122 results on '"Rongzhen Xu"'
Search Results
2. Research on in-situ test of lake evaporation in the Baiyangdian Lake
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Xiaoyan WANG, Dechao YIN, Yushan WANG, Bin WU, Yonghui AN, Rongzhen XU, Xi WANG, and Yun LIU
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lake evaporation ,in-situ test ,e601 evaporation station ,20 m2 evaporation pool ,baiyangdian lake ,Geology ,QE1-996.5 - Abstract
The Baiyangdian Lake is located in Xiongan New Area, which has a fragile ecological environment and a shortage of water resources. Lake evaporation is one of the main discharge of the Baiyangdian Lake, and research on lake evaporation is of important practical significance and scientific value for understanding lake water circulation and evaluating ecological water demand and for recovery of lake ecological function. However, the actual observed data on evaporation in the Baiyangdian Lake is limited, so it is usually estimated by converting the data of nearby land observation stations or empirical models, which cannot accurately estimate the lake evaporation because of large calculation error. In this work, in-situ experiments were carried out in the Baiyangdian Lake. This study established an E601 evaporation station and a 20 m2 evaporation pool to observe the lake evaporation at the center of the Baiyangdian Lake, and an automatic weather station was established simultaneously to get meteorological data. The correlation between evaporation by E601 evaporation station and meteorological factors is analyzed by methods of correlation analysis and multiple linear regression model. The evaporation of the E601 evaporation station is compared with the data of the 20 m2 evaporation pool and the simulated evaporation. The results indicate that in the Baiyangdian Lake in summer, the diurnal variation of lake evaporation is intense, ranging from 0.4 mm/d to 6.6 mm/d, and the maximum evaporation occurs in June, but decreases with the increasing rainfall from July to August. Evaporation of lake water is more affected by radiation and humidity. The evaporation of 20 m2 evaporation pool is taken as the evaporation of lake water. The observed evaporation of E601 evaporation station is higher than the actual evaporation of Baiyangdian Lake, which can be used to estimate lake evaporation more accurately by local evaporation conversion coefficient. In this experiment, the evaporation conversion coefficient between the 20 m2 evaporation pool and the E601 evaporation station is about 0.98, which is slightly greater than the previous studies. The results of this study provides a basic basis for the calculation of water surface evaporation in the Baiyangdian area.
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- 2023
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3. An oral triple pill-based cocktail effectively controls acute myeloid leukemia with high translation
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Mengyuan Li, Shuwen Zheng, Qinyuan Gong, Haifeng Zhuang, Zhaoxing Wu, Ping Wang, Xuzhao Zhang, and Rongzhen Xu
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Acute myeloid leukemia ,HHT ,Bcl-2i ,P-gpi ,Cocktail therapy ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Acute myeloid leukemia (AML) is a deadly hematological malignancy characterized by oncogenic translational addiction that results in over-proliferation and apoptosis evasion of leukemia cells. Various chemo- and targeted therapies aim to reverse this hallmark, but most show only modest efficacy. Here we report a single oral pill containing a low-dose triple small molecule-based cocktail, a highly active anti-cancer therapy (HAACT) with unique mechanisms that can effectively control AML. The cocktail comprises oncogenic translation inhibitor HHT, drug efflux pump P-gpi ENC and anti-apoptotic protein Bcl-2i VEN. Mechanistically, the cocktail can potently kill both leukemia stem cells (LSC) and bulk leukemic cells via co-targeting oncogenic translation, apoptosis machinery, and drug efflux pump, resulting in deep and durable remissions of AML in diverse model systems. We also identified EphB4/Bcl-xL as the cocktail response biomarkers. Collectively, our studies provide proof that a single pill containing a triple combination cocktail might be a promising avenue for AML therapy.
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- 2023
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4. Inhibition of the CDK2 and Cyclin A complex leads to autophagic degradation of CDK2 in cancer cells
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Jiawei Zhang, Yichao Gan, Hongzhi Li, Jie Yin, Xin He, Liming Lin, Senlin Xu, Zhipeng Fang, Byung-wook Kim, Lina Gao, Lili Ding, Eryun Zhang, Xiaoxiao Ma, Junfeng Li, Ling Li, Yang Xu, David Horne, Rongzhen Xu, Hua Yu, Ying Gu, and Wendong Huang
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Science - Abstract
CDK2 can drive the proliferation of cancer cells. Here, the authors screened for a non-ATP competitive inhibitor of the CDK2/cylinA complex and find that Homoharringtonine can disrupt the complex and promote the degradation of CDK2.
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- 2022
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5. Unique and complementary suppression of cGAS-STING and RNA sensing- triggered innate immune responses by SARS-CoV-2 proteins
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Yajuan Rui, Jiaming Su, Si Shen, Ying Hu, Dingbo Huang, Wenwen Zheng, Meng Lou, Yifei Shi, Meng Wang, Shiqi Chen, Na Zhao, Qi Dong, Yong Cai, Rongzhen Xu, Shu Zheng, and Xiao-Fang Yu
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Medicine ,Biology (General) ,QH301-705.5 - Abstract
Abstract The emergence of SARS-CoV-2 has resulted in the COVID-19 pandemic, leading to millions of infections and hundreds of thousands of human deaths. The efficient replication and population spread of SARS-CoV-2 indicates an effective evasion of human innate immune responses, although the viral proteins responsible for this immune evasion are not clear. In this study, we identified SARS-CoV-2 structural proteins, accessory proteins, and the main viral protease as potent inhibitors of host innate immune responses of distinct pathways. In particular, the main viral protease was a potent inhibitor of both the RLR and cGAS-STING pathways. Viral accessory protein ORF3a had the unique ability to inhibit STING, but not the RLR response. On the other hand, structural protein N was a unique RLR inhibitor. ORF3a bound STING in a unique fashion and blocked the nuclear accumulation of p65 to inhibit nuclear factor-κB signaling. 3CL of SARS-CoV-2 inhibited K63-ubiquitin modification of STING to disrupt the assembly of the STING functional complex and downstream signaling. Diverse vertebrate STINGs, including those from humans, mice, and chickens, could be inhibited by ORF3a and 3CL of SARS-CoV-2. The existence of more effective innate immune suppressors in pathogenic coronaviruses may allow them to replicate more efficiently in vivo. Since evasion of host innate immune responses is essential for the survival of all viruses, our study provides insights into the design of therapeutic agents against SARS-CoV-2.
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- 2021
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6. Aberrantly Activated APOBEC3B Is Associated With Mutant p53-Driven Refractory/Relapsed Diffuse Large B-Cell Lymphoma
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Xuzhao Zhang, Zhaoxing Wu, Yuanyuan Hao, Teng Yu, Xian Li, Yun Liang, Jinfan Li, Liansheng Huang, Yang Xu, Xiuzhen Li, Xiaohua Xu, Weiqin Wang, Genbo Xu, Xiaohong Zhang, Qinghua Lv, Yongming Fang, Rongzhen Xu, and Wenbin Qian
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TP53 mutation ,APOBEC3B ,DLBCL ,refractory ,relapse ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Tumor protein 53 (TP53) mutation predicts an unfavorable prognosis in diffuse large B-cell lymphoma (DLBCL), but the molecular basis for this association remains unclear. In several malignancies, the cytidine deaminase apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) has been reported to be associated with the TP53 G/C-to-A/T mutation. Here, we show that the frequency of this mutation was significantly higher in relapsed/refractory (R/R) than in non-R/R DLBCL, which was positively associated with the APOBEC3B expression level. APOBEC3B overexpression induced the TP53 G/C-to-A/T mutation in vitro, resulting in a phenotype similar to that of DLBCL specimens. Additionally, APOBEC3B-induced p53 mutants promoted the growth of DLBCL cells and enhanced drug resistance. These results suggest that APOBEC3B is a critical factor in mutant p53-driven R/R DLBCL and is therefore a potential therapeutic target.
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- 2022
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7. Identification of Monobenzone as a Novel Potential Anti-Acute Myeloid Leukaemia Agent That Inhibits RNR and Suppresses Tumour Growth in Mouse Xenograft Model
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Jingwen Dong, Tingting Zhong, Zhijian Xu, Haiyi Chen, Xianjun Wang, Lili Yang, Zhiyuan Lou, Yuanling Xu, Tingjun Hou, Rongzhen Xu, Weiliang Zhu, and Jimin Shao
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acute myeloid leukaemia ,ribonucleotide reductase ,monobenzone ,anti-proliferative activity ,combination therapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Acute myeloid leukaemia (AML) is one of the most common types of haematopoietic malignancy. Ribonucleotide reductase (RNR) is a key enzyme required for DNA synthesis and cell proliferation, and its small subunit RRM2 plays a key role for the enzymatic activity. We predicted monobenzone (MB) as a potential RRM2 target compound based on the crystal structure of RRM2. In vitro, MB inhibited recombinant RNR activity (IC50 = 0.25 μM). Microscale thermophoresis indicated that MB inhibited RNR activity by binding to RRM2. MB inhibited cell proliferation (MTT IC50 = 6–18 μM) and caused dose-dependent DNA synthesis inhibition, cell cycle arrest, and apoptosis in AML cells. The cell cycle arrest was reversed by the addition of deoxyribonucleoside triphosphates precursors, suggesting that RNR was the intracellular target of the compound. Moreover, MB overcame drug resistance to the common AML drugs cytarabine and doxorubicin, and treatment with the combination of MB and the Bcl-2 inhibitor ABT-737 exerted a synergistic inhibitory effect. Finally, the nude mice xenografts study indicated that MB administration produced a significant inhibitory effect on AML growth with relatively weak toxicity. Thus, we propose that MB has the potential as a novel anti-AML therapeutic agent in the future.
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- 2022
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8. Homoharringtonine Combined with the Heat Shock Protein 90 Inhibitor IPI504 in the Treatment of FLT3-ITD Acute Myeloid Leukemia
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Zhaoxing Wu, Haifeng Zhuang, Qingfeng Yu, Xuzhao Zhang, Xudong Jiang, Xiaoya Lu, Ying Xu, Linlin Yang, Bowen Wu, An Ma, Lei Zhang, Xibin Xiao, Yun Liang, Ruilan Gao, Jianping Shen, and Rongzhen Xu
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
As a heterogeneous group of clonal disorders, acute myeloid leukemia with internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD) mutation usually shows an inferior prognosis. In the present study, we found that homoharringtonine (HHT), a protein translation inhibitor of plant alkaloid in China, exhibited potent cytotoxic effect against FLT3-ITD (+) cell lines and primary leukemia cells, and a remarkable synergistic anti-leukemia action was demonstrated in vitro and in vivo in xenograft mouse models when co-treated with the heat shock protein 90 inhibitor IPI504. Mechanistically, HHT combined with IPI504 synergistically inhibited the growth of leukemia cells by inducing apoptosis and G1 phase arrest. This synergistic action resulted in a prominent reduction of total and phosphorylated FLT3 (p-FLT3) as well as inhibition of its downstream signaling molecules such as STAT5, AKT, ERK and 4E-BP1. Furthermore, co-treatment of HHT and IPI504 led to a synergistic or additive effect on 55.56%(10/18) of acute myeloid leukemia cases tested, including three relapsed/refractory patients. In conclusion, our findings indicate that the combination of HHT and HSP90 inhibitor provides an alternative way for the treatment of FLT3-ITD positive acute myeloid leukemia, especially for relapsed/refractory AML.
