16 results on '"Jun Yan"'
Search Results
2. KIF11 Promotes Proliferation of Hepatocellular Carcinoma among Patients with Liver Cancers.
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Zhan-Dong Hu, Ying Jiang, Hong-Mei Sun, Jing-wen Wang, Li-Li Zhai, Zhi-Qi Yin, and Jun Yan
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CELL proliferation ,ADENOSINE triphosphatase ,CELL lines ,HEPATOCELLULAR carcinoma ,IMMUNOHISTOCHEMISTRY ,SURVIVAL ,DISEASE progression - Abstract
Background. Hepatocellular carcinoma (HCC) lacks effective treatments and has a poor prognosis. Therefore it is needed to develop more effective drug targets. Kinesin family member 11 (KIF11) has been reported to affect the progression of several cancers, and its high expression associates with the prognosis of patients. However, the relevant mechanisms of KIF11 in HCC progression have not been studied. Method. Through the cancer genome atlas (TCGA) database and immunohistochemical (IHC) staining of patients' specimens, we determined that KIF11 was highly expressed in HCC tissues and associated with prognosis. We established a KIF11 stably depleted hepatoma cell line, through cell-cloning experiments and cell counting kit-8 (CCK-8) assays to detect the effects on proliferation in vitro. The role of KIF11 in promoting cell proliferation was verified in mice. Result. The expression of KIF11 was negatively correlated with the overall survival (OS) and disease-free survival (DFS) and positively correlated with tumor size of HCC patients. KIF11 depletion inhibits cell proliferation and tumor growth in vitro and in vivo. Conclusion. KIF11 can be used as a positive correlation marker for HCC prognosis and served as a potential therapeutic target. [ABSTRACT FROM AUTHOR]
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- 2021
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3. Small Nucleolar RNA, C/D Box 16 (SNORD16) Acts as a Potential Prognostic Biomarker in Colon Cancer.
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He, Jun-yan, Liu, Xin, Qi, Zhen-hua, Wang, Qi, Lu, Wen-qing, Zhang, Qing-tong, He, Shu-ya, and Wang, Zhi-dong
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NON-coding RNA , *COLON cancer , *CELL growth , *MULTIVARIATE analysis , *CELL lines - Abstract
Colon cancer (CC) is considered one of the most common and lethal malignancies occurring both in male and female. Its widespread prevalence demonstrates the need for novel diagnostic and prognostic biomarkers for CC. Emerging evidence has shown that small nucleolar RNAs play critical roles in tumor development. In this study, we investigated the expression profile and functions of SNORD16 in CC. Our data showed that SNORD16, rather than its host gene (RPL4), was upregulated in CC cell lines. Compared to matched adjacent normal tissues, CC tissues showed higher SNORD16 expression levels, and no correlation was found between SNORD16 and RPL4. Patients with high SNORD16 expression levels had a worse prognosis, and multivariate analysis showed the high SNORD16 expression was an independent prognostic factor for CC. In vitro gain- and loss-of-function studies revealed that SNORD16 can promote cell growth, proliferation, migration, and invasion of CC cells by inhibiting apoptosis. These results suggested that SNORD16 has an oncogenic role in CC and might be a novel diagnostic and prognostic biomarker for CC. [ABSTRACT FROM AUTHOR]
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- 2020
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4. Repaglinide-irbesartan drug interaction: effects of SLCO1B1 polymorphism on repaglinide pharmacokinetics and pharmacodynamics in Chinese population.
