This review highlights the recent research progress on diarylethene-based multi-responsive molecular switches with special emphasis on the modulation of their photophysical properties by multiple external stimuli.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a potent cancer cell-specific apoptosis-inducing cytokine with little toxicity to most normal cells. However, acquired resistance of cancer cells to TRAIL is a roadblock. Agents that can either potentiate the effect of TRAIL or overcome resistance to TRAIL are urgently needed. This article reports that ginsenoside compound K (CK) potentiates TRAIL-induced apoptosis in HCT116 colon cancer cells and sensitizes TRAIL-resistant colon cancer HT-29 cells to TRAIL. On a cellular mechanistic level, CK downregulated cell survival proteins including Mcl-1, Bcl-2, surviving, X-linked inhibitor of apoptosis protein and Fas-associated death domain-like IL-1-converting enzyme-inhibitory protein, upregulated cell pro-apoptotic proteins including Bax, tBid and cytochrome c, and induced the cell surface expression of TRAIL death receptor DR5. Reduction of DR5 levels by siRNAs significantly decreases CK- and TRAIL-mediated apoptosis. Importantly, our results indicate, for the first time, that DR5 upregulation is mediated by autophagy, as blockade of CK-induced autophagy by 3-MA, LY294002 or Atg7 siRNAs substantially decreases DR5 upregulation and reduces the synergistic effect. Furthermore, CK-stimulated autophagy is mediated by the reactive oxygen species–c-Jun NH2-terminal kinase pathway. Moreover, we found that p53 and the C/EBP homologous (CHOP) protein is also required for DR5 upregulation but not related with autophagy. Our findings contribute significantly to the understanding of the mechanism accounted for the synergistic anticancer activity of CK and TRAIL, and showed a novel mechanism related with DR5 upregulation.
Abstract Abstract AIM:To study the effects of magnolol and honokiol on isolated smooth muscle of gastrointestinal tract and their relationship with Ca 2+ , and on the gastric emptying and the intestinal propulsive activity in mice. METHODS:Routine experimental methods using isolated gastric fundus strips of rats and isolated ileum segments of guinea pigs were adopted to measure the smooth muscle tension. The effects of magnolol 10 -3 , 10 -4 , 10 -5 mol/L, and honokiol 10 -4 , 10 -5 , 10 -6 mol/L on the contractility of gastric fundus strips of rats and ileum of guinea pigs induced by acetylcholine (Ach) and 5-hydroxytryptamine (5-HT) was assessed respectively. The method using nuclein and pigment methylene blue was adopted to measure the gastric retention rate of nuclein and the intestinal propulsive ratio of a nutritional semi-solid meal for assessing the effect of magnolol and honokiol (0.5, 2, 20 mg/kg) on gastric emptying and intestinal propulsion. RESULTS:Magnolol and honokiol significantly inhibited the contractility of isolated gastric fundus strips of rats treated with Ach or 5-HT and isolated ileum guinea pigs treated with Ach or CaCl 2 , and both of them behaved as non-competitive muscarinic antagonists. Magnolol and honokiol inhibited the contraction induced by Ach in Ca 2+ -free medium and extracellular Ca 2+ -dependent contraction induced by Ach. Each group of magnolol and honokiol experiments significantly decreased the residual rate of nuclein in the stomach and increased the intestinal propulsive ratio in mice. CONCLUSION:The inhibitory effect of magnolol and honokiol on contractility of the smooth muscles of isolated gastric fundus strips of rats and isolated ileum of guinea pigs is associated with a calcium-antagonistic effect. Magnolol and honokiol can improve the gastric emptying of a semi-solid meal and intestinal propulsive activity in mice. © 2005The WJG Press and Elsevier Inc. All rights reserved. Key words: Magnolol and honokiol; Gastrointestinal movementZhang WW, Li Y, Wang XQ, Tian F, Cao H, Wang MW, Sun QS. Effects of magnolol and honokiol derived from traditional Chinese herbal remedies on gastrointestinal movement. World
Nucleoside 5′-triphosphates (NTPs) play key roles in biology and medicine. However, these compounds are notoriously difficult to synthesize. We describe a one-pot method to prepare NTPs from nucleoside 5′-H-phosphonate monoesters via pyridinium phosphoramidates, and we used this approach to synthesize ATP, UTP, GTP, CTP, ribavirin-TP, and 6-methylpurine ribonucleoside-TP (6MePTP). Poliovirus RNA-dependent RNA polymerase efficiently employed 6MePTP as a substrate, suggesting that the cognate nucleoside, a poorly understood antiviral agent, may damage viral RNA.Nucleoside 5′-triphosphates (NTPs) are critical mediators of myriad biological processes including DNA replication, transcription, and translation. Correspondingly, synthetic mimics of NTPs have been widely used as molecular probes and biological assay components and represent active metabolites of certain drugs such as the antiviral agent ribavirin. Despite their importance in biology and medicine, the diversity of commercially available NTPs is limited because these compounds are often difficult to prepare and isolate in pure form. 1 Traditional approaches for the synthesis of NTPs include the "one-pot, three-step" method and the method of Ludwig and Eckstein. 2,3 Although these strategies work well for some substrates, others are plagued by low yields and difficulties in purification. 4 More recently, Ahmadibeni reported 5 a solid-phase route to NTPs, and Borch reported 6 a method for the preparation of activated phosphoramidates that can be converted to NTPs by reaction with tris(tetra-n-butylammonium) hydrogen pyrophosphate. The final coupling step employed by Borch was found to proceed in remarkably high yield, but the required four-step synthesis of We hypothesized that nucleoside 5′-H-phosphonates might provide novel and more readily synthesized precursors to NTPs. This hypothesis was based on reported syntheses of phosphates, phosphoramidates, and other phosphate derivatives from these precursors. [7][8][9][10] After conversion to silyl phosphites with TMSCl, H-phosphonate monoesters can be oxidized by elemental iodine and other reagents to generate electrophilic intermediates. 11,12 These intermediates are known to react with a variety of nucleophiles to afford addition products, but surprisingly, this strategy has not been previously investigated for the synthesis of NTPs.We report here a one-pot approach for the synthesis of NTPs from nucleoside 5′-Hphosphonate monoesters, relatively stable compounds that can be easily prepared from 2′,3′-O-isopropylidene-protected nucleosides. 13 We demonstrate that fully deprotected ribonucleoside 5′-H-phosphonate monoesters can be converted in situ to pyridinium phosphoramidate intermediates. Upon addition of nucleophilic tris(tetra-n-butylammonium) hydrogen pyrophosphate, NTPs can be isolated by use of a two-step purification protocol.As shown in Scheme 1, starting with the known 2′,3′-O-isopropylidene-protected nucleosides 1-6, 13-15 phosphitylation 16 with salicyl phosphorochlorodite or PCl 3 provi...
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