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- 2019
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9. Natural small molecule triptonide inhibits lethal acute myeloid leukemia with FLT3-ITD mutation by targeting Hedgehog/FLT3 signaling
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Ying Xu, Ping Wang, Mengyuan Li, Zhaoxing Wu, Xian Li, Jianping Shen, and Rongzhen Xu
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FLT3-ITD-driven AML ,Triptonide ,GLI2 ,Hedgehog signaling ,FLT3 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Acute myeloid leukemia harboring internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD AML) is a subset of highly aggressive malignancies with poor clinical outcome. Despite some advances in the development of FLT3 tyrosine kinase inhibitors (FLT3 inhibitors), most of FLT3-ITD AML patients suffer from lethal disease relapse, suggesting the requirement of novel targets and agents. Here we describe a natural small molecule, triptonide that can efficiently inhibit FLT3-ITD-driven AML in vitro and in vivo. Mechanistically, triptonide targeted Hedgehog/FLT3 signaling by inhibiting its critical effectors, which are GLI2, c-Myc and FLT3 and induced apoptosis of FLT3-ITD-driven leukemia cells. In addition, we also observed that triptonide activated tumor suppressor p53. In vivo, triptonide treatment markedly suppressed lethal FLT3-ITD-driven AML with good tolerance and prolonged survival time in orthotopic mouse model. Our studies identify Hedgehog/FLT3 axis as a novel target for treating FLT3-ITD-driven leukemia and demonstrate that triptonide is an active lead compound that can kill FLT3-ITD-driven leukemia cells.
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- 2021
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10. Novel synthetic tosyl chloride-berbamine regresses lethal MYC-positive leukemia by targeting CaMKIIγ/Myc axis
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Qingfeng Yu, Ping Wang, Linlin Yang, Zhaoxing Wu, Shu Li, Ying Xu, Bowen Wu, An Ma, Xiaoxian Gan, and Rongzhen Xu
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Acute leukemia ,Tosyl chloride-berbamine ,CaMKIIγ ,MYC ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Proto-oncogene Myc, a key transcription factor, is frequently deregulated in human leukemia with aggressive and poor clinical outcome, but the development of MYC inhibitors remains challenging due to MYC helix-loop-helix topology lacking druggable domains. Here we describe a novel oral active small molecule analog of berbamine, tosyl chloride-berbamine (TCB), that efficiently eliminates MYC-positive leukemia in vitro and in vivo. Mechanistically, TCB potently reduced MYC protein by inhibiting CaMKIIγ, a critical enzyme that stabilizes MYC protein, and induces apoptosis of MYC-positive leukemia cells. In vivo, oral administration of TCB markedly eliminated lethal MYC-positive acute lymphoblastic leukemia (ALL) with well tolerability in orthotopic mouse model. Our studies identify CaMKIIγ/Myc axis as a valid target for developing small molecule-based new therapies for treating MYC-mediated leukemia and demonstrate that TCB is an orally active analog of berbamine that kills MYC-positive leukemia cells.
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- 2019
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11. A method of case adaptation for variant design integrating data mining
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Rongzhen Xu, Qi Gao, and Xinyue Li
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Mechanical engineering and machinery ,TJ1-1570 - Abstract
Case-based reasoning has proven to be a promising methodology for obtaining new mechanical products by adapting previous cases. However, case adaptation is still a bottleneck in case-based reasoning. The key issue in case adaptation is acquiring the adaptation knowledge. To realize the automation of case adaptation for variant design, a novel case adaptation method is proposed. The method consists of two parts. In the first part, a data mining technique is introduced to acquire the adaptation rules that reflect the relationship between the changes in design requirements and design results. In the second part, the most similar case is retrieved by first using the adaptation rules to weight the design requirements. Then, suitable adaptation rules are selected and used to realize the case adaptation. To validate the proposed method, two experiments are performed. The results show that our method outperforms other methods when the design requirements and design results have both numerical and categorical attributes.
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- 2017
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12. GPBAR1/TGR5 mediates bile acid-induced cytokine expression in murine Kupffer cells.
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Guiyu Lou, Xiaoxiao Ma, Xianghui Fu, Zhipeng Meng, Wenyu Zhang, Yan-Dong Wang, Carl Van Ness, Donna Yu, Rongzhen Xu, and Wendong Huang
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Medicine ,Science - Abstract
GPBAR1/TGR5 is a novel plasma membrane-bound G protein-coupled bile acid (BA) receptor. BAs are known to induce the expression of inflammatory cytokines in the liver with unknown mechanism. Here we show that without other external stimuli, TGR5 activation alone induced the expression of interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α) in murine macrophage cell line RAW264.7 or murine Kupffer cells. The TGR5-mediated increase of pro-inflammatory cytokine expression was suppressed by JNK inhibition. Moreover, the induced pro-inflammatory cytokine expression in mouse liver by 1% cholic acid (CA) diet was blunted in JNK-/- mice. TGR5 activation by its ligands enhanced the phosphorylation levels, DNA-binding and trans-activities of c-Jun and ATF2 transcription factors. Finally, the induced pro-inflammatory cytokine expression in Kupffer cells by TGR5 activation correlated with the suppression of Cholesterol 7α-hydroxylase (Cyp7a1) expression in murine hepatocytes. These results suggest that TGR5 mediates the BA-induced pro-inflammatory cytokine production in murine Kupffer cells through JNK-dependent pathway. This novel role of TGR5 may correlate to the suppression of Cyp7a1 expression in hepatocytes and contribute to the delicate BA feedback regulation.
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- 2014
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13. Expression patterns of non-coding spliced transcripts from human endogenous retrovirus HERV-H elements in colon cancer.
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Qiaoyi Liang, Zefeng Xu, Rongzhen Xu, Lijun Wu, and Shu Zheng
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Medicine ,Science - Abstract
BACKGROUND: Up-regulation of the most abundant H family human endogenous retrovirus (HERV-H), especially env-related transcripts, correlates with colon cancer. However, expression pattern of spliced non-coding transcripts of HERV-H is not clear. METHODOLOGY/PRINCIPAL FINDINGS: In this study, expression of HERV-H spliced transcripts in colon cancer was investigated by a RT-PCR strategy using primers targeting the tRNA(His) primer-binding site and the R region in the 3' long terminal repeat (LTR), followed by cloning and sequencing of the amplicons. Sequences were then assigned to individual HERV-H loci by employing private nucleotide differences between loci. Different expression patterns of HERV-H spliced transcripts from distinct active elements were found in colon cancer cell lines HT29, LS 174T, RKO, SW480 and SW620. Furthermore, the expression patterns in SW480 and RKO were significantly changed by demethylation treatment. Interestingly, more HERV-H elements were found to be transcriptionally active in colon tumor tissues than in adjacent normal tissues (14 vs. 7). CONCLUSIONS/SIGNIFICANCE: This is the first research to study the character of expression of non-coding spliced transcripts of HERV-H elements in colon cancer. Expression patterns of HERV-H spliced transcripts differed among colon cancer cell lines and could be affected by genomic DNA methylation levels. More importantly, besides the commonly accepted view of up-regulation of HERV-H expression in colon tumor tissues, we found more active HERV-H loci in colon tumor as compared with adjacent normal tissues.
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- 2012
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14. High prevalence and genetic diversity of HCV among HIV-1 infected people from various high-risk groups in China.
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Hong Shang, Ping Zhong, Jing Liu, Xiaoxu Han, Di Dai, Min Zhang, Ke Zhao, Rongzhen Xu, and Xiao-Fang Yu
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Medicine ,Science - Abstract
Co-infection with HIV-1 and HCV is a significant global public health problem and a major consideration for anti-HIV-1 treatment. HCV infection among HIV-1 positive people who are eligible for the newly launched nationwide anti-HIV-1 treatment program in China has not been well characterized.A nationwide survey of HIV-1 positive injection drug uses (IDU), former paid blood donors (FBD), and sexually transmitted cases from multiple provinces including the four most affected provinces in China was conducted. HCV prevalence and genetic diversity were determined. We found that IDU and FBD have extremely high rates of HCV infection (97% and 93%, respectively). Surprisingly, people who acquired HIV-1 through sexual contact also had a higher rate of HCV infection (20%) than the general population. HIV-1 subtype and HCV genotypes were amazingly similar among FBD from multiple provinces stretching from Central to Northeast China. However, although patterns of overland trafficking of heroin and distinct HIV-1 subtypes could be detected among IDU, HCV genotypes of IDU were more diverse and exhibited significant regional differences.Emerging HIV-1 and HCV co-infection and possible sexual transmission of HCV in China require urgent prevention measures and should be taken into consideration in the nationwide antiretroviral treatment program.
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- 2010
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15. Distinct determinants in HIV-1 Vif and human APOBEC3 proteins are required for the suppression of diverse host anti-viral proteins.
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Wenyan Zhang, Gongying Chen, Anna Maria Niewiadomska, Rongzhen Xu, and Xiao-Fang Yu
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Medicine ,Science - Abstract
BackgroundAPOBEC3G (A3G) and related cytidine deaminases of the APOBEC3 family of proteins are potent inhibitors of many retroviruses, including HIV-1. Formation of infectious HIV-1 requires the suppression of multiple cytidine deaminases by Vif. HIV-1 Vif suppresses various APOBEC3 proteins through the common mechanism of recruiting the Cullin5-ElonginB-ElonginC E3 ubiquitin ligase to induce target protein polyubiquitination and proteasome-mediated degradation. The domains in Vif and various APOBEC3 proteins required for APOBEC3 recognition and degradation have not been fully characterized.Methods and findingsIn the present study, we have demonstrated that the regions of APOBEC3F (A3F) that are required for its HIV-1-mediated binding and degradation are distinct from those reported for A3G. We found that the C-terminal cytidine deaminase domain (C-CDD) of A3F alone is sufficient for its interaction with HIV-1 Vif and its Vif-mediated degradation. We also observed that the domains of HIV-1 Vif that are uniquely required for its functional interaction with full-length A3F are also required for the degradation of the C-CDD of A3F; in contrast, those Vif domains that are uniquely required for functional interaction with A3G are not required for the degradation of the C-CDD of A3F. Interestingly, the HIV-1 Vif domains required for the degradation of A3F are also required for the degradation of A3C and A3DE. On the other hand, the Vif domains uniquely required for the degradation of A3G are dispensable for the degradation of cytidine deaminases A3C and A3DE.ConclusionsOur data suggest that distinct regions of A3F and A3G are targeted by HIV-1 Vif molecules. However, HIV-1 Vif suppresses A3F, A3C, and A3DE through similar recognition determinants, which are conserved among Vif molecules from diverse HIV-1 strains. Mapping these determinants may be useful for the design of novel anti-HIV inhibitors.
