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971.
Sehee Park Jin Il Kim Ilseob Lee Sangmoo Lee Min-Woong Hwang Joon-Yong Bae Jun Heo Donghwan Kim Seok-Il Jang Hyejin Kim Hee Jin Cheong Jin-Won Song Ki-Joon Song Luck Ju Baek Man-Seong Park 《PloS one》2014,9(7)
Antiviral drugs are being used for therapeutic purposes against influenza illness in humans. However, antiviral-resistant variants often nullify the effectiveness of antivirals. Combined medications, as seen in the treatment of cancers and other infectious diseases, have been suggested as an option for the control of antiviral-resistant influenza viruses. Here, we evaluated the therapeutic value of combination therapy against oseltamivir-resistant 2009 pandemic influenza H1N1 virus infection in DBA/2 mice. Mice were treated for five days with favipiravir and peramivir starting 4 hours after lethal challenge. Compared with either monotherapy, combination therapy saved more mice from viral lethality and resulted in increased antiviral efficacy in the lungs of infected mice. Furthermore, the synergism between the two antivirals, which was consistent with the survival outcomes of combination therapy, indicated that favipiravir could serve as a critical agent of combination therapy for the control of oseltamivir-resistant strains. Our results provide new insight into the feasibility of favipiravir in combination therapy against oseltamivir-resistant influenza virus infection. 相似文献
972.
Eun Sun Yang Myoung Uk Jin Jae Hyun Hong Yun Sook Kim So Young Choi Tae Heon Kim Yi Sul Cho Yong Chul Bae 《PloS one》2014,9(10)
Background
There is increasing evidence that peripheral glutamate signaling mechanism is involved in the nociceptive transmission during pathological conditions. However, little is known about the glutamate signaling mechanism and related specific type of vesicular glutamate transporter (VGLUT) in the dental pulp following inflammation. To address this issue, we investigated expression and protein levels of VGLUT1 and VGLUT2 in the dental pulp and trigeminal ganglion (TG) following complete Freund’s adjuvant (CFA) application to the rat dental pulp by light microscopic immunohistochemistry and Western blot analysis.Results
The density of VGLUT2− immunopositive (+) axons in the dental pulp and the number of VGLUT2+ soma in the TG increased significantly in the CFA-treated group, compared to control group. The protein levels of VGLUT2 in the dental pulp and TG were also significantly higher in the CFA-treated group than control group by Western blot analysis. The density of VGLUT1+ axons in the dental pulp and soma in the TG remained unchanged in the CFA-treated group.Conclusions
These findings suggest that glutamate signaling that is mediated by VGLUT2 in the pulpal axons may be enhanced in the inflamed dental pulp, which may contribute to pulpal axon sensitization leading to hyperalgesia following inflammation. 相似文献973.
Ji-Hyun Yun Yong-Joon Cho Jongsik Chun Dong-Wook Hyun Jin-Woo Bae 《Standards in genomic sciences》2014,9(3):495-504
Leucobacter salsicius M1-8T is a member of the Microbacteriaceae family within the class Actinomycetales. This strain is a Gram-positive, rod-shaped bacterium and was previously isolated from a Korean fermented food. Most members of the genus Leucobacter are chromate-resistant and this feature could be exploited in biotechnological applications. However, the genus Leucobacter is poorly characterized at the genome level, despite its potential importance. Thus, the present study determined the features of Leucobacter salsicius M1-8T, as well as its genome sequence and annotation. The genome comprised 3,185,418 bp with a G+C content of 64.5%, which included 2,865 protein-coding genes and 68 RNA genes. This strain possessed two predicted genes associated with chromate resistance, which might facilitate its growth in heavy metal-rich environments. 相似文献
974.
