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Targeting Non-proteolytic Protein Ubiquitination for the Treatment of Diffuse Large B Cell Lymphoma
Yang, Y.,Kelly, P.,Shaffer, A.L.,Schmitz, R.,Yoo, H.M.,Liu, X.,Huang, D.W.,Webster, D.,Young, R.M.,Nakagawa, M.,Ceribelli, M.,Wright, G.W.,Yang, Y.,Zhao, H.,Yu, X.,Xu, W.,Chan, W.C.,Jaffe, E.S.,Gascoy Cell Press 2016 CANCER CELL Vol.29 No.4
Chronic active B cell receptor (BCR) signaling, a hallmark of the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), engages the CARD11-MALT1-BCL10 (CBM) adapter complex to activate IκB kinase (IKK) and the classical NF-κB pathway. Here we show that the CBM complex includes the E3 ubiquitin ligases cIAP1 and cIAP2, which are essential mediators of BCR-dependent NF-κB activity in ABC DLBCL. cIAP½ attach K63-linked polyubiquitin chains on themselves and on BCL10, resulting in the recruitment of IKK and the linear ubiquitin chain ligase LUBAC, which is essential for IKK activation. SMAC mimetics target cIAP½ for destruction, and consequently suppress NF-κB and selectively kill BCR-dependent ABC DLBCL lines, supporting their clinical evaluation in patients with ABC DLBCL.
Zhao, Z.L.,Kim, S.C.,Zhang, J.,Liu, H.F.,Lee, B.H.,Jang, E.Y.,Lee, C.W.,Cho, I.J.,An, W.G.,Yang, C.H.,Kim, Y.W.,Zhao, R.J.,Wu, Y.Y. Elsevier Science B.V., Amsterdam 2016 JOURNAL OF ACUPUNCTURE AND MERIDIAN STUDIES Vol.9 No.1
A previous study demonstrated that acupuncture at ST36 (Zu-San-Li) attenuates ethanol withdrawal (EW)-induced hyperactivation of the hypothalamic-pituitary-adrenal axis in rats. The current study investigated the involvement of hypothalamic norepinephrine (NE) in that process. Rats were intraperitoneally treated with 3 g/kg/d of ethanol or saline for 28 days. After 24 hours of EW, acupuncture was applied to rats at bilateral ST36 points or at nonacupoints (tail) for 1 minute. A high-performance liquid chromatography analysis showed that EW significantly increased both the NE and the 3-methoxy-4-hydroxy-phenylglycol (MHPG) levels in the hypothalamic paraventricular nucleus (PVN). Western blot analysis also revealed that EW markedly elevated the phosphorylation rates of tyrosine hydroxylase (TH), but spared TH protein expression in the PVN. However, acupuncture at ST36, but not at nonacupoints, greatly inhibited the increase in the hypothalamic NE, MHPG, and phosphorylation rates of TH. Additionally, postacupuncture infusion of NE into the PVN significantly attenuated the inhibitory effects of acupuncture at ST36 on the oversecretion of plasma corticosterone during EW. These results suggest that acupuncture at ST36 inhibits EW-induced hyperactivation of the hypothalamic NEergic system to produce therapeutic effects on the hypothalamic-pituitary-adrenal axis.