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- 2008
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16. Co‐Targeting c‐Myc and Bcl‐2 by Oral Small Molecule Combination of WBC100 and Venetoclax Effectively Controls Acute Myeloid Leukemia in Preclinical Models
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Ping Wang, Mengyuan Li, Shuwen Zheng, Haifeng Zhuang, Hong Zhou, Qinyuan Gong, Zhaoxing Wu, Xuzhao Zhang, and Rongzhen Xu
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Pharmacology ,Biochemistry (medical) ,Pharmaceutical Science ,Medicine (miscellaneous) ,Pharmacology (medical) ,Genetics (clinical) - Published
- 2023
17. Supplementary Table 3 from Berbamine Inhibits the Growth of Liver Cancer Cells and Cancer-Initiating Cells by Targeting Ca2+/Calmodulin-Dependent Protein Kinase II
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Wendong Huang, Rongzhen Xu, Yun Yen, Jun Wu, Yafan Wang, Guiyu Lou, Jinfen Tang, Hong Zhou, Yichao Gan, Carl Van Ness, Xiaoqiong Wang, Xiaoxiao Ma, Tao Li, and Zhipeng Meng
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XLSX file, 12K, Phosphorylation of CAMKII in liver cancer patients.
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- 2023
18. Supplementary Table 2 from Berbamine Inhibits the Growth of Liver Cancer Cells and Cancer-Initiating Cells by Targeting Ca2+/Calmodulin-Dependent Protein Kinase II
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Wendong Huang, Rongzhen Xu, Yun Yen, Jun Wu, Yafan Wang, Guiyu Lou, Jinfen Tang, Hong Zhou, Yichao Gan, Carl Van Ness, Xiaoqiong Wang, Xiaoxiao Ma, Tao Li, and Zhipeng Meng
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XLSX file, 11K, Sphere formation (2 independent trials).
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- 2023
19. Supplementary Figures from Berbamine Inhibits the Growth of Liver Cancer Cells and Cancer-Initiating Cells by Targeting Ca2+/Calmodulin-Dependent Protein Kinase II
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Wendong Huang, Rongzhen Xu, Yun Yen, Jun Wu, Yafan Wang, Guiyu Lou, Jinfen Tang, Hong Zhou, Yichao Gan, Carl Van Ness, Xiaoqiong Wang, Xiaoxiao Ma, Tao Li, and Zhipeng Meng
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PDF file, 1752K, Figure S1. (Related to Figure 2) BBM suppresses the xenograft growth of Huh7 and SK-Hep-1 cells; Figure S2. (Related to Figure 3) BBM is localized in cytoplasm and affects cell survival; Figure S3. (Related to Figure 4) BBM suppressed the CD133+ population in Huh7 cells; Figure S4. (Related to Figure 5B). The chemical inhibitor of CAMKII, KN93, suppresses CD133+ population in Huh7 cells; Figure S6. (Related to Figure 6C). The knockdown of CAMKIIgamma suppresses liver cancer growth.
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- 2023
20. Supplementary Figure Legends from Berbamine Inhibits the Growth of Liver Cancer Cells and Cancer-Initiating Cells by Targeting Ca2+/Calmodulin-Dependent Protein Kinase II
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Wendong Huang, Rongzhen Xu, Yun Yen, Jun Wu, Yafan Wang, Guiyu Lou, Jinfen Tang, Hong Zhou, Yichao Gan, Carl Van Ness, Xiaoqiong Wang, Xiaoxiao Ma, Tao Li, and Zhipeng Meng
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PDF file, 51K.
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- 2023
21. Supplementary Table 1 from Berbamine Inhibits the Growth of Liver Cancer Cells and Cancer-Initiating Cells by Targeting Ca2+/Calmodulin-Dependent Protein Kinase II
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Wendong Huang, Rongzhen Xu, Yun Yen, Jun Wu, Yafan Wang, Guiyu Lou, Jinfen Tang, Hong Zhou, Yichao Gan, Carl Van Ness, Xiaoqiong Wang, Xiaoxiao Ma, Tao Li, and Zhipeng Meng
- Abstract
XLSX file, 9K, IC50s of berbamine on liver cancer cells.
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- 2023
22. Unique and complementary suppression of cGAS-STING and RNA sensing- triggered innate immune responses by SARS-CoV-2 proteins
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Jiaming Su, Shu Zheng, Meng Lou, Yifei Shi, Qi Dong, Yajuan Rui, Dingbo Huang, Si Shen, Meng Wang, Na Zhao, Wenwen Zheng, Rongzhen Xu, Xiao-Fang Yu, Yong Cai, Shiqi Chen, and Ying Hu
- Subjects
0301 basic medicine ,Cancer Research ,viruses ,Population ,lcsh:Medicine ,Biology ,Microbiology ,Article ,law.invention ,Ligases ,Mice ,Viral Proteins ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,law ,Immunity ,Genetics ,Animals ,Humans ,education ,lcsh:QH301-705.5 ,education.field_of_study ,Innate immune system ,SARS-CoV-2 ,HEK 293 cells ,lcsh:R ,Membrane Proteins ,RNA ,biochemical phenomena, metabolism, and nutrition ,Nucleotidyltransferases ,Immunity, Innate ,Cell biology ,Sting ,HEK293 Cells ,030104 developmental biology ,lcsh:Biology (General) ,A549 Cells ,RNA, Viral ,Infectious diseases ,Suppressor ,Chickens ,030217 neurology & neurosurgery ,HeLa Cells ,Signal Transduction - Abstract
The emergence of SARS-CoV-2 has resulted in the COVID-19 pandemic, leading to millions of infections and hundreds of thousands of human deaths. The efficient replication and population spread of SARS-CoV-2 indicates an effective evasion of human innate immune responses, although the viral proteins responsible for this immune evasion are not clear. In this study, we identified SARS-CoV-2 structural proteins, accessory proteins, and the main viral protease as potent inhibitors of host innate immune responses of distinct pathways. In particular, the main viral protease was a potent inhibitor of both the RLR and cGAS-STING pathways. Viral accessory protein ORF3a had the unique ability to inhibit STING, but not the RLR response. On the other hand, structural protein N was a unique RLR inhibitor. ORF3a bound STING in a unique fashion and blocked the nuclear accumulation of p65 to inhibit nuclear factor-κB signaling. 3CL of SARS-CoV-2 inhibited K63-ubiquitin modification of STING to disrupt the assembly of the STING functional complex and downstream signaling. Diverse vertebrate STINGs, including those from humans, mice, and chickens, could be inhibited by ORF3a and 3CL of SARS-CoV-2. The existence of more effective innate immune suppressors in pathogenic coronaviruses may allow them to replicate more efficiently in vivo. Since evasion of host innate immune responses is essential for the survival of all viruses, our study provides insights into the design of therapeutic agents against SARS-CoV-2.
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- 2021
23. The Transcriptional Factor ONECUT3 Is a Driver and Therapeutic Target for Complex Karyotype MDS
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Yingwan Luo, Xiaomin Feng, Wei Lang, Chen Mei, Rongzhen Xu, Gang Huang, and Hongyan Tong
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
24. 2-methylbenzoyl berbamine, a multi-targeted inhibitor, suppresses the growth of human osteosarcoma through disabling NF-κB, ERK and AKT signaling networks
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W. Li, Jie Zhao, Jun Li, Zengfeng Xin, Kai Hang, Hejia Hu, Xiuguo Han, Yan Li, Wenjia Tian, and Rongzhen Xu
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MAPK/ERK pathway ,musculoskeletal diseases ,Aging ,MAP Kinase Signaling System ,proliferation ,Mice, Nude ,Antineoplastic Agents ,Bone Neoplasms ,Berbamine ,migration ,Benzylisoquinolines ,chemistry.chemical_compound ,Mice ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Protein kinase B ,neoplasms ,Cell Proliferation ,Osteosarcoma ,apoptosis ,NF-kappa B ,NF-κB ,Cell Biology ,medicine.disease ,berbamine ,Gene Expression Regulation, Neoplastic ,chemistry ,Cell culture ,Apoptosis ,Cancer research ,Proto-Oncogene Proteins c-akt ,Research Paper - Abstract
Osteosarcoma is the most common malignant bone tumor in children and young adults, and it has a survival rate of only 60% with current cytotoxic chemotherapy combined with aggressive surgery. The aim of this study was to evaluate the therapeutic efficacy of the berbamine derivative 2-methylbenzoyl berbamine (BBD24) for osteosarcoma in vitro and in vivo. We used human osteosarcoma cell lines, primary osteosarcoma cells and mouse models to evaluate the inhibitory effects of BBD24 on osteosarcoma and to determine the molecular mechanism. Our results showed that BBD24 inhibited the growth of the human osteosarcoma cell lines HOS and MG63 in a time- and dose-dependent manner. BBD24 also exhibited significant inhibitory effects on primary osteosarcoma cells. In contrast, BBD24 did not affect normal blood cells under the same conditions. Treatment with BBD24 induced apoptosis, necrosis and autophagy in osteosarcoma cells. Western blot analysis revealed that BBD24 activated the caspase-dependent pathway and downregulated the NF-kB, AKT, and ERK pathways. Finally, BBD24 treatment induced a significant inhibitory effect on the growth of osteosarcoma in nude mice. Our findings indicate that BBD24 is a multitarget inhibitor and may represent a new type of anticancer agent for osteosarcoma treatment.
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- 2020
25. The diagnostic and prognostic value of cell division cycle associated gene family in Hepatocellular Carcinoma
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Yichao Gan, Ying Xu, Bowen Wu, Yu Huang, Yingwan Luo, Rongzhen Xu, Zhaoxing Wu, and An Ma
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cell division cycle ,0301 basic medicine ,Hippo signaling pathway ,Cell division ,DNA damage ,DNA repair ,hepatocellular carcinoma ,Biology ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Tumor progression ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,gene family ,medicine ,Cancer research ,Gene family ,Gene ,Research Paper - Abstract
Cell division cycle associated (CDCA) gene family plays an important role in cells. However, some researchers revealed that overexpression of CDCAs might contribute to the tumor progression in several cancers. Here, we analyzed the role of this gene family in hepatocellular carcinoma (HCC). We used several web tools and found that most of CDCAs were highly expressed in tumor tissues compared to the paracancer tissues in HCC. We then used RT-qPCR to confirm our results. The results showed that CDCA2, CDCA3, CDCA5 and CDCA8 were up-regulated in HCC. We also found that these genes were associated with poor overall survival and relapse free survival except CDCA7. The functional analysis showed that this gene family might take part in many processes, including cell division, apoptosis, DNA damage and DNA repair, which might contribute to the tumor progression. The KEGG pathway analysis showed that these genes participated in several important pathways such as PI3K-Akt signaling pathway and hippo signaling pathway. In conclusion, our findings suggested that CDCA2, CDCA3, CDCA4, CDCA5, and CDCA8 might have potential diagnostic and prognostic values for hepatocellular carcinoma.
