ONCOGENE
·
2020
·Vol. 39
·期 11
·2408-2423
·
IF 7.971
Guan Yun-feng,Huang Qiao-ling,Ai Yuan-li,Chen Qi-tao,Zhao Wen-xiu,Wang Xiao-min,Wu Qiao,Chen Hang-zi
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Orphan nuclear receptor Nur77, which is low expressed in HCC, functions as a tumor suppressor to suppress HCC. However, the detailed mechanism is still not well understood. Here, we demonstrate that Nur77 could inhibit HCC development via transcriptional activation of the lncRNA WAP four-disulfide core domain 21 pseudogene (WFDC21P). Nur77 binds to its response elements on the WFDC21P promoter to directly induce WFDC21P transcription, which inhibits HCC cell proliferation, tumor growth, and tumor metastasis both in vitro and in vivo. In clinical HCC samples, WFDC21P expression positively correlated with that of Nur77, and the loss of WFDC21P is associated with worse prognosis. Mechanistically, WFDC21P could inhibit glycolysis by simultaneously interacting with PFKP and PKM2, two key enzymes in glycolysis. These interactions not only abrogate the tetramer formation of PFKP to impede its catalytic activity but also prevent the nuclear translocation of PKM2 to suppress its function as a transcriptional coactivator. Cytosporone-B (Csn-B), an agonist for Nur77, could stimulate WFDC21P expression and suppress HCC in a WFDC21P-dependent manner. Therefore, our study reveals a new HCC suppressor and connects the glycolytic remodeling of HCC with the Nur77-WFDC21P-PFKP/PKM2 axis.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2023
·
IF 5.6
Niu Ting,Wei Zhiying,Fu Jiao,Chen Shu,Wang Ru,Wang Yuya,Zheng Ruihe
Introduction: Venlafaxine is one of the most commonly used anti-depressant and antineoplastic drug. Previous studies have predicted venlafaxine as an anti-cancer compound, but the therapeutic effects of venlafaxine in melanoma have not yet been demonstrated. Nur77 is an orphan nuclear receptor that highly expressed in melanoma cells and can interact with Bcl-2 to convert Bcl-2 from an antiapoptotic to a pro-apoptotic protein.Method: We examined the effects of venlafaxine in MV3 cells in vitro and MV3 xenograft tumor in nude mice. Western-blot, PCR, TUNEL assay and immunofluorescence were used to reveal the growth of melanoma cells.Results: Here, our data revealed that venlafaxine could reduce the growth, and induce apoptosis of melanoma cells through a Nur77-dependent way. Our results also showed that treatment with venlafaxine (20 mg/kg, i.p.) potently inhibited the growth of melanoma cells in nude mice. Mechanistically, venlafaxine activated JNK1/2 signaling, induced Nur77 expressions and mitochondrial localization, thereby promoting apoptosis of melanoma cells. Knockdown of Nur77 and JNK1/2, or inhibition of JNK1/2 signaling with its inhibitor SP600125 attenuated the anti-cancer effects of venlafaxine.Conclusion: In summary, our results suggested venlafaxine as a potential therapy for melanoma.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
·
2024
·
IF 4
Hua Fang,Xiumei Wang,Mengyu Li,Mengxian Huang,Yiping Zhang,Taige Zhao,Cuiling Sun,Min Xu,Wenhui Jin,Weizhu Chen,Meijuan Fang
In this study, twenty-five novel carboxylic acid DHA-alkanolamine derivatives were synthesized by the reaction of cis -docosa-4,7,10,13,16,19-hexaenoic acid-alkanolamine (DHA-AA) with various carboxylic acids, including Naproxen (S1), Ibuprofen (S2), Ferulic acid (S3), Mefenamic acid (S4), and Aspirin (S5). Their molecular structures were characterized using 1 H/ 13 C NMR and HRMS techniques. To evaluate the anti-inflammatory activities of synthesized compounds, RAW264.7 macrophage cells pretreated with or without these compounds, were stimulated by LPS, and the levels of pro-inflammatory cytokines (NO, TNF-α, IL-1β, and IL-6) were then measured by ELISA, qPCR, and Western Blot. The cell-based assays showed that compound 11 had marked anti-inflammatory activity. In addition, the molecular docking study and SPR assay demonstrated that compound 11 exhibited good Nur77-binding affinity (K D = 3.61 × 10 −6 M). Moreover, compound 11 was found to inhibit NF-κB activation in a Nur77-dependent manner. Notably, compound 11 could attenuate LPS-induced inflammation in the mouse acute lung injury (ALI) model. In conclusion, these derivatives are potential Nur77-targeting anti-inflammatory agents against versatile inflammatory and autoimmune disorders.