Juwon Park Eun-Kyung Bae Chansu Lee Jee-Hye Choi Woo June Jung Kwang-Sung Ahn Sung-Soo Yoon 《BMB reports》2014,47(5):274-279
Bortezomib has been known as the most promising anti-cancer drug for multiple myeloma (MM). However, recent studies reported that not all MM patients respond to bortezomib. To overcome such a stumbling-block, studies are needed to clarify the mechanisms of bortezomib resistance. In this study, we established a bortezomib-resistant cell line (U266/velR), and explored its biological characteristics. The U266/velR showed reduced sensitivity to bortezomib, and also showed crossresistance to the chemically unrelated drug thalidomide. U266/velR cells had a higher proportion of CD138 negative subpopulation, known as stem-like feature, compared to parental U266 cells. U266/velR showed relatively less inhibitory effect of prosurvival NF-κB signaling by bortezomib. Further analysis of RNA microarray identified genes related to ubiquitination that were differentially regulated in U266/velR. Moreover, the expression level of CD52 in U266 cells was associated with bortezomib response. Our findings provide the basis for developing therapeutic strategies in bortezomib-resistant relapsed and refractory MM patients. [BMB Reports 2014; 47(5): 274-279] 相似文献
975.
Jin Young Im Woo-Kie Min Min Hee Park NamOh Kim Jong Kil Lee Hee Kyung Jin Je-Yong Choi Shin-Yoon Kim Jae-sung Bae 《BMB reports》2014,47(8):439-444
Inhibition of an increase of osteoclasts has become the most important treatment for osteoporosis. The CXCR4 antagonist, AMD3100, plays an important role in the mobilization of osteoclast precursors within bone marrow (BM). However, the actual therapeutic impact of AMD3100 in osteoporosis has not yet been ascertained. Here we demonstrate the therapeutic effect of AMD3100 in the treatment of ovariectomy-induced osteoporosis in mice. We found that treatment with AMD3100 resulted in direct induction of release of SDF-1 from BM to blood and mobilization of hematopoietic stem/progenitor cells (HSPCs) in an osteoporosis model. AMD3100 prevented bone density loss after ovariectomy by mobilization of HSPCs, suggesting a therapeutic strategy to reduce the number of osteoclasts on bone surfaces. These findings support the hypothesis that treatment with AMD3100 can result in efficient mobilization of HSPCs into blood through direct blockade of the SDF-1/CXCR4 interaction in BM and can be considered as a potential new therapeutic intervention for osteoporosis. [BMB Reports 2014; 47(8): 439-444] 相似文献
976.
S-H Lee J-Y Lee C L Jung I H Bae K H Suh Y G Ahn D-H Jin T W Kim Y-A Suh S J Jang 《Cell death & disease》2014,5(10):e1477
In the effort to develop an efficient chemotherapy drug for the treatment of non-small-cell lung cancer (NSCLC), we analyzed the anti-tumorigenic effects of a novel small molecule targeting the inhibitor of apoptosis (IAPs), HM90822B, on NSCLC cells. HM90822B efficiently decreased IAP expression, especially that of XIAP and survivin, in several NSCLC cells. Interestingly, cells overexpressing epidermal growth factor receptor (EGFR) due to the mutations were more sensitive to HM90822B, undergoing cell cycle arrest and apoptosis when treated. In xenograft experiments, inoculated EGFR-overexpressing NSCLC cells showed tumor regression when treated with the inhibitor, demonstrating the chemotherapeutic potential of this agent. Mechanistically, decreased levels of EGFR, Akt and phospho-MAPKs were observed in inhibitor-treated PC-9 cells on phosphorylation array and western blotting analysis, indicating that the reagent inhibited cell growth by preventing critical cell survival signaling pathways. In addition, gene-specific knockdown studies against XIAP and/or EGFR further uncovered the involvement of Akt and MAPK pathways in HM90822B-mediated downregulation of NSCLC cell growth. Together, these results support that HM90822B is a promising candidate to be developed as lung tumor chemotherapeutics by targeting oncogenic activities of IAP together with inhibiting cell survival signaling pathways.Resistance to apoptosis is a hallmark of many solid tumors, including lung cancer, and is, therefore, an important target mechanism for controlling cancer proliferation. The inhibitor of apoptosis (IAP) is a family of proteins containing one or more conserved cysteine and histidine-rich baculoviral IAP repeat (BIR) in their N-terminal domains and a C-terminal RING (really interesting new gene) domain. The BIR domains of IAPs form zinc figure-like structures that bind to active caspases to