Korea Research Institute of Bioscience and Biotechnology
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Elucidation of the role and usefulness as a therapeutic target of Rnd1 in obesity and the metabolic syndrome
No full text비만 및 대사질환에서 Rnd1의 역할 규명 및 치료 표적으로서 유용성 검증OGM488201
The reactive oxygen species as pathogenic factors of fragmented microplastics to macrophages
No full textThe presence of microplastics in the various food web raised concerns on human health, but little is known about the target cells and mechanism of toxicity of microplastics. In this study, we evaluated the toxicity of microplastics using relevant cell lines to the oral route of exposure. Approximately 100 μm-sized fragment-type polypropylene (PP) and polystyrene (PS) particles were prepared by sieving after pulverization and further applied the accelerated weathering using ultraviolet and heat. Thus, the panel of microplastics includes fresh PP (f-PP), fresh PS (f-PS), weathered PP (w-PP), and weathered PS (w-PS). The spherical PS with a similar size was used as a reference particle. Treatment of all types of PP and PS did not show any toxic effects to the Caco-2 cells and HepG2 cells. However, the treatment of microplastics to THP-1 macrophages showed significant toxicity in the order of f-PS > f-PP > w-PS > w-PP. The weathering process significantly reduced the reactive oxygen species (ROS) generation potential of both microplastics because the weathered microplastics have an increased affinity to bind serum protein which acts as a ROS scavenger. The intrinsic ROS generation potential of microplastics showed a good correlation with the toxicity endpoints including cytotoxicity and pro-inflammatory cytokines in THP-1 macrophages. In conclusion, the results of this study suggest that the target cell type of microplastics via oral administration can be macrophages and the pathogenic factor to THP-1 macrophages is the intrinsic ROS generation potential of microplastics. Nevertheless, the toxic effect of microplastics tested in this study was much less than that of nano-sized particles.
Orphan nuclear receptor ERR-γ regulates hepatic FGF23 production in acute kidney injury
No full textFibroblast growth factor 23 (FGF23), a hormone generally derived from bone, is important in phosphate and vitamin D homeostasis. In acute kidney injury (AKI) patients, high-circulating FGF23 levels are associated with disease progression and mortality. However, the organ and cell type of FGF23 production in AKI and the molecular mechanism of its excessive production are still unidentified. For insight, we investigated folic acid (FA)-induced AKI in mice. Interestingly, simultaneous with FGF23, orphan nuclear receptor ERR-γ expression is increased in the liver of FA-treated mice, and ectopic overexpression of ERR-γ was sufficient to induce hepatic FGF23 production. In patients and in mice, AKI is accompanied by up-regulated systemic IL-6, which was previously identified as an upstream regulator of ERR-γ expression in the liver. Administration of IL-6 neutralizing antibody to FA-treated mice or of recombinant IL-6 to healthy mice confirms IL-6 as an upstream regulator of hepatic ERR-γ-mediated FGF23 production. A significant (P < 0.001) interconnection between high IL-6 and FGF23 levels as a predictor of AKI in patients that underwent cardiac surgery was also found, suggesting the clinical relevance of the finding. Finally, liver-specific depletion of ERR-γ or treatment with an inverse ERR-γ agonist decreased hepatic FGF23 expression and plasma FGF23 levels in mice with FA-induced AKI. Thus, inverse agonist of ERR-γ may represent a therapeutic strategy to reduce adverse plasma FGF23 levels in AKI.
Hypoxia-inducible factor (HIF) inhibitors: a patent survey (2016-2020)
No full textIntroduction: Hypoxia-inducible factor (HIF) is a master regulator of oxygen homeostasis. The increased expression of genes targeted by HIF is associated with many human diseases, including ischemic cardiovascular disease, stroke, chronic lung disease, and cancer.
Areas covered: This patent survey summarizes the information about patented HIF inhibitors over the last 5 years.
Expert opinion: HIF inhibitors have shown promise for the treatment of hypoxic pulmonary hypertension, a circadian rhythm disorder, calcific aortic valve disease, cerebrovascular accident, and heterotopic ossification. In addition, HIF-2α inhibitors can be used for the treatment or prevention of iron overload disorders, Crohn’s disease, ulcerative colitis, and thyroid eye disease, or to improve muscle generation and repair. PT2385 completed phase I clinical trials for the treatment of clear cell renal cell carcinoma. It exerted a higher synergistic inhibitory effect on tumor growth in combination with anti？PD-1 antibody, in comparison with each treatment alone, indicating that effective immunotherapy for solid tumors counteracts of the immunosuppression induced by hypoxia. Therefore, considering the effects of hypoxia on cancer cells, stromal cells, and effector immune cells, it is important to develop inhibitors of molecular pathways activated by hypoxia for successful treatments.
