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Astragaloside IV suppresses post-ischemic natural killer cell infiltration and activation in the brain: involvement of histone deacetylase inhibition

Baokai Dou, Shichun Li, Luyao Wei, Lixin Wang, Shiguo Zhu, Zhengtao Wang, Zunji Ke, Kaixian Chen, Zhifei Wang

《医学前沿（英文）》 2021年 第15卷 第1期   页码 79-90 doi: 10.1007/s11684-020-0783-8

摘要： Natural killer (NK) cells, a type of cytotoxic lymphocytes, can infiltrate into ischemic brain and exacerbate neuronal cell death. Astragaloside IV (ASIV) is the major bioactive ingredient of , a Chinese herbal medicine, and possesses potent immunomodulatory and neuroprotective properties. This study investigated the effects of ASIV on post-ischemic brain infiltration and activation of NK cells. ASIV reduced brain infarction and alleviated functional deficits in MCAO rats, and these beneficial effects persisted for at least 7 days. Abundant NK cells infiltrated into the ischemic hemisphere on day 1 after brain ischemia, and this infiltration was suppressed by ASIV. Strikingly, ASIV reversed NK cell deficiency in the spleen and blood after brain ischemia. ASIV inhibited astrocyte-derived CCL2 upregulation and reduced CCR2 NK cell levels in the ischemic brain. Meanwhile, ASIV attenuated NK cell activating receptor NKG2D levels and reduced interferon-γ production. ASIV restored acetylation of histone H3 and the p65 subunit of nuclear factor-κB in the ischemic brain, suggesting inhibition of histone deacetylase (HDAC). Simultaneously, ASIV prevented p65 nuclear translocation. The effects of ASIV on reducing CCL2 production, restoring acetylated p65 levels and preventing p65 nuclear translocation were mimicked by valproate, an HDAC inhibitor, in astrocytes subjected to oxygen-glucose deprivation. Our findings suggest that ASIV inhibits post-ischemic NK cell brain infiltration and activation and reverses NK cell deficiency in the periphery, which together contribute to the beneficial effects of ASIV against brain ischemia. Furthermore, ASIV’s effects on suppressing NK cell brain infiltration and activation may involve HDAC inhibition.

关键词： astragaloside IV     brain ischemia     natural killer cells     histone deacetylase     nuclear factor-κB    

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Inhibition of NF-kappa B can enhance Fas-mediated apoptosis in leukemia cell line HL-60

Li WANG, Shi ZHAO, Hong-Xiang WANG, Ping ZOU

《医学前沿（英文）》 2010年 第4卷 第3期   页码 323-328 doi: 10.1007/s11684-010-0026-5

摘要： This study explored the effects of nuclear factor-kappa B (NF-κB) inhibitor Bay 11-7082 on Fas/FasL system and Fas-mediated apoptosis in cell line HL-60 cells. The mRNA and protein levels of Fas, FasL, and X-linked inhibitor of apoptosis protein (XIAP) were detected by reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry (FCM); the level of sFasL was evaluated by enzyme-linked immunosorbent assay (ELISA); and apoptosis was determined by FCM. After treatment with Bay 11-7082, the mRNA and protein levels of FasL and XIAP in HL-60 cells were significantly lower than in the controls ( <0.05), but the mRNA and protein levels of Fas and sFasL did not change significantly ( >0.05). Apoptotic rate of HL-60 cells treated with Bay 11-7082 was significantly higher than in the controls ( <0.05). Therefore, we conclude that Bay 11-7082 can enhance Fas-mediated apoptosis in HL-60 cells by downregulating FasL and XIAP levels.

关键词： nuclear factor-kappa B     Fas/FasL system     HL-60     Bay 11-7082    

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Expression of STAT6 and NF-κB p65 in the colon mucosa of patients with ulcerative colitis

Rui ZHU MD, Heng FAN MD, Lin SHEN MD, Jianguo LIU BD, Jia ZHAO MM,

《医学前沿（英文）》 2009年 第3卷 第4期   页码 475-479 doi: 10.1007/s11684-009-0086-6

摘要： The expression of signal transducer and activator of transcription 6 (STAT6) and nuclear factor-κB (NF-κB) in the colonic mucosa of patients with ulcerative colitis (UC) was examined. Real-time polymerase chain reaction and immunohistochemistry were used to detect the expression of STAT6 and NF-κB p65 at both mRNA and protein levels in the colonic mucosa of patients with UC and healthy volunteers. The results showed that the expression levels of STAT6 and NFκB p65 in the colonic mucosa of patients with UC were significantly higher than in normal controls at both mRNA and protein levels. These data suggest that STAT6 and NFκB p65 perhaps play an important role in the pathogenesis of UC and underscore the potential value of anti-UC strategies in the clinical management of this disease.