- Published
- 2020
26. HIV-2/SIV Vpx targets a novel functional domain of STING to selectively inhibit cGAS–STING-mediated NF-κB signalling
- Author
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Lu Yin, Zhenbang Zhou, Wei Wei, Xiao-Fang Yu, Ting Chen, Richard B. Markham, Hanchu Xiong, Jiaming Su, Rongzhen Xu, Meng Lou, Yajuan Rui, Wei Zhang, Yong Cai, Na Zhao, Si Shen, Shu Zheng, and Zhengguo Zhang
- Subjects
Adult ,Male ,Microbiology (medical) ,viruses ,animal diseases ,Immunology ,Simian Acquired Immunodeficiency Syndrome ,HIV Infections ,Biology ,Applied Microbiology and Biotechnology ,Microbiology ,SAM Domain and HD Domain-Containing Protein 1 ,Young Adult ,03 medical and health sciences ,Immunity ,Genetics ,Animals ,Humans ,Viral Regulatory and Accessory Proteins ,Amino Acid Sequence ,Gene ,030304 developmental biology ,Mice, Inbred BALB C ,0303 health sciences ,Innate immune system ,030306 microbiology ,HEK 293 cells ,NF-kappa B ,Membrane Proteins ,virus diseases ,vpr Gene Products, Human Immunodeficiency Virus ,Cell Biology ,biochemical phenomena, metabolism, and nutrition ,Nucleotidyltransferases ,Immunity, Innate ,Cell biology ,Disease Models, Animal ,Sting ,HEK293 Cells ,HIV-2 ,Female ,Simian Immunodeficiency Virus ,Signal transduction ,Function (biology) ,HeLa Cells ,Signal Transduction ,SAMHD1 - Abstract
Innate immunity is the first line of host defence against pathogens. Suppression of innate immune responses is essential for the survival of all viruses. However, the interplay between innate immunity and HIV/SIV is only poorly characterized. We have discovered Vpx as a novel inhibitor of innate immune activation that associates with STING signalosomes and interferes with the nuclear translocation of NF-κB and the induction of innate immune genes. This new function of Vpx could be separated from its role in mediating degradation of the antiviral factor SAMHD1, and is conserved among diverse HIV-2/SIV Vpx. Vpx selectively suppressed cGAS-STING-mediated nuclear factor-κB signalling. Furthermore, Vpx and Vpr had complementary activities against cGAS-STING activity. Since SIVMAC lacking both Vpx and Vpr was less pathogenic than SIV deficient for Vpr or Vpx alone, suppression of innate immunity by HIV/SIV is probably a key pathogenic determinant, making it a promising target for intervention.
- Published
- 2019
27. Homoharringtonine Combined with the Heat Shock Protein 90 Inhibitor IPI504 in the Treatment of FLT3-ITD Acute Myeloid Leukemia
- Author
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Xuzhao Zhang, Ying Xu, Rui-lan Gao, Xibin Xiao, An Ma, Linlin Yang, Xudong Jiang, Yun Liang, Haifeng Zhuang, Rongzhen Xu, Lei Zhang, Qingfeng Yu, Zhaoxing Wu, Jianping Shen, Bowen Wu, and Xiaoya Lu
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Cancer Research ,Original article ,Chemistry ,Myeloid leukemia ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,Hsp90 inhibitor ,03 medical and health sciences ,Leukemia ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Apoptosis ,030220 oncology & carcinogenesis ,Homoharringtonine ,Heat shock protein ,hemic and lymphatic diseases ,medicine ,Cancer research ,Protein kinase B - Abstract
As a heterogeneous group of clonal disorders, acute myeloid leukemia with internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD) mutation usually shows an inferior prognosis. In the present study, we found that homoharringtonine (HHT), a protein translation inhibitor of plant alkaloid in China, exhibited potent cytotoxic effect against FLT3-ITD (+) cell lines and primary leukemia cells, and a remarkable synergistic anti-leukemia action was demonstrated in vitro and in vivo in xenograft mouse models when co-treated with the heat shock protein 90 inhibitor IPI504. Mechanistically, HHT combined with IPI504 synergistically inhibited the growth of leukemia cells by inducing apoptosis and G1 phase arrest. This synergistic action resulted in a prominent reduction of total and phosphorylated FLT3 (p-FLT3) as well as inhibition of its downstream signaling molecules such as STAT5, AKT, ERK and 4E-BP1. Furthermore, co-treatment of HHT and IPI504 led to a synergistic or additive effect on 55.56%(10/18) of acute myeloid leukemia cases tested, including three relapsed/refractory patients. In conclusion, our findings indicate that the combination of HHT and HSP90 inhibitor provides an alternative way for the treatment of FLT3-ITD positive acute myeloid leukemia, especially for relapsed/refractory AML.
- Published
- 2019
28. Natural small molecule triptonide inhibits lethal acute myeloid leukemia with FLT3-ITD mutation by targeting Hedgehog/FLT3 signaling
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Zhaoxing Wu, Mengyuan Li, Ying Xu, Xian Li, Rongzhen Xu, Ping Wang, and Jianping Shen
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0301 basic medicine ,GLI2 ,Apoptosis ,Hedgehog signaling ,Mice, SCID ,0302 clinical medicine ,fluids and secretions ,Mice, Inbred NOD ,hemic and lymphatic diseases ,FLT3 ,Triptonide ,Chemistry ,Myeloid leukemia ,Nuclear Proteins ,hemic and immune systems ,General Medicine ,Hedgehog signaling pathway ,Gene Expression Regulation, Neoplastic ,Leukemia ,Leukemia, Myeloid, Acute ,Tandem Repeat Sequences ,030220 oncology & carcinogenesis ,embryonic structures ,Female ,Tyrosine kinase ,psychological phenomena and processes ,Signal Transduction ,Antineoplastic Agents ,RM1-950 ,Zinc Finger Protein Gli2 ,Acute Myeloid Leukemia with FLT3/ITD Mutation ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Hedgehog Proteins ,Hedgehog ,Pharmacology ,FLT3-ITD-driven AML ,Cell Cycle Checkpoints ,medicine.disease ,Xenograft Model Antitumor Assays ,Triterpenes ,030104 developmental biology ,fms-Like Tyrosine Kinase 3 ,Cancer research ,Therapeutics. Pharmacology ,Tumor Suppressor Protein p53 - Abstract
Acute myeloid leukemia harboring internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD AML) is a subset of highly aggressive malignancies with poor clinical outcome. Despite some advances in the development of FLT3 tyrosine kinase inhibitors (FLT3 inhibitors), most of FLT3-ITD AML patients suffer from lethal disease relapse, suggesting the requirement of novel targets and agents. Here we describe a natural small molecule, triptonide that can efficiently inhibit FLT3-ITD-driven AML in vitro and in vivo. Mechanistically, triptonide targeted Hedgehog/FLT3 signaling by inhibiting its critical effectors, which are GLI2, c-Myc and FLT3 and induced apoptosis of FLT3-ITD-driven leukemia cells. In addition, we also observed that triptonide activated tumor suppressor p53. In vivo, triptonide treatment markedly suppressed lethal FLT3-ITD-driven AML with good tolerance and prolonged survival time in orthotopic mouse model. Our studies identify Hedgehog/FLT3 axis as a novel target for treating FLT3-ITD-driven leukemia and demonstrate that triptonide is an active lead compound that can kill FLT3-ITD-driven leukemia cells.
- Published
- 2021
29. Aberrant activated APOBEC3B is associated with p53 mutant-driven refractory/relapsed Diffuse Large B-cell Lymphoma
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Xiaohong Zhang, Zhaoxing Wu, Qingfeng Yu, Xuzhao Zhang, Xiuzhen Li, Yong-ming Fang, Weiqin Wang, Xiaofang Yu, An Ma, Liansheng Huang, Xuteng Zhang, Genbo Xu, Xiao-hua Xu, Jinfan Li, Teng Yu, Xiaoying Zhao, Yun Liang, Rongzhen Xu, Yang Xu, and Qinghua Lv
- Subjects
Refractory ,immune system diseases ,Chemistry ,hemic and lymphatic diseases ,Mutant ,Cancer research ,medicine ,medicine.disease ,neoplasms ,Diffuse large B-cell lymphoma - Abstract
BackgroundAlthough treatment of diffuse large B-cell lymphoma (DLBCL) has progressed considerably in recent years, treatment failure still occurs in about 40% of patients who are refractory/relapse. Recent studies suggest that TP53 mutation may be an important cause of refractory/relapse in DLBCL, but the cause of TP53 mutation remains unclear. MethodsIn the present study, the correlation between TP53 mutation status and APOBEC3A and APOBEC3B expression in DLBCL specimens was searched by detecting the correlation between TP53 mutation and APOBEC3B expression in combination with database informatics analysis. Further, the relationship between APOBEC3B expression and TP53 mutation was analyzed by constructing APOBEC3B induced expression DLBCL cell lines. The effects of APOBEC3B-induced TP53 mutants on DLBCL cell proliferation and drug resistance were also tested. ResultsWe identify APOBEC3B as a critical factor that regulates p53-mutant driven drug resistance of DLBCL. APOBEC3B induces TP53 mutations of DLBCL cells, and its mutation patterns are similar to those in DLBCL patients. Moreover, APOBEC3B-induced p53 mutants promoted growth of DLBCL cells as well as contributed to drug resistance. In human DLBCL, APOBEC3B is aberrantly activated and associated with p53 mutant-mediated refractory/relapsed DLBCL. ConclusionThese findings yield insights into the mechanism of refractory/relapsed DLBCL induced by p53 mutants and reveal APOBEC3B as a new therapeutic target.
