INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 12
·10031
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IF 5.6
Haiping Liu,Haixiang Ma,Xingyue Zeng,Chengyan Wu,Srijan Acharya,Sarabjeet Kour Sudan,Xiaohan Zhang
A class-A GPCR dopamine D2 receptor (D2R) plays a critical role in the proper functioning of neuronal circuits through the downstream activation of both G-protein- and β-arrestin-dependent signaling pathways. Understanding the signaling pathways downstream of D2R is critical for developing effective therapies with which to treat dopamine (DA)-related disorders such as Parkinson’s disease and schizophrenia. Extensive studies have focused on the regulation of D2R-mediated extracellular-signal-regulated kinase (ERK) 1/2 signaling; however, the manner in which ERKs are activated upon the stimulation of a specific signaling pathway of D2R remains unclear. The present study conducted a variety of experimental techniques, including loss-of-function experiments, site-directed mutagenesis, and the determination of protein interactions, in order to investigate the mechanisms underlying β-arrestin-biased signaling-pathway-mediated ERK activation. We found that the stimulation of the D2R β-arrestin signaling pathway caused Mdm2, an E3 ubiquitin ligase, to move from the nucleus to the cytoplasm and interact with tyrosine phosphorylated G-protein-coupled receptor kinase 2 (GRK2), which was facilitated by Src, a non-receptor tyrosine kinase. This interaction led to the ubiquitination of GRK2, which then moved to the plasma membrane and interacted with activated D2R, followed by the phosphorylation of D2R as well as the mediation of ERK activation. In conclusion, Mdm2-mediated GRK2 ubiquitination, which is selectively triggered by the stimulation of the D2R β-arrestin signaling pathway, is necessary for GRK2 membrane translocation and its interaction with D2R, which in turn mediates downstream ERK signaling. This study is primarily novel and provides essential information with which to better understand the detailed mechanisms of D2R-dependent signaling.Keywords:GRK2 ubiquitination;D2R-biased signaling;Src;ERK signaling
研究领域:
神经科学
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药理学
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细胞信号
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DOI
PubMed
高影响因子
Heliyon
·
2023
·
IF 4
Xiao-Ping Zhao,Xiao-Li Zheng,Min Huang,Ya-Jia Xie,Xiao-Wen Nie,Ali Adnan Nasim,Xiao-Jun Yao,Xing-Xing Fan
Although some important advances have been achieved in clinical and diagnosis in the past few years, the management of non-small cell lung cancer (NSCLC) is ultimately dissatisfactory due to the low overall cure and survival rates. Epidermal growth factor (EGFR) has been recognized as a carcinogenic driver and is a crucial pharmacological target for NSCLC. DMU-212, an analog of resveratrol, has been reported to have significant inhibitory effects on several types of cancer. However, the effect of DMU-212 on lung cancer remains unclear. Therefore, this study aims to determine the effects and underlying mechanism of DMU-212 on EGFR-mutant NSCLC cells. The data found that the cytotoxicity of DMU-212 on three EGFR-mutant NSCLC cell lines was significantly higher than that of normal lung epithelial cell. Further study showed that DMU-212 can regulate the expression of cell cycle-related proteins including p21 and cyclin B1 to induce G2/M phase arrest in both H1975 and PC9 cells. Moreover, treatment with DMU-212 significantly promoted the activation of AMPK and simultaneously down-regulated the expression of EGFR and the phosphorylation of PI3K, Akt and ERK. In conclusion, our study suggested that DMU-212 inhibited the growth of NSCLCs via targeting of AMPK and EGFR.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
高影响因子
Lipids in Health and Disease
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2025
·Vol. 24
·期 1
·1-15
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IF 4.2
An He,Cheng Dong-liang,Xia Xian-ru,Li Xian-dong,Ruan Zhi-hua,Peng Chun-yan
