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20(S)-ginsenoside Rh2 ameliorates ATRA resistance in APL by modulating lactylation-driven METTL3
Siyu Cheng,Langqun Chen,Jiahui Ying,Ying Wang,Wenjuan Jiang,Qi Zhang,Hong Zhang,Jiahe Wang,Chen Wang,Huimin Wu,Jing Ye,Liang Zhang 고려인삼학회 2024 Journal of Ginseng Research Vol.48 No.3
Background: 20(S)-ginsenoside Rh2(GRh2), an effective natural histone deacetylase inhibitor, can inhibit acute myeloid leukemia (AML) cell proliferation. Lactate regulated histone lactylation, which has different temporal dynamics from acetylation. However, whether the high level of lactylation modification that we first detected in acute promyelocytic leukemia (APL) is associated with all-trans retinoic acid (ATRA) resistance has not been reported. Furthermore, Whether GRh2 can regulate lactylation modification in ATRA-resistant APL remains unknown. Methods: Lactylation and METTL3 expression levels in ATRA-sensitive and ATRA-resistant APL cells were detected by Western blot analysis, qRT-PCR and CO-IP. Flow cytometry (FCM) and APL xenograft mouse models were used to determine the effect of METTL3 and GRh2 on ATRA-resistance. Results: Histone lactylation and METTL3 expression levels were considerably upregulated in ATRA-resistant APL cells. METTL3 was regulated by histone lactylation and direct lactylation modification. Overexpression of METTL3 promoted ATRA-resistance. GRh2 ameliorated ATRA-resistance by downregulated lactylation level and directly inhibiting METTL3. Conclusions: This study suggests that lactylation-modified METTL3 could provide a promising strategy for ameliorating ATRA-resistance in APL, and GRh2 could act as a potential lactylation-modified METTL3 inhibitor to ameliorate ATRA-resistance in APL.
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Wang, Shuaifei,Li, Fangyuan,Qiao, Ruirui,Hu, Xi,Liao, Hongwei,Chen, Lumin,Wu, Jiahe,Wu, Haibin,Zhao, Meng,Liu, Jianan,Chen, Rui,Ma, Xibo,Kim, Dokyoon,Sun, Jihong,Davis, Thomas P.,Chen, Chunying,Tian, American Chemical Society 2018 ACS NANO Vol.12 No.12
<P>Ferroptosis, an iron-based cell-death pathway, has recently attracted great attention owing to its effectiveness in killing cancer cells. Previous investigations focused on the development of iron-based nanomaterials to induce ferroptosis in cancer cells by the up-regulation of reactive oxygen species (ROS) generated by the well-known Fenton reaction. Herein, we report a ferroptosis-inducing agent based on arginine-rich manganese silicate nanobubbles (AMSNs) that possess highly efficient glutathione (GSH) depletion ability and thereby induce ferroptosis by the inactivation of glutathione-dependent peroxidases 4 (GPX4). The AMSNs were synthesized <I>via</I> a one-pot reaction with arginine (Arg) as the surface ligand for tumor homing. Subsequently, a significant tumor suppression effect can be achieved by GSH depletion-induced ferroptosis. Moreover, the degradation of AMSNs during the GSH depletion contributed to <I>T</I><SUB>1</SUB>-weighted magnetic resonance imaging (MRI) enhancement as well as on-demand chemotherapeutic drug release for synergistic cancer therapy. We anticipate that the GSH-depletion-induced ferroptosis strategy by using manganese-based nanomaterials would provide insights in designing nanomedicines for tumor-targeted theranostics.</P> [FIG OMISSION]</BR>
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Genetically predicted physical activity is associated with lower serum urate concentrations
Guan Ying,Wei Jiahe,Meng Lifeng,Li Yasong,Wang Tianle,Chen Dingwan,Qian Qilin 한국유전학회 2022 Genes & Genomics Vol.44 No.7
Background: Physical activity (PA) is considered to play an important role in the reduced gout risk. However, the epidemiology results are inconsistent and causality remains unclear. Objective: To investigate the causal relationship of PA with serum urate concentrations and gout risk by a bidirectional Mendelian randomization (MR) approach. Method: Two genome-wide association studies (GWASs) from UK Biobank were used to identify instrumental variables for self-reported moderate-to-vigorous PA (including 377,234 European individuals), accelerometer-measured 'average acceleration' PA (including 91,084 European individuals) and accelerometer-measured overall PA (including 91,105 European individuals). The summary data for serum urate (including 110,347 European individuals) and gout (including 2,115 cases and 67,259 controls) were derived from GWAS of Global Urate Genetics Consortium. Moreover, reverse direction Mendelian randomization study was conducted. The inverse-variance weighted, weighted median, Mendelian randomization Egger regression, simple mode and weighted mode and Mendelian Randomization Pleiotropy RESidual Sum and Outlier were methods we performed. Result: Genetic predisposition to accelerometer-measured 'average acceleration' PA [beta = -0.038; 95% confidence interval (CI) = -0.060,-0.015; P = 0.001] and accelerometer-measured overall PA (beta = -0.339; 95% CI = -0.522,-0.156; P = 2.8E-4) were significantly associated with decreased serum urate concentrations. Besides, there was no evidence supporting the causal association between PA and gout risk. In the reverse direction analysis, genetic predisposition to both urate and gout were not associated with PA being investigated. Conclusions: In MR study, we found that PA may reduce serum urate concentrations but not the risk of gout. Moreover, serum urate concentrations and gout were not associated with PA.
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Hu, Xi,Sun, Jihong,Li, Fangyuan,Li, Ruiqing,Wu, Jiahe,He, Jie,Wang, Nan,Liu, Jianan,Wang, Shuaifei,Zhou, Fei,Sun, Xiaolian,Kim, Dokyoon,Hyeon, Taeghwan,Ling, Daishun American Chemical Society 2018 Nano letters Vol.18 No.2
<P>Although metallic nanomaterials with high X-ray attenuation coefficients have been widely used as X-ray computed tomography (CT) contrast agents, their intrinsically poor biodegradability requires them to be cleared from the body to avoid any potential toxicity. On the other hand, extremely small-sized nanomaterials with outstanding renal clearance properties are not much effective for tumor targeting because of their too rapid clearance in vivo. To overcome this dilemma, here we report on the hollow bismuth subcarbonate nanotubes (BNTs) assembled from renal-clearable ultrasmall bismuth subcarbonate nanoclusters for tumor-targeted imaging and chemoradiotherapy. The BNTs could be targeted to tumors with high efficiency and exhibit a high CT contrast effect. Moreover, simultaneous radio- and chemotherapy using drug-loaded BNTs could significantly suppress tumor volumes, highlighting their potential application in CT imaging-guided therapy. Importantly, the elongated nanotubes could be disassembled into isolated small nanoclusters in the acidic tumor microenvironment, accelerating the payload release and kidney excretion. Such body clearable CT contrast agent with high imaging performance and multiple therapeutic functions shall have a substantial potential for biomedical applications.</P>
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