关键词： ulcerative colitis     signal transducer and activator of transcription 6 (STAT6)     nuclear factor-κ     B p65 (NF-κ     B p65)    

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Expression of integrin in hepatic fibrosis and intervention of resveratrol

Jianye WU, Chuanyong GUO, Jun LIU, Xuanfu XUAN

《医学前沿（英文）》 2009年 第3卷 第1期   页码 100-107 doi: 10.1007/s11684-009-0013-x

摘要： The aim of this study was to explore the expression of integrin-β1 in different stages of hepatic fibrosis and intervention of resveratrol as well as the way by which integrin-β1 promoted hepatic fibrosis. Hepatic fibrosis models of male Sprague Dawley (SD) rats were created and intragastric administration of resveratrol was given in low (40 mg/kg), middle (120 mg/kg) and high (200 mg/kg) dose groups. The expression of integrin-β1, tumor growth factor-β (TGF-β) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in different stages of hepatic fibrosis was detected by using RT-PCR. The expression of hexadecenoic acid (HA) and precollagen III (pc III) was assayed by radioimmunoassay. The expression of integrin-β1, TGF-β and TIMP-1 was determined in each group. Liver function and pathological sections of each group in different stages of hepatic fibrosis was tested to judge the therapeutic efficacy of resveratrol at different doses. The expression of integrin-β1 in normal control group was low and steady and was not increased as the development of hepatic fibrosis, but it is increased in other groups. The expression levels of integrin-β1 in the model control group (0.878±0.03, <0.01) and low dose group (0.855±0.04, <0.01) were higher than other groups, but there was no difference between model control group and low dose group ( >0.05). The expression levels of integrin-β1 and TGF-β in middle dose group and high dose group were higher than other groups ( <0.01). The expression levels of integrin-β1 and TGF-β in model control group and low dose group were lower than the normal control group ( <0.01). The expression levels of TIMP-1 in the model control and low dose groups were higher than the other groups ( <0.01). The expression levels of TIMP-1 in the middle dose group and the high dose group were lower than the normal control group ( <0.01). The expression of integrin-β1 existed in all stages of hepatic fibrosis of SD rats, and it was increased as the development of hepatic fibrosis. The expression of TGF-β and TIMP-1 was consistent with that of integrin-β1 in different stages of hepatic fibrosis. Resveratrol could improve the degree of hepatic fibrosis of SD rats and decrease the expression of integrin-β1 markedly at a dose of 120 mg/kg.

关键词： liver fibrosis     integrin-β1     resveratrol     tumor growth factor-β     tissue inhibitor of metalloproteinase-1    

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Tramadol reinforces antidepressant effects of ketamine with increased levels of brain-derived neurotrophic factorand tropomyosin-related kinase B in rat hippocampus

null

《医学前沿（英文）》 2012年 第6卷 第4期   页码 411-415 doi: 10.1007/s11684-012-0226-2

摘要：

Ketamine exerts rapid and robust antidepressant properties in both animal models and depressed patients and tramadol possesses potential antidepressant effects. Brain-derived neurotrophic factor (BDNF) is an important biomarker for mood disorders and tropomyosin-related kinase B (TrkB) is a high affinity catalytic receptor for BDNF. We hypothesized that tramadol pretreatment might reinforce ketamine-elicited antidepressant effects with significant changes in hippocampal BDNF and TrkB levels in rats. Immobility time of rats receiving different treatment in the forced swimming test (FST) was observed. Levels of BDNF and TrkB in hippocampus were measured by enzyme linked immunosorbent assay. Results showed that tramadol (5 mg/kg) administrated alone neither elicited antidepressant effects nor altered BDNF or TrkB level. However, pretreatment with tramadol (5 mg/kg) enhanced the ketamine (10 mg/kg) -elicited antidepressant effects and upregulated the BDNF and TrkB levels in hippocampus. In conclusion, tramadol pretreatment reinforces the ketamine-elicited antidepressant effects, which is associated with the increased levels of BDNF and TrkB in rat hippocampus.

