Atmospheric Mercury Isotope Shifts in Response to Mercury Emissions from Underground Coal Fires.

Pollutant emissions from coal fires have caused serious concerns in major coal-producing countries. Great efforts have been devoted to suppressing them in China, notably at the notorious Wuda Coalfield in Inner Mongolia. Recent surveys revealed that while fires in this coalfield have been nearly extinguished near the surface, they persist underground. However, the impacts of Hg volatilized from underground coal fires remain unclear. Here, we measured concentrations and isotope compositions of atmospheric Hg in both gaseous and particulate phases at an urban site near the Wuda Coalfield. The atmospheric Hg displayed strong seasonality in terms of both Hg concentrations (5-7-fold higher in fall than in winter) and isotope compositions. Combining characteristic isotope compositions of potential Hg sources and air mass trajectories, we conclude that underground coal fires were still emitting large amounts of Hg into the atmosphere that have been transported to the adjacent urban area in the prevailing downwind direction. The other local anthropogenic Hg emissions were only evident in the urban atmosphere when the arriving air masses did not pass directly through the coalfield. Our study demonstrates that atmospheric Hg isotope measurement is a useful tool for detecting concealed underground coal fires.

Year-round observations of stable carbon isotopic composition of carboxylic acids, oxoacids and α-Dicarbonyls in fine aerosols at Tianjin, North China: Implications for origins and aging.

To better understand the origins and photochemical processing (aging) of organic aerosols (OA), we studied fine aerosols (PM2.5) collected at urban (Nankai District (ND)) and suburban (Haihe Education Park (HEP)) Tianjin, North China over a one-year period (2018-2019) for stable carbon isotopic composition (δ13C) of water-soluble diacids, oxoacids, α-dicarbonyls and fatty acids. Maleic (M, -18.3 ± 10.9‰ at ND and -23.5 ± 10.2‰ at HEP) and fumaric (F, -22.0 ± 12.1‰ at ND and -22.5 ± 10.5‰ at HEP) acids were found to be most enriched with 13C followed by oxalic acid (C2, -24.7 ± 3.9‰ at ND and -25.9 ± 4.7‰ at HEP) during the campaign. Based on seasonal changes in δ13C of selected marker species: C6 and C9 diacids, phthalic, glyoxylic and pyruvic acids and glyoxal, and their comparison with the source signatures, we found that water-soluble OA in Tianjin were mainly originated from fossil fuel combustion and biomass burning emissions and were subjected for significant aging. The contribution from fossil fuel combustion including coal combustion was high in autumn and winter, especially at ND. Considering the enrichment of 13C in specific species together with linear relations of δ13C of selected species with their concentrations, with mass ratios and with the relative abundance of C2 diacid, we inferred that the photochemical transformations of longer-chain diacids, oxidation of α-dicarbonyls (Gly and mGly), preferably in gas phase, were important in warm period (March-September), whereas the oxidation of Gly, mGly and other precursors in aqueous phase were major in cold period (October-February).

Discovery of the First Human Arylsulfatase A Reversible Inhibitor Impairing Mouse Oocyte Fertilization.

Arylsulfatase A (ARSA) plays a crucial role in the reproduction of mammals due to its involvement in the specific gamete interaction preceding sperm and egg fusion leading to fertilization. Recently, it has been shown that zona pellucida (ZP) sperm binding and in vivo fertilization in mice are markedly hampered by using a specific anti-ARSA antibody. Herein, the design and discovery of the first ARSA small molecule inhibitor based on a coumarin-containing polycycle are presented. Through a structure-based approach applied on our in-house library, compound 1r was identified as an ARSA reversible inhibitor (ARSAi); then its activity was validated through both surface plasmon resonance and biochemical inhibition experiments, the first providing a KD value of 21 µM and the latter an IC50 value of 13.2 µM. Further investigations highlighted that compound 1r induced 20% sperm death at 25 µM and also impaired sperm motility; nevertheless both the effects were mediated by ROS production, since they were rescued by the cotreatment of 1r and N-acetyl cysteine (NAC). Interestingly, while 1r was not able to hamper the ZP/sperm binding, it markedly decreased the in vitro oocyte fertilization by mouse sperm up to 60%. Notably, this effect was not hampered by 1r/NAC coadministration, hence allowing the ruling out of an ROS-dependent mechanism. In conclusion, herein is reported the first ever hit of ARSAi as a chemical tool that will enable better exploration of ARSA's biological role in fertilization as well as provide a starting point for developing 1r structure optimization aimed at increasing enzyme inhibition potency but also providing a deeper understanding of the involvement of ARSA in the fertilization pathway mechanism.

Novel coumarin- and quinolinone-based polycycles as cell division cycle 25-A and -C phosphatases inhibitors induce proliferation arrest and apoptosis in cancer cells.