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Pei, Qi, Liu, Jun-Yan, Yin, Ji-Ye, Yang, Guo-Ping, Liu, Shi-Kun, Zheng, Yi, Xie, Pan, Guo, Cheng-Xian, Luo, Mi, Zhou, Hong-Hao, Li, Xi, and Liu, Zhao-Qian
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BLOOD sugar monitoring , *CELL lines , *DRUG interactions , *GENETIC polymorphisms , *HYPOGLYCEMIC agents , *PEPTIDES , *IRBESARTAN , *LOSARTAN , *VALSARTAN , *IN vitro studies , *MEMBRANE transport proteins , *PHARMACODYNAMICS - Abstract
Purpose: On account of the potential inhibition of OATP1B1 (organic anion transporting polypeptide) by angiotensin II receptor blockers (ARBs) and the effects of SLCO1B1 (solute carrier organic anion transporter family member) polymorphism, the aim of current study is to assess the impact of ARBs on the pharmacokinetics (PK) and pharmacodynamics (PD) of repaglinide in Chinese healthy volunteers with different SLCO1B1 genotypes.Methods: The in vitro study was conducted on irbesartan, valsartan, olmesartan, and losartan by using HEK293 cells transfected with OATP1B1. Data on drug interactions between repaglinide and irbesartan from 21 healthy Chinese-Han male volunteers were collected and analyzed.Results: IC50 from in vitro study suggested irbesartan was the most potent inhibitor of OATP1B1 transporter. Clinical data from single dose of repaglinide indicated SLCO1B1 c.521 T>C polymorphism influenced the PK and PD of repaglinide in healthy Chinese-Han male volunteers. In subjects with SLCO1B1 c.521 TT genotype, irbesartan comedication increased the exposure of repaglinide. In details, the peak plasma concentration [Cmax] increased 84% (P = 0.003) and the area under the curve of plasma concentration 0-8 h [AUC0-8] increased 34% (P = 0.004), while the minimum blood glucose concentration [Cmin] decreased 33.8% (P = 0.005). No significant change was observed in repaglinide exposure in subjects with SLCO1B1 c.521 TC genotype in presence or absence of irbesartan.Conclusion: SLCO1B1 c.521 T>C polymorphism affects the PK of repaglinide in Chinese population. Irbesartan increased repaglinide exposure in subjects with SLCO1B1 c.521 TT genotype, but not SLCO1B1 c.521 TC genotype. [ABSTRACT FROM AUTHOR]
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- 2018
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5. Neuroprotective Effects of Dammarane-Type Saponins from Panax notoginseng on Glutamate-Induced Cell Damage in PC12 Cells.
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Zhang, Bao-Bao, Hu, Xiao-Long, Wang, Yu-Yan, Li, Jun-Yan, Pham, Thi-Anh, and Wang, Hao
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GLUTAMIC acid ,BIOMARKERS ,PROTEIN kinases ,GLYCOSIDES ,SUPEROXIDE dismutase ,APOPTOSIS ,CELL survival ,MITOCHONDRIA ,MALONDIALDEHYDE ,CELLULAR signal transduction ,NEUROPROTECTIVE agents ,LACTATE dehydrogenase ,PLANT extracts ,CELL lines ,COLORIMETRY ,REACTIVE oxygen species ,MOLECULAR structure ,GINSENG ,DAMMARANES ,NEURODEGENERATION ,PHOSPHORYLATION - Abstract
Dammarane-type saponins, the main active ingredients of Panax notoginseng , have substantial neuroprotective effects in different animal models of neurodegenerative diseases. However, because these compounds have different structures, the level of protection provided by individual compounds varies, and highly active compounds can be selected based on structure-activity relationships. Glutamate is a major excitatory neurotransmitter that plays an important role in synaptic response development. However, excessive extracellular glutamate levels lead to neuronal dysfunctions in the central nervous system. Herein, we investigated the neuroprotective effects of nine saponins (compounds 1 – 9) on glutamate-treated PC12 cells in the concentration range of 0.1 – 10 µM. The MTT assay revealed that these compounds increased cell viability to 65.6, 69.8, 76.9, 91.7, 74.4, 63.3, 59.9, 64.7, and 59.9%, respectively, compared with the glutamate-treated cells (44.6%). Protopanaxatriol (compound 4) was the most neuroprotective compound, and subsequent experiments revealed that pretreatment with compound 4 significantly reverses mitochondrial membrane potential collapse, increases superoxide dismutase activity, and decreases lactate dehydrogenase leakage, malondiadehyde levels, reactive oxygen species generation, and cell apoptosis. Compound 4 also decreased the Bax/Bcl-2 ratio, cleaved caspase-3, N -methyl-D-aspartic receptor 1, and Ca
2+ -/calmodulin-dependent protein kinase II expression, and inhibited glutamate-induced cytochrome C release and phosphorylation of apoptosis signal-regulating kinase 1, c-Jun N-terminal kinase, and p38. Overall, the results indicate that protopanaxatriol has significant neuroprotective effects, and might be a promising neuroprotective agent for preventing and treating neurodegenerative diseases. [ABSTRACT FROM AUTHOR]- Published
- 2019
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6. Antiviral activity of PHA767491 against human herpes simplex virus in vitro and in vivo.
