Cancer Cell International
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2024
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IF 5.3
Boya Deng,Siyang Zhang,Yingying Zhou,Ting Sun,Ying Zhu,Jing Fei,Ailin Li,Yuan Miao
Coiled-coil domain containing 88C (CCDC88C) is a component of non-canonical Wnt signaling, and its dysregulation causes colorectal cancer metastasis. Dysregulated expression of CCDC88C was observed in lymph node metastatic tumor tissues of breast cancer. However, the role of CCDC88C in breast cancer metastasis remains unclear. To address this, the stable BT549 and SKBR3 cell lines with CCDC88C overexpression or knockdown were developed. Loss/gain-of-function experiments suggested that CCDC88C drove breast cancer cell motility in vitro and lung and liver metastasis in vivo. We found that CCDC88C led to c-JUN-induced transcription activation. Overlapping genes were identified from the genes modulated by CCDC88C and c-JUN. CEMIP , one of these overlapping genes, has been confirmed to confer breast cancer metastasis. We found that CCDC88C regulated CEMIP mRNA levels via c-JUN and it exerted pro-metastatic capabilities in a CEMIP-dependent manner. Moreover, we identified the CCDC88C as a substrate of polypeptide N-acetylgalactosaminyltransferase 6 (GALNT6). GALNT6 was positively correlated with CCDC88C protein abundance in the normal breast and breast cancer tissues, indicating that GALNT6 might be associated with expression patterns of CCDC88C in breast cancer. Our data demonstrated that GALNT6 maintained CCDC88C stability by promoting its O-linked glycosylation, and the modification was critical for the pro-metastatic potential of CCDC88C. CCDC88C also could mediate the pro-metastatic potential of GALNT6 in breast cancer. Collectively, our findings uncover that CCDC88C may increase the risk of breast cancer metastasis and elucidate the underlying molecular mechanisms. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-024-03413-2.
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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生物化学
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PubMed
高影响因子
PLANTA MEDICA
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2022
·Vol. 88
·期 13
·1233-1244
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IF 3.007
Shipeng Chen,Yinan Liao,Jinyan Lv,Huaxin Hou,Jie Feng
The aim of the present study was to investigate the cytotoxic effects and underlying molecular mechanisms of nitidine chloride (NC) in hepatocellular carcinoma cells via quantitative proteomics. MTT assays were used to detect the inhibitory effects of NC in Bel-7402 liver cancer cells, and the number of apoptotic cells was measured by flow cytometry. Quantitative proteomics technology based on iTRAQ was used to discover differential expressed proteins after NC treatment, and bioinformatic techniques were further used to screen potential targets of NC. Molecular docking was applied to evaluate the docking activity of NC with possible upstream proteins, and their expression was detected at the mRNA and protein levels by quantitative reverse transcription PCR and western blotting. NC inhibited the proliferation of Bel-7402 cells after 24 h of treatment and stimulated apoptosis in vitro. The proteomics experiment showed that NC triggers mitochondrial damage in HCC cells and transcription factor AP-1 (c-Jun) may be a potential target of NC (fold change = 4.36 ± 0.23). Molecular docking results revealed the highest docking score of NC with c-Jun N-terminal kinase (JNK), one of the upstream proteins of c-Jun. Moreover, the mRNA and protein expression of c-Jun and JNK were significantly increased after NC treatment (p
研究领域:
癌症生物学
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分子生物学
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药理学
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蛋白质组学
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PubMed
高影响因子
PHYTOMEDICINE
·
2023
·
IF 7.9
Qi-Rui Hu,Qing-Xin Huang,Huan Hong,Yao Pan,Ting Luo,Jing Li,Ze-Yuan Deng,Fang Chen
s Background Liver cancer is a topical global health issue. The treatment of liver cancer meets significant challenges in the high recurrence rate and invasive incidence. Therefore, the treatment strategies that target epithelial-mesenchymal transition (EMT) induced by cyclooxygenase 2 (COX2)/ prostaglandin E2 (PGE2) pathway have become epidemic. Ginsenoside Rh2 has been proved to inhibit the EMT. However, the underlying mechanisms remain unclear. Moreover, the octyl ester derivative of Rh2 (Rh2-O) exhibited superior anti-proliferative and immunomodulatory effects than Rh2 in our previous researches, which indicated that Rh2-O might also exert inhibitory effects on invasion and metastasis . Purpose The aim of current study is to explore the inhibitory effects of Rh2 and Rh2-O on invasion and metastasis of hepatocellular carcinoma , and to investigate whether these effects are dependent on the c-Jun/COX2/PGE2 pathway. Study Design The Huh-7 liver cancer cells and the H22 tumor-bearing mice were treated with Rh2 and Rh2-O. Method In this paper, the inhibitory effects of Rh2 and Rh2-O on invasion and metastasis were tested by wound healing, trans-well assay and tumor-bearing mice, and the involvement of c-Jun/COX2/PGE2 pathway were verified by exogenous PGE2, activation of COX2 and overexpression of c-Jun. Results The results showed that Rh2 and Rh2-O could efficiently inhibit the invasion and metastasis in a dose-dependent manner ( p < 0.05). And the Rh2-O showed stronger effects than Rh2. Moreover, the exogenous PGE2, activation of COX2 by exogenous LPS and the overexpression of c-Jun by transfection all reversed the inhibitory effects of Rh2 and Rh2-O on metastasis or EMT ( p < 0.05). Conclusion Rh2 and Rh2-O could inhibit the invasion and metastasis of hepatocellular carcinoma via restraining the EMT, which was mediated by c-Jun/COX2/PGE2 pathway.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2024