关键词： tramadol     ketamine     antidepressant     brain-derived neurotrophic factor     tropomyosin-related kinase B    

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Inhibition of the nuclear export of p65 and IQCG in leukemogenesis by NUP98-IQCG

null

《医学前沿（英文）》 2016年 第10卷 第4期   页码 410-419 doi: 10.1007/s11684-016-0489-0

摘要：

NUP98 fuses with approximately 34 different partner genes via translocation in hematological malignancies. Transgenic or retrovirus-mediated bone marrow transplanted mouse models reveal the leukemogenesis of some NUP98-related fusion genes. We previously reported the fusion protein NUP98-IQ motif containing G (IQCG) in a myeloid/T lymphoid bi-phenoleukemia patient with t(3;11) and confirmed its leukemogenic ability. Herein, we demonstrated the association of NUP98-IQCG with CRM1, and found that NUP98-IQCG expression inhibits the CRM1-mediated nuclear export of p65 and enhances the transcriptional activity of nuclear factor-κB. Moreover, IQCG could be entrapped in the nucleus by NUP98-IQCG, and the fusion protein interacts with calmodulin via the IQ motif in a calcium-independent manner. Therefore, the inhibition of nuclear exports of p65 and IQCG might contribute to the leukemogenesis of NUP98-IQCG.

关键词： NUP98-IQCG     nuclear export     NF-κB     CRM1    

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Early and marked up-regulation of TNF-α in acute respiratory distress syndrome after cardiopulmonary bypass

null

《医学前沿（英文）》 2012年 第6卷 第3期   页码 296-301 doi: 10.1007/s11684-012-0219-1

摘要：

Despite the technique of cardiopulmonary bypass (CPB) improved the development of modern cardiac surgery, many factors during CPB have been reported to induce acute respiratory distress syndrome (ARDS). The present study was to investigate which pro-inflammatory factors involved in the early phase of ARDS. Ten patients underwent valve replacement surgery with or without ARDS were enrolled for analysis of pulmonary function and inflammatory factors release including white blood cell (WBC), neutrophils, CD11b, CD18, interleukin (IL)-8 and tumor necrosis factor-α (TNF-α). The results demonstrated that the ratio of arterial oxygen tension/fraction of inspire oxygen (PaO2/FiO2) was greatly reduced in ARDS patients, but only the release of TNF-α was significantly increased, which was reversely correlated to the values of PaO2/FiO2. Also, the count of neutrophils adhesive to pulmonary endothelial cells was significantly increased in ARDS patients. Therefore, we concluded that TNF-α was quickly up-regulated and involved in the pathogenesis of CPB-induced ARDS via guiding primed neutrophils to pulmonary interstitium.

关键词： tumor necrosis factor-α     cardiopulmonary bypass     inflammation     acute respiratory distress syndrome    

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Ultraviolet-B induced expression of hypoxia-inducible factor 1α, transferrin receptor through EGFR/PI3K

