Korea Research Institute of Bioscience and Biotechnology
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Distinctive nanogels as high-efficienty transdermal carriers for skin wound healing
No full textWe propose that nanogels (HLGs) prepared by simply blending an epidermal growth factor (EGF)-loaded hyaluronan (HA)-based nanoformulation and poloxamers can be efficient transdermal drug carriers. In particular, due to the thermogelling behavior of poloxamer, when the HLGs, which are liquid at room temperature, are applied to the skin's surface, they form a gel at skin temperature. First, lipid-based nanoformulations (EGF-LNs) were fabricated by the lipid thin film method and then chemically conjugated with HA on the surface of the films to prepare EGF-loaded HA-based nanoformulations (EGF-HLNs). Both EGF-LNs and EGF-HLNs exhibited a uniform size and spherical lamellar structure. The EGF-HLN was added to a poloxamer solution to form EGF-HLG, which is a liquid at room temperature and a gel at skin temperature. HLGs have been shown to be able to deliver and permeate EGF well into the skin using both in vitro and in vivo systems, thus serving as an effective transdermal delivery system. In addition, it has been confirmed that this system could be a possible implantable drug carrier. Therefore, HLGs, which are uncomplicated and easily prepared, are expected to be easily used not only in the pharmaceutical field but also in the cosmetic field.
Exploration of certain 1,3-oxazole- and 1,3-thiazole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents
No full textSeveral novel series of hydroxamic acids bearing 2-benzamidooxazole/thiazole (5a-g, 6a-g) or 2-phenylsulfonamidothiazole (8a-c) were designed and synthesized. The compounds were obtained straightforwards via a two step pathway, starting from commercially available ethyl 2-aminooxazole-4-carboxylate or ethyl 2-aminothiazole-4-carboxylate. Biological evaluation showed that these hydroxamic acids generally exhibited good cytotoxicity against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung cancer), with IC50 values in low micromolar range and comparable to that of SAHA. These compounds also comparably inhibited HDACs with IC50 values in sub-micromolar range (0.010-0.131 μM) and some compounds (e.g 5f, IC50, 0.010 μM) were even more potent than SAHA (IC50, 0.025 μM) in HDAC inhibition. Representative compounds 6a and 8a appeared to arrest the SW620 cell cycle at G2 phase and significantly induced both early and late apoptosis of SW620 colon cancer cells. Docking experiments on HDAC2 and HDAC6 isozymes revealed favorable interactions at the tunnel of the HDAC active site which positively contributed to the inhibitory activity of synthesized compound. The binding affinity predicted by docking program showed good correlation with the experimental IC50 values. This study demonstrates that simple 1,3-oxazole- and 1,3-thiazole-based hydroxamic acids are also promising as antitumor agents and HDAC inhibitors and these results should provide valuable information for further design of more potent HDAC inhibitors and antitumor agents.
Effects of different nutrient and trace metal concentrations on growth of the toxic dinoflagellate Gymnodinium catenatum isolated from Korean coastal waters
No full textThe effects of the addition of nutrients (nitrate: N; phosphate: P; and vitamin B1) and trace metals (iron: Fe; Copper: Cu; and selenium: Se) on the growth of Gymnodinium catenatum, which was isolated from Korean coastal waters, were investigated. The Korean isolate of G. catenatum grew under a wide range of concentrations of N and P. Whilst high concentrations of N (> N: P ratio of 23.5) did not stimulate the growth rate, an enhanced growth rate and cell density were observed with the addition of P. The experimental addition of vitamin B1 revealed that G. catenatum is not dependent on vitamin B1 for growth. Moreover, the addition of Fe and Cu resulted in no significant differences in the growth patterns and rates of G. catenatum between the controls and treatments. It is thus possible that growth of the Korean isolate of G. catenatum does not require high concentrations of Fe and Cu. However, the cell densities were enhanced in the stationary phases of treatments upon addition of Se, and the maximum cell densities were higher than those in the culture experiments upon additions of other nutrient and trace metals. Our findings indicate that G. catenatum prefers P and Se for proliferation, rather than other nutritional sources.