Background Dyslipidemia has been extensively documented as a key driver of cardiovascular pathology. Regulating lipid homeostasis holds promise for treating atherosclerosis (AS). Although the protein phosphatase 2 catalytic subunit beta (PPP2CB) is involved in post-transcriptional gene regulation, its role in AS-associated dyslipidemia is not well understood. Methods The study included both human participants and animal models. The following techniques were employed: cell culture, extraction of exosomes, preparation of pooled hyperlipidemic serum (HS), transfection, western blotting, immunofluorescence staining, quantitative reverse transcription polymerase chain reaction (qRT-PCR), co-immunoprecipitation, low-density lipoprotein cholesterol (LDL-C) uptake assay, biochemical assays, assessment of aortic atherosclerotic lesions, as well as statistical analysis. Results This study identified a marked upregulation of PPP2CB expression in peripheral blood leukocytes of AS patients, artery plaque of ApoE −/− mice given a high-fat diet, and hepatic cells exposed to hyperlipidemic stimuli. Overexpression of PPP2CB in hepatic cells exacerbated lipid accumulation and low-density lipoprotein uptake, whereas silencing PPP2CB mitigated this effect. Immunofluorescence co-localization and co-immunoprecipitation analysis confirmed a direct interaction between PPP2CB and lectin-like oxidized LDL receptor-1 (LOX-1). Notably, PPP2CB manipulation disrupted hyperlipidemia-induced LOX-1 expression. Additionally, PPP2CB-mediated lipid dysregulation was linked to the activation of the LOX-1/ mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) signaling cascade. Conclusions These results unveil PPP2CB as a novel lipid regulator in the progression of pathological AS and highlight its involvement in signaling regulation during abnormal lipid metabolism. PPP2CB could be considered a promising candidate for biomarker development and therapeutic intervention in AS.
研究领域:
生物学
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医学
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药理学
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DOI
PubMed
高影响因子
PLoS One
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2025
·Vol. 20
·期 5
·e0322056
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IF 2.6
Wenyue Hou,Ting Zou,Yichao Yan,Yaolong Zhuang,Shaomei Gao,Huijun Ju,Fei Yao,Qin Yuan,Liang Zhou,Guoqiang Liang,Xiudao Song,Lurong Zhang
5-O-Methylvisammioside (5OMV), a flavonol compound derived from the traditional Chinese medicine plant Saposhnikovia divaricat , has been shown to inhibit vasospasm induced by High Mobility Group Box 1 (HMGB1) protein. However, its therapeutic potential and molecular mechanisms in HMGB1-induced tumor angiogenesis remain unexplored. Through comprehensive in vitro assays, we demonstrated that 5OMV significantly attenuates HMGB1-induced proliferation, migration, tube formation, and angiogenic activity in human umbilical vein endothelial cells (HUVECs). Parallel in vivo studies using an orthotopic hepatocellular carcinoma model in C57BL/6 mice revealed that 5OMV treatment markedly reduced tumor progression and microvascular density. Mechanistic studies identified that 5OMV downregulates both total and phosphorylated forms of RAGE, MEK, and ERK in HUVECs and tumor tissues. These findings collectively establish that 5OMV exerts anti-tumor effects in hepatocellular carcinoma through targeted modulation of the HMGB1/RAGE/MEK/ERK signaling axis.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
MOLECULES
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2022
·Vol. 27
·期 15
·4996
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IF 4.927
Guang-Xi Yu,Ying Hu,Wei-Xin Zhang,Xin-Yi Tian,Sai-Yang Zhang,Yan Zhang,Shuo Yuan,Jian Song
[1,2,4]Triazolo[1,5-a]pyrimidine and indole skeletons are widely used to design anticancer agents. Therefore, in this work, a series of [1,2,4]triazolo[1,5-a]pyrimidine indole derivatives were designed and synthesized by the molecular hybridization strategy. The antiproliferative activities of the target compoundsH1–H18against three human cancer cell lines, MGC-803, HCT-116 and MCF-7, were tested. Among them, compoundH12exhibited the most active antiproliferative activities against MGC-803, HCT-116 and MCF-7 cells, with IC50values of 9.47, 9.58 and 13.1 μM, respectively, which were more potent than that of the positive drug5-Fu. In addition, compoundH12could dose-dependently inhibit the growth and colony formation of MGC-803 cells. CompoundH12exhibited significant inhibitory effects on the ERK signaling pathway, resulting in the decreased phosphorylation levels of ERK1/2, c-Raf, MEK1/2 and AKT. Furthermore, compound12induced cell apoptosis and G2/M phase arrest, and regulated cell cycle-related and apoptosis-related proteins in MGC-803 cells. Taken together, we report here that [1,2,4]triazolo[1,5-a]pyrimidine indole derivatives, used as anticancer agents via the suppression of ERK signaling pathway and the most active compound,H12, might be a valuable hit compound for the development of anticancer agents.Keywords:[1,2,4]triazolo[1,5-a]pyrimidine;indole;antiproliferative activities;ERK signaling pathway