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- 2020
30. A Selective Small‐Molecule c‐Myc Degrader Potently Regresses Lethal c‐Myc Overexpressing Tumors
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Ying Xu, Qingfeng Yu, Ping Wang, Zhaoxing Wu, Lei Zhang, Shuigao Wu, Mengyuan Li, Bowen Wu, Hongzhi Li, Haifeng Zhuang, Xuzhao Zhang, Yu Huang, Xiaoxian Gan, and Rongzhen Xu
- Subjects
Ubiquitin ,Ubiquitin-Protein Ligases ,General Chemical Engineering ,General Engineering ,General Physics and Astronomy ,Medicine (miscellaneous) ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Proto-Oncogene Proteins c-myc ,Mice ,Cell Line, Tumor ,Proteolysis ,Animals ,Humans ,General Materials Science - Abstract
MYC oncogene is involved in the majority of human cancers and is often associated with poor outcomes, rendering it an extraordinarily desirable target, but therapeutic targeting of c-Myc protein has been a challenge for30 years. Here, WBC100, a novel oral active molecule glue that selectively degrades c-Myc protein over other proteins and potently kills c-Myc overexpressing cancer cells is reported. WBC100 targets the nuclear localization signal 1 (NLS1)-Basic-nuclear localization signal 2 (NLS2) region of c-Myc and induces c-Myc protein degradation through ubiquitin E3 ligase CHIP mediated 26S proteasome pathway, leading to apoptosis of cancer cells. In vivo, WBC100 potently regresses multiple lethal c-Myc overexpressing tumors such as acute myeloid leukemia, pancreatic, and gastric cancers with good tolerability in multiple xenograft mouse models. Identification of the NLS1-Basic-NLS2 region as a druggable pocket for targeting the "undruggable" c-Myc protein and that single-agent WBC100 potently regresses c-Myc overexpressing tumors through selective c-Myc proteolysis opens new perspectives for pharmacologically intervening c-Myc in human cancers.
- Published
- 2022
31. Identification of the novel Np17 oncogene in human leukemia
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Mengyuan Li, Ying Xu, Xiaofang Yu, Yichao Gan, Ying Gu, Xiaoxian Gan, Bowen Wu, Xuzhao Zhang, Chen Wang, Haifeng Zhuang, Jiawei Zhang, Ping Wang, Jinfan Li, Rongzhen Xu, Linlin Yang, Zhipeng Meng, Wendong Huang, Ganyu Xu, and Zhaoxing Wu
- Subjects
Aging ,THP-1 Cells ,Viral Oncogene ,HL-60 Cells ,Mice, SCID ,Np9 ,Biology ,chemistry.chemical_compound ,Mice, Inbred NOD ,oncogene ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Nuclear protein ,Cell Proliferation ,Oncogene Proteins ,Gene knockdown ,P53 ,Leukemia ,Oncogene ,Gene Expression Regulation, Leukemic ,Np17 ,Ubiquitination ,Myeloid leukemia ,Proto-Oncogene Proteins c-mdm2 ,Cell Biology ,medicine.disease ,Neoplasm Proteins ,chemistry ,Case-Control Studies ,Proteolysis ,Cancer research ,biology.protein ,Mdm2 ,Female ,Growth inhibition ,Tumor Suppressor Protein p53 ,K562 Cells ,Signal Transduction ,Research Paper - Abstract
We previously defined the HERV-K Np9 as a viral oncogene. Here we report the discovery of a novel oncogene, Np17, which is homologous to the viral Np9 gene and predominantly present in Hominoidea. Np17 is located on chromosome 8, consists of 7 exons, and encodes a 16.8kDa nuclear protein with149 amino-acid residue. Functionally, knockdown of Np17 induced growth inhibition of leukemia cells, whereas enforced expression of Np17 promoted growth of leukemia cells in vitro and in vivo. In human leukemia, Np17 was detected in 59.65% (34/57) of acute myeloid leukemia (AML) patients examined and associated with refractory/relapsed AML. Mechanistically, Np17 decreased p53 levels and its mechanism might be involved in recruiting nuclear MDM2 to p53 for ubiquitin-mediated degradation. These findings reveal that Np17 is a novel oncogene associated with refractory/relapsed leukemia.
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- 2020
32. CAMKIIγ is a targetable driver of multiple myeloma through CaMKIIγ/ Stat3 axis
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Ping Wang, Ying Xu, Zhaoxing Wu, Yun Liang, Linlin Yang, Rongzhen Xu, Mengyuan Li, and Bowen Wu
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Adult ,Male ,STAT3 Transcription Factor ,Aging ,MAP Kinase Signaling System ,Apoptosis ,Kaplan-Meier Estimate ,Biology ,Benzylisoquinolines ,Stat3 Signaling Pathway ,Mice ,Downregulation and upregulation ,Cell Line, Tumor ,Animals ,Humans ,Phosphorylation ,STAT3 ,Extracellular Signal-Regulated MAP Kinases ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Gene knockdown ,Stat3 ,Cell growth ,Cell Biology ,Cell cycle ,Middle Aged ,poor prognosis ,Xenograft Model Antitumor Assays ,Up-Regulation ,multiple myeloma ,Gene Knockdown Techniques ,Cancer research ,biology.protein ,CaMKIIγ ,Ectopic expression ,Female ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Research Paper - Abstract
Aberrant activation of CAMKIIγ has been linked to leukemia and T-cell lymphoma, but not multiple myeloma (MM). The purpose of this study was to explore the role of CaMKIIγ in the pathogenesis and therapy of MM. In this study, we found that CaMKIIγ was aberrantly activated in human MM and its expression level was positively correlated with malignant progression and poor prognosis. Ectopic expression of CaMKIIγ promoted cell growth, colony formation, cell cycle progress and inhibited apoptosis of MM cell lines, whereas, knockdown of CAMKIIγ expression suppressed MM cell growth in vitro and in vivo. Mechanically, we observed that CaMKIIγ overexpression upregulated p-ERK and p-Stat3 levels and suppression of CaMKIIγ had opposite effects. CaMKIIγ is frequently dysregulated in MM and plays a critical role in maintaining MM cell growth through upregulating STAT3 signaling pathway. Furthermore, our preclinical studies suggest that CaMKIIγ is a potential therapeutic target in MM, and could be intervened pharmacologically by small-molecule berbamine analogues.
- Published
- 2020
33. An Automatic Adaptation-Oriented Case Retrieval Method for Case-Based Design
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Rongzhen Xu and Qi Gao
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0209 industrial biotechnology ,Measure (data warehouse) ,Multidisciplinary ,Point (typography) ,Computer science ,media_common.quotation_subject ,Workload ,Context (language use) ,02 engineering and technology ,computer.software_genre ,Adaptability ,020901 industrial engineering & automation ,0202 electrical engineering, electronic engineering, information engineering ,Key (cryptography) ,020201 artificial intelligence & image processing ,Quality (business) ,Data mining ,Adaptation (computer science) ,computer ,media_common - Abstract
Case retrieval is a key issue in case-based design. The purpose of retrieval is to select the most suitable case for reusing. In the context of rule-based automatic case adaptation, the prerequisite to adapt a case automatically is that all the required adaptation rules can be found in the rule base. In addition, the adaptation performance is also influenced by the quality of the required adaptation rules and the workload of the adaptation. To retrieve the most suitable case for rule-based automatic case adaptation, a new case retrieval method is proposed. First, the rule maturity of each case is calculated to measure the sufficiency and quality of the required adaptation rules. Then, the adaptability of each case is calculated to measure the adaptation workload. Finally, the suitability of the cases is obtained by synthesizing the maturity and the adaptability. The case with the largest suitability is selected as the starting point of the new design. Two comparative experiments were performed, and the results show that the cases retrieved by the proposed method were more suitable for automatic adaptation.
- Published
- 2018
34. The role of peripheral blood, bone marrow aspirate and especially bone marrow trephine biopsy in distinguishing atypical chronic myeloid leukemia from chronic granulocytic leukemia and chronic myelomonocytic leukemia
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Xubo, Gong, Xingguo, Lu, Xianguo, Wu, Rongzhen, Xu, Xibin, Xiao, Lin, Wang, Lei, Zhu, Xiaohong, Zhang, Genbo, Xu, and Xiaoying, Zhao
- Published
- 2009
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35. CAMK2γ in intestinal epithelial cells modulates colitis-associated colorectal carcinogenesis via enhancing STAT3 activation
- Author
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Xiaoqiong Wang, Zhenzhou Xiao, Walter Tsark, Rongzhen Xu, Lihua Jin, Ying Gu, Min He, Byung-Wook Kim, Xiaoxian Gan, Jiawei Zhang, Hua Yu, Zhipeng Meng, John E. Shively, Xiaoxiao Ma, Wendong Huang, and Lili Ding
- Subjects
Colitis-associated colorectal cancer ,STAT3 Transcription Factor ,0301 basic medicine ,Cancer Research ,Carcinogenesis ,Inflammation ,Biology ,medicine.disease_cause ,digestive system ,Article ,STAT3 ,Mice ,03 medical and health sciences ,HT29 Cells ,0302 clinical medicine ,Growth factor receptor ,Intestinal mucosa ,Genetics ,medicine ,Animals ,Humans ,cardiovascular diseases ,Intestinal Mucosa ,Molecular Biology ,Cell Proliferation ,Mice, Knockout ,CAMK2γ ,nutritional and metabolic diseases ,Epithelial Cells ,Colitis ,HCT116 Cells ,3. Good health ,Mice, Inbred C57BL ,WNT5A ,030104 developmental biology ,inflammation ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,STAT protein ,biology.protein ,medicine.symptom ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Colorectal Neoplasms - Abstract
Inflammation is one of the major risk factors for cancer. Here, we show that calcium/calmodulin-dependent protein kinase II gamma (CAMK2γ) in intestinal epithelial cells (IECs) modulates inflammatory signals and promotes colitis-associated cancer (CAC) in mice. We have identified CAMK2γ as a downstream target of colitis-induced WNT5A signaling. Furthermore, we have shown that CAMK2γ protects against intestine tissue injury by increasing IEC survival and proliferation. Calcium/calmodulin-dependent protein kinase II gamma knockout mice displayed reduced CAC. Furthermore, we used bone marrow transplantation to reveal that CAMK2γ in IECs, but not immune cells, was crucial for its effect on CAC. Consistently, transgenic over-expression of CAMK2γ in IECs accelerated CAC development. Mechanistically, CAMK2γ in IECs enhanced epithelial signal transducer and activator of transcription 3 (STAT3) activation to promote survival and proliferation of colonic epithelial cells during CAC development. These results thus identify a new molecular mechanism mediated by CAMK2γ in IECs during CAC development, thereby providing a potential new therapeutic target for CAC.