LI Yanhua, BI Zhigang

《医学前沿（英文）》 2007年 第1卷 第1期   页码 79-86 doi: 10.1007/s11684-007-0016-4

摘要： The aim of this research was to explore the effects and signaling pathway of ultraviolet-B (UVB) irradiation on the expression of hypoxia-inducible factor 1α (HIF-1α) and transferrin receptor (TfR). HIF-1α protein was measured by Western blot method. Expressions of epidermal growth factor receptor (EGFR), phosphor-EGF-R and TfR after UVB irradiation were determined with flow cytometry. After UVB irradiation, mRNA levels of HIF-1α and TfR were detected by real time-PCR. Results showed that compared with control groups, UVB was able to induce HIF1α and TfR protein expression in a dose- and time-dependent manner in HaCat cells (<0.05). TfR mRNA was expressed in a dose-dependent manner and reached a peak at the 8th hour in HaCat cells (<0.05) whereas HIF-1α mRNA expression was not affected by UVB treatment (>0.05). The EGFR/PI3K/AKT signaling pathway was required for the induction of HIF-1α and TfR expression induced by UVB. UVB induced activation of EGFR in HaCat cells and EGFR regulated expression of TfR and HIF-1α. EGFR (-/-) MEF did not increase the HIF1 expression following UVB irradiation (>0.05). In contrast, EGFR (+/+) MEF strongly enhanced HIF1α expression after UVB irradiation (<0.05). PD153035, a selective inhibitor of EGFR tyrosine kinase, inhibited the TfR protein expression in UVB-treated cells in a dose-dependent manner (P<0.05). PI3K inhibitors, LY294002 and wortmannin, inhibited HIF-1? and TfR expressions induced by UVB (P<0.05). The DEC1 (-/-) Ha-Cat cells did not increase their TfR and HIF-1α expressions following UVB irradiation (>0.05). In contrast, DEC1 (+/+) HaCat cells strongly enhanced TfR and HIF-1? protein expression after UVB irradiation (P<0.05). We conclude that UVB induces TfR and HIF-1αexpressions via EGFR/PI3K/AKT/DEC1 signaling pathway.
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Effect of compound Sophorae Flavescentis Jiechangrong capsule on expression of NF-κB p65 and STAT6

Heng FAN MD, Jia ZHAO MM, Lin SHEN BM, Qing TANG MD, Zhexin SHOU MM, Li LIANG BM, Yi LIAO BM, Xiaoyan CHEN BM,

《医学前沿（英文）》 2009年 第3卷 第4期   页码 480-484 doi: 10.1007/s11684-009-0083-9

摘要： The effects of compound Sophorae Flavescentis Jiechangrong capsule (CSFJC) on the expression of nuclear factor-κB p65 (NF-κB p65) and signal transducer and activator of transcription 6 (STAT6) in the intestinal mucosa of patients with ulcerative colitis and the possible mechanism were investigated. Eighteen patients with ulcerative colitis were randomly divided into a traditional Chinese medicine (TCM) group ( = 11) treated by CSFJC and a western medicine (WM) group ( = 7) treated by Sulfasalazine tablets. The treatment duration lasted eight weeks. Before and after the treatment, the symptoms and the physical signs were observed, and the routine stool test, the colonoscopy, and pathological examination were performed in the two groups. The expression levels of NF-κBp65 and STAT6 were detected by using immunohistochemistry. The results showed that the total effective rate of the curative effectiveness in TCM and WM groups was 100% and 71.4%, respectively, and the total effective rate of colonic mucosa lesion in TCM and WM groups was 90.9% and 71.4%, respectively, with the differences being significant (all < 0.05). The total effective rate of syndromes of damp-heat blocking according to the TCM in TCM and WM groups was 90.9% and 71.4%, respectively. After the treatment, the expression of NF-κB p65 and STAT6 in the two groups was decreased, and the decrease of NF-κB p65 and STAT6 expression in TCM group was more significant than in WM group ( < 0.05). It was concluded that CSFJC can inhibit the activation and expression of NF-κB p65 and STAT6 in the intestinal mucosa of patients with ulcerative colitis, which is a possible mechanism for CSFJC treating ulcerative colitis.

关键词： colitis     ulcerative     compound Sophorae Flavescentis Jiechangrong capsule     nuclear factor-κ     B p65 (NF-κ     B p65)     signal transducer and activator of transcription 6 (STAT6)    

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Metabonomic study of the biochemical profiles of heterozygous myostatin knockout swine

Jianxiang XU,Dengke PAN,Jie ZHAO,Jianwu WANG,Xiaohong HE,Yuehui MA,Ning LI

《农业科学与工程前沿（英文）》 2015年 第2卷 第1期   页码 90-99 doi: 10.15302/J-FASE-2015045

摘要： Myostatin is a transforming growth factor-β family member that normally acts to limit skeletal muscle growth. Myostatin gene ( ) knockout (KO) mice show possible effects for the prevention or treatment of metabolic disorders such as obesity and type 2 diabetes. We applied chromatography and mass spectrometry based metabonomics to assess system-wide metabolic response of heterozygous KO ( ) swine. Most of the metabolic data for swine were similar to the data for wild type (WT) control swine. There were, however, metabolic changes related to fatty acid metabolism, glucose utilization, lipid metabolism, as well as BCAA catabolism caused by monoallelic depletion.The statistical analyses suggested that: (1) most metabolic changes were not significant in swine compared to WT swine; (2) only a few metabolic properties were significantly different between KO and WT swine, especially for lipid metabolism. Significantly, these minor changes were most evident in female KO swine and suggested differences in gender sensitivity to myostatin.