研究领域:
药理学
·
炎症研究
·
药物化学
✓ 已验证
DOI
高影响因子
Marine Drugs
·
2020
·Vol. 18
·期 7
·375
·
IF 4.073
Mi Zhou,Bo-Rong Peng,Wenjing Tian,Jui-Hsin Su,Guanghui Wang,Ting Lin,Dequan Zeng,Jyh-Horng Sheu,Haifeng Chen
12-Deacetyl-12-epi-scalaradial, a scalarane sesterterpenoid from a marine spongeHippospongia sp, has been reported to possess cytotoxic activity on HepG2, MCF-7, and HCT-116 cells. However, there is no research to indicate that 12-deacetyl-12-epi-scalaradial exhibited anticancer effect on cervical cancer HeLa cells. The aim of this study was to investigate the anticancer activity of 12-deacetyl-12-epi-scalaradial against HeLa cells and to explore the mechanism. The results from a methylthiazolyldiphenyl-tetrazolium (MTT) assay suggested that 12-deacetyl-12-epi-scalaradial suppressed the proliferation of HeLa cells and flow cytometry analysis showed 12-deacetyl-12-epi-scalaradial could induce the apoptosis of HeLa cells in dose- and time-dependent manner. Western blotting analysis demonstrated that 12-deacetyl-12-epi-scalaradial triggered apoptosis via mediating the extrinsic pathway and was found to suppress MAPK/ERK pathway which was associate with cancer cell death. Nur77, a critical number of orphan nuclear receptors, plays diverse roles in tumor development as a transcription factor and has been considered as a promising anticancer drug target. The dual-luciferase reporter assays suggested that 12-deacetyl-12-epi-scalaradial could selectively enhance the trans-activation activity of Nur77. Furthermore, Western blotting analysis and fluorescence quenching showed that 12-deacetyl-12-epi-scalaradial could induce the phosphorylation of Nur77 and interact with the ligand-binding domain (LBD) of Nur77. Our research confirmed 12-deacetyl-12-epi-scalaradial as a potential agent for cervical cancer therapy and provided a view that 12-deacetyl-12-epi-scalaradial may be a modulator of Nur77.Keywords:12-deacetyl-12-epi-scalaradial;HeLa cells;apoptosis;Nur77;MAPK/ERK pathway
研究领域:
海洋化学
·
癌症研究
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2022
·
IF 10.753
Fangwei Yang,Yixuan Li,Yunfei Xie,Weirong Yao,Fazheng Ren
Plenty of population epidemiology and cohort studies have found dialkyl phosphates (DAPs) in the urine were related to endocrine hormone disorders. However, we did not know whether these effects were caused by parent organophosphorus pesticides (OPs) or metabolite DAPs, especially the non-specific metabolite diethyl phosphate (DEP), which was the metabolic end product of most widely used diethyl OPs. In this study, animal experiments ( in vivo ), cell experiments ( in vitro ), small molecule-protein binding interaction experiments and computer molecular simulations ( in silico ) were used to explore the disturbing effects and molecular mechanisms of DEP on the hypothalamic-pituitary-adrenal (HPA) axis endocrine hormones. The animal experiments showed that chronic DEP exposure significantly disturbed the serum contents of HPA axis hormones in adult male rats. The target genes of glucocorticoid receptor (GR) in rat liver, including 11β-hsd1 and Pepck1 and PEPCK protein expressions, were down-regulated. Moreover, the gluconeogenic abilities of rats were impaired. However, it did not affect the expression of GR in the rat hypothalamus. These results indicated that the physiological functions of glucocorticoids and GR were damaged. Furthermore, spectroscopy experiments, cell experiments, molecular docking and molecular dynamics simulations also suggested that DEP can bind to nuclear receptors GR and Nur77, affecting their transcription factor functions, and the transcriptional expression levels of their downstream target genes were reduced. The biosynthesis and secretion of adrenocorticotropic hormone and glucocorticoids were blocked. Therefore, DEP can inhibit the production and physiological functions of HPA axis endocrine hormones by disrupting these related proteins and antagonizing nuclear receptors. These results were considered to provide a theoretical basis for strictly controlling the residue limits of OPs and their metabolites in foods, agricultural products and the environment. They also revealed new targets for evaluating the toxicities and risks of pesticide metabolites.
