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  • Springer Science and Business Media LLC  (7)
  • 1
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2022-05-11)
    Abstract: Recent development of the chemical inhibitors specific to oncogenic KRAS (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog) mutants revives much interest to control KRAS-driven cancers. Here, we report that AIMP2-DX2, a variant of the tumor suppressor AIMP2 (aminoacyl-tRNA synthetase-interacting multi-functional protein 2), acts as a cancer-specific regulator of KRAS stability, augmenting KRAS-driven tumorigenesis. AIMP2-DX2 specifically binds to the hypervariable region and G-domain of KRAS in the cytosol prior to farnesylation. Then, AIMP2-DX2 competitively blocks the access of Smurf2 (SMAD Ubiquitination Regulatory Factor 2) to KRAS, thus preventing ubiquitin-mediated degradation. Moreover, AIMP2-DX2 levels are positively correlated with KRAS levels in colon and lung cancer cell lines and tissues. We also identified a small molecule that specifically bound to the KRAS-binding region of AIMP2-DX2 and inhibited the interaction between these two factors. Treatment with this compound reduces the cellular levels of KRAS, leading to the suppression of KRAS-dependent cancer cell growth in vitro and in vivo. These results suggest the interface of AIMP2-DX2 and KRAS as a route to control KRAS-driven cancers.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2553671-0
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  • 2
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 6, No. 1 ( 2016-03-15)
    Abstract: Osteoclast cells (OCs) are differentiated from bone marrow-derived macrophages (BMMs) by activation of receptor activator of nuclear factor κB (NF-κB) ligand (RANKL). Activation of NADPH oxidase (Nox) isozymes is involved in RANKL-dependent OC differentiation, implicating Nox isozymes as therapeutic targets for treatment of osteoporosis. Here, we show that a novel pyrazole derivative, Ewha-18278 has high inhibitory potency on Nox isozymes. Blocking the activity of Nox with Ewha-18278 inhibited the responses of BMMs to RANKL, including reactive oxygen species (ROS) generation, activation of mitogen-activated protein (MAP) kinases and NF-κB, and OC differentiation. To evaluate the anti-osteoporotic function of Ewha-18278, the derivative was applied to estrogen-deficient ovariectomized (OVX) ddY mice. Oral administration of Ewha-18278 (10 mg/kg/daily, 4 weeks) into the mice recovered bone mineral density, trabecular bone volume, trabecular bone length, number and thickness, compared to control OVX ddY mice. Moreover, treatment of OVX ddY mice with Ewha-18278 increased bone strength by increasing cortical bone thickness. We provide that Ewha-18278 displayed Nox inhibition and blocked the RANKL-dependent cell signaling cascade leading to reduced differentiation of OCs. Our results implicate Ewha-18278 as a novel therapeutic agent for the treatment of osteoporosis.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2016
    detail.hit.zdb_id: 2615211-3
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  • 3
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2021-05-18)
    Abstract: This study aimed to investigate the effect of intraoperative fluid volume on the postoperative ileus (POI) recovery period. A retrospective review of the Korean robot-assisted radical cystectomy database identified 718 patients who underwent robot-assisted radical cystectomy (RARC). Regression analyses were performed to identify the associations between the amount of intraoperative fluid administration (crystalloid/colloid/total), POI period (time to flatus/bowel movements), and length of hospital stay (LOS) after adjusting for covariates. In addition, we analyzed the risk factors for gastrointestinal complications and prolonged POI using a logistic regression model. An increasing volume of the administered crystalloid/total fluid was associated with prolonged POI (crystalloid R 2  = 0.0725 and P  〈  0.0001; total amount R 2  = 0.0812 and P  〈  0.0001), and the total fluid volume was positively associated with the LOS (R 2  = 0.099 and P  〈  0.0001). The crystalloid amount was a risk factor for prolonged POI (P  〈  0.001; odds ratio, 1.361; 95% confidence interval, 1.133–1.641; P  〈  0.001). In the context of RARC, increased intravenous fluids are associated with prolonged POI and longer LOS.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2615211-3
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  • 4
    In: Parasites & Vectors, Springer Science and Business Media LLC, Vol. 7, No. 1 ( 2014-12)
    Abstract: Plasmodium vivax is the most widespread human malaria in tropical and subtropical countries, including the Republic of Korea. Vivax malaria is characterized by hypnozoite relapse and long latency infection by the retained liver stage of P. vivax , and somewhat surprisingly, little is known of the liver stage antigens of this parasite. Here, we report for the first time the characterization of a liver stage antigen of P. vivax (PvLSA). Methods Five peptides located inside PvLSA were synthesized, and specific anti-sera to the respective peptides were used to localize PvLSA on P. vivax parasites in human liver cells by immunofluorescence. Western blotting and enzyme-linked immunosorbent assay were performed using the five peptides and sera collected from vivax malaria patients and from normal healthy controls. Results PvLSA was localized on P. vivax parasites in human liver cells. Vivax malaria-infected patients were detected using the five peptides by western blotting. Furthermore, the peptides reacted with the sera of vivax malaria patients. Conclusions These results suggest that PvLSA may function during the liver stage of P. vivax .
