhejiang Province. Yiwu is a node in the global distribution of Chinese ‘small commodities’ and home to merchants and traders from across Asia and beyond. The article explores the role played by traders from Afghanistan in connecting the city of Yiwu to markets and trading posts in the world beyond. It seeks to bring attention to the diverse types of networks involved in such forms of trade, as well as their emergence and development over the past thirty years

Guidelines for the diagnosis, prevention and management of osteoporosis

Osteoporosis poses a significant public health issue. National Societies have developed Guidelines for the diagnosis and treatment of this disorder with an effort of adapting specific tools for risk assessment on the peculiar characteristics of a given population. The Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS) has recently revised the previously published Guidelines on the diagnosis, riskassessment, prevention and management of primary and secondary osteoporosis. The guidelines were first drafted by a working group and then approved by the board of SIOMMMS. Subsequently they received also the endorsement of other major Scientific Societies that deal with bone metabolic disease. These recommendations are based on systematic reviews of the best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on leading experts' experience and opinion, and on good clinical practice. The osteoporosis prevention should be based on the elimination of specific risk factors. The use of drugs registered for the treatment of osteoporosis are recommended when the benefits overcome the risk, and this is the case only when the risk of fracture is rather high as measured with variables susceptible to pharmacological effect. DeFRA (FRAX® derived fracture risk assessment) is recognized as a useful tool for easily estimate the long-term fracture risk. Several secondary forms of osteoporosis require a specific diagnostic and therapeutic management