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- 2017
36. CAMK2γ antagonizes mTORC1 activation during hepatocarcinogenesis
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Wendong Huang, X Gan, C Van Ness, Ying Gu, Xiaoqiong Wang, Rongzhen Xu, Min He, Jingying Zhang, Xin-Yuan Fu, Xiaoxiao Ma, Z Fang, Zhipeng Meng, J Du, D E Schones, and W Han
- Subjects
0301 basic medicine ,Kinase ,Cancer Research ,Carcinogenesis ,mTORC1 ,Mechanistic Target of Rapamycin Complex 1 ,Biology ,Article ,Mice ,03 medical and health sciences ,Growth factor receptor ,Cell Line, Tumor ,Genetics ,Animals ,Humans ,Diethylnitrosamine ,Rapamycin ,Molecular Biology ,Protein kinase B ,Cell Proliferation ,CAMK2γ ,Cell Death ,TOR Serine-Threonine Kinases ,AKT ,Liver Neoplasms ,Hepatocellular Carcinoma ,HCCS ,3. Good health ,IRS1 ,030104 developmental biology ,Multiprotein Complexes ,Hepatocytes ,Cancer research ,Signal transduction ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Proto-Oncogene Proteins c-akt ,Gene Deletion ,Signal Transduction - Abstract
Hepatocellular carcinoma (HCC) is one of the most deadly cancers that still lacks effective treatments. Dysregulation of kinase signaling has frequently been reported to contribute to HCC. In this study, we used bioinformatic approaches to identify kinases that regulate gene expression changes in human HCCs and two murine HCC models. We identified a role for calcium/calmodulin-dependent protein kinases II gamma isoform (CAMK2γ) in hepatocarcinogenesis. CAMK2γ−/− mice displayed severely enhanced chemical-induced hepatocarcinogenesis compared with wild-type controls. Mechanistically, CAMK2γ deletion potentiates hepatic activation of mechanistic target of rapamycin complex 1 (mTORC1), which results in hyperproliferation of hepatocytes. Inhibition of mTORC1 by rapamycin effectively attenuates the compensatory proliferation of hepatocytes in CAMK2γ−/− livers. We further demonstrated that CAMK2γ suppressed growth factor- or insulin-induced mTORC1 activation by inhibiting IRS1/AKT signaling. Taken together, our results reveal a novel mechanism by which CAMK2γ antagonizes mTORC1 activation during hepatocarcinogenesis.
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- 2016
37. 4-Chlorbenzoyl Berbamine, a Novel Derivative of the Natural Product Berbamine, Potently Inhibits the Growth of Human Myeloma Cells by Modulating the NF-κB and JNK Signalling Pathways
- Author
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Lei Zhang, Xi Qiu, Yun Liang, Rongzhen Xu, Xiaoying Zhao, Xian Li, Xuzhao Zhang, Xiaohong Zhang, and Xin He
- Subjects
0301 basic medicine ,Cancer Research ,Cell Survival ,Antineoplastic Agents ,Apoptosis ,Berbamine ,Benzylisoquinolines ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,Survivin ,medicine ,Humans ,Phosphorylation ,Multiple myeloma ,Cell Proliferation ,Biological Products ,Natural product ,business.industry ,Cell Cycle ,JNK Mitogen-Activated Protein Kinases ,NF-kappa B ,NF-κB ,General Medicine ,medicine.disease ,Cell biology ,030104 developmental biology ,Oncology ,chemistry ,Biochemistry ,Protein Biosynthesis ,030220 oncology & carcinogenesis ,Multiple Myeloma ,business ,Nuclear localization sequence ,Signal Transduction - Abstract
Multiple myeloma (MM) remains incurable despite the development and the use of new agents. In our studies, we found that 4-chlorbenzoyl berbamine (BBMD9), a novel synthetic derivative of berbamine, inhibited the proliferation of MM cells in dose- and time-dependent manners. Flow cytometric (FCM) analysis revealed that MM cells were arrested in the G1 phase and that apoptotic cells increased in a time-dependent manner. Moreover, the BBMD9 treatment downregulated IKKα and IKKβ, inhibited p-IκBα, and blocked p65 nuclear localization. Consistently, NF-κB downstream targets, such as cyclinD1 and survivin, were also reduced. In addition, BBMD9 phosphorylated the activity of JNK and c-Jun.
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- 2016
38. Research on Innovation Mechanism of Network Loan Clustering Based on CAS Theory
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Rongzhen Xu, Mengke He, and Meiqi Wang
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Computer science ,Loan ,Data mining ,Cluster analysis ,computer.software_genre ,computer ,Mechanism (sociology) - Published
- 2019
39. Factors Associated with Thrombolysis Outcome in Ischemic Stroke Patients with Atrial Fibrillation
- Author
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Min Ye, Meijuan Zhang, Rongzhen Xu, Xiaobo Li, Bei Wang, Qiuyun Zhao, Qian-Tao Cheng, Guiyun Cui, Guo-Fang Chen, Yan Chen, Peng Zhang, Shanshan Hong, Ming Yu, Junshan Zhou, Yongjun Cao, Xiue Wei, Hong Ding, Yun Xu, and Wanli Dong
- Subjects
Male ,medicine.medical_specialty ,Tomography Scanners, X-Ray Computed ,Physiology ,medicine.medical_treatment ,030204 cardiovascular system & hematology ,Severity of Illness Index ,Tissue plasminogen activator ,03 medical and health sciences ,0302 clinical medicine ,Fibrinolytic Agents ,Risk Factors ,Internal medicine ,Atrial Fibrillation ,Outcome Assessment, Health Care ,medicine ,Humans ,cardiovascular diseases ,Stroke ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,General Neuroscience ,Atrial fibrillation ,General Medicine ,Thrombolysis ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Thrombosis ,Surgery ,Blood pressure ,Tissue Plasminogen Activator ,Heart failure ,Cardiology ,Female ,Original Article ,business ,030217 neurology & neurosurgery ,Fibrinolytic agent ,medicine.drug - Abstract
The outcome of early intravenous thrombolysis for ischemic stroke in patients with atrial fibrillation (AF) is worse than that without thrombosis. How to increase the efficacy of intravenous thrombolysis for AF-related ischemic stroke remains largely unknown. In this study, we investigated factors that influence the effect of intravenous thrombolysis in these patients. Our results showed that thrombolysis was independently associated with a favorable outcome (P
- Published
- 2016
40. Identification of a novel RNA giant nuclear body in cancer cells
- Author
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Qi Dong, Rongzhen Xu, Byung-Wook Kim, Xiaoya Lu, Jiawei Zhang, Ying Gu, Xiaoxian Gan, Shu Zheng, Xiaohua Xu, Hong Zhou, Wendong Huang, Weiwei Zheng, and Yichao Gan
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Blotting, Western ,Intranuclear Inclusion Bodies ,Fluorescent Antibody Technique ,Biology ,03 medical and health sciences ,Neoplasms ,Internal medicine ,Tumor Cells, Cultured ,medicine ,Humans ,Nuclear protein ,cancer cell ,Cell Proliferation ,RNA, Nuclear ,Cell Nucleus ,Messenger RNA ,Hematology ,Cancer prevention ,nuclear RNA trafficking ,Nuclear Proteins ,Cancer ,RNA ,medicine.disease ,3. Good health ,Cell nucleus ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Case-Control Studies ,Cancer cell ,Cancer research ,RNA giant nuclear body ,Cell Nucleolus ,Research Paper - Abstract
// Hong Zhou 1, 2, 5, * , Jiawei Zhang 2, 3, * , Ying Gu 1, 2, 3, * , Xiaoxian Gan 3, 4 , Yichao Gan 1, 2 , Weiwei Zheng 1, 2 , Byung-Wook Kim 3 , Xiaohua Xu 1 , Xiaoya Lu 1, 2 , Qi Dong 2 , Shu Zheng 2 , Wendong Huang 3 , Rongzhen Xu 1, 2 1 Department of Hematology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China 2 Cancer Institute of Zhejiang University, Hangzhou 310009, China 3 Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA 4 Zhejiang Academy of Medical Sciences, Hangzhou 310012, China 5 Hangzhou First People’s Hospital, Hangzhou 310006, China * These authors contributed equally to this work. Correspondence to: Rongzhen Xu, e-mail: zrxyk10@zju.edu.cn Wendong Huang, e-mail: whuang@coh.org Keywords: cancer cell, RNA giant nuclear body, nuclear RNA trafficking Received: August 25, 2015 Accepted: November 25, 2015 Published: December 15, 2015 ABSTRACT Constitutive synthesis of oncogenic mRNAs is essential for maintaining the uncontrolled growth of cancer cells. However, little is known about how these mRNAs are exported from the nucleus to the cytoplasm. Here, we report the identification of a RNA giant nuclear body (RNA-GNB) that is abundant in cancer cells but rare in normal cells. The RNA-GNB contains a RNA core surrounded by a protein shell. We identify 782 proteins from cancer-associated RNA-GNBs, 40% of which are involved in the nuclear mRNA trafficking. RNA-GNB is required for cell proliferation, and its abundance is positively associated with tumor burden and outcome of therapies. Our findings suggest that the RNA-GNB is a novel nuclear RNA trafficking organelle that may contribute to the nuclear mRNA exporting and proliferation of cancer cells.
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- 2015
41. Abstract 4747: Genomic and transcriptomic landscape of AFP-producing gastrointestinal adenocarcinoma
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Qian Xiao, Lina Zhang, Xinlin Li, Xiao-Ming Xu, Yeting Hu, Yu Tian, Xiangxing Kong, Qiancheng Ye, Jing-Song Li, Yue Liu, Jun Li, and Rongzhen Xu
- Subjects
Cancer Research ,Biology ,medicine.disease ,HNF1A ,Transcriptome ,MRNA Sequencing ,Oncology ,Gastric Hepatoid Adenocarcinoma ,Cancer research ,medicine ,Adenocarcinoma ,Epigenetics ,Gene ,Exome sequencing - Abstract
AFP-producing gastrointestinal adenocarcinoma (APA-GI) is a rare type of cancer, typically with hepatoid differentiation, chemotherapy resistance and poor prognosis. As the mechanisms of its AFP production and hepatoid differentiation remain unclear, the present study aims to reveal the pathogenesis of APA-GI through genomic and transcriptomic profile analysis. We firstly performed 200 × whole exome sequencing of 29 APA-GI and 8 non-APA-GI cases from our hospital, but found no significant difference in single nucleotide variants (SNV) or insertion/deletion(indels). Additionally, there was no overlap gene when compared with the known genes harbored at 20q11.21-13.12 reported in gastric hepatoid adenocarcinoma. We then performed single-cell mRNA sequencing in one APA-GI, and observed several hepatoid differentiation markers in AFP positive cells including HNF4A and HNF1A. To further determine the specific alterations of APA-GI, we divided 339 gastric cancer patients from TCGA database into AFP-low group and AFP-high group by the level of AFP transcription through a dynamic grouping method named grid search. We performed a series differentially expressed genes detections within different grouping strategies and no significant SNV or indels difference was recognized. We identified hepatoid differentiation markers (i.e. HNF4A, HNF1A and ALB, et al) in AFP-high patients in mRNA level. As the difference of hepatoid differentiation markers only occurred in the mRNA level without DNA alteration, we hypothesized that it was probably caused by epigenetic regulation. We further compared these genes with an epigenetic regulators database named EpiFactors. Finally, it showed CCCTC-Binding Factor Like (CTCFL) was stably related with AFP producing within the grid search. In conclusion, comprehensive genomic analysis of APA-GI shows significant hepatoid differentiation at the transcriptomic level without disease-specific DNA alteration. The pathogenesis of APA-GI may be associated with other mechanisms like epigenetic regulation. Further study was needed to confirm the role of epigenetic regulators we detected in the present study in the development of APA-GI. Citation Format: Jun Li, Xinlin Li, Qiancheng Ye, Yu Tian, Xiangxing Kong, Yue Liu, Xiaoming Xu, Lina Zhang, Qian Xiao, Yeting Hu, Rongzhen Xu, Jingsong Li. Genomic and transcriptomic landscape of AFP-producing gastrointestinal adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4747.