Cell division cycle phosphatases CDC25 A, B and C are involved in modulating cell cycle processes and are found overexpressed in a large panel of cancer typology. Here, we describe the development of two novel quinone-polycycle series of CDC25A and C inhibitors on the one hand 1a-k, coumarin-based, and on the other 2a-g, quinolinone-based, which inhibit either enzymes up to a sub-micro molar level and at single-digit micro molar concentrations, respectively. When tested in six different cancer cell lines, compound 2c displayed the highest efficacy to arrest cell viability, showing in almost all cell lines sub-micro molar IC50 values, a profile even better than the reference compound NCS95397. To investigate the putative binding mode of the inhibitors and to develop quantitative structure-activity relationships, molecular docking and 3-D QSAR studies were also carried out. Four selected inhibitors, 1a, 1d, 2a and 2c have been also tested in A431 cancer cells; among them, compound 2c was the most potent one leading to cell proliferation arrest and decreased CDC25C protein levels together with its splicing variant. Compound 2c displayed increased phosphorylation levels of histone H3, induction of PARP and caspase 3 cleavage, highlighting its contribution to cell death through pro-apoptotic effects.

Synthesis of amphiphilic seleninic acid derivatives with considerable activity against cellular membranes and certain pathogenic microbes.

Selenium compounds play a major role in Biology, where they are often associated with pronounced antioxidant activity or toxicity. Whilst most selenium compounds are not necessarily hazardous, their often selective cytotoxicity is interesting from a biochemical and pharmaceutical perspective. We have synthesized a series of amphiphilic molecules which combine a hydrophilic seleninic acid head group - which at the same time serves as thiol-specific warhead - with a hydrophobic tail. These molecules possess a surface activity similar to the one of SDS, yet their biological activity seems to exceed by far the one of a simple surfactant (e.g. SDS) or seleninic acid (e.g. phenyl seleninic acid). Such compounds effectively haemolyse Red Blood Cells and exhibit pronounced activity against Saccharomyces cerevisiae. From a chemical perspective, the seleninic warheads are likely to attack crucial cysteine proteins of the cellular thiolstat.

4-Bromo-2-(piperidin-1-yl)thiazol-5-yl-phenyl methanone (12b) inhibits Na+/K(+)-ATPase and Ras oncogene activity in cancer cells.

The in vitro growth inhibitory activity of 26 thiazoles (including 4-halogeno-2,5-disubtituted-1,3-thiazoles) and 5 thienothiazoles was assessed on a panel of 6 human cancer cell lines, including glioma cell lines. (4-Chloro-2-(piperidin-1-yl)thiazol-5-yl)(phenyl)methanone (12a) and (4-bromo-2-(piperidin-1-yl)thiazol-5-yl)(phenyl)methanone (12b) displayed ~10 times greater in vitro growth inhibitory activity than perillyl alcohol (POH), which therapeutically benefits glioma patients through the inhibition of both alpha-1 Na(+)/K(+)-ATPase (NAK) and Ras oncogene activity. The in vitro cytostatic activities (as revealed by quantitative videomicroscopy) displayed by 12a and 12b were independent of the intrinsic resistance to pro-apoptotic stimuli associated with cancer cells. Compounds 12a and 12b displayed relatively similar inhibitory activities on purified guinea pig brain preparations that mainly express NAK alpha-2 and alpha-3 subunits, whereas only compound 12b was efficacious against purified guinea pig kidney preparations that mainly express the NAK alpha-1 subunit, which is also expressed in gliomas, melanomas and non-small-cell lung cancers NSCLCs.

Proanthocyanidins: oligomeric structures with unique biochemical properties and great therapeutic promise.

Proanthocyanidins represent a unique class of oligomeric and polymeric secondary metabolites found ubiquitously and in considerable amounts in plants and some algae. These substances exhibit a range of rather surprising physical and chemical properties which, once applied to living organisms, are translated into a multitude of biological activities. The latter include antioxidant properties, cancer chemoprevention, anti-inflammatory and anti-diabetic effects as well as some exceptional, yet highly interesting activities, such as anti-nutritional and antimicrobial activity. Despite the wide range of activities and possible medical/agricultural applications of proanthocyanidins, many questions still remain, including issues related to bioavailability, metabolism and the precise biochemical, extra- and intracellular targets and mode(s) of action of these highly potent materials. Among the various physical and chemical interactions of such substances, strong binding to proteins appears to form the basis of many of their biological activities. Once easy-to-use synthetic methods to produce appropriate quantities of pure proanthocyanidins are available, it will be possible to identify the prime biological targets of these oligomers, study oligomer-protein interactions in more detail and develop possible practical applications in medicine and agriculture.