研究领域:
毒理学
·
内分泌学
·
药理学
·
分子生物学
·
环境科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2026
·
IF 6.7
Jiaqi Xiao,Lihua Qu,Xuan Qin,Chao Chen,Yuan Xu,Xinyu Que,Yaoyao Ma,Wentao Huang,Haoxiang Ou,Chao Wu,Yongfen Bao,Shigang Shan
Aging is accompanied by chronic low-grade inflammation (inflammaging), driving age-related diseases. Urolithin A (UA), a gut microbial metabolite, possesses anti-inflammatory properties, yet its mechanism in hepatic aging remains unclear. This study investigated UA’s effects on aging-associated inflammation and the involvement of Nur77 in D-galactose-induced macrophage senescence and mouse liver aging models using molecular docking, Western blotting, and immunoprecipitation. UA alleviated cellular senescence markers (p53, p21), suppressed pro-inflammatory factors (IL-6, IL-1β), and elevated anti-inflammatory IL-10. Mechanistically, UA enhanced Nur77 protein stability by inhibiting MDM2-mediated ubiquitination and degradation, thereby restoring inflammatory homeostasis. In vivo, UA ameliorated D-gal-induced liver injury and modulated the hepatic Nur77-MDM2 axis. Conclusion: UA stabilizes Nur77 by inhibiting its ubiquitination, alleviating hepatic aging-associated inflammation. This study identifies the MDM2-Nur77 axis as a potential therapeutic target for hepatic aging.
✓ 已验证
产品关联
DOI
高影响因子
MOLECULAR CELL
·
2018
·
IF 14.248
Xiao-xue Li,Zhi-jing Wang,Yu Zheng,Yun-feng Guan,Peng-bo Yang,Xiang Chen,Cong Peng,Jian-ping He,Yuan-li Ai,Sheng-fu Wu,Kun-Yi Chien,Qiao Wu,Hang-zi Chen
Summary Fatty acid oxidation (FAO) is crucial for cells to overcome metabolic stress by providing ATP and NADPH. However, the mechanism by which FAO is regulated in tumors remains elusive. Here we show that Nur77 is required for the metabolic adaptation of melanoma cells by protecting FAO. Glucose deprivation activates ERK2 to phosphorylate and induce Nur77 translocation to the mitochondria, where Nur77 binds to TPβ, a rate-limiting enzyme in FAO. Although TPβ activity is normally inhibited by oxidation under glucose deprivation, the Nur77-TPβ association results in Nur77 self-sacrifice to protect TPβ from oxidation. FAO is therefore able to maintain NADPH and ATP levels and prevent ROS increase and cell death. The Nur77-TPβ interaction further promotes melanoma metastasis by facilitating circulating melanoma cell survival. This study demonstrates a novel regulatory function of Nur77 with linkage of the FAO-NADPH-ROS pathway during metabolic stress, suggesting Nur77 as a potential therapeutic target in melanoma.