关键词： myostatin     transforming growth factor-β family     skeletal muscle     metabolic disorders     chromatography     mass spectrometry     metabonomics    

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Hepatitis B virus X protein upregulates tumor necrosis factor-α expression of rat mesangial cell

Hong-Zhu LU MD, Dan LIU BM, Qi-Hong FAN BM, Jian-Hua ZHOU MD,

《医学前沿（英文）》 2010年 第4卷 第1期   页码 106-111 doi: 10.1007/s11684-010-0004-y

摘要： Hepatitis B virus X protein (HBx), a 17-kd protein encoded by X gene of hepatitis B virus (HBV), has been shown to function as a transcriptional trans-activator of a variety of viral and cellular promoter/enhancer elements. The aim of the study is to investigate the extracellular regulated protein kinases (ERKs) pathway of HBx on glomerular mesangial cell (GMC) proliferation and tumor necrosis factor-α (TNF-α) expression. The HBV X gene was amplified by polymerase chain reaction (PCR), inserted into the eukaryotic expression vector pCI-neo and confirmed by restriction endonuclease digestion and sequence analysis. PCI-neo containing HBV X gene (pCI-neo-X) was then transfected into cultured GMC line via liposome. GMC proliferation, TNF-α and its mRNA expression were compared in the condition of with or without U0126 in culture media. HBx, ERK and p-ERK expression in GMCs was assessed by Western blotting. TNF-α mRNA expression was assessed by semi-quantitative reverse transcription-PCR (RT-PCR). TNF-α level in supernatants was measured by ELISA. GMC proliferation was detected by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) kit. The results showed that HBx expression was found in transfected GMCs and became prominent at 36th and 48th h after transfection whether with or without U0126 in culture media. TNF-α mRNA expression was significantly decreased in U0126 group compared with U0126-free group. TNF-α levels in supernatants in PCI-neo-X transfection without U0126 group were (189.0±18.1) and (172.3±24.3) pg/mL at 36th and 48th h after transfection, respectively. In contrast, TNF-α levels in supernatants with U0126 were (65.6±11.6) and (84.0±24.6) pg/mL at 36th and 48th h, respectively. The TNF-α levels in the latter groups were significantly lower than those in the former groups (<0.05). GMCs proliferation was also lower in added U0126 group at 36th and 48th h after transfection. From above, we can conclude that HBx could induce GMC proliferation and increase TNF-α mRNA expression and its protein production. HBx upregulates TNF-α expression and induces cell proliferation of GMC line partly through ERK signal transduction pathway.

关键词： hepatitis B virus     X gene     glomerular mesangial cell line     extracellular regulated protein kinases     tumor necrosis factor-α    

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Optimized human factor IX expression cassettes for hepatic-directed gene therapy of hemophilia B

null

《医学前沿（英文）》 2015年 第9卷 第1期   页码 90-99 doi: 10.1007/s11684-015-0390-2

摘要：

Gene therapy provides a potential cure for hemophilia B, and significant progress has been achieved in liver-directed gene transfer mediated by adeno-associated viral vectors. Recent clinical trials involving the use of a self-complementary adeno-associated virus serotype 8-human codon-optimized factor IX (AAV8-hFIXco) vector demonstrated encouraging efficacy with hFIX expression stabilized at 1% to 6% of normal level in patients, but safety concerns related to high vector doses are still present. Thus, further improvement of AAV vectors and hFIX expression cassette may positively contribute to the ultimate success of hemophilia B gene therapy. In this study, to obtain a higher expression level of hFIX that potentiates the coagulant capacity of recipients, human FIX expression vector was optimized by upgrading the codon adaption index and adjusting the GC content, inserting a Kozak sequence (GCCACC), and introducing a gain-of-function mutation, R338L (FIX Padua). The efficiency of the published and the presently constructed cassettes was compared through in vivo screening. In addition, the regulatory elements that control the FIX gene expression in these cassettes were screened for liver-specific effectiveness. Among all the constructed cassettes, scAAV-Pre-hFIXco-SIH-R338L, which was the construct under the control of the prothrombin enhancer and prealbumin promoter, resulted in the highest level of coagulant activity, and the expression levels of two constructed cassettes (scAAV-Chi-hFIXco-SIH-R338L and scAAV-Pre-hFIXco-SIH-R338L) were also higher than that of the published cassette (scAAV-LP1-hFIXco-SJ). In summary, our strategies led to a substantial increase in hFIX expression at the protein level or a remarkably elevated coagulant activity. Thus, these reconstructs of hFIX with AAV vector may potentially contribute to the creation of an efficacious gene therapy of hemophilia B.