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Jue Hou, Zili Zhang, Qiang Huang, Jun Yan, Xiaohu Zhang, Xiaoliang Yu, Guihua Tan, Chunfu Zheng, Feng Xu, Sudan He, Hou, Jue, Zhang, Zili, Huang, Qiang, Yan, Jun, Zhang, Xiaohu, Yu, Xiaoliang, Tan, Guihua, Zheng, Chunfu, Xu, Feng, and He, Sudan
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HERPES simplex treatment ,TREATMENT of encephalitis ,ACYCLOVIR ,WESTERN immunoblotting ,VIRAL genes ,DNA polymerase genetics ,THERAPEUTICS ,ANIMALS ,ANTIVIRAL agents ,BIOLOGICAL models ,CELL lines ,DRUG resistance in microorganisms ,GENES ,HERPES simplex ,HERPESVIRUSES ,HETEROCYCLIC compounds ,MICE ,MICROBIAL sensitivity tests ,PIPERIDINE ,PROTEINS ,CHEMICAL inhibitors ,PHARMACODYNAMICS - Abstract
Background: Herpes simplex virus (HSV) is a common human pathogen that causes a variety of diseases, including oral-labial, genital lesions and life-threatening encephalitis. The antiviral nucleoside analogues such as acyclovir are currently used in anti-HSV therapies; however, clinical overuse of these drugs has led to the emergence of drug-resistant viral strains. Hence, there is an urgent need to develop new anti-HSV agents.Methods: To identify novel anti-HSV-1 compounds, we screened the LOPAC small scale library of 1280 bioactive compounds to identify inhibitors of HSV-1-induced necroptosis. Further experiments including western blot analysis, Q-PCR analysis and immunohistochemistry were performed to explore the antiviral mechanism of the compounds.Results: Here, we identified PHA767491 as a new inhibitor of HSV. PHA767491 potently blocked the proliferation of HSV in cells, as well as HSV induced cell death. Further, we found that PHA767491 strongly inhibited HSV infection post viral entry. Moreover, PHA767491 reduced the expression of viral genes required for DNA synthesis including UL30/42 DNA polymerase and UL5/8/52 helicase-primase complex. The essential immediate early (IE) genes such as ICP4 and ICP27 are critical for the expression of the early and late genes. Of note, PHA767491 inhibited the expression of all IE genes of both HSV-1 and HSV-2. Importantly, PHA767491 reduced viral titers in the tissues from the mice infected with HSV-1. Consistently, immunohistochemistry analysis showed that PHA767491 dramatically attenuated expression of viral protein gB in the livers.Conclusions: Taken together, PHA767491 has potent anti-HSV activity by inhibiting viral replication both in vitro and in mouse model. Thus, PHA767491 could be a promising agent for the development of new anti-HSV therapy. [ABSTRACT FROM AUTHOR]- Published
- 2017
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7. N-butanol Extract from Melilotus Suaveolens Ledeb Affects Pro- and Anti-Inflammatory Cytokines and Mediators.
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Lei Zhao, Jun-Yan Tao, Shu-Ling Zhang, Feng Jin, Ran Pang, and Ji-Hua Dong
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PLANT extracts , *SWEET clover , *CYTOKINES , *TRADITIONAL medicine , *CELL lines - Abstract
Melilotus suaveolens Ledeb is a traditional medicinal plant for treating inflammation-related disease. This explores the inner anti-inflammatory mechanism of n-butanol extract from M. suaveolens Ledeb. Inflammatory cellular model was established by lipopolysaccharide intervention on RAW264.7 cell line. Levels of secreted cytokines TNF-α, IL-1β, IL-6, NO and IL-10 in supernatant, mRNA expression of TNF-α, COX-2, iNOS and HO-1, protein expression of COX-2 and HO-1, activation of NF-κB and ingredients in the extract were assayed by ELISA, real time quantitative PCR, western blot, immunocytochemical test and HPLC fingerprint test, respectively. As a result, the extract could not only markedly reduce the production of pro-inflammatory mediators to different extents by blocking NF-κB activation but also promote the release of anti-inflammatory mediator HO-1 significantly. Each 1 g extract contained 0.023531 mg coumarin and another two high polar ingredients, probably saponins. It can be concluded that the extract has similar effects on antagonizing pro-inflammatory mediators and cytokines like Dexamethasone, and has effects on promoting the production of anti-inflammatory mediators. [ABSTRACT FROM PUBLISHER]
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- 2010
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8. Blocking TLR2 Activity Attenuates Pulmonary Metastases of Tumor.