研究领域:
药物化学
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肿瘤学
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药理学
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DOI
PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
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2015
·Vol. 2015
·期 1
·414965
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IF 1.88
Chunxiao Wu,Jiao Wang,Chun Li,Guoping Zhou,Xiuhong Xu,Xin Zhang,Xiao Lan
Background . EA therapy is a traditional therapeutic approach for alleviation of cerebral I/R-induced brain injury. We investigated the effect of EA on MCAO rat model to examine the mechanism of apoptosis in the rat hippocampus. Methods . 200 male Sprague-Dawley rats were randomly divided into sham, I/R, EA, ERK inhibitor (PD), and ERK inhibitor+EA (PD+EA) groups. Each group was subdivided into 5 groups according to different time points. Locomotor behaviors were evaluated using neurological scales and morphological examination was performed using HE staining. Apoptosis index of neural cells in local infarcted area was measured by TUNEL and p-ERK expression was detected using immunohistochemistry technique and western blot analysis. Results . Neurological deficit scores and neural apoptosis in the EA group were lower than I/R group at the same time points, respectively. At different time points, p-ERK level was increased in the ischemic hippocampal CA1 in the EA group as compared to I/R group; the increased level was increased most at 1 day, 3 days, and 1 week ( p < 0.01). Conclusion . EA alleviates neurological deficit, reduces apoptosis index, and simultaneously upregulates the expression of p-ERK signal pathway in rats subjected to I/R injury.
研究领域:
神经生物学
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中西医结合
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分子医学
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脑血管病学
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针灸学
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DOI
高影响因子
ACS Applied Materials & Interfaces
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2025
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IF 8.2
Bin Zhao,Chong Wang,Xinjie Qiu,Xinyue Zeng,Xin Yin,Lina Zhang,Xuedan Yan,Shaobang Wu,Xiuyun Ren
Oral ulcer is a common oral mucosal injury disease that causes significant inconvenience and discomfort for patients. Traditional treatments, such as drugs, ointments, and patches, have limitations, including low local drug utilization, short residence time on the affected area, and the risk of secondary injury from manual application. To address these issues, this study developed a sprayable temperature-sensitive hydrogel (PEI/PAA/PF127-CHO/AA2G@MSN-NH2 hydrogel, PMAG) without manual contact on injuryed mucosa by combining aldehyde-modified Pluronic F-127 (PF127-CHO), ascorbic acid 2-glucoside-loaded amino-mesoporous silica (AA2G@MSN-NH2), polyethylenimine (PEI), and polyacrylic acid (PAA) through Schiff base reaction and physical crosslinking. When sprayed onto an oral ulcer, PMAG exhibits excellent temperature sensitivity and adhesion, rapidly adapting to oral temperature and forming a protective film that closely adheres to the ulcer surface. This creates a stable healing environment by isolating the wound from external stimuli. PMAG has demonstrated significant abilities in promoting epithelial cell proliferation and migration, as well as antioxidant, anti-inflammatory, and antibacterial properties. RNA sequencing revealed that the tissue repair-promoting effects of PMAG are primarily mediated by activating the nerve growth factor receptor/extracellular signal-regulated kinase (NGFR/ERK) signaling pathway. In summary, PMAG represents a significant advancement in improving the treatment of oral ulcers and offers a more convenient option for patients.