研究领域:
癌症生物学
·
分子生物学
·
细胞生物学
·
代谢
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Pei Xie,Li-Jun Yan,Hong-Ling Zhou,Hui-Hui Cao,Yuan-Ru Zheng,Zi-Bin Lu,Hua-Yi Yang,Jia-Mei Ma,Yu-Yao Chen,Chuying Huo,Chunyang Tian,Jun-Shan Liu,Lin-Zhong Yu
Background: Acute lung injury (ALI) is a serious inflammatory disease with clinical manifestations of hypoxemia and respiratory failure. Presently, there is no effective treatment of ALI. Although emodin from Rheum palmatum L. exerts anti-ALI properties, the underlying mechanisms have not been fully explored.
Purpose: This study aimed to investigate the therapeutic effect and mechanism of emodin on LPS-induced ALI in mice.
Methods: RAW264.7 cells and zebrafish larvae were stimulated by LPS to establish inflammatory models. The anti-inflammatory effect of emodin was assessed by ELISA, flow cytometric analysis, and survival analysis. In vitro mechanisms were explored by using Western blotting, luciferase assay, electrophoretic mobility shift assay (EMSA), and small interfering RNA (siRNA) approach. The acute lung injury model in mice was established by the intratracheal administration of LPS, and the underlying mechanisms were assessed by detecting changes in histopathological and inflammatory markers and Western blotting in lung tissues.
Results: Emodin inhibited the inflammatory factor production and oxidative stress in RAW264.7 cells, and prolonged the survival of zebrafish larvae after LPS stimulation. Emodin suppressed the expression levels of phosphorylated JNK at Thr183/tyr182 and phosphorylated Nur77 at Ser351 and c-Jun, and increased the expression level of Nur77 in LPS-stimulated RAW264.7 cells, while these regulatory effects of emodin on Nur77/c-Jun were counteracted by JNK activators. The overexpression of JNK dampened the emodin-mediated increase in Nur77 luciferase activity and Nur77 expression. Moreover, the inhibitory effect of emodin on c-Jun can be attenuated by Nur77 siRNA. Furthermore, emodin alleviated LPS-induced ALI in mice through the regulation of the JNK/Nur77/c-Jun pathway.
Conclusions: Emodin protects against LPS-induced ALI through regulation on JNK/Nur77/c-Jun signaling. Our results indicate the potential of emodin in the treatment of ALI.Keywords: acute lung injury, inflammation, lipopolysaccharide, emodin, JNK/Nur77/c-Jun
研究领域:
药理学
·
免疫学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2026
·
IF 5.2
Jiaqi Li,Haoyu Chen,Zhengxin Lu,Yuanbiao Ma,Shanshan Li,Zhiyu Chen,Zhewen Deng,Qi Zhang,Bo Ma
Pristimerin (Pri), a natural triterpenoid from the Celastraceae family, exhibits potent anti-tumor and anti-inflammatory activities, yet its further development as a drug candidate is hampered by severe male reproductive toxicity and precise target cells and underlying mechanisms remain unclear. Therefore, this study aimed to identify the target cells and elucidate these mechanisms. In vivo , male mice were administered Pri to evaluate testicular injury, sperm quality, and BTB integrity, while LC-MS/MS was used to detect Pri distribution in testis, epididymis, and sperm, as well as its cellular uptake. In vitro , CCK-8 assessed cell viability, and inhibitor interventions identified contributions of distinct cell death pathways. Annexin V/PI, C11-BODIPY, and DCFH-DA/DHE were used to assess apoptosis and ferroptosis-related oxidative damage. Transcriptomics, RT-qPCR, Western blotting, and immunohistochemistry were performed to examine activation of the NUR77-ATF3-CHOP axis and molecular docking, MD simulations, CETSA, and siRNA-mediated knockdown validated direct NUR77 binding by Pri. Pri exposure induced testicular atrophy, BTB disruption, and sperm impairment, with accumulation in reproductive tissues. In vitro , Pri inhibited TM4 cell viability. Cell death was partially rescued by Z-VAD-FMK and Fer-1, indicating that Pri triggers apoptosis and ferroptosis. Mechanistically, Pri activated the NUR77-ATF3-CHOP axis and directly bound to NUR77, as confirmed by docking, MD simulations, and CETSA. Knockdown of NUR77 improved cell viability and suppressed Pri-induced ATF3 upregulation. Collectively, this study demonstrates that Pri directly targets NUR77, activating the NUR77-ATF3-CHOP axis and inducing both apoptosis and ferroptosis in Sertoli cells, leading to spermatogenesis dysfunction, thereby providing critical insights into Pri-induced testicular injury.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