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Hong-Zhen Yang, Bing Cui, Han-Zhi Liu, Su Mi, Jun Yan, Hui-Min Yan, Fang Hua, Heng Lin, Wen-Feng Cai, Wen-Jie Xie, Xiao-Xi Lv, Xiao-Xing Wang, Bing-Mu Xin, Qi-Min Zhan, and Zhuo-Wei Hu
- Subjects
CANCER invasiveness ,CANCER patients ,METASTASIS ,MELANOMA ,CANCER cells ,CELL lines ,PROTEINS ,CYTOKINES ,CHEMOKINES - Abstract
Background: Metastasis is the most pivotal cause of mortality in cancer patients. Immune tolerance plays a crucial role in tumor progression and metastasis. Methods and Findings: In this study, we investigated the potential roles and mechanisms of TLR2 signaling on tumor metastasis in a mouse model of intravenously injected B16 melanoma cells. Multiple subtypes of TLRs were expressed on B16 cells and several human cancer cell lines; TLR2 mediated the invasive activity of these cells. High metastatic B16 cells released more heat shock protein 60 than poor metastatic B16-F1 cells. Importantly, heat shock protein 60 released by tumor cells caused a persistent activation of TLR2 and was critical in the constitutive activation of transcription factor Stat3, leading to the release of immunosuppressive cytokines and chemokines. Moreover, targeting TLR2 markedly reduced pulmonary metastases and increased the survival of B16-bearing mice by reversing B16 cells induced immunosuppressive microenvironment and restoring tumor-killing cells such as CD8
+ T cells and M1 macrophages. Combining an anti-TLR2 antibody and a cytotoxic agent, gemcitabine, provided a further improvement in the survival of tumor-bearing mice. Conclusions and Significance: Our results demonstrate that TLR2 is an attractive target against metastasis and that targeting immunosuppressive microenvironment using anti-TLR2 antibody is a novel therapeutic strategy for combating a life-threatening metastasis. [ABSTRACT FROM AUTHOR]- Published
- 2009
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9. Anti-inflammatory effects of ethyl acetate fraction from Melilotus suaveolens Ledeb on LPS-stimulated RAW 264.7 cells
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Tao, Jun-Yan, Zheng, Guo-Hua, Zhao, Lei, Wu, Jian-Guo, Zhang, Xiao-Yu, Zhang, Shu-Ling, Huang, Zhi-Jun, Xiong, Fu-Liang, and Li, Chong-Ming
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ANTI-inflammatory agents , *ACETATES , *SWEET clover , *ENDOTOXINS , *CELL lines , *INTERLEUKIN-10 , *TUMOR necrosis factors , *GENETIC regulation , *THERAPEUTICS - Abstract
Abstract: Aim of the study: This paper aimed to elucidate the anti-inflammatory effects of EtOAc fraction prepared from Melilotus suaveolens Ledeb ethanol extract with a cellular model of LPS-stimulated RAW 264.7 cell. Materials and methods: Some key pro-inflammatory cytokines and mediators including IL-1β, IL-6, NO, iNOS, COX-2 and TNF-α, two important anti-inflammatory cytokines and mediators IL-10 and HO-1, I-κB and NF-κB were studied by sandwich ELISA, real-time PCR, western blot analysis and immunocytochemistry. At last a HPLC fingerprint was taken to evaluate the fraction. Results: The EtOAc fraction could significantly inhibit the production of IL-1β, IL-6, NO, TNF-α, COX-2 in LPS-stimulated cell than that of single LPS-stimulated cell (p <0.01 or p <0.05), and the extract could increase the production of IL-10 and HO-1 than that of single LPS intervention cell (p <0.01 or p <0.05). Meanwhile, the extract also could inhibit the production of NF-κB compared to single LPS-stimulated cell. All the results showed that the extract had a good anti-inflammatory effect on LPS-stimulated RAW264.7 cell. Conclusions: Taken together, the anti-inflammatory actions of M. suaveolens Ledeb EtOAc fraction might be due to the down-regulation of IL-1β, IL-6, NO, TNF-α and COX-2 via the suppression of NF-κB activation, and another pathway was up regulating the production of IL-10 and HO-1. Meanwhile, the EtOAc fraction might be further studied to isolate the active anti-inflammatory ingredients besides coumarin. [Copyright &y& Elsevier]
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- 2009
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10. Anti-Inflammatory Mechanism of a Folk Herbal Medicine, Duchesnea indica (Andr) Focke at RAW264.7 Cell Line.