Lindera obtusiloba attenuates oxidative stress and airway inflammation in a murine model of ovalbumin-challenged asthma
No full textLindera obtusiloba is widespread in northeast Asia and used for treatment of improvement of blood circulation and anti-inflammation. In this study, we investigated anti-inflammatory and anti-oxidant effects of the methanolic extract of L. obtusiloba leaves (LOL) in an ovalbumin (OVA)-challenged allergic asthma model and tumor necrosis factor (TNF)-α-stimulated NCI-H292 cell. Female BALB/c mice were sensitized with OVA by intraperitoneal injection on days 0 and 14, and airway-challenged with OVA from days 21 to 23. Mice were administered 50 and 100 mg/kg of LOL by oral gavage 1 h before the challenge. LOL treatment effectively decreased airway hyper-responsiveness and inhibited inflammatory cell recruitment, Th2 cytokines, mucin 5AC (MUC5AC) in bronchoalveolar lavage fluid in OVA-challenged mice, which were accompanied by marked suppression of airway inflammation and mucus production in the lung tissue. LOL pretreatment inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) with suppression of activator protein (AP)-1 and MUC5AC in the lung tissue. LOL also down-regulated expression of inflammatory cytokines, and inhibited the activation of NF-κB in TNF-α-stimulated NCI-H292 cells. LOL elevated the translocation of nuclear factor-erythroid 2-related factor (Nrf-2) into nucleus concurrent with increase of heme oxyngenase-1 (HO-1) and NAD(P)H quinine oxidoreductase 1 (NQO1). Moreover, LOL treatment exhibited a marked increase in the anti-oxidant enzymes activities, whereas effectively suppressed the production of reactive oxygen species and nitric oxide, as well as lipid peroxidation in lung tissue of OVA-challenged mice and TNF-α-stimulated NCI-H292 cells. These findings suggest that LOL might serve as a therapeutic agent for the treatment of allergic asthma.
Tuning surface functionalities of sub-10 nm-sized nanocarriers to target outer retina in designing drug delivery agents for intravitreal administration
No full textAge-related macular degeneration (AMD) is one of the leading causes of irreversible blindness, generally affecting people over 50 years of age in industrialized countries. Despite the effectiveness of anti-vascular endothelial growth factor (VEGF) therapy in attenuating the growth of new blood vessels, substantial visual improvements are rare with this complex disease. Furthermore, the current regimen of repeated monthly intravitreal injections of drugs can result in serious side effects. Combination therapies-to complement anti-VEGF alone-with a prolonged therapeutic effect and efficient delivery to the intended site are urgently needed, which could be realized through the use of carefully designed nanocarriers. To understand the physicochemical effects (e.g., size, charge, geometry) of intravitreally administered nanocarriers on their bioavailability, distribution, and targeting efficiency across multiple layers of the retina, here we prepared seven different types of surface-functionalized water-soluble dendritic nanocarriers with hydrodynamic sizes mostly under 5 nm. A similar stoichiometric amount of fluorophore was covalently attached to each of these biocompatible nanocarriers for quantitative analyses by confocal microscopy of cryosectioned healthy mouse eyes. Interestingly, at 24 h post-injection, the nanocarrier with multiple copies of glucosamine on the surface (DNSG) accumulated predominantly in the photoreceptor layer and the retinal pigment epithelium (RPE), which are speculated to be associated with AMD pathogenesis (i.e., target sites). Furthermore, extended residence at these outer retinal layers was demonstrated by DNSG, which appeared to gradually turn into micron-scale particles potentially through aggregation. Our systematic findings may provide useful guidelines for the rational design of intravitreal nanocarriers to treat vision-threatening retinal diseases, including AMD.
Peroxiredoxin II inhibits alcohol-induced apoptosis in L02 hepatocytes through AKT/β-catenin signaling pathway
No full textBackground: Peroxiredoxin II (PRDX2) performs unique roles in cells. It can reduce peroxides through cysteine residues, and helps prevent the effects of oxidative stress on cells. It is closely related to the occurrence and development of various diseases, especially alcoholic liver injury and even liver cancer. The metabolism of alcohol in hepatocytes leads to the increase in the levels of reactive oxygen species (ROS), oxidative stress, injury, and apoptosis. Therefore, this study focused on the investigating the protection conferred by PRDX2 against alcohol-induced apoptosis of hepatocytes.
Materials and methods: PRDX2 inhibition of alcohol-induced apoptosis in L02 hepatocytes was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, fluorescence microscopy, flow cytometry, western blotting and hematoxylin and eosin staining.
Results: The results showed that the levels of reactive oxygen species, protein kinase B, β-catenin, B-cell lymphoma-2 (BCL2), BCL-XL, BCL2-associated X, cleaved caspase-3, and cleaved poly (ADP-ribose) polymerase in PRDX2-silenced cells were increased significantly after the treatment of cells with ethanol. Similar results were obtained in an in vivo Prdx2-knockout mouse model of alcoholic liver injury. Therefore, PRDX2 may regulate the phosphorylation of the AKT signal protein by eliminating reactive oxygen species from cells, and it inhibits the downstream mitochondria-dependent apoptosis pathway, and, thereby, the apoptosis of cells.
Conclusion: Thus, PRDX2 may be a potential molecular target for the prevention and treatment of alcoholic liver injury.
