Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation1, has a key role in organ injury, degenerative disease and vulnerability of therapy-resistant cancers2. Although substantial progress has been made in understanding the molecular processes relevant to ferroptosis, additional cell-extrinsic and cell-intrinsic processes that determine cell sensitivity toward ferroptosis remain unknown. Here we show that the fully reduced forms of vitamin K—a group of naphthoquinones that includes menaquinone and phylloquinone3—confer a strong anti-ferroptotic function, in addition to the conventional function linked to blood clotting by acting as a cofactor for γ-glutamyl carboxylase. Ferroptosis suppressor protein 1 (FSP1), a NAD(P)H-ubiquinone reductase and the second mainstay of ferroptosis control after glutathione peroxidase-44,5, was found to efficiently reduce vitamin K to its hydroquinone, a potent radical-trapping antioxidant and inhibitor of (phospho)lipid peroxidation. The FSP1-mediated reduction of vitamin K was also responsible for the antidotal effect of vitamin K against warfarin poisoning. It follows that FSP1 is the enzyme mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle6. The FSP1-dependent non-canonical vitamin K cycle can act to protect cells against detrimental lipid peroxidation and ferroptosis.
A dual-polarization 10-channel mode (de)multiplexer is proposed and realized with cascaded dual-core adiabatic tapers on a silicon-on-insulator (SOI) platform. The mode demultiplexer has a 2.3 μm-wide multimode bus waveguide, which supports six mode-channels of TE polarization and four mode-channels of TM polarization. These ten mode-channels are (de)multiplexed with five cascaded dual-core adiabatic tapers based on SOI nanowires. The widths for these dual-cores are chosen optimally according to the dispersion curves of the dual-core SOI nanowire, so that the desired highest-order modes of TE-and TM-polarizations are extracted simultaneously. These two extracted mode-channels are coupled very efficiently to the fundamental modes of TE-and TM-polarizations (TE 0 and TM 0 ) in the narrow waveguide, respectively, which are then separated by using a polarization beam splitter based on bent directional couplers. A chip consisting of a pair of 10-channel mode (de)multiplexers is fabricated and then tested with data transmission of 30Gbps/channel. The measurement results show that all TM-and TE mode-channels have low crosstalks (-15ß-25 dB) and low excess losses (0.2ß1.8 dB) over a broad wavelength band of ß90 nm, which makes it WDM (wavelength-division-multiplexing)-compatible and thus suitable for high capacity on-chip optical interconnects.
Radical substitution on tetrasulfides is demonstrated to be a highly effective means to prepare unsymmetric disulfides. Alkyl and aryl radicals generated thermally or photochemically underwent substitution on readily prepared dialkyl, diaryl, and diacyl tetrasulfides to yield the corresponding disulfides in good to excellent yields. Classic and contemporary thermal and photochemical radical sources could be employed; while photoredox catalysis approaches led to either oxidation or reduction of the tetrasulfide, energy transfer photocatalysis was particularly useful. The success of the approach is driven by the thermodynamic stability of the perthiyl radicals formed upon substitution on the tetrasulfide; they simply combine under the reaction conditions to provide the starting tetrasulfide. Competition kinetic experiments reveal that alkyl radical substitution on tetrasulfides is a rapid reaction (6 × 105 M–1 s–1) that is enhanced at least 6-fold upon moving from dialkyl tetrasulfide to diacyl tetrasulfide due to favorable polar effects. This unique and versatile reaction enables introduction of disulfide moieties from a variety of radical precursors and straightforward access to hydropersulfides.
Hydropersulfides (RSSH) are believed to serve important roles in vivo, including as scavengers of damaging oxidants and electrophiles. The α-effect makes RSSH not only much better nucleophiles than thiols (RSH), but also much more potent H-atom transfer agents. Since HAT is the mechanism of action of the most potent small-molecule inhibitors of phospholipid peroxidation and associated ferroptotic cell death, we have investigated their reactivity in this context. Using the fluorescence-enabled inhibited autoxidation (FENIX) approach, we have found RSSH to be highly reactive toward phospholipid-derived peroxyl radicals (k inh = 2 × 10 5 M −1 s −1 ), equaling the most potent ferroptosis inhibitors identified to date. Related (poly)sulfide products resulting from the rapid self-reaction of RSSH under physiological conditions (e.g., disulfide, trisulfide, H 2 S) are essentially unreactive, but combinations from which RSSH can be produced in situ (i.e., polysulfides with H 2 S or thiols with H 2 S 2 ) are effective. In situ generation of RSSH from designed precursors which release RSSH via intramolecular substitution or hydrolysis improve the radical-trapping efficiency of RSSH by minimizing deleterious self-reactions. A brief survey of structure−reactivity relationships enabled the design of new precursors that are more efficient. The reactivity of RSSH and their precursors translates from (phospho)lipid bilayers to cell culture (mouse embryonic fibroblasts), where they were found to inhibit ferroptosis induced by inactivation of glutathione peroxidase-4 (GPX4) or deletion of the gene encoding it. These results suggest that RSSH and the pathways responsible for their biosynthesis may act as a ferroptosis suppression system alongside the recently discovered FSP1/ubiquinone and GCH1/BH 4 /DHFR systems.
The direct conversion of carboxylica cids into disulfides is described. The approach employs oxidative photocatalysis for base-promoted decarboxylation of the substrate,w hich yields an alkylr adical that reacts with at risulfide dioxide through homolytic substitution. The trisulfide dioxides are easily prepared by an ewly described approach.1 8 8,2 8 8,a nd 38 8 carboxylic acids with varied substitution are good substrates,i ncluding amino acids and substrates with highly activated CÀHbonds.Trisulfide dioxides are also used to achieve the g-C(sp 3 )ÀHd isulfuration of amides through aradical relaysequence.Inboth reactions,the sulfonyl radical that results from substitution propagates the reaction. Factors governing the selectivity of substitution at S2 versus S3 of the trisulfide dioxides have been explored.
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