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Zhao, Lei, Zhang, Shu-Ling, Tao, Jun-Yan, Jin, Feng, Pang, Ran, Guo, Yuan-Jin, Ye, Pian, Dong, Ji-Hua, and Zheng, Guo-Hua
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ANTI-inflammatory agents ,HERBAL medicine ,PLANT extracts ,CELL lines ,MESSENGER RNA ,ENZYME-linked immunosorbent assay ,WESTERN immunoblotting ,INFLAMMATION treatment - Abstract
This study is to explore the anti-inflammatory mechanism of the ethanol extract of Duchesnea indica (Andr) Focke. An inflammatory cellular model was established by addition of lipopolysaccharide (LPS) on RAW264.7 cell line. The cellular secretion of TNF-α, IL-1β, IL-6, NO and IL-10 in supernatant, mRNA expression of TNF-α, COX-2, iNOS and HO-1, protein expression of COX-2 and HO-1, and activation of NF-κB were assayed by ELISA, the Griess method, real-time quantitative PCR, and Western blot and immunocytochemistry method, respectively. The ethanol extract of D. indica not only reduced production of pro-inflammatory cytokines and mediators and blocked NF-κB activation, but also slightly promoted release of the anti-inflammatory mediator HO-1 and suppressed IL-10 secretion. In conclusion, the anti-inflammatory effects of the extract of D. indica are attributed to the suppression of pro-inflammatory cytokines and mediators by blocking NF-κB activation. The extract of D. indica can also slightly promote HO-1 production to reduce inflammation. [ABSTRACT FROM AUTHOR]
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- 2008
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11. Anti-inflammatory Mechanism of Rungia pectinata (Linn.) Nees.
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Zhao, Lei, Tao, Jun-Yan, Zhang, Shu-Ling, Jin, Feng, Pang, Ran, Dong, Ji-Hua, Guo, Yuan-Jin, and Ye, Pian
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CELL lines , *CELL culture , *INFLAMMATORY mediators , *IMMUNOREGULATION , *CELLULAR immunity - Abstract
This study is to explore the inner anti-inflammatory mechanism of the ethanol extract of Rungia pectinata (Linn.) Nees. As a result, the ethanol extract of Rungia pectinata (Linn.) Nees could not only strongly reduce production of pro-inflammatory cytokines and mediators via blocking NF-κB activation but slightly promote release of anti-inflammatory mediator HO-1 and suppress IL-10 secretion. In conclusion, compared to Dexamethasone, Rungia pectinata (Linn.) Nees has not only similar effects on antagonizing pro-inflammatory mediators and cytokines but also mild effects on promoting production of anti-inflammatory mediators. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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12. Selective requirement for Mediator MED23 in Ras-active lung cancer.
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Xu Yang, Meng Zhao, Min Xia, Yuting Liu, Jun Yan, Hongbin Ji, and Wang, Gang
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MOLECULAR genetics ,LUNG cancer ,GENE expression ,CANCER cells ,CELL lines ,RAS oncogenes ,GENETIC mutation ,FIBROBLASTS - Abstract
The article discusses a study that was conducted to examine the role of MED23 in lung cancer. The study used viral-mediated shRNA to inhibit Med23 expression in human lung cancer cell lines in combination with a Ras mutation. The findings of the study indicate that MED23 controls the proliferation of lung cancer cells in a Ras-dependent manner. It also revealed that Med23 deficiency in fibroblasts inhibited oncogenic transformation by Ras.
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- 2012
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13. Transcription factor c-Maf is a checkpoint that programs macrophages in lung cancer.