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IF 6.8
Yi Huang,Fengling Liu,Shuhua Ren,Yuanqing Ding,Man Chi,Weiwei Huang,Wenjing Gu,Hewen Qian,Yaxia Yuan,Shurong Hou,Xiabin Chen,Lei Ma
Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease with an elusive etiology. Aberrant activation of c-Jun N-terminal kinase 1 (JNK1) has been implicated in its pathogenesis. Through a combination of structure-based drug design and structure–activity relationship (SAR) optimization, a series of pyrimidine-2,4-diamine scaffold derivatives have been developed as potent JNK1 inhibitors. Compound E1 was identified with low nanomolar JNK1 inhibitory potency (IC50 = 2.7 nM). The introduction of a dimethylamine side chain has significantly enhanced the ability of E1 to inhibit c-Jun phosphorylation, surpassing the clinical candidate CC-90001. Molecular dynamics simulations revealed a binding free energy of −50.46 kcal/mol for E1. Moreover, E1 displayed satisfactory pharmacokinetic properties, with a bioavailability of 69% in rats. Furthermore, compound E1 exerted significant antifibrotic effects in a bleomycin-induced IPF mouse model and prevented a TGF-β-induced epithelial-to-mesenchymal transition in vitro. These findings position E1 as a promising lead for further drug development targeting IPF.
研究领域:
药理学
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药物化学
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肺科学
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药物发现
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PubMed
高影响因子
EXPERIMENTAL EYE RESEARCH
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2021
·
IF 3.467
Lei Tao,Danxue He,Chunyan Liao,Binxiang Cai,Chao Chen,Yan Wang,Jingmeng Chen,Zuguo Liu,Yalin Wu
Retinal pigment epithelium (RPE) cell apoptosis arising from all- trans -retinal (atRAL) is in close contact with the etiology of dry age-related macular degeneration (AMD) and autosomal recessive Stargardt's disease (STGD1), but its underlying mechanisms remain elusive. In this study, we reported that c-Jun N -terminal kinase (JNK) activation facilitated atRAL-induced apoptosis of RPE cells. Reactive oxygen species production and endoplasmic reticulum stress were identified as two of major upstream events responsible for activating JNK signaling in atRAL-loaded RPE cells. Inhibiting JNK signaling rescued RPE cells from apoptosis induced by atRAL through attenuating caspase-3 activation leading to poly-ADP-ribose polymerase (PARP) cleavage, and DNA damage response . Abca4 −/− Rdh8 −/− mice upon light exposure exhibit rapidly increased accumulation of atRAL in the retina , and display severe RPE degeneration, a primary attribute of dry AMD and STGD1. Reducing JNK signaling by intraperitoneally injected JNK–IN-8 was highly effective in preventing RPE atrophy and apoptosis in light-exposed Abca4 −/− Rdh8 −/− mice. These findings afford a further understanding for contribution of JNK activation by atRAL to retinal damage .
研究领域:
眼科学
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分子生物学
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细胞生物学
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神经退行性疾病
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高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2019
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IF 6.054
Xiaodong Dou,Huixia Huang,Yibo Li,Lan Jiang,Yanxing Wang,Hongwei Jin,Ning Jiao,Lihe Zhang,Liangren Zhang,Zhenming Liu
Alzheimer’s disease (AD) is one of the most challenging diseases around the world with no effective clinical treatment. Previous studies have suggested c-Jun N-terminal kinase 3 (JNK3) as an attractive therapeutic target for AD. Herein, we report 3-substituted indolin-2-one derivatives as the first isoform-selective JNK3 inhibitors by multistage screening. In this study, comparative structure-based virtual screening was performed, and J30-8 was identified with a half-maximal inhibitory concentration of 40 nM, which exhibited over 2500-fold isoform selectivity and marked kinome-wide selectivity. Further study indicated that 1 μM J30-8 exhibited neuroprotective activity in vitro so as to alleviate the spatial memory impairment in vivo through reducing plaque burden and inhibiting the phosphorylation of JNKs, Aβ precursor protein, and Tau protein. All of these indicated J30-8 as proved isoform-selective JNK3 inhibitors that might serve as a useful tool for further JNK3 studies with AD as well as for the development of JNK3 inhibitors for the potential treatment of neurodegenerative diseases.