    Type of Medium: Online Resource
    ISSN: 1756-3305
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2014
    detail.hit.zdb_id: 2409480-8
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  • 5
    In: Malaria Journal, Springer Science and Business Media LLC, Vol. 22, No. 1 ( 2023-06-14)
    Abstract: Gabon is a malaria-threatened country with a stable and hyperendemic transmission of Plasmodium falciparum monoinfection. Malaria drug resistance is widely spread in many endemic countries around the world, including Gabon. The molecular surveillance of drug resistance to antifolates and artemisinin-based combination therapy (ACT) is one of the strategies for combating malaria. As Plasmodium parasites continue to develop resistance to currently available anti-malarial drugs, this study evaluated the frequency of the polymorphisms and genetic diversity associated with this phenomenon among the parasites isolates in Gabon. Methods To assess the spread of resistant haplotypes among the malaria-infected population of Libreville, single nucleotide polymorphisms linked to sulfadoxine–pyrimethamine (SP) and artemisinin drugs resistance were screened for P. falciparum dihydrofolate reductase ( Pfdhfr ), P. falciparum dihydropteroate synthase ( Pfdhps ), and P. falciparum kelch 13-propeller domain ( Pfk13 ) point mutations. Results The analysis of 70 malaria-positive patient samples screened for polymorphism showed 92.65% (n  = 63) mutants vs. 7.35% ( n  = 5) wild parasite population in Pfdhfr , with high prevalence mutations at S 108 N(88.24%, n  = 60), N 51 I(85.29%, n  = 58), C 59 R(79.41%, n  = 54); however, I 164 L(2.94%, n  = 2) showed low frequency mutation. No wild haplotype existed for Pfdhps , and there were no mutations at the K 540 E, A 581 G, and A 613 T/S positions. However, the mutation rate at A 437 G(93.38%, n  = 62) was the highest, followed by S 436 A/F(15.38%, n  = 10). A higher frequency of quadruple IRNI–SGKAA (69.84%) than quintuple IRNI–(A/F)GKAA (7.94%) mutations was observed in the Pfdhfr – Pfdhps combination. Furthermore, none of the mutations associated with ACT resistance, especially those commonly found in Africa, were observed in Pfk13 . Conclusions High polymorphism frequencies of Pfdhfr and Pfdhps genes were observed, with alternative alanine/phenylalanine mutation at S 436 A/F (7.69%, n  = 5) for the first time. Similar to that of other areas of the country, the patterns of multiple polymorphisms were consistent with selection owing to drug pressure. Although there was no evidence of a medication failure haplotype in the studied population, ACT drug efficacy should be regularly monitored in Libreville, Gabon.
    Type of Medium: Online Resource
    ISSN: 1475-2875
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2091229-8
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  • 6
    In: Malaria Journal, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2015-12)
    Type of Medium: Online Resource
    ISSN: 1475-2875
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2015
    detail.hit.zdb_id: 2091229-8
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  • 7
    In: Parasites & Vectors, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2020-12)
    Abstract: The encystation of Acanthamoeba leads to the development of resilient cysts from vegetative trophozoites. This process is essential for the survival of parasites under unfavorable conditions. Previous studies have reported that, during the encystation of A. castellanii , the expression levels of encystation-related factors are upregulated. However, the regulatory mechanisms for their expression during the encystation process remains unknown. Proteins in the sirtuin family, which consists of nicotinamide adenine dinucleotide-dependent deacetylases, are known to play an important role in various cellular functions. In the present study, we identified the Acanthamoeba silent-information regulator 2-like protein (AcSir2) and examined its role in the growth and encystation of Acanthamoeba. Methods We obtained the full-length sequence for AcSir2 using reverse-transcription polymerase chain reaction. In Acanthamoeba transfectants that constitutively overexpress AcSir2 protein, SIRT deacetylase activity was measured, and the intracellular localization of AcSir2 and the effects on the growth and encystation of trophozoites were examined. In addition, the sirtuin inhibitor salermide was used to determine whether these effects were caused by AcSir2 overexpression Results AcSir2 was classified as a class-IV sirtuin. AcSir2 exhibited functional SIRT deacetylase activity, localized mainly in the nucleus, and its transcription was upregulated during encystation. In trophozoites, AcSir2 overexpression led to greater cell growth, and this growth was inhibited by treatment with salermide, a sirtuin inhibitor. When AcSir2 was overexpressed in the cysts, the encystation rate was significantly higher; this was also reversed with salermide treatment. In AcSir2-overexpressing encysting cells, the transcription of cellulose synthase was highly upregulated compared with that of control cells, and this upregulation was abolished with salermide treatment. Transmission electron microscope-based ultrastructural analysis of salermide-treated encysting cells showed that the structure of the exocyst wall and intercyst space was impaired and that the endocyst wall had not formed. Conclusions These results indicate that AcSir2 is a SIRT deacetylase that plays an essential role as a regulator of a variety of cellular processes and that the regulation of AcSir2 expression is important for the growth and encystation of A. castellanii .
    Type of Medium: Online Resource
    ISSN: 1756-3305
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2409480-8
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