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Min Liu, Zan Tong, Chuanlin Ding, Fengling Luo, Shouzhen Wu, Caijun Wu, Albeituni, Sabrin, Liqing He, Xiaoling Hu, Tieri, David, Rouchka, Eric C., Michito Hamada, Satoru Takahashi, Gibb, Andrew A., Goetz Kloecker, Huang-ge Zhang, Michael Bousamra II, Bradford G. Hill, Xiang Zhang, and Jun Yan
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TREATMENT of lung tumors , *LUNG cancer treatment , *TUMOR treatment , *LUNG cancer , *PROTEINS , *RESEARCH , *ANIMAL experimentation , *RESEARCH methodology , *LUNG tumors , *MACROPHAGES , *EVALUATION research , *MEDICAL cooperation , *COMPARATIVE studies , *IMMUNITY , *GENES , *RESEARCH funding , *TUMORS , *CELLULAR immunity , *CELL lines , *T cells , *MONOCYTES , *MICE - Abstract
Macrophages have been linked to tumor initiation, progression, metastasis, and treatment resistance. However, the transcriptional regulation of macrophages driving the protumor function remains elusive. Here, we demonstrate that the transcription factor c-Maf is a critical controller for immunosuppressive macrophage polarization and function in cancer. c-Maf controls many M2-related genes and has direct binding sites within a conserved noncoding sequence of the Csf-1r gene and promotes M2-like macrophage-mediated T cell suppression and tumor progression. c-Maf also serves as a metabolic checkpoint regulating the TCA cycle and UDP-GlcNAc biosynthesis, thus promoting M2-like macrophage polarization and activation. Additionally, c-Maf is highly expressed in tumor-associated macrophages (TAMs) and regulates TAM immunosuppressive function. Deletion of c-Maf specifically in myeloid cells results in reduced tumor burden with enhanced antitumor T cell immunity. Inhibition of c-Maf partly overcomes resistance to anti-PD-1 therapy in a subcutaneous LLC tumor model. Similarly, c-Maf is expressed in human M2 and tumor-infiltrating macrophages/monocytes as well as circulating monocytes of human non-small cell lung carcinoma (NSCLC) patients and critically regulates their immunosuppressive activity. The natural compound β-glucan downregulates c-Maf expression on macrophages, leading to enhanced antitumor immunity in mice. These findings establish a paradigm for immunosuppressive macrophage polarization and transcriptional regulation by c-Maf and suggest that c-Maf is a potential target for effective tumor immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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14. Synthesis and antitumor activity of some cholesterol-based selenocyanate compounds.
- Author
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Huang, Yan-Min, Cheng, Yang, Peng, Zi-Ning, Pang, Li-Ping, Li, Jun-Yan, Xiao, Jun-An, Zhang, Yuan-Fei, and Cui, Jian-Guo
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ANTINEOPLASTIC agents , *ABIRATERONE acetate , *ANNEXINS , *CELL lines , *CELL death , *CERVICAL cancer - Abstract
[Display omitted] The introduction of selenium-containing functional groups into steroids to study the biological activities of related derivatives is rarely reported in the literature. In the present study, using cholesterol as raw material, four cholesterol-3-selenocyanoates and eight B-norcholesterol selenocyanate derivatives were synthesized, respectively. The structures of the compounds were characterized by NMR and MS. The results of the in vitro antiproliferative activity test showed that the cholesterol-3-selenocyanoate derivatives did not exhibit obvious inhibitory on the tested tumor cell lines. However, the B-norcholesterol selenocyanate derivatives obtained by structural modification of cholesterol showed good inhibitory activity against the proliferation of tumor cell. Among them, compounds 9b - c , 9f and 12 showed similar inhibitory activity against tested tumor cells as positive control 2-methoxyestradiol, and better than Abiraterone. At the same time, these B-norcholesterol selenocyanate derivatives displayed a strong selective inhibitory against Sk-Ov-3 cell line. Except for compound 9g , the IC 50 value of all B-norcholesterol selenocyanate compounds against Sk-Ov-3 cells was less than 10 µM, and compound 9d was 3.4 µM. In addition, Annexin V-FITC/PI double staining was used to analyze the cell death mechanism. The results showed that compound 9c could induce Sk-Ov-3 cells to enter programmed apoptosis in a dose-dependent manner. Furthermore, the in vivo antitumor experiments of compound 9f against zebrafish xenograft tumor showed that 9f displayed obvious inhibitory effect on the growth of human cervical cancer (HeLa) xenograft tumor in zebrafish. Our results provide new thinking for the study of such compounds as new antitumor drugs. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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15. Inhibition of mutant KrasG12D-initiated murine pancreatic carcinoma growth by a dual c-Raf and soluble epoxide hydrolase inhibitor t-CUPM.