研究领域:
药学
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生物医学工程
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分子生物学
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DOI
PubMed
高影响因子
ONCOLOGY REPORTS
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2017
·Vol. 38
·期 6
·3668-3676
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IF 2.662
Yulin Jiang,Feihu Ji,Yifeng Liu,Mengjia He,Zhiqian Zhang,Junhong Yang,Nian Wang,Changli Zhong,Qianni Jin,Xiangsen Ye,Tingmei Chen
Breast cancer is a common cause of cancer‑related deaths in women. Treatment with cisplatin exhibits some therapeutic efficacy. However, treatment optimization is required, and the mechanisms underlying the cisplatin's proapoptotic effects remain unclear. In the present study, we demonstrated that cisplatin induced apoptosis and autophagy in breast cancer cells. Autophagy induced by cisplatin played a protective role in breast cancer cells, which impaired its proapoptotic effect. Mechanistically, for the first time, we found that cisplatin treatment activated the MAPK signaling pathway and promoted autophagy via the ERK signaling pathway. Notably, we found that nuclear translocation of yes-associated protein (YAP) was regulated by cisplatin-induced autophagy, and we identified YAP as a survival input that promoted survival in cisplatin-treated breast cancer cells. These findings revealed that administration of cisplatin along with an autophagy inhibitor is a promising therapeutic strategy for treating breast cancer.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
Cell Death Discovery
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2023
·Vol. 9
·期 1
·1-15
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IF 7
Ye Jianfeng,Liu Wangmin,Yu Xueyang,Wu Lina,Chen Zhengjie,Yu Yufei,Wang Jianfeng,Bai Song,Zhang Mo
Homeobox A5 (HOXA5), a homeodomain transcription factor, is considered a tumor suppressor in cancer progression; however, its function in prostate cancer (PCa) remains unclear. This study focused on the relevance of HOXA5 in PCa progression. We identified the downregulation of HOXA5 in PCa tissues based on the TCGA database and further verified in 30-paired PCa and adjacent normal tissues. Functional studies revealed that HOXA5 upregulation impaired the stem-like characteristics and malignant behaviors of PCa cells in vitro and in vivo. Mechanistically, HOXA5 was found to be regulated by tumor necrosis factor receptor-associated factor 7 (TRAF7), a putative E3-ubiquitin ligase. We observed that TRAF7 was overexpressed in PCa and subsequently enhanced the degradation of HOXA5 protein via its ubiquitin ligase activity, contributing to the acquisition of an aggressive PCa phenotype. For its downstream mechanism, we demonstrated that sprouty RTK signaling antagonist 2 (SPRY2) served as a downstream target of HOXA5. HOXA5 could directly bind to the SPRY2 promoter, thereby regulating the SPRY2-mediated MEK/ERK signaling pathway. Silencing SPRY2 largely compromised the tumor-suppressive effect of HOXA5 in PCa progression and cancer stemness. Our findings highlight the previously-underappreciated signaling axis of TRAF7–HOXA5–SPRY2, which provides a novel prognostic and therapeutic target for PCa treatment.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2025
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IF 4.8
Zibo Li,Ziyang Huang,Zhiyi Wang,Zhenzhen Guo,Baoying Wang,Yucheng Li,Erping Xu
Background: Chaihu Longgu Muli Decoction (CLM) is a classical herbal formula originally documented in Shang Han Lun. With an 1800-year clinical history, CLM remains widely prescribed for depression (“Yu Zheng” in Traditional Chinese Medicine theory). Emerging evidence suggests that chronic stress-induced depression is closely linked to lung cancer progression and metastasis. However, the therapeutic potential of CLM in this context remains unexplored.Methods: A lung cancer cell xenograft model combined with chronic unpredictable mild stress (CUMS) was used to evaluate the effect of CLM on lung cancer growth. Proteomic analysis was performed to explore the underlying mechanisms by which CLM alleviates CUMS-induced lung cancer progression. Western blot and qPCR were conducted to detect changes in Rap1/ERK-mediated epithelial-mesenchymal transition (EMT) progression. Finally, Rap1 agonists were utilized to determine the therapeutic mechanism of CLM on cortisol or corticosterone (Cort)-induced EMT progression in lung cancer cells and a mouse lung cancer model.Results: In our study, CUMS promoted lung cancer xenograft growth, increased the expression of the proliferation marker Ki67, and elevated serum Cort levels. CLM treatment not only alleviated CUMS-induced depression-like behaviors, but also suppressed stress-driven tumor growth. These effects were replicated in a urethane-induced lung cancer model combined with CUMS. Proteomic analysis revealed that CLM’s anti-tumor effects were associated with modulation of the Rap1 pathway. Mechanistically, CUMS downregulated Rap1GAP, activating Rap1 and subsequent ERK1/2 phosphorylation, thereby promoting EMT in lung cancer tissues. CLM effectively reversed these effects by inhibiting Rap1/ERK-mediated EMT. In vitro, CLM suppressed cortisol-induced migration, invasion, and EMT in lung cancer cells, and these effects were attenuated by Rap1 agonists. Furthermore, CLM inhibited Cort-induced EMT and depression-like behaviors in vivo, while Rap1 activation diminished CLM’s efficacy against Cort-driven tumor growth.Conclusion: These findings suggest that Rap1/ERK-mediated EMT is a hallmark of chronic stress-associated lung cancer progression. CLM exerts its therapeutic effects by targeting this pathway, offering a novel strategy to mitigate stress-aggravated oncogenesis.