Zhao, Jian,Wu, Hui,Khosravi, Melanie,Cui, Huijuan,Qian, Xiaoxia,Kelly, Jennifer A.,Kaufman, Kenneth M.,Langefeld, Carl D.,Williams, Adrienne H.,Comeau, Mary E.,Ziegler, Julie T.,Marion, Miranda C.,Adl Public Library of Science 2011 PLoS genetics Vol.7 No.5
<▼1><P>Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the <I>CFH</I>-<I>CFHRs</I> region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic <I>CFH</I> SNP (rs6677604, in intron 11, <I>P</I><SUB>meta</SUB> = 6.6×10<SUP>−8</SUP>, OR = 1.18) and an intergenic SNP between <I>CFHR1</I> and <I>CFHR4</I> (rs16840639, <I>P</I><SUB>meta</SUB> = 2.9×10<SUP>−7</SUP>, OR = 1.17) rather than to previously identified disease-associated <I>CFH</I> exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ∼146 kb block extending from intron 9 of <I>CFH</I> to downstream of <I>CFHR1</I>. Within this block, the deletion of <I>CFHR3</I> and <I>CFHR1</I> (<I>CFHR3-1</I>Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of <I>CFHR3-1</I>Δ (<I>P</I><SUB>meta</SUB> = 3.2×10<SUP>−7</SUP>, OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (<I>P</I><SUB>meta</SUB> = 3.5×10<SUP>−4</SUP>, OR = 1.14). These results suggested that the <I>CFHR3-1</I>Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of <I>CFH</I>, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE.</P></▼1><▼2><P><B>Author Summary</B></P><P>Systemic lupus erythematosus (SLE) is a complex autoimmune disease, associated with increased complement activation. Previous studies have provided evidence for the presence of SLE susceptibility gene(s) in the chromosome 1q31-32 locus. Within 1q32, genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) may contribute to the development of SLE, because genetic variants of these genes impair complement regulation and predispose to various human diseases. In this study, we tested association of genetic variants in the region containing <I>CFH</I> and <I>CFHRs</I> with SLE. We identified genetic variants predisposing to SLE in European American, African American, and Asian populations, which might be attributed to the deletion of <I>CFHR3</I> and <I>CFHR1</I> genes but not previously identified disease-associated exonic variants of <I>CFH</I>. This study provides the first evidence for consistent association between <I>CFH/CFHRs</I> and SLE across multi-ancestral SLE datasets, providing new insights into the role of complement regulators in the pathogenesis of SLE.</P></▼2>
Zhao, J.,Harper, A.F.,Webb, K.E. Jr.,Kuehn, L.A.,Gilbert, E.,Xiao, X.,Wong, E.A. Asian Australasian Association of Animal Productio 2008 Animal Bioscience Vol.21 No.12
Cytokines play a central role in the mucosal immune response and are involved in regulation of nutrient absorption, metabolism and animal growth. This study investigated the effect of diet manipulation with specialized protein or peptide sources on expression of cytokine (IL-1, IL-6, IL-10, and TNF-${\alpha}$) mRNA abundance in different intestinal regions and at different ages post-weaning in piglets. A total of 48 (17 days of age, $6.16{\pm}0.34kg\;BW$) weanling pigs were fed either a corn-soy/whey protein basal diet, the basal diet supplemented with spray-dried plasma protein (SDPP), or the basal diet supplemented with $Peptiva^{(R)}$, a hydrolyzed marine plant protein. A fourth treatment group was fed the SDPP diet, but the feed intake level was limited (SDPP-LF). Pigs were killed at 3 and 10 d, and intestinal cytokine mRNA was measured by real-time PCR using the relative quantification method. The SDPP-LF group exhibited an increased TNF-${\alpha}$ mRNA abundance compared with the ad libitum SDPP group (p<0.05). The TNF-${\alpha}$ and IL-10 mRNA abundance increased from the proximal to distal part of the intestine, and the mRNA abundance was greater (p<0.01) in the distal intestine as compared with the proximal and middle intestine. The cytokines IL-1-${\beta}$, IL-10 and TNF-${\alpha}$ mRNA abundance also increased from d3 to d10 postweaning (p<0.01). In summary, restricted feeding increased the TNF-${\alpha}$ mRNA abundance in the small intestine, however neither SDPP nor peptide supplementation affected cytokine mRNA expression. Abundance of mRNA for most cytokines examined in this study increased with age post-weaning, suggesting that during 10 d after weaning the mucosal immune system is still under development.