Eif2b3 mutants recapitulate phenotypes of vanishing white matter disease and validate novel disease alleles in zebrafish
No full textLeukodystrophy with vanishing white matter (VWM), also called Childhood Ataxia with Central Nervous System Hypomyelination, is caused by mutations in the subunits of the eukaryotic translation initiation factor, EIF2B1, EIF2B2, EIF2B3, EIF2B4 or EIF2B5. However, little is known regarding the underlying pathogenetic mechanisms, and there is no curative treatment for VWM. In this study, we established the first EIF2B3 animal model for VWM disease in vertebrates by CRISPR mutagenesis of the highly conserved zebrafish ortholog eif2b3. Using CRISPR, we generated two mutant alleles in zebrafish eif2b3, 10- and 16-bp deletions, respectively. The eif2b3 mutants showed defects in myelin development and glial cell differentiation, and increased expression of genes in the induced stress response pathway. Interestingly, we also found ectopic angiogenesis and increased VEGF expression. Ectopic angiogenesis in the eif2b3 mutants was reduced by the administration of VEGF receptor inhibitor SU5416. Using the eif2b3 mutant zebrafish model together with in silico protein modeling analysis, we demonstrated the pathogenicity of 18 reported mutations in EIF2B3, as well as of a novel variant identified in a 19-month-old female patient: c.503 T > C (p.Leu168Pro). In summary, our zebrafish mutant model of eif2b3 provides novel insights into VWM pathogenesis and offers rapid functional analysis of human EIF2B3 gene variants.
Discovery of novel pyrimidine-based capsid assembly modulators as potent anti-HBV agents
No full textCore assembly modulators of viral capsid proteins have been developed as an effective treatment of chronic hepatitis B virus (HBV) infection. In this study, we synthesized novel potent pyrimidine derivatives as core assembly modulators, and their antiviral effects were evaluated in in vitro and in vivo biological experiments. One of the synthesized derivatives, compound 23h (R1 = MeSO2, R2 = 1-piperidin-4-amine, R3 = 3-Cl-4-F-aniline) displayed potent inhibitory effects in the in vitro assays (52% inhibition in the protein-based assay at 100 nM and an IC50 value of 181 nM in the serum HBV DNA quantification assay). Moreover, treatment with compound 23h for 5 weeks significantly decreased serum levels of HBV DNA levels (3.35 log reduction) in a human liver-chimeric uPA/SCID mouse model, and these effects were significantly increased when 23h was combined with tenofovir, a nucleotide analogue inhibitor of reverse transcriptase used for the treatment of HBV infection.
Description of desferrioxamine-producing bacterium Chitinophaga agrisoli sp. nov., isolated from soil
No full textA Gram-stain-negative, non-motile, yellow-pigmented and non-spore forming rod-shaped bacterium, designated strain BN140078T, was isolated from farmland soil, Chungbuk, Republic of Korea. It was able to grow aerobically at 10-40 °C (optimum 28 °C), pH 5.5-7.5 (optimum pH 7.0) and with 0-2.0% (w/v) NaCl concentration (optimum 1.0%) on Reasoner's 2A (R2A) agar medium. Comparative 16S rRNA gene sequence analysis showed that the strain BN140078T had 96.9%, 96.5% and 96.1% 16S rRNA gene similarities with Chitinophaga ginsengihumi KACC 17604T, Chitinophaga rupis KACC 14521T and Chitinophaga japonensis KACC 12057T, respectively. The predominant respiratory quinone was menaquinone MK-7 and the major fatty acids (≥ 5%) were C16:1 ω5c, iso-C15:0, iso-C17:0 3-OH and Summed Feature 3 (C16:1 ω7c and/or C16:1 ω6c). The polar lipids were composed of phosphatidylethanolamine, four unidentified amino lipids and six unidentified lipids. The genomic DNA G+C content was 49.5 mol%. The genome of strain BN140078T comprises a number of biosynthetic gene clusters for secondary metabolites, in particular those for non-ribosomal peptide products. The polyphasic taxonomic study clearly distinguished this strain from its closest phylogenetic neighbors. Thus, we propose that the BN140078T represents a novel species of the genus Chitinophaga, for which the name Chitinophaga agrisoli sp. nov. was proposed. The type strain is BN140078T (=KCTC 62555T = CCTCC AB 2018162T).