The clonal repopulation of HSPC gene modified with anti？HIV-1 RNAi is not affected by preexisting HIV-1 infection
No full textDespite advances in hematopoietic stem/progenitor cell (HSPC) transplant for HIV-1？infected patients, the impact of a preexisting HIV-1 infection on the engraftment and clonal repopulation of HSPCs remains poorly understood. We have developed a long terminal repeat indexing-mediated integration site sequencing (LTRi-Seq) method that provides a multiplexed clonal quantitation of both anti？HIV-1 RNAi (RNA interference) gene-modified and control vector-modified cell populations, together with HIV-1？infected cells？all within the same animal. In our HIV-1？preinfected humanized mice, both therapeutic and control HSPCs repopulated efficiently without abnormalities. Although the HIV-1？mediated selection of anti？HIV-1 RNAi-modified clones was evident in HIV-1？infected mice, the organ-to-organ and intra-organ clonal distributions in infected mice were indistinguishable from those in uninfected mice. HIV-1？infected cells showed clonal patterns distinct from those of HSPCs. Our data demonstrate that, despite the substantial impact of HIV-1 infection on CD4+ T cells, HSPC repopulation remains polyclonal, thus supporting the use of HSPC transplant for anti-HIV treatment.
Description of Shewanella salipaludis sp. nov., isolated from a salt marsh
No full textA Gram-stain-negative and flagellated bacterial strain, SHSM-M6T, was isolated from salt marsh from Yellow Sea, Republic of Korea. Neighbor-joining phylogenetic tree of 16S rRNA gene sequences showed that strain SHSM-M6T belongs to the genus Shewanella. 16S rRNA gene sequence similarity values between strain SHSM-M6T and the type strains of Shewanella species were <98.0%. The average nucleotide identity and DNA？DNA hybridization values between genomic sequences of strain SHSM-M6T and the type strains of Shewanella species were <73.3 and 20.7%, respectively. Strain SHSM-M6T contained MK-6 as predominant menaquinone and Q-7 and Q-8 as the predominant ubiquinones. The novel strain contained C16:1ω7c and/or C16:1ω6c, iso-C15:0 and C16:0 as major fatty acids. Major polar lipids of strain SHSM-M6T were phosphatidylethanolamine, phosphatidylglycerol, one unidentified lipid, one unidentified aminolipid and one unidentified phospholipid. Differential phenotypic properties of strain SHSM-M6T, together with its phylogenetic and genetic distinctiveness, revealed that strain SHSM-M6T is separated from recognized Shewanella species. On the basis of the data presented, strain SHSM-M6T is considered to represent a novel species of the genus Shewanella, for which the name Shewanella salipaludis sp. nov. is proposed. The type strain is SHSM-M6T (=KACC 19901T = NBRC 113646T).
DNA data storage in Perl
No full textHere we report a simple and flexible method for DNA data storage based on Perl script. For this approach, the text data of the preamble of the “Universal Declaration of Human Rights” consisting of 2,046 words was encoded into the corresponding 8,148 base pairs of DNA using Perl-based encoding with a hash table. The encoded DNA sequences were then artificially synthesized for storage. The information DNA consisted of a total of 22 chemically synthesized DNA fragments with 400 nucleotides each, which were inserted into a cloning vector to multiply the plasmid DNA. The nucleotide integrity of the data-carrying DNA sequences were ensured under the accelerated aging conditions. Also, an erroneous nucleotide in the information DNA sequences was successfully corrected using the overlap extension PCR method. The stored DNA was read by sequencing, and the resulting DNA sequence information was successfully decoded to convert the DNA records back to the original document. Our results indicate that textual data can be stored in DNA using a simple, easy, and flexible Perl by running a script from the command line.
Design and characterization of cereblon-mediated androgen receptor proteolysis-targeting chimeras
No full textProteolysis-targeting chimera (PROTAC)-mediated protein degradation is a rapidly emerging therapeutic intervention that induces the degradation of targeted proteins. Herein, we report the design and biological evaluation of a series of androgen receptor (AR) PROTAC degraders for the treatment of metastatic castration-resistant prostate cancer. Predominantly, instead of thalidomide, we utilized the TD-106 scaffold, a novel cereblon (CRBN) binder that was identified in our previous study. Our results suggest that the linker position in the TD-106 CRBN binder is critical for the efficiency of AR degradation. The compounds attached to the 6-position of TD-106 promoted better degradation of AR than those at the 5- and 7-positions. Among the synthesized AR PROTACs, the representative degrader 33c (TD-802) effectively induced AR protein degradation, with a degradation concentration 50% of 12.5 nM and a maximum degradation of 93% in LNCaP prostate cancer cells. Additionally, most AR PROTAC degraders, including TD-802, displayed good liver microsomal stability and in vivo pharmacokinetic properties. Finally, we showed that TD-802 effectively inhibited tumor growth in an in vivo xenograft study.