Lee, E.K.,Kim, S.Y.,Noh, K.W.,Joo, E.H.,Zhao, B.,Kieff, E.,Kang, M.S. Elsevier/North-Holland 2014 ANTIVIRAL RESEARCH Vol.104 No.-
The replication and persistence of extra chromosomal Epstein-Barr virus (EBV) episome in latently infected cells are primarily dependent on the binding of EBV-encoded nuclear antigen 1 (EBNA1) to the cognate EBV oriP element. In continuation of the previous study, herein we characterized EBNA1 small molecule inhibitors (H20, H31) and their underlying inhibitory mechanisms. In silico docking analyses predicted that H20 fits into a pocket in the EBNA1 DNA binding domain (DBD). However, H20 did not significantly affect EBNA1 binding to its cognate sequence. A limited structure-relationship study of H20 identified a hydrophobic compound H31, as an EBNA1 inhibitor. An in vitro EBNA1 EMSA and in vivo EGFP-EBNA1 confocal microscopy analysis showed that H31 inhibited EBNA1-dependent oriP sequence-specific DNA binding activity, but not sequence-nonspecific chromosomal association. Consistent with this, H31 repressed the EBNA1-dependent transcription, replication, and persistence of an EBV oriP plasmid. Furthermore, H31 induced progressive loss of EBV episome. In addition, H31 selectively retarded the growth of EBV-infected LCL or Burkitt's lymphoma cells. These data indicate that H31 inhibition of EBNA1-dependent DNA binding decreases transcription from and persistence of EBV episome in EBV-infected cells. These new compounds might be useful probes for dissecting EBNA1 functions in vitro and in vivo.
Zhao, Yang,Wang, Jingwen,Tanaka, Tsutomu,Hosono, Akihiro,Ando, Ryosuke,Soeripto, Soeripto,Triningsih, F.X. Ediati,Triono, Tegu,Sumoharjo, Suwignyo,Astuti, E.Y. Wenny,Gunawan, Stephanus,Tokudome, Shink Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.4
Background: Helicobacter pylori is an important gastrointestinal pathogen related to the development of not only atrophic gastritis and peptic ulcer, but also gastric cancer. Human leukocyte antigens (HLA) may play particular roles in host immune responses to bacterial antigens. This study aimed to investigate the association between HLA-DQA1 and DQB1 genotypes and haplotypes vs H. pylori infection in an Indonesian population. Methods: We selected 294 healthy participants in Mataram, Lombok Island, Indonesia. H. pylori infection was determined by urea breath test (UBT). We analyzed HLA-DQA1 and DQB1 genotypes by PCR-RFLP and constructed haplotypes of HLA-DQA1 and DQB1 genes. Multiple comparisons were conducted according to the Bonferroni method. Results: The H. pylori infection rate was 11.2% in this Indonesian population. The DQB1*0401 genotype was noted to be associated with a high risk of H. pylori infection, compared with the DQB1*0301 genotype. None of the HLA-DQA1 or DQB1 haplotypes were related to the risk of H. pylori infection. Conclusions: The study suggests that HLADQB1 genes play important roles in H. pylori infection, but there was no statistically significant association between HLA-DQA1 or DQB1 haplotypes and H.pylori infection in our Lombok Indonesian population.
Effects of (−)-Sesamin on Chronic Stress-Induced Anxiety Disorders in Mice
Zhao, T. T.,Shin, K. S.,Park, H. J.,Yi, B. R.,Lee, K. E.,Lee, M. K. Springer Science + Business Media 2017 Neurochem Res Vol.42 No.4
<P>This study investigated the effects of (-)-sesamin on chronic electric footshock (EF) stress-induced anxiety disorders in mice. Mice were treated with (-)-sesamin (25 and 50 mg/kg) orally once a day for 21 days prior to exposure to EF stress (0.6 mA, 1 s every 5 s, 3 min). Mice treated with (-)-sesamin (25 and 50 mg/kg) exhibited less severe decreases in the number of open arm entries and time spent on open arms in the elevated plus-maze test and the distance traveled in the open field test following exposure to chronic EF stress. Similarly, mice treated with (-)-sesamin exhibited significantly less severe decreases in brain levels of dopamine, norepinephrine, and serotonin following exposure to chronic EF stress. Increases in serum levels of corticosterone and expression of c-Fos were also less pronounced in mice treated with (-)-sesamin (25 and 50 mg/kg). These results suggest that (-)-sesamin may protect against the effects of chronic EF stress-induced anxiety disorders by modulating dopamine, norepinephrine, and serotonin levels, c-Fos expression, and corticosterone levels.</P>