关键词： factor IX     hemophilia B     liver-specific regulatory elements     hydrodynamic gene transfer    

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Presence of multiple abnormal immunologic markers is an independent prognostic factor of diffuse largeB-cell lymphoma

Yiwen Cao, Zhenhua Liu, Wen Wu, Ying Qian, Qin Shi, Rong Shen, Binshen Ouyang, Pengpeng Xu, Shu Cheng, Jin Ye, Yiming Lu, Chaofu Wang, Chengde Yang, Li Wang, Weili Zhao

《医学前沿（英文）》 2019年 第13卷 第1期   页码 94-103 doi: 10.1007/s11684-019-0680-1

摘要：

Autoimmune diseases (ADs) increase the risk of non-Hodgkin’s lymphoma and contribute to poor prognosis of patients. However, the association between immunologic markers and clinical outcome has rarely been investigated. This study aims to analyze the prognostic value of pretreatment immunologic markers in newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL). We retrospectively reviewed the data on 502 patients with DLBCL treated in our institution from January 2013 to March 2018. Survival functions were estimated using Kaplan–Meier method and Cox regression model. The 3-year progression free survival (PFS) and overall survival (OS) rates were 70.2% and 80.9%, respectively, and the complete remission (CR) rate was 78.1%. Among the patients, those with multiple (≥3) abnormal immunologic markers had significantly shorter 3-year PFS (52.7% vs. 77.3%, P<0.001) and OS (68.5% vs. 85.8%, P=0.001) than those without multiple abnormal immunologic markers. Multivariate analysis revealed that the presence of multiple abnormal immunologic markers and the elevated serum levels of lactate dehydrogenase were the independent adverse prognostic factors for PFS (P=0.008, P<0.001) and OS (P=0.003, P<0.001). Meanwhile, advanced Ann Arbor stage was an independent adverse prognostic factor for PFS (P=0.001) and age>60 years for OS (P=0.014). In conclusion, the immunologic status was closely related to lymphoma progression, and this study provides new insights into the risk stratification of patients with DLBCL.

关键词： immunologic marker     diffuse large B-cell lymphoma     prognosis    

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转录因子HNF1A、HNF4A和FOXA2调节肝细胞蛋白质N-糖基化 Article

Vedrana Vičić Bočkor,Nika Foglar,Goran Josipović,Marija Klasić,Ana Vujić,Branimir Plavša,Toma Keser,Samira Smajlović,Aleksandar Vojta,Vlatka Zoldoš

《工程（英文）》 2024年 第32卷 第1期   页码 58-69 doi: 10.1016/j.eng.2023.09.019

摘要：

Hepatocyte nuclear factor 1 alpha (HNF1A), hepatocyte nuclear factor 4 alpha (HNF4A), and forkhead box protein A2 (FOXA2) are key transcription factors that regulate a complex gene network in the liver, creating a regulatory transcriptional loop. The Encode and ChIP-Atlas databases identify the recognition sites of these transcription factors in many glycosyltransferase genes. Our in silico analysis of HNF1A, HNF4A, and FOXA2 binding to the 10 candidate glyco-genes studied in this work confirms a significant enrichment of these transcription factors specifically in the liver. Our previous studies identified HNF1A as a master regulator of fucosylation, glycan branching, and galactosylation of plasma glycoproteins. Here, we aimed to functionally validate the role of the three transcription factors on downstream glyco-gene transcriptional expression and the possible effect on glycan phenotype. We used the state-of-the-art clustered regularly interspaced short palindromic repeats/dead Cas9 (CRISPR/dCas9) molecular tool for the downregulation of the HNF1A, HNF4A, and FOXA2 genes in HepG2 cells—a human liver cancer cell line. The results show that the downregulation of all three genes individually and in pairs affects the transcriptional activity of many glyco-genes, although downregulation of glyco-genes was not always followed by an unambiguous change in the corresponding glycan structures. The effect is better seen as an overall change in the total HepG2 N-glycome, primarily due to the extension of biantennary glycans. We propose an alternative way to evaluate the N-glycome composition via estimating the overall complexity of the glycome by quantifying the number of monomers in each glycan structure. We also propose a model showing feedback loops with the mutual activation of HNF1A–FOXA2 and HNF4A–FOXA2 affecting glyco-genes and protein glycosylation in HepG2 cells.