- Author
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Liao, Jie, Hwang, Sung Hee, Li, Haonan, Yang, Yihe, Yang, Jun, Wecksler, Aaron T., Liu, Jun-Yan, Hammock, Bruce D., and Yang, Guang-Yu
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PANCREATIC cancer treatment , *TUMOR growth , *RAF genes , *EPOXIDE hydrolase , *CELLULAR signal transduction , *WESTERN immunoblotting , *ANIMAL experimentation , *ANTHROPOMETRY , *ANTI-infective agents , *ANTINEOPLASTIC agents , *CELL lines , *CELL physiology , *COMPARATIVE studies , *DISEASE susceptibility , *DOSE-effect relationship in pharmacology , *HYDROLASES , *RESEARCH methodology , *MEDICAL cooperation , *MICE , *GENETIC mutation , *ONCOGENES , *ORAL drug administration , *PANCREATIC tumors , *PHOSPHORYLATION , *RESEARCH , *RESEARCH funding , *TRANSFERASES , *UNSATURATED fatty acids , *UREA , *VITAMIN B complex , *PHENOTYPES , *EVALUATION research , *DUCTAL carcinoma , *PROTEIN kinase inhibitors , *CHEMICAL inhibitors , *PHARMACODYNAMICS - Abstract
Mutant Kras and chronic pancreatitis are the most common pathological events involved in human pancreatic cancer. It has been demonstrated that c-Raf is responsible for transmitting signals from mutant Ras to its downstream signals including MEK-ERK and for initiating carcinogenesis. The soluble epoxide hydrolase (sEH), a pro-inflammatory enzyme, generally inactivates anti-inflammatory and anti-pain epoxyeicosatrienoic acids (EETs). Herein, we have synthesized a novel compound of trans-4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-cyclohexyloxy}-pyridine-2-carboxylic acid methylamide (t-CUPM) via modifying the central phenyl ring of sorafenib and confirmed its dual inhibition of sEH and c-Raf by recombinant kinase activity assay. Pharmacokinetic analysis revealed that oral dosing of t-CUPM resulted in higher blood levels than that of sorafenib throughout the complete time course (48 h). The effect of t-CUPM on the inhibition of mutant Kras(G12D)-initiated murine pancreatic cancer cell growth was determined using the mouse pancreatic carcinoma cell model obtained from LSL-Kras(G12D)/Pdx1-Cre mice and showed that t-CUPM significantly inhibited this murine pancreatic carcinoma cell growth both in vitro and in mice in vivo. Inhibition of mutant Kras-transmitted phosphorylations of cRAF/MEK/ERK was demonstrated in these pancreatic cancer cells using Western blot assay and immunohistochemical approach. Modulation of oxylipin profile, particularly increased EETs/DHET ratio by sEH inhibition, was observed in mice treated with t-CUPM. These results indicate that t-CUPM is a highly potential agent to treat pancreatic cancer via simultaneously targeting c-Raf and sEH. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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16. Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model.
- Author
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Waugh Kinkade, Carolyn, Castillo-Martin, Mireia, Puzio-Kuter, Anna, Jun Yan, Foster, Thomas H., Hui Gao, Yvonne Sun, Xuesong Ouyang, Gerald, William L., Cordon-Cardo, Carlos, Abate-Shen, Cory, Kinkade, Carolyn Waugh, Yan, Jun, Gao, Hui, Sun, Yvonne, and Ouyang, Xuesong
- Subjects
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UROLOGY , *PROSTATE cancer , *GENITOURINARY diseases , *LABORATORY rats , *CANCER cells , *CELL lines , *CELL culture - Abstract
The AKT/mammalian target of rapamycin (AKT/mTOR) and ERK MAPK signaling pathways have been shown to cooperate in prostate cancer progression and the transition to androgen-independent disease. We have now tested the effects of combinatorial inhibition of these pathways on prostate tumorigenicity by performing preclinical studies using a genetically engineered mouse model of prostate cancer. We report here that combination therapy using rapamycin, an inhibitor of mTOR, and PD0325901, an inhibitor of MAPK kinase 1 (MEK; the kinase directly upstream of ERK), inhibited cell growth in cultured prostate cancer cell lines and tumor growth particularly for androgen-independent prostate tumors in the mouse model. We further showed that such inhibition leads to inhibition of proliferation and upregulated expression of the apoptotic regulator Bcl-2-interacting mediator of cell death (Bim). Furthermore, analyses of human prostate cancer tissue microarrays demonstrated that AKT/mTOR and ERK MAPK signaling pathways are often coordinately deregulated during prostate cancer progression in humans. We therefore propose that combination therapy targeting AKT/mTOR and ERK MAPK signaling pathways may be an effective treatment for patients with advanced prostate cancer, in particular those with hormone-refractory disease. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
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