an-integrated-system-to-remotely-trigger-intracellular-signal

An Integrated System to Remotely Trigger Intracellular Signal Transduction by Upconversion Nanoparticle-mediated Kinase Photoactivation

Upconversion nanoparticle (UCNP)-mediated photoactivation is a new approach to remotely control bioeffectors with much less phototoxicity and with deeper ...

Academia Sinica

National Taiwan University

Using a combination of N-ethyl-N-nitrosourea-mediated mutagenesis and metabolomics-guided screening, we identified mice with elevated blood levels of short-chain C4-acylcarnitine and increased urine isobutyryl-glycine. Genome-wide homozygosity screening, followed by fine mapping, located the disease gene to 15-25 Mb of mouse chromosome 9 where a candidate gene, Acad8, encoding mitochondrial isobutyryl-CoA dehydrogenase was located. Genomic DNA sequencing revealed a single-nucleotide mutation at -17 of the first intron of Acad8 in affected mice. cDNA sequencing revealed an intronic 28-bp insertion at the site of the mutation, which caused a frame shift with a premature stop codon. In vitro splicing assay confirmed that the mutation was sufficient to activate an upstream, aberrant 3' splice site. There was a reduction in the expression of Acad8 at both the mRNA and protein levels. The mutant mice grew normally but demonstrated cold intolerance at young age with a progressive hepatic steatosis. Homozygous mutant mice hepatocytes had abnormal mitochondria with crystalline inclusions, suggestive of mitochondriopathy. This mouse model of isobutyryl-CoA dehydrogenase deficiency could provide us a better understanding of the possible role of IBD deficiency in mitochondriopathy and fatty liver.

Alternative splicing in Acad8 resulting a mitochondrial defect and progressive hepatic steatosis in mice.

15,16-Dihydrotanshinone I (DHTS) is extracted from Salvia miltiorrhiza Bunge which is a functional food in Asia. In this study, we investigated the apoptotic effect of DHTS on the human acute myeloid leukemia (AML) type III HL-60 cell line. We found that treatment with 1.5 μg/mL DHTS increased proapoptotic Bax and Bad protein expressions and activated caspases-3, -8, and -9, thus leading to poly ADP ribose polymerase (PARP) cleavage and resulting in cell apoptosis. DHTS induced sustained c-Jun N-terminal kinase (JNK) phosphorylation and Fas ligand (FasL) expression. The anti-Fas blocking antibody reversed the DHTS-induced cell death, and the JNK-specific inhibitor, SP600125, inhibited DHTS-induced caspase-3, -8, -9, and PARP cleavage. In a xenograft nude mice model, 25 mg/kg DHTS showed a great effect in attenuating HL-60 tumor growth. Taken together, these results suggest that DHTS can induce HL-60 cell apoptosis in vitro and inhibit HL-60 cell growth in vivo; the underlying mechanisms might be mediated through activation of the JNK and FasL signal pathways.

15,16-Dihydrotanshinone I from the Functional Food Salvia miltiorrhiza Exhibits Anticancer Activity in Human HL-60 Leukemia Cells: in Vitro and in Vivo Studies.

Two water-soluble near-infrared luminescent probes, which possess both conventional intense Stokes fluorescence and unique single-photon frequency upconversion luminescence (FUCL), were developed for sensitive and selective detection of pH changes in live cells. The water solubility and biocompatibility of these probes were achieved by introducing mannose residues through 2,2'-(ethylenedioxy)diethylamine tethered spacers to a near-infrared conventional fluorescence (CF) and FUCL organic fluorophore. At a pH higher than 7.4, the probes have ring-closed spirocyclic lactam structures, thus are colorless and nonfluorescent. Nevertheless, they sensitively respond to acidic pH values, with a drastic structural change to ring-opened spirocyclic lactam forms, which cause significant absorbance increases at 714 nm. Correspondingly, their near-infrared CF and FUCL intensities at 740 nm are also significantly enhanced when excited by 690 and 808 nm, respectively. The probes hold a variety of advantages such as high sensitivity, excellent reversibility and selectivity to pH over metal ions, low cellular autofluorescence background interference, good cell membrane permeability and photostability, as well as low cytotoxicity. Our results have successfully proven that these probes can visualize intracellular lysosomal pH changes in live cells by monitoring both near-infrared CF and FUCL changes.

Tzu-Ho Chen

Institute of Chemistry

Academia Sinica

An Integrated System to Remotely Trigger Intracellular Signal Transduction by Upconversion Nanoparticle-mediated Kinase Photoactivation

Tzu-Ho Chen

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Institute of Chemistry

Academia Sinica

An Integrated System to Remotely Trigger Intracellular Signal Transduction by Upconversion Nanoparticle-mediated Kinase Photoactivation

Institute of Chemistry