INTERNATIONAL JOURNAL OF ONCOLOGY
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2023
·Vol. 62
·期 5
·1-21
·
IF 5.2
Ting Xue,Yaodong Chen,Jia Xu,Weiqin Du,Pengzhou Kong,Xinri Zhang
Lung cancer is the leading cause of cancer‑related mortality worldwide. Non‑small cell lung cancer (NSCLC) is the most common pathological subtype of lung cancer and is associated with low 5‑year overall survival rates. Therefore, novel and effective chemotherapeutic drugs are urgently required for improving the survival outcomes of patients with lung cancer. Cyclovirobuxine D (CVB‑D) is a natural steroidal alkaloid, used for the treatment of cardiovascular diseases in Traditional Chinese Medicine. Several studies have also demonstrated the antitumor effects of CVB‑D. Therefore, in the present study, the therapeutic effects of CVB‑D in lung cancer and the underlying mechanisms were investigated using the in vivo xenograft model of NSCLC in nude mice and in vitro experiments with the NSCLC cell lines. Bioinformatics analyses of RNA‑sequencing data, and cell‑based functional assays demonstrated that CVB‑D treatment significantly inhibited in vitro and in vivo NSCLC cell proliferation, survival, invasion, migration, angiogenesis, epithelial‑to‑mesenchymal transition and G2/M phase cell cycle. CVB‑D exerted its antitumor effects by inhibiting the KIF11‑CDK1‑CDC25C‑cyclinB1 G2/M phase transition regulatory oncogenic network and the NF‑κB/JNK signaling pathway. CVB‑D treatment significantly reduced the sizes and weights and malignancy of xenograft NSCLC tumors in the nude mice. In conclusion, the present study demonstrated that CVB‑D inhibited the growth and progression of NSCLC cells by inhibiting the KIF11‑CDK1‑CDC25C‑CyclinB1 G2/M phase transition regulatory network and the NF‑κB/JNK signaling pathway. Therefore, CVB‑D is a promising drug for the treatment of NSCLC patients.
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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DOI
PubMed
高影响因子
iScience
·
2023
·
IF 5.8
Fangyu Song,Wenshuo Zhang,Xiaohui Li,Xiaoqing Chen,Xuejun Yuan,Mingjin Jiang,Yunhe Zhao,Qingxin Liu,Zizhang Zhou
The main cause of high mortality in cancer patients is tumor metastasis. Exploring the underlying mechanism of tumor metastasis is of great significance for clinical treatments. Here, we identify the transcription factor Apt/FSBP is a suppressor for tumor metastasis. In Drosophila wing disc, knockdown of apt is able to trigger cell migration, whereas overexpression of ap t hampers scrib -RNAi-induced tumor cell migration. Further studies show that loss of apt promotes cell migration through activating the JNK pathway. To investigate the role of FSBP, the homolog of Apt in mammals, we construct Fsbp liver-specific knockout mice. Knockout of Fsbp in liver does not cause any detectable physiological defects, but predisposes to tumorigenesis on DEN and CCl 4 treatment. In addition, loss of Fsbp accelerates tumor metastasis from liver to diaphragm. Taken together, this study uncovers FSBP is a novel tumor suppressor, and provides it as a considerable drug target for tumor treatment.
研究领域:
癌症生物学
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分子遗传学
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细胞生物学
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PubMed
高影响因子
MICROBIOLOGICAL RESEARCH
·
2026
·
IF 8.5
Juan Li,Lei Zhao,Mei Yang,Jingyu Hu,Haimin Li,Wei Yin,Yan Yan,Jinyan Gu,Jiyong Zhou
Pseudorabies virus (PRV) reprograms host inflammatory responses and epitranscriptomics, yet how these processes are connected remains unclear. Here, we report a JNK-WTAP-m⁶A-DUSP5 regulatory circuit that coordinates viral replication and inflammatory responses. PRV infection activated c-Jun N-terminal kinase (JNK), which phosphorylated wilms tumor-associated protein (WTAP) to drive its nuclear export and disrupt the activity of the m⁶A methyltransferase complex. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and biochemical analyses revealed a global reduction of N6-methyladenosine (m⁶A) on host transcripts, particularly on proinflammatory cytokines, alongside widespread m⁶A modification sites on viral transcripts. Consequently, reduced m⁶A prolonged the half-lives of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-18 (IL-18) mRNAs, as well as viral transcripts, thereby synergistically promoting PRV replication. Inhibition of JNK activity or restoration of m⁶A modification suppressed PRV replication in vitro and in vivo . Moreover, the m⁶A hypomethylation stabilized dual-specificity phosphatase 5 (DUSP5) transcripts at early infection, transiently restraining JNK activation and forming a negative feedback loop. These findings demonstrate that PRV reprograms the m⁶A machinery via JNK-mediated WTAP phosphorylation and highlights RNA methylation restoration as a promising antiviral strategy.
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高影响因子
CANCER RESEARCH
·
2017
·Vol. 77
·期 10
·2735-2745
·
IF 9.122
Fang Min,Li Yongkui,Huang Kai,Qi Shanshan,Zhang Jian,Zgodzinski Witold,Majewski Marek,Wallner Grzegorz,Gozdz Stanislaw,Macek Pawel,Kowalik Artur,Pasiarski Marcin,Grywalska Ewelina,Vatan Linda,Nagarsheth Nisha,Li Wei,Zhao Lili,Kryczek Ilona,Wang Guobin,Wang Zheng,Zou Weiping,Wang Lin
The expression and biological role of IL33 in colon cancer is poorly understood. In this study, we show that IL33 is expressed by vascular endothelial cells and tumor cells in the human colon cancer microenvironment. Administration of human IL33 and overexpression of murine IL33 enhanced human and murine colon cancer cell growth in vivo , respectively. IL33 stimulated cell sphere formation and prevented chemotherapy-induced tumor apoptosis. Mechanistically, IL33 activated core stem cell genes NANOG, NOTCH3 , and OCT3 / 4 via the ST2 signaling pathway, and induced phosphorylation of c-Jun N terminal kinase (JNK) activation and enhanced binding of c-