block caspase activity, while the RING domain acts as an ubiquitin ligase to facilitate proteasome degradation of caspases. Several IAPs have been identified in mammals, including X-linked IAP (XIAP), cellular IAP-1 and -2 (cIAP-1 and cIAP-2) and survivin. Among these IAP proteins, XIAP is a central regulator of both the death receptor- and mitochondria-mediated apoptosis pathways. Consistent with their role in the inhibition of apoptosis, XIAP and survivin are highly expressed in a diverse array of tumors and are often associated with resistance to apoptosis and low sensitivity to chemotherapy drugs in some tumor types.1, 2, 3Recent studies have shown that inhibition of the expression level or function of survivin and/or XIAP with anti-sense RNA, short interfering RNA (siRNA), dominant-negative mutants, or small molecules induces apoptotic cell death in tumor cells but not in normal cells.4 Several chemical IAP antagonists, such as AT-406, LCL-161, GDC-0152, TL-32711, LBW242 and HGS-1029, which mimic the interactions of IAP proteins with secondary mitochondria-derived activator of caspase (SMAC) N-terminal peptide (an endogenous antagonist of IAP proteins), have been developed and are currently being evaluated in clinical settings.5, 6, 7, 8 The elucidation of the mechanism of antagonism and identification of biomarkers that indicate apoptotic cell death in tumors are key issues in the development of IAP antagonists. As such, the role of IAPs in regulating the apoptotic response and as molecular targets for achieving selective therapeutic effects in tumor cells has attracted great attention in an effort to identify peptide antagonists or small-molecule inhibitors.Lung cancer is the leading cause of cancer-related death worldwide, with more than one million mortalities each year. Almost 85% of all lung cancer cases are diagnosed as non-small-cell lung cancers (NSCLC), which are further classified histologically as adenocarcinoma, squamous cell carcinoma or large cell carcinoma. Platinum-based chemotherapy represents the recommended standard first-line systemic treatment for advanced NSCLC, although the results of this approach are limited to a modest increase in survival rates. Epidermal growth factor receptor (EGFR) is often hyper-activated in many lung cancers due to the presence of a mutation in the kinase domain, causing the activation of multiple cell survival signals, especially Akt and mitogen-activated protein kinase (MAPK) pathways. This finding has led to the development of targeted therapeutics against the kinase, such as erlotinib and gefitinib, which becomes one of the most promising strategies for cancer treatment. The targeted therapeutics has often failed, however, due to the development of resistance through multiple mechanisms, indicating that additional adjuvants are necessary to achieve effective results.In this study, we investigated the therapeutic potential of HM90822B, originally synthesized to inhibit IAP activity, on NSCLC cells and in a xenograft mouse model and analyzed the cellular effects of the drug to elucidate its mechanism of action. Our results showed that HM90822B inhibits cell growth resulting in cell cycle arrest and apoptosis by targeting XIAP and survivin in conjunction with the inhibition of EGFR-MAPK pathway, primarily AKT, p38 and c-jun phosphorylation. These results indicate that the IAP inhibitor HM90822B is a promising therapeutics for the treatment of NSCLC. 相似文献
977.
To overcome the limitations of monomeric pH probes for acidic tumor environments, this study designed a mixed micelle pH probe composed of polyethylene glycol (PEG)-b-poly(l-histidine) (PHis) and PEG-b-poly(l-lactic acid) (PLLA), which is well-known as an effective antitumor drug carrier. Unlike monomeric histidine and PHis derivatives, the mixed micelles can be structurally destabilized by changes in pH, leading to a better pH sensing system in nuclear magnetic resonance (NMR) techniques. The acidic pH-induced transformation of the mixed micelles allowed pH detection and pH mapping of 0.2-0.3 pH unit differences by pH-induced "on/off"-like sensing of NMR and magnetic resonance spectroscopy. The micellar pH probes sensed pH differences in nonbiological phosphate buffer and biological buffers such as cell culture medium and rat whole blood. In addition, the pH-sensing ability of the mixed micelles was not compromised by loaded doxorubicin. In conclusion, PHis-based micelles could have potential as a tool to simultaneously treat and map the pH of solid tumors in vivo. 相似文献
978.
