Impact of Trivalent Arsenicals on Selenoprotein Synthesis

BACKGROUND: Exposure to arsenic has been associated with development of skin, lung, bladder, liver, and kidney cancer. Recent evidence suggests that an increase in oxidative stress in cells treated with arsenicals represents the molecular mechanism behind arsenic-induced carcinogenesis. Selenium, in the form of selenocysteine, is necessary for the activity of several enzymes with a role in defense against reactive oxygen species. A mutual sparing effect between arsenic and selenium has been shown in animal studies when both metalloids are present in high concentrations. OBJECTIVES: To determine whether changes in selenoprotein synthesis may be an underlying mechanism behind arsenic-induced carcinogenesis, we analyzed the new synthesis of selenoproteins within cells after exposure to inorganic or methylated arsenicals using a human keratinocyte cell model. RESULTS: Addition of arsenite to culture medium blocked new synthesis of selenoproteins when selenium was present in the form of selenite, and appeared to stimulate the use of serum-derived selenium. Monomethylarsonous acid (MMA(III)) treatment of cells, in contrast, did not block all new synthesis of selenoproteins but did result in an increase in cytosolic thioredoxin reductase (TrxR1) at both the mRNA and protein levels. MMA(III) also reduced the new synthesis of cellular glutatione peroxidase (cGpx) and other smaller selenoproteins. Dimethylarsinous acid (DMA(III)) stimulated selenoprotein synthesis by an as yet unknown mechanism. CONCLUSIONS: These results suggest that arsenite and MMA(III) are key metabolites that trigger higher levels of TrxR1, and both lead to a reduction in the expression of cGpx. Together these effects certainly could lead to carcinogenesis given the knowledge that many cancers have higher levels of TrxR, and reduced Gpx levels will reduce the cell’s ability to defend against reactive oxygen species. Based on these results, the impact of the trivalent arsenicals arsenite and MMA(III) on selenoprotein synthesis may indeed represent a potential molecular mechanism for the higher rates of cancer observed in populations exposed to high levels of arsenic

Pristup procjeni zdravstvenoga rizika za ljude prilikom izgradnje gradskoga parka

A Human Health Risk Assessment (HHRA) was undertaken for a proposed park development “River Landing”, to be constructed along the north bank of the South Saskatchewan River in the City of Saskatoon, Saskatchewan, Canada. The purpose of the HHRA was to determine whether chemical constituents identified at the site, including polycyclic aromatic hydrocarbons (PAHs), petroleum hydrocarbons (PHCs), and toxic and heavy metals, would adversely affect the health of construction workers and potential park users. Although more traditional remediation options were considered, the risk assessment approach was chosen since it represented the best available technology. The HHRA was undertaken using protocols and methodologies proposed and readily accepted by the Canadian Council of Ministers of the Environment (CCME), Health Canada, and the United States Environmental Protection Agency (US EPA). Results of the risk assessment revealed that the magnitude and distribution of the chemicals at the site were such that extensive remediation was not required, and that the site could be developed without any significant restrictions on the proposed use. The assessment revealed that potential exposure to soil constituents would not result in adverse health risk to construction workers involved in park development or future park users.Napravljena je procjena zdravstvenoga rizika za ljude (izv. human health risk assessment, HHRA) za projekt gradskoga parka “River Landing” koji bi se trebao izgraditi duž sjeverne obale rijeke South Saskatchewan u Saskatoonu, saveznoj državi Saskatchewan u Kanadi. Svrha je procjene bila utvrditi mogu li kemijski spojevi zatečeni na gradilištu, uključujući policikličke aromatske ugljikovodike, naftne ugljikovodike te toksične i teške metale, štetno utjecati na zdravlje građevinskih radnika i korisnika parka. Premda je razmotrena i uporaba tradicionalnijih metoda sanacije, izabran je ovaj pristup procjeni rizika zbog toga što rabi najbolju dostupnu tehnologiju. Procjena rizika provedena je prema protokolima i metodama koje je odmah usvojio Kanadski savjet ministara za zaštitu okoliša (izv. Canadian Council of Ministers of the Environment, CCME), savezni ured za zdravlje Health Canada te Agencija za zaštitu okoliša Sjedinjenih Država (izv. United States Environmental Protection Agency, US EPA). Procjena rizika pokazala je da količina i rasprostranjenost kemikalija na gradilištu nisu takvi da zahtijevaju opsežniju sanaciju, te da se lokacija može izgraditi bez značajnih ograničenja u namjeni. Procjenom je također utvrđeno da eventualno izlaganje sastavnicama tla neće dovesti do štetnih posljedica za zdravlje građevinskih radnika koji rade na parku, a niti za buduće korisnike parka

The First Asymmetric Pilot-Scale Synthesis of TV-45070

TV-45070 is a small-molecule lactam containing a chiral spiro-ether that has been reported as a potential topical therapy for pain associated with the Na_v1.7 sodium ion channel encoded by the gene SCN9A. A pilot-scale synthesis is presented that is highlighted by an asymmetric aldol coupling at ambient temperature, used to create a quaternary chiral center. Although only a moderate ee is obtained, the removal of the undesired isomer is achieved through preferential precipitation of a near racemic mixture from the reaction, leaving the enantiopure isomer in solution. Cyclization to form the final API uses an uncommon diphenylphosphine-based leaving group which proved successful on the neopentyl system when other traditional leaving groups failed