关键词： Clustered regularly interspaced short palindromic repeats/dead Cas9 (CRISPR/dCas9)     Epigenetics     Hepatocyte nuclear factor 1 alpha (HNF1A)     Hepatocyte nuclear factor 4 alpha (HNF4A)     Forkhead box protein A2 (FOXA2)     N-glycosylation     HepG2 cells    

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A small-molecule pan-HER inhibitor alone or in combination with cisplatin exerts efficacy against nasopharyngeal carcinoma

《医学前沿（英文）》 2023年 第17卷 第2期   页码 275-289 doi: 10.1007/s11684-022-0945-y

摘要： The abnormal activation of HER family kinase activity is closely related to the development of human malignancies. In this study, we used HER kinases as targets for the treatment of nasopharyngeal carcinoma (NPC) and explored the anti-tumor effects of the novel pan-HER inhibitor HM781-36B, alone or in combination with cisplatin. We found that HER family proteins were positively expressed in tumor tissues of some NPC patients, and the high levels of those proteins were significantly related to poor prognosis. HM781-36B inhibited NPC in vitro and in vivo. HM781-36B exerted synergistic effects with cisplatin on inhibiting proliferation and promoting apoptosis of NPC cells. In NPC xenograft models in nude mice, HM781-36B and cisplatin synergistically inhibited tumor growth. Downregulating the activity of HER family proteins and their downstream signaling pathways and regulating tumor microenvironment may explain the synergistic anti-tumor effects of HM781-36B and cisplatin. In conclusion, our study provides evidence for HER family proteins as prognostic biomarkers and potential therapeutic targets for NPC. The pan-HER inhibitor HM781-36B alone or in combination with cisplatin represents promising therapeutic effects for the treatment of NPC patients, which provides a new idea for the comprehensive treatment of NPC.

关键词： epidermal growth factor receptor     ErbB receptors     HM781-36B     nasopharyngeal carcinoma     molecular targeted therapy     cisplatin    

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标题 作者 时间 类型 操作

Astragaloside IV suppresses post-ischemic natural killer cell infiltration and activation in the brain: involvement of histone deacetylase inhibition

Baokai Dou, Shichun Li, Luyao Wei, Lixin Wang, Shiguo Zhu, Zhengtao Wang, Zunji Ke, Kaixian Chen, Zhifei Wang

期刊论文

Inhibition of NF-kappa B can enhance Fas-mediated apoptosis in leukemia cell line HL-60

Li WANG, Shi ZHAO, Hong-Xiang WANG, Ping ZOU

期刊论文

Expression of STAT6 and NF-κB p65 in the colon mucosa of patients with ulcerative colitis

Rui ZHU MD, Heng FAN MD, Lin SHEN MD, Jianguo LIU BD, Jia ZHAO MM,

期刊论文

Expression of integrin in hepatic fibrosis and intervention of resveratrol

Jianye WU, Chuanyong GUO, Jun LIU, Xuanfu XUAN

期刊论文

Tramadol reinforces antidepressant effects of ketamine with increased levels of brain-derived neurotrophic factorand tropomyosin-related kinase B in rat hippocampus

null

期刊论文

Inhibition of the nuclear export of p65 and IQCG in leukemogenesis by NUP98-IQCG

null

期刊论文

Early and marked up-regulation of TNF-α in acute respiratory distress syndrome after cardiopulmonary bypass

null

期刊论文

Ultraviolet-B induced expression of hypoxia-inducible factor 1α, transferrin receptor through EGFR/PI3K

LI Yanhua, BI Zhigang

期刊论文

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