·
2022
·Vol. 78
·期 4
·777-791
·
IF 5.08
Li Ling,Bai Yu,Du Runyu,Tang Lei,Li Ling
Gestational diabetes mellitus (GDM) is a common pregnancy complication with a high incidence in women. Orphan nuclear receptor NUR77 is involved in regulating glucose metabolism. However, its role in GDM has not been fully elucidated yet. In this study, an animal model of GDM was established by feeding mice with a high-fat diet (HFD) before and during pregnancy. NUR77 expression was abnormally upregulated in placenta tissues of GDM mice. We performed gain- and loss-of-function studies of NUR77 in HTR-8/SVneo cells. Cells were incubated with 1 × 10 −6 M insulin for 48 h to induce insulin resistance (IR). The expression of NUR77 was downregulated in HTR-8/SVneo cells following IR induction. Overexpression of NUR77 promoted cell proliferation, migration, and invasion. Notably, NUR77 promoted glucose uptake and enhanced insulin sensitivity in vitro. NUR77 increased the ratio of p-insulin receptor β (IRβ) Tyr1361 /IRβ, p-insulin receptor substrate (IRS)-1 Tyr612 /IRS-1, p-Akt/Akt and decreased p-IRS-1 Ser307 /IRS-1, as well as lowered the expression of glucose transport protein type 1 (GLUT1) and elevated GLUT4. These results suggest the involvement of IRβ/IRS/Akt/GLUT4 signaling activation in the regulatory effects of NUR77 on IR in HTR-8/SVneo cells. Silencing of NUR77 displayed opposite effects. Besides, NUR77 enhanced the expression of autophagy-related protein Beclin 1 and the ratio of LC3II/LC3I. Further study demonstrated that the inhibitory effect of NUR77 on IR was partially attributed to the activation of autophagy. Therefore, we demonstrate that NUR77 enhances insulin sensitivity in HTR-8/SVneo cells likely through activating IRβ/IRS/Akt/GLUT4 pathway and regulating autophagy.
研究领域:
内分泌学
·
妇产科学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Jiaxin Li,Jingna Bao,Yihong Lui,Meiling Chen,Yuqi Chen,Lina Tuolihong,Fuhui Jiang,Shihao Xie,Fengyuan Lyu,Ye Sun,Yan Cao,Huarong Chen,Zhongqing Chen,Zhenhua Zeng
Hepatic ischemia-reperfusion injury (HIRI) is an essential clinical concern caused by liver transplantation, resection, trauma, and shock that must be addressed immediately. Although the mechanisms underlying HIRI are well-documented, effective prevention and treatment strategies are still lacking. Inflammation is a central mechanism of HIRI, with macrophages playing a crucial role in initiating and amplifying the inflammatory response. Numerous plant polysaccharides exhibit substantial anti-inflammatory and hepatoprotective properties. However, the function of Lentinan (LNT) in HIRI has not been fully explored. Thus, this study aims to investigate the preventive potential of LNT in HIRI. Here, we reveal that oral administration of LNT considerably reduces hepatic inflammation and improves liver pathology in mice with HIRI by modulating gut microbiota. Specifically, LNT considerably increased microbiota-derived isodeoxycholic acid (IsoUDCA). Further experiments showed that IsoUDCA alleviates hepatic injury by suppressing macrophage inflammation. Mechanically, IsoUDCA directly binds to and activates the neuron-derived clone 77 (Nur77) transcription factor, inhibiting the NF-κB signaling pathway in macrophages. Our findings shed light on the significant role of the LNT–microbiota–IsoUDCA–Nur77 axis in attenuating macrophage inflammation during HIRI, offering novel insights into potential therapeutic targets and avenues for preventing HIRI.
研究领域:
药理学
·
免疫学
·
胃肠病学
·
微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）