Origins of stereoselectivity in the oxido-alkylidenation of alkynes

A mild, convenient oxido-alkylidenation of alkynes is described. The three-step sequence involves the 1,3-dipolar cycloaddition of a nitrone and an alkynoate, oxidation of the resulting isoxazoline, and stereoselective extrusion of nitrosomethane. Quantum mechanical calculations identified the interactions of R3 with the oxidant and the preferred conformation of a diradical intermediate as major factors controlling the stereoselectivity of the oxidation and torquoselectivity of the extrusion.     

Almost Spherical Convex Hypersurfaces in R4

It is shown that if a ratio of two mean curvature functions of a closed convex hypersurface in the four-dimensional Euclidean space is sufficiently close to a constant, then the hypersurface lies between two concentric round spheres of sufficiently close radii.     

Effects on the Reactivity by Changing the Electrophilic Center from CO to CS: Contrasting Reactivity of Hydroxide,p‐Chlorophenoxide,and Butan‐2,3‐dione Monoximate in DMSO/H2O Mixtures

Second‐order rate constants have been measured spectrophotometrically for the reactions of O‐p‐nitrophenyl thionobenzoate ( 1 , PNPTB) with HO^?, butan‐2,3‐dione monoximate (Ox^?, α‐nucleophile), and p‐chlorophenoxide (p‐ClPhO^?, normal nucleophile) in DMSO/H₂O of varying mixtures at (25.0±0.1) °C. Reactivity of these nucleophiles significantly increases with increasing DMSO content. HO^? is less reactive than p‐ClPhO^? toward 1 up to 70 mol % DMSO although HO^? is over six pK_a units more basic in these media. Ox^? is more reactive than p‐ClPhO^? in all media studied, indicating that the α‐effect is in effect. The magnitude of the α‐effect (i.e., k/k_p) increases with the DMSO content up to 50 mol % DMSO and decreases beyond that point. However, the dependency of the α‐effect profile on the solvent for reactions of 1 contrasts to that reported previously for the corresponding reactions of p‐nitrophenyl benzoate ( 2 , PNPB); reactions of 1 result in much smaller α‐effects than those of 2 . Breakdown of the α‐effect into ground‐state (GS) and transition‐state (TS) effects shows that the GS effect is not responsible for the α‐effect across the solvent mixtures. The role of the solvent has been discussed on the basis of the bell‐shaped α‐effect profiles found in the current study as well as in our previous studies, that is, a GS effect in the H₂O‐rich region through H‐bonding interactions and a TS effect in the DMSO‐rich media through mutual polarizability interactions.     

Hepatocyte-specific Prominin-1 protects against liver injury-induced fibrosis by stabilizing SMAD7

Prominin-1 (PROM1), also known as CD133, is expressed in hepatic progenitor cells (HPCs) and cholangiocytes of the fibrotic liver. In this study, we show that PROM1 is upregulated in the plasma membrane of fibrotic hepatocytes. Hepatocellular expression of PROM1 was also demonstrated in mice (Prom1^CreER; R26^TdTom) in which cells expressed TdTom under control of the Prom1 promoter. To understand the role of hepatocellular PROM1 in liver fibrosis, global and liver-specific Prom1-deficient mice were analyzed after bile duct ligation (BDL). BDL-induced liver fibrosis was aggravated with increased phosphorylation of SMAD2/3 and decreased levels of SMAD7 by global or liver-specific Prom1 deficiency but not by cholangiocyte-specific Prom1 deficiency. Indeed, PROM1 prevented SMURF2-induced SMAD7 ubiquitination and degradation by interfering with the molecular association of SMAD7 with SMURF2. We also demonstrated that hepatocyte-specific overexpression of SMAD7 ameliorated BDL-induced liver fibrosis in liver-specific Prom1-deficient mice. Thus, we conclude that PROM1 is necessary for the negative regulation of TGFβ signaling during liver fibrosis.Subject terms: Cell signalling, Apoptosis, Post-translational modifications, Mechanisms of disease     

Induction of Nanog in neural progenitor cells for adaptive regeneration of ischemic brain

NANOG plays a key role in cellular plasticity and the acquisition of the stem cell state during reprogramming, but its role in the regenerative process remains unclear. Here, we show that the induction of NANOG in neuronal cells is necessary for the physiological initiation of neuronal regeneration in response to ischemic stress. Specifically, we found that NANOG was preferentially expressed in undifferentiated neuronal cells, and forced expression of Nanog in neural progenitor cells (NPCs) promoted their self-renewing expansion both in ex-vivo slice cultures and in vitro limiting dilution analysis. Notably, the upstream region of the Nanog gene contains sequence motifs for hypoxia-inducible factor-1 alpha (HIF-1α). Therefore, cerebral neurons exposed to hypoxia significantly upregulated NANOG expression selectively in primitive (CD133⁺) cells, but not in mature cells, leading to the expansion of NPCs. Notably, up to 80% of the neuronal expansion induced by hypoxia was attributed to NANOG-expressing neuronal cells, whereas knockdown during hypoxia abolished this expansion and was accompanied by the downregulation of other pluripotency-related genes. Moreover, the number of NANOG-expressing neuronal cells were transiently increased in response to ischemic insult, predominantly in the infarct area of brain regions undergoing neurogenesis, but not in non-neurogenic loci. Together, these findings reveal a functional effect of NANOG-induction for the initiation of adaptive neuronal regeneration among heterogeneous NPC subsets, pointing to cellular plasticity as a potential link between regeneration and reprogramming processes.Subject terms: Stem-cell research, Experimental models of disease     

Effect of oxychlorination treatment on the regeneration of Pt–Sn/Al2O3 catalyst for propane dehydrogenation

Research on Chemical Intermediates - Propane dehydrogenation and regeneration of Pt–Sn/θ-Al2O3 catalysts was evaluated with oxychlorination treatment. It was observed that the catalytic...     

Identification of protoberberine alkaloids as novel histone methyltransferase G9a inhibitors by structure-based virtual screening

The protein lysine methyltransferase G9a, which controls gene expression by epigenetic regulation of H3K9 methylation, is related to various human diseases, including cancer, drug addiction, and mental retardation. In recent years, genetic, biological, and physiological evidence has established G9a inhibitors as potential chemotherapeutic agents for cancer treatment. In this study, we identified protoberberine alkaloid pseudodehydrocorydaline (CT13) as a novel G9a inhibitor, by structure-based virtual screening of in-house library containing natural product compounds. The activity of CT13 was determined by biophysical analyses involving MALDI-TOF mass spectrometry and western blot analysis. CT13 showed selective inhibitory activity against G9a and suppressed the level of H3K9me2 in MCF7 human breast cancer cells. Molecular docking analysis suggested the binding mode of CT13 which occupies the binding site of histone H3 substrate. CT13 provides a novel scaffold for further development of analogous synthetic G9a inhibitors.

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