Complete mitochondrial genome and phylogenetic analysis of the copper shark Carcharhinus brachyurus (Gunther, 1870)
No full textCopper shark (Carcharhinus brachyurus Gunther, 1870) is one of the most widely distributed but least known species in the family Carcharhinidae. Herein, we report the first complete mitogenome of C. brachyurus. The overall structure of the 16,704？bp C. brachyurus mitogenome was similar to that of other Carcharhinus species and showed the highest average nucleotide identity (97.1%) with the spinner shark (Carcharhinus brevipinna). Multigene phylogeny using 13 protein-coding genes (PCGs) in the mitogenome resolved C. brachyurus clustered with other species within the genus; the overall tree topology was congruent with recent phylogenetic studies of this species. These results provide important information for conservation genetics and further evolutionary studies of sharks.
Culture condition optimization and FT-IR analysis of Polygonum multiflorum Thunb. adventitious root cultures grown in an air-lift bioreactor system
No full textBioreactor cultures have been used for biomass production and bioactive compounds accumulation in adventitious root cultures of medicinal plants. In this study, we evaluated the effects of different auxin types [indole-3-butyric acid (IBA) and 1-naphthaleneacetic acid (NAA)] and concentrations (0.5, 1.0, 2.0 and 4.0 mg·L？1), Murashige and Skoog (MS) medium salt strength (0.25, 0.5, 0.75, 1.0, 1.5 and 2X), and sucrose concentrations (0, 1.5, 3, 5, 7 and 10%) on Polygonum multiflorum Thunb. adventitious root cultures in a 3-L balloon-type bubble bioreactor (BTBB). IBA (1, 2, and 4 mg·L？1) was more effective than NAA in promoting root growth. Additionally, low MS salt strength (0.25 and 0.5X MS) increased the accumulation of total phenolics and flavonoids but reduced biomass accumulation. Four weeks of culture in full-strength MS medium supplemented with 2 mg·L？1 IBA and 5% sucrose resulted in the highest root biomass [98.46 g·L？1 fresh weight (FW); 13.46 g·L？1 dry weight (DW)] and bioactive compounds accumulation (total phenolics compounds, 53.08 mg·g？1 DW; total flavonoids, 25.10 mg·g？1 DW). To determine whether metabolic fingerprinting of whole-cell extracts could be used to compare metabolic equivalence of P. multiflorum root samples, we treated adventitious roots with different culture conditions, and analyzed the treated adventitious roots and natural roots by Fourier transform infrared (FT-IR) spectroscopy. The results showed that the metabolic pattern of adventitious root samples was similar under different culture conditions; however, these samples could be discriminated from each other in pilot-scale bioreactors. Overall, our study provides useful information for industrial-scale cultivation of P. multiflorum adventitious roots.
Lentibacillus saliphilus. sp. nov., a moderately halophilic bacterium isolated from a saltern in Korea
No full textA novel moderately halophilic bacterial strain, designated YIM 93176T, was isolated from a saltern in Korea and subjected to a polyphasic taxonomic study. This isolate YIM 93176T was observed to grow in the presence of 0？22% (w/v) NaCl and at pH 6.0？10.0 and 10？45 °C; optimum growth was observed with 5？10% (w/v) NaCl and at pH 7.0？9.0 and 28？37 °C. Based on 16S rRNA gene sequences analysis, the nearest relatives were Lentibacillus alimentarius M2024T (96.5% similarity), followed by Virgibacillus carmonensis LMG 20964T (96.0%) and the other type strains of the family Bacillaceae, but phylogenetic analysis indicated that strain YIM 93176T belonged to the cluster comprising type species of the genus Lentibacillus. Genome sequencing of strain YIM 93176T revealed a genome size of 3.2 Mb and a DNA G？+？C content of 40.5 mol%. The major fatty acids were anteiso-C15:0 (40.7%) and iso-C15:0 (26.4%), while the predominant respiratory quinone was menaquinone 7. The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. These genotypic and chemotaxonomic characteristics supported affiliation of strain YIM 93176T to the genus Lentibacillus. In addition, phenotypic characteristics could distinguish strain YIM 93176T from its closely related species in genus Lentibacillus. Based on the cumulative evidences from the polyphasic taxonomic study, strain YIM 93176T represents a novel species of the genus Lentibacillus, for which name Lentibacillus saliphilus sp. nov. (type strain YIM 93176T？=？CCTCC AB 208139T？=？DSM 21375T) is proposed.