- Published
- 2020
42. Aberrant activation of RPB1 is critical for cell overgrowth in acute myeloid leukemia
- Author
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Xuzhao Zhang, Qingfeng Yu, Ping Wang, Yun Liang, Ying Xu, Linlin Yang, Rongzhen Xu, Zhaoxing Wu, Lei Zhang, Haifeng Zhuang, Bowen Wu, Ying Gu, Xiaoxian Gan, Xiaofang Yu, Jinfan Li, and Shu Zheng
- Subjects
0301 basic medicine ,THP-1 Cells ,Cell ,Apoptosis ,HL-60 Cells ,Biology ,Cell Line ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Gene silencing ,POLR2A ,neoplasms ,Cell Proliferation ,Retrospective Studies ,Oncogene ,Gene Expression Regulation, Leukemic ,Cell growth ,Gene Expression Profiling ,Myeloid leukemia ,Cell Biology ,medicine.disease ,Leukemia, Myeloid, Acute ,Haematopoiesis ,Leukemia ,HEK293 Cells ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,Female ,RNA Polymerase II ,Apoptosis Regulatory Proteins - Abstract
Acute myeloid leukemia (AML) is a group of highly aggressive malignancies with a 5-year overall survival of less than 40%. Cell overgrowth with defective apoptosis is a hallmark of AML, but little is known about how it occurs. Here, we show that aberrant activation of the largest subunit of RNA polymerase II (RPB1) encoded by POLR2A gene is critically involved in this hallmark. We retrospectively analyzed the expression profiles of POLR2A and RPB1 in a panel of AML cell lines, primary AML patients and peripheral blood samples. Meanwhile, correlation analysis was used to explore the correlation between the expression of RPB1 with tumor burden and overall survival time in untreated AML samples. RNA-Seq approach was performed to identify the differentially expressed genes between RPB1 silencing AML cells with control cells after knocking out RPB1. Furthermore, orthotopic AML models were established with RPB1 silencing and control cells to investigate the effects of RPB1 protein level on leukemia cell growth. In most AML patients, RPB1 was aberrantly activated and closely associated with poor prognosis, but not in normal hematopoietic cells. Global transcriptomic analysis revealed that POLR2A knockout strongly impaired growth of AML cells by selectively depleting a substantial set of AML-related oncogenic and anti-apoptosis genes such as MYC, RUNX2, MEIS1, CDC25A and BCL-2. Silencing RPB1 by genetic technology led to a potent regression of human refractory AML in mouse models. These findings reveal that dysregulated RPB1 is a central oncogenic hub that drives overgrowth by hijacking an array of oncogenic and anti-apoptosis factors. Targeting RPB1 is a potential therapeutic for treating AML.
- Published
- 2019
43. Novel synthetic tosyl chloride-berbamine regresses lethal MYC-positive leukemia by targeting CaMKIIγ/Myc axis
- Author
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Xiaoxian Gan, Zhaoxing Wu, Ping Wang, An Ma, Linlin Yang, Qingfeng Yu, Rongzhen Xu, Bowen Wu, Ying Xu, and Shu Li
- Subjects
0301 basic medicine ,Tosyl chloride-berbamine ,Transcription, Genetic ,Administration, Oral ,Antineoplastic Agents ,Apoptosis ,MYC ,RM1-950 ,Berbamine ,Benzylisoquinolines ,Proto-Oncogene Mas ,Proto-Oncogene Proteins c-myc ,Tosyl Compounds ,Inhibitory Concentration 50 ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,RNA, Messenger ,Transcription factor ,Cell Proliferation ,Pharmacology ,Acute leukemia ,Leukemia ,Gene Expression Regulation, Leukemic ,General Medicine ,medicine.disease ,In vitro ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,CaMKIIγ ,Cancer research ,Therapeutics. Pharmacology ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Signal Transduction ,MYC Positive - Abstract
Proto-oncogene Myc, a key transcription factor, is frequently deregulated in human leukemia with aggressive and poor clinical outcome, but the development of MYC inhibitors remains challenging due to MYC helix-loop-helix topology lacking druggable domains. Here we describe a novel oral active small molecule analog of berbamine, tosyl chloride-berbamine (TCB), that efficiently eliminates MYC-positive leukemia in vitro and in vivo. Mechanistically, TCB potently reduced MYC protein by inhibiting CaMKIIγ, a critical enzyme that stabilizes MYC protein, and induces apoptosis of MYC-positive leukemia cells. In vivo, oral administration of TCB markedly eliminated lethal MYC-positive acute lymphoblastic leukemia (ALL) with well tolerability in orthotopic mouse model. Our studies identify CaMKIIγ/Myc axis as a valid target for developing small molecule-based new therapies for treating MYC-mediated leukemia and demonstrate that TCB is an orally active analog of berbamine that kills MYC-positive leukemia cells.
- Published
- 2019
44. Novel synthetic 4-chlorobenzoyl berbamine inhibits c-Myc expression and induces apoptosis of diffuse large B cell lymphoma cells
- Author
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Lei Zhang, Xiaoying Zhao, Yun Liang, Rongzhen Xu, Xin He, Jiefeng Tong, and Lei Zhu
- Subjects
0301 basic medicine ,STAT3 Transcription Factor ,medicine.medical_specialty ,Apoptosis ,Berbamine ,Benzylisoquinolines ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Transcription (biology) ,hemic and lymphatic diseases ,Internal medicine ,Cell Line, Tumor ,medicine ,Humans ,Inducer ,STAT3 ,Cell Proliferation ,Hematology ,biology ,Chemistry ,General Medicine ,Janus Kinase 2 ,medicine.disease ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Normal blood ,Lymphoma, Large B-Cell, Diffuse ,Diffuse large B-cell lymphoma ,Signal Transduction - Abstract
C-Myc expression is associated with poor prognosis and aggressive progression of diffuse large B cell lymphoma (DLBCL), and the development of drug-like c-Myc inhibitors remains challenging. In this study, we report a novel berbamine derivative termed 4-chlorobenzoyl berbamine (CBBM) that potently induced the apoptosis of c-Myc-overexpressing DLBCL cells but spared normal blood cells. The compound showed IC50 values ranging from 1.93 to 3.89 μmol/L in DLCBL cells and exhibited a 4.75- to 9.64-fold increase in anti-tumor activity compared to berbamine. Additionally, CBBM inhibited the proliferation of the DLBCL line OCI-Ly3 cells through G0/G1 cell-cycle arrest and induced apoptosis. Further studies have shown that CBBM treatment leads to the proteasome-dependent degradation of c-Myc protein in OCI-Ly3 cells. Interestingly, we found that the inhibitory effect of CBBM was positively correlated with basal levels of CaMKIIγ, which is a key inducer of c-Myc expression in DLBCL cells. We also observed that CBBM inhibits the JAK2/STAT3 pathway, leading to reduced c-Myc transcription. Collectively, these findings suggest that CBBM could be a promising lead compound for treatment of c-Myc-driven DLBCL.
- Published
- 2018
45. Small-molecule induction of phospho-eIF4E sumoylation and degradation via targeting its phosphorylated serine 209 residue
- Author
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Weiwei Zheng, Ying Gu, Xiaoya Lu, Xiaoxian Gan, Lu Xinliang, Jianghua Chen, Xiaoxiao Ma, Yun Liang, Hong Zhou, Zhipeng Meng, Rongzhen Xu, Ganyu Xu, Yichao Gan, Wendong Huang, X.B. Zhang, Hongzhi Li, Xiaohua Xu, Jiawei Zhang, and Xichun Wang
- Subjects
Harringtonines ,Proteasome Endopeptidase Complex ,Blotting, Western ,SUMO protein ,SUMO2 ,Mice, SCID ,acute myeloid leukemia ,Serine ,small molecular inhibitor ,Mice, Inbred NOD ,hemic and lymphatic diseases ,Cell Line, Tumor ,Tumor Cells, Cultured ,Medicine ,Animals ,Humans ,Phosphorylation ,Ubiquitins ,proteasome-dependent degradation ,Mice, Knockout ,Dose-Response Relationship, Drug ,Molecular Structure ,business.industry ,phospho-eIF4E ,Myeloid leukemia ,Sumoylation ,Small molecule ,Antineoplastic Agents, Phytogenic ,Xenograft Model Antitumor Assays ,Cell biology ,homoharritonine ,Eukaryotic Initiation Factor-4E ,Oncology ,Leukemia, Myeloid ,Homoharringtonine ,Cancer cell ,Acute Disease ,Proteolysis ,Small Ubiquitin-Related Modifier Proteins ,Protein Multimerization ,business ,Research Paper ,Interleukin Receptor Common gamma Subunit - Abstract
As phospho-eIF4E (p-eIF4E), unlike total eIF4E (t-eIF4E) essential for normal cells, is specifically required by cancer cells, it is an attractive, yet unrealized, target for anti-tumor intervention. Here we identify a small molecule, homoharringtonine (HHT), that antagonizes p-eIF4E function and eradicates acute myeloid leukemia (AML) expressing high level of p-eIF4E in vitro and in vivo. HHT selectively reduces p-eIF4E levels of leukemia cells without affecting t-eIF4E. HHT targets the phosphorylated serine 209 residue of p-eIF4E and induces p-eIF4E oligomerization, which enhances its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in proteasome-dependent degradation of p-eIF4E via SUMO2/3-mediated SUMOylation. These results suggest that the phosphorylated serine 209 residue of p-eIF4E might be a potential target for developing small molecule-based new therapies for leukemia.