研究领域:
神经科学
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药理学
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药物发现
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高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2022
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IF 5.895
Wan Wang,Cong Xu,Xuan Zhou,Le Zhang,Liya Gu,Zhijing Liu,Jiage Ma,Juncai Hou,Zhanmei Jiang
Probiotics and prebiotics have received attention in alleviating neurodegenerative diseases. Lactobacillus plantarum (L. plantarum) 69-2 was combined with galactooligosaccharides (GOS) and supplemented in a d-galactose (d-gal)-induced neurodegeneration and memory impairment mice model to explore its effects on the brain and the regulation of short-chain fatty acids. The results showed that the L. plantarum-GOS supplementation inhibited d-gal-induced oxidative stress and increased the brain’s nuclear factor erythroid 2-related factor 2 (Nrf2) levels. Butyrate, a metabolite of the gut microbiota regulated by L. plantarum combined with GOS, inhibits p-JNK expression, downregulates pro-apoptotic proteins expression and the activation of inflammatory mediators, and upregulates synaptic protein expression. This might be a potential mechanism for L. plantarum 69-2 combined with GOS supplementation to alleviate d-gal-induced neurodegeneration and memory impairment. This study sheds new light on the development of aging-related neuroprotective dietary supplements based on the gut–brain axis.
研究领域:
神经科学
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微生物学
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营养学
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药理学
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分子生物学
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PubMed
高影响因子
Frontiers in Pharmacology
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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
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免疫学
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分子生物学
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PubMed
高影响因子
Cell Reports
·
2026
·Vol. 45
·期 3
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IF 7.7
Chao Li,Han Zhao,Jingjing Wang,Chenfei Liu,Shiqing He,Jingchao Zhou,Liangyu Li,Yiyao Liu,Qingping Wang,Xiaojing Shen,Junjie Wu,Guangquan Chen,Yu Wang,Liang Yang,Bin Du
Tumor-resident microbiota are identified as a critical modulator in the carcinogenesis and progression of cervical malignancies. However, the mechanisms linking these microbiota to cervical cancer remain poorly understood. In this study, we find that patients with cervical cancer exhibit increased microbiota diversity, characterized by eight distinct bacterial species that distinguish them from control subjects. Intratumoral or intravenous administration of an isolated strain, Gordonia polyisoprenivorans GP-2, derived from tumor-resident microbiota, significantly promotes the growth and metastasis of cervical cancer in mice. Further investigation reveals that GP-2 metabolizes host-derived choline to produce the bacterial metabolite lysophosphatidylcholine (lysoPC). We propose and validate the biosynthetic pathway for lysoPC in strain GP-2 and demonstrate that lysoPC activates the classical tumorigenic genes c-Jun / c-Fos using cervical tumor organoids derived from patients. These findings elucidate the mechanisms underlying microbiota-host crosstalk in cervical cancer and highlight a potential therapeutic target for intervening in tumor-resident bacteria.
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高影响因子
MOLECULAR NEUROBIOLOGY
·
2021
·Vol. 59
·期 1
·429-444
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IF 5.59
Zou Ying,Zhang Jiaqi,Liu Jingmin,Xu Jiawei,Fu Lanya,Ma Xinrui,Xu Yizhou,Xu Shuyi,Wang Xianghai,Guo Jiasong
Silent information regulator 6 (SIRT6) is a mammalian homolog of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin family. Previous studies have been reported a pro-regenerative role of SIRT6 in central nervous system injury. However, the role of SIRT6 in peripheral nerve injury is still unknown. Given the importance and necessity of Schwann cell dedifferentiation response to peripheral nerve injury, we aim to investigate the molecular mechanism of SIRT6 steering Schwann cell dedifferentiation during Wallerian degeneration in injured peripheral nerve. Herein, we first examined the expression pattern of SIRT6 after peripheral nerve injury. Using the explants of sciatic nerve, an ex vivo model of nerve degeneration, we provided evidences indicating that SIRT6 inhibitor accelerates Schwann cell dedifferentiation as well as axonal and myelin degeneration, while SIRT6 activator attenuates this process. Moreover, in an in vitro Schwann cell dedifferentiation model, we found SIRT6 inhibitor promotes Schwann cell dedifferentiation through upregulating the expression of c-Jun. In addition, downregulation of c-Jun reverse the effects of SIRT6 inhibition on the Schwann cells dedifferentiation and axonal and myelin degeneration. In summary, we first described SIRT6 acts as a negative regulator for Schwann cells dedifferentiation during Wallerian degeneration and c-Jun worked as a direct downstream partner of SIRT6 in injured peripheral nerve.