研究领域:
肿瘤学
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分子生物学
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药理学
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应激与疾病
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转化医学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2019
·
IF 8.456
Fei Jia,Suya Lin,Xuzhao He,Jiamin Zhang,Shuxian Shen,Zhiying Wang,Bolin Tang,Cheng Li,Yongjun Wu,Lingqing Dong,Kui Cheng,Wenjian Weng
The surface electric potential of biomaterials has been extensively proven to play a critical role in stem cells’ fate. However, there are ambiguous reports on the relation of stem cells’ osteogenic capacity to surface potential characteristics (potential polarity and intensity). To address this, we adopted a surface with a wide potential range and both positive/negative polarity in a comprehensive view to get insight into surface potential-regulating cellular osteogenic differentiation. TbxDy1–xFe2 alloy/poly(vinylidene fluoride-trifluoroethylene) magnetoelectric films were prepared, and the film could provide controllable surface potential characteristics with positive or negative polarity and potential (ϕME) intensity variation from 0 to ±120 mV as well as keep the surface chemical composition and microstructure unchanged. Cell culture results showed that osteogenic differentiation of mesenchymal stem cells on both positive and negative potential films was obviously upregulated when the /ϕME/ intensities were set from 0–55 mV. Differently, the highest upregulated osteogenic differentiation on the positive potential films corresponded to the /ϕME/ intensity from 35–55 mV and was better than that on the negative potential films whereas the highest on the negative potential films corresponded to the /ϕME/ intensity from 0–35 mV and was better than that on the positive potential films. This fact could illustrate why previous reports appeared ambiguously; i.e., the comparative result in osteogenic differentiation between the positive and negative potential films strongly depends on the selection of surface potential intensity. On the basis of assaying of the exposed functional sites (RGD and PHSRN) of the adsorbed fibronectin (FN) and the expression of cellular integrin α5 and β1 subunits, the difference in the behavior between the positive and negative potential films was attributed to the distinct conformation of adsorbed fibronectin (FN) and the opposite changing trend with /ϕME/ for the two films, which triggers the osteogenesis-related FAK/ERK signaling pathway to a different extent. This study could provide new cognition for the in-depth understanding of the regulation mechanism underlying surface potential characteristics in cell behaviors.
研究领域:
生物材料学
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细胞生物学
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组织工程学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
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2022
·
IF 3.973
Nian-jie Zhang,Yuanwei Zhang,Shuo Yin,Du-ji Ruan,Nian He,Xu Chen,Xue-feng Yang
Nonylphenol (NP) is a widely used chemical, which has been considered a kind of endocrine-disrupting chemical and is involved in the occurrence and development of many types of cancers. Our recent studies demonstrated that NP exposure is related to colorectal cancer (CRC) progression. In this study, we also found epithelial–mesenchymal transition (EMT) promoted by NP treatment in CRC cells. However, the mechanism of NP on tumor metastasis is still unclear. In this study, we focused on the effect of the regulator of cell cycle (RGCC) induced by NP treatment. The cancer genome atlas (TCGA) analysis suggested that the expression of RGCC increased in CRC tissues, and our clinical samples showed that the expression of RGCC in tumor tissues is positively correlated with the serum level of NP in CRC patients. Further studies revealed that overexpression of RGCC could enhance the NP-induced EMT process in CRC cells and activate ERK signaling pathways. Inhibiting ERK signaling by ERK inhibitors or the knockdown of RGCC could attenuate the NP-induced EMT process. In addition, both RGCC overexpression and NP treatment could activate ERK pathways and attenuate the effect of ERK inhibitors on the EMT process in CRC cells. Altogether, this study demonstrated that NP could induce cell invasion and migration by increasing the expression of RGCC to enhance the EMT process, which might be through the activation of ERK signaling pathways. This finding supported a potential target for studying NP exposure-related colorectal cancers.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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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）