Chanhyung Bae Jeet Kalia Inhye Song JeongHeon Yu Ha Hyung Kim Kenton J. Swartz Jae Il Kim 《PloS one》2012,7(12)
A unique peptide toxin, named double-knot toxin (DkTx), was recently purified from the venom of the tarantula Ornithoctonus huwena and was found to stably activate TRPV1 channels by targeting the outer pore domain. DkTx has been shown to consist of two inhibitory cysteine-knot (ICK) motifs, referred to as K1 and K2, each containing six cysteine residues. Beyond this initial characterization, however, the structural and functional details about DkTx remains elusive in large part due to the lack of a high yielding methodology for the synthesis and folding of this cysteine-rich peptide. Here, we overcome this obstacle by generating pure DkTx in quantities sufficient for structural and functional analyses. Our methodology entails expression of DkTx in E. coli followed by oxidative folding of the isolated linear peptide. Upon screening of various oxidative conditions for optimizing the folding yield of the toxin, we observed that detergents were required for efficient folding of the linear peptide. Our synthetic DkTx co-eluted with the native toxin on HPLC, and irreversibly activated TRPV1 in a manner identical to native DkTx. Interestingly, we find that DkTx has two interconvertible conformations present in a 1∶6 ratio at equilibrium. Kinetic analysis of DkTx folding suggests that the K1 and K2 domains influence each other during the folding process. Moreover, the CD spectra of the toxins shows that the secondary structures of K1 and K2 remains intact even after separating the two knots. These findings provide a starting point for detailed studies on the structural and functional characterization of DkTx and utilization of this toxin as a tool to explore the elusive mechanisms underlying the polymodal gating of TRPV1. 相似文献
979.
Clonorchis sinensis is a carcinogenic human liver fluke. The present study monitored eggs produced by long-term maintained adult worms of C. sinensis to confirm their egg productivity in vitro. The worms from infected rabbits were incubated in vitro in 1× Locke’s solution and broth media (RPMI-1640, DMEM and IMDM). Numbers of expelled eggs were counted sequentially and their morphological changes were monitored by microscopy after 1, 30, 60, and 90 days of cultivation. On the 1–3 days of cultivation, the eggs counted maximum 4,756±202 eggs/worm/day in IMDM medium. The number of eggs gradually decreased less than 1,000 at 7–14 days and below 100 at 21days but continued to pass eggs after 56 days in all media. Length of the eggs were reduced about 1 µm at 30 days, and the length/width ratio was maintained around 1.8 at 30 days but decreased to 1.7 at 60 days and 1.5 at 90 days. Faust-Meleney index (FMI) decreased as the cultivation duration increased and lowest FMI (5662.9±974.7) observed in IMDM media at day 90 (P = 0.001). Microscopic findings of the eggs recognized the miracidium in most of eggs at 60 days but not in those at 90 days. Instead, the eggs contained dark granules or vacuoles in the deformed shell at 90 days. Scanning electron microscopy revealed partial loss of wrinkles on the deformed egg surface and prominent abopercular knob. Eggs viability decreased as the cultivation progressed and showed significant positive correlation with FMI and length/width ratio. In conclusion, the cultivated worms pass only the eggs which are preformed in their uterus before cultivation. One gravid C. sinensis contains about 37,000 eggs in its uterus and produces about 4,000 eggs every day. The deformed eggs with FMI less than 7,000 and length/width ratio lower than 1.7 are non-viable. 相似文献
980.
Kyu Yun Jang Yo Na Kim Jun Sang Bae Myoung Ja Chung Woo Sung Moon Myoung Jae Kang Dong Geun Lee Ho Sung Park 《Translational oncology》2012,5(5):370-378