- Published
- 2015
46. A non-cytotoxic dendrimer with innate and potent anticancer and anti-metastatic activities
- Author
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Meng Wang, Jingxing Si, Rongzhen Xu, Jian-Qing Gao, Shiqun Shao, Jianbin Tang, Xiangrui Liu, Quan Zhou, Youqing Shen, and Kai Wang
- Subjects
Tumor angiogenesis ,Angiogenesis ,Biomedical Engineering ,Medicine (miscellaneous) ,Bioengineering ,02 engineering and technology ,Pharmacology ,010402 general chemistry ,021001 nanoscience & nanotechnology ,medicine.disease ,01 natural sciences ,0104 chemical sciences ,Computer Science Applications ,Metastasis ,chemistry.chemical_compound ,chemistry ,In vivo ,Dendrimer ,medicine ,Cytotoxic T cell ,0210 nano-technology ,Cytotoxicity ,Ethylene glycol ,Biotechnology - Abstract
The structural perfection and multivalency of dendrimers have made them useful for biodelivery and bioactivity via peripheral functionalization and the modulation of core-forming structures and dendrimer generations. Yet only few dendrimers have shown inherent therapeutic activity arising from their inner repeating units. Here, we report the synthesis and characterization of a polyacylthiourea dendrimer with inherent potent anticancer activity and the absence of cytotoxicity in mice. The poly(ethylene glycol)-functionalized fourth generation of the dendrimer, which can be efficiently synthesized from sequential click reactions of orthogonal monomers, displays low in vivo acute and subacute toxicities yet potently inhibits tumour growth and metastasis. The dendrimer’s in vivo anticancer activity arises from the depletion of bioavailable copper and the subsequent inhibition of angiogenesis and cellular proliferation. When compared with some clinically used cytotoxin drugs, the dendrimer exerts inherent anticancer activity via non-cytotoxic pathways and leads to higher therapeutic efficacy, yet without cytotoxin-induced side effects. A dendrimer that depletes bioavailable copper and leads to the suppression of tumour angiogenesis acts as a potent and non-cytotoxic anticancer therapeutic.
- Published
- 2016
47. Research on the Development Path of Competitive Intelligence System of Commercial Banks Based on SCP
- Author
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Jiashan Han, Rongzhen Xu, and Meiqi Wang
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Competition (economics) ,Dilemma ,History ,Work (electrical) ,Competitive intelligence ,Financial intelligence (business) ,Position (finance) ,Business ,Industrial organization ,Information science ,Computer Science Applications ,Education ,PATH (variable) - Abstract
Competition is the essence of market economy, and how commercial Banks reform and develop and occupy a dominant position in competition is a common concern in the fields of finance and information science. By sorting out relevant results, it can provide reference for the development and research of commercial Banks. Starting from financial intelligence, this paper discusses the development evolution of commercial Banks from the perspective of competitive intelligence. Based on SCP analysis of the development dilemma of commercial Banks, this paper proposes the development path of competitive intelligence system of commercial Banks. Putting forward new ideas for the development of commercial Banks, combined with the needs of the industry, in-depth competition intelligence collection and processing work for the innovation and development of commercial Banks is of great significance.
- Published
- 2019
48. Berbamine Inhibits the Growth of Liver Cancer Cells and Cancer-Initiating Cells by Targeting Ca2+/Calmodulin-Dependent Protein Kinase II
- Author
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Jun Wu, Zhipeng Meng, Guiyu Lou, Xiaoqiong Wang, Yichao Gan, Tao Li, Yafan Wang, Wendong Huang, Rongzhen Xu, Xiaoxiao Ma, Jinfen Tang, Yun Yen, Carl Van Ness, and Hong Zhou
- Subjects
Cancer Research ,medicine.medical_specialty ,Apoptosis ,Berbamine ,Biology ,Benzylisoquinolines ,Article ,Mice ,chemistry.chemical_compound ,Ca2+/calmodulin-dependent protein kinase ,Internal medicine ,medicine ,Animals ,Humans ,Cell Proliferation ,Gene knockdown ,Cell growth ,Liver Neoplasms ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Endocrinology ,Oncology ,chemistry ,Cancer cell ,Cancer research ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Liver cancer - Abstract
Liver cancer is the third leading cause of cancer deaths worldwide but no effective treatment toward liver cancer is available so far. Therefore, there is an unmet medical need to identify novel therapies to efficiently treat liver cancer and improve the prognosis of this disease. Here, we report that berbamine and one of its derivatives, bbd24, potently suppressed liver cancer cell proliferation and induced cancer cell death by targeting Ca2+/calmodulin-dependent protein kinase II (CAMKII). Furthermore, berbamine inhibited the in vivo tumorigenicity of liver cancer cells in NOD/SCID mice and downregulated the self-renewal abilities of liver cancer–initiating cells. Chemical inhibition or short hairpin RNA–mediated knockdown of CAMKII recapitulated the effects of berbamine, whereas overexpression of CAMKII promoted cancer cell proliferation and increased the resistance of liver cancer cells to berbamine treatments. Western blot analyses of human liver cancer specimens showed that CAMKII was hyperphosphorylated in liver tumors compared with the paired peritumor tissues, which supports a role of CAMKII in promoting human liver cancer progression and the potential clinical use of berbamine for liver cancer therapies. Our data suggest that berbamine and its derivatives are promising agents to suppress liver cancer growth by targeting CAMKII. Mol Cancer Ther; 12(10); 2067–77. ©2013 AACR.
- Published
- 2013
49. The viral oncogene Np9 acts as a critical molecular switch for co-activating β-catenin, ERK, Akt and Notch1 and promoting the growth of human leukemia stem/progenitor cells
- Author
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X Gan, Jie Jin, Yan Fang, Zhipeng Meng, Hong Zhou, Rongzhen Xu, F Xu, Xiaoqiong Wang, Xiaohua Xu, S Zheng, G Xu, J Wu, Y Gu, C Van Ness, X Zhang, Yichao Gan, Jinfen Tang, Wendong Huang, Tianhui Chen, and L Huang
- Subjects
MAPK/ERK pathway ,Cancer Research ,MAP Kinase Signaling System ,Viral Oncogene ,HL-60 Cells ,Leukemia inhibitory factor receptor ,Mice, SCID ,Biology ,Genes, env ,Jurkat Cells ,Mice ,Promyelocytic leukemia protein ,Mice, Inbred NOD ,Cancer stem cell ,Cell Line, Tumor ,Neoplasms ,hemic and lymphatic diseases ,Animals ,Humans ,Receptor, Notch1 ,Progenitor cell ,Extracellular Signal-Regulated MAP Kinases ,Protein kinase B ,beta Catenin ,ABL ,Gene Products, env ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Hematopoietic Stem Cells ,Genes, pol ,Cell biology ,Oncology ,Leukemia, Myeloid ,Neoplastic Stem Cells ,biology.protein ,K562 Cells ,Proto-Oncogene Proteins c-akt ,Neoplasm Transplantation - Abstract
HERV-K (human endogenous retrovirus type K) type 1-encoded Np9 is a tumor-specific biomarker, but its oncogenic role and targets in human leukemia remain elusive. We first identified Np9 as a potent viral oncogene in human leukemia. Silencing of Np9 inhibited the growth of myeloid and lymphoblastic leukemic cells, whereas expression of Np9 significantly promoted the growth of leukemia cells in vitro and in vivo. Np9 not only activated ERK, AKT and Notch1 pathways but also upregulated β-catenin essential for survival of leukemia stem cells. In human leukemia, Np9 protein level in leukemia patients was substantially higher than that in normal donors (56% vs 4.5%). Moreover, Np9 protein level was correlated with the number of leukemia stem/progenitor cells but not detected in normal CD34(+) hematopoietic stem cells. In addition, Np9-positive samples highly expressed leukemia-specific pol-env polyprotein, env and transmembrane proteins as well as viral particles. Thus, the viral oncogene Np9 is a critical molecular switch of multiple signaling pathways regulating the growth of leukemia stem/progenitor cells. These findings open a new perspective to understand the etiology of human common leukemia and provide a novel target for treating leukemia.
- Published
- 2013
50. Deletion of IFNγ enhances hepatocarcinogenesis in FXR knockout mice
- Author
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Chao He, Hong Zhou, Jun Wu, Xiaoqiong Wang, Yichao Gan, Guiyu Lou, Hua Yu, Yunfeng Zhang, Wendong Huang, Rongzhen Xu, Zhipeng Meng, and Carl Van Ness
- Subjects
STAT3 Transcription Factor ,Carcinoma, Hepatocellular ,MAP Kinase Kinase 4 ,Receptors, Cytoplasmic and Nuclear ,Interferon-gamma ,Mice ,chemistry.chemical_compound ,Downregulation and upregulation ,Risk Factors ,medicine ,Animals ,Diethylnitrosamine ,Genetic Predisposition to Disease ,Interferon gamma ,STAT3 ,Receptor ,Mice, Knockout ,Hepatology ,biology ,Liver Neoplasms ,NF-kappa B ,NF-κB ,NFKB1 ,Molecular biology ,Mice, Inbred C57BL ,Disease Models, Animal ,chemistry ,Knockout mouse ,Cancer research ,biology.protein ,Farnesoid X receptor ,Tumor Suppressor Protein p53 ,Gene Deletion ,Signal Transduction ,medicine.drug - Abstract
Background & Aims Liver tumor, especially hepatocellular carcinoma (HCC), is closely associated with chronic inflammation. We previously showed that farnesoid X receptor knockout ( FXR − / − ) mice displayed chronic inflammation and developed spontaneous liver tumors when they aged. However, the mechanism by which inflammation leads to HCC in the absence of FXR is unclear. Because IFNγ is one of the most upregulated pro-inflammatory cytokines in FXR − / − livers, we generated IFNγ − / − FXR − / − double knockout mice to determine IFNγ's roles in hepatocarcinogenesis. Methods IFNγ − / − mice were crossed with an FXR − / − C57BL/6 background or injected i.p. with the hepatocarcinogen diethylnitrosamine (DEN). Hepatocarcinogenesis was analyzed with biochemical and histological methods. Results IFNγ deletion accelerated spontaneous hepatocarcinogenesis in FXR − / − mice and increased the susceptibility to DEN-induced hepatocarcinogenesis. IFNγ deletion enhanced activation of HCC promoters STAT3 and JNK/c-Jun, but abolished induction of p53 in IFNγ − / − livers after acute DEN-induced injury. Furthermore, hepatic p53 expression increased in aged wild type mice but not in aged IFNγ − / − and IFNγ − / − FXR − / − mice, while activation of STAT3 and JNK/c-Jun was enhanced in aged IFNγ − / − and IFNγ − / − FXR − / − mice. In addition, IFNγ inhibited liver cancer xenograft growth and impaired IL-6-induced STAT3 phosphorylation by inducing SOCS1/3 expression. Conclusions Increased IFNγ expression in FXR − / − livers represents a protective response of the liver against chronic injury and tumorigenesis. IFNγ suppresses hepatocarcinogenesis by inducing p53 expression and preventing STAT3 activation.
- Published
- 2012
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