研究领域:
神经科学
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分子生物学
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细胞生物学
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PubMed
高影响因子
CANCER LETTERS
·
2026
·
IF 11.8
Shuangshuang Ma,Minxin Chen,Xiaozheng Sun,Baochao Wei,Fengxin Sun,Xueqi Xie,Yiheng Huang,Zhaoyun Liu,Rong Xiao,Ling Wei,Fei Wang,Ying Xu,Jinming Yu,Dawei Chen,Meng Wu
Tamoxifen has been commonly used in endocrinotherapy for estrogen receptor (ER)-positive breast cancer. In recent years, the immunomodulatory effects of high-dose tamoxifen have been discovered. The immunosuppressive tumor microenvironment (TME), however, remains a major obstacle to the efficacy of radiotherapy. Whether high-dose tamoxifen can reprogram TME to synergistically enhance radiation efficacy is still ambiguous. Here, we have found high-dose tamoxifen could dramatically enhance radiation-induced antitumor effects without significant side effects in immunocompetent mice. Flow cytometry and multiplex immunofluorescence experiments revealed that radiation combined with tamoxifen resulted in significant enrichment of effector CD8 + T cells and M1 tumor associated macrophages (TAMs). While depletion of TAMs and CD8 + T cells impaired the synergistic antitumor effects mediated by combination treatment of radiation and tamoxifen. Furthermore, spatial proximity analysis demonstrated a dramatically reduced nearest-neighbor distance between CD8 + T cells and M1-like TAMs in the combination group, indicating enhanced cellular interaction within the TME. In vitro experiments demonstrated that tamoxifen directly acted on TAMs, rather than CD8 + T cells, to promote M1 polarization and subsequently enhanced the activation and effector function of CD8 + T cells, regardless of ER expression in tumor cells and macrophages. Mechanistically, RNA-sequencing and experimental validation uncovered that tamoxifen and tumor cell-derived TNF-α and IL-1β after irradiation synergistically activated the JNK/c-JUN pathway and promoted M1 polarization of TAMs. In conclusion, our study revealed the immunomodulatory effects of high-dose tamoxifen in the context of radiation and provided preclinical evidence for combination therapy of high-dose tamoxifen and radiotherapy in both ER-positive and ER-negative cancers.
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PubMed
高影响因子
Cell Death & Disease
·
2017
·Vol. 8
·期 7
·e2935
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IF 5.965
Zhou Wei,Yao Jihong,Wang Guangzhi,Chen Zhao,Li Zhenlu,Feng Dongcheng,Li Yang,Qasim Wasim,Tan Wenzhi,Ning Shili,Tian Xiaofeng
Intestinal ischemia–reperfusion (I/R) is a common clinical problem that occurs during various clinical pathological processes. Excessive apoptosis has an indispensable role in intestinal I/R injury. Tumor necrosis factor receptor-associated factor 2 (TRAF2) and PKC ζ have an essential role in apoptosis. Here, we aimed to investigate the effects of PKC ζ and TRAF2 and to explore the correlation between PKC ζ and TRAF2 in intestinal I/R injury. Mice were subjected to intestinal I/R injury in vivo . In vitro experiments were conducted by treating Caco-2 cells with hypoxia/reoxygenation (H/R) stimulation to simulate intestinal I/R. Intestinal tissue samples and Caco-2 cells were examined using various approaches. Intestinal I/R induced the membrane translocation and phosphorylation of PKC ζ . Pretreatment with the PKC ζ activator phosphatidylcholine remarkably attenuated gut injury by suppressing apoptosis. H/R induced PKC ζ to combine with TRAF2, which was phosphorylated by PKC ζ at Ser 55 , but not at Ser 11 , under intestinal I/R or H/R conditions. In addition, TRAF2 Ser 55 phosphorylation increased cell survival by inhibiting cell apoptosis in the H/R model. Mechanistically, TRAF2 Ser 55 phosphorylation promoted NF- κ B activation but suppressed c-Jun activation in Caco-2 cells under H/R conditions. The results of this study demonstrate that the PKC ζ /TRAF2 pathway represents a novel protective mechanism against intestinal I/R injury. Therefore, the PKC ζ /TRAF2 pathway is a novel target for potential treatments of intestinal I/R injury-related diseases.
研究领域:
分子生物学
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细胞生物学
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病理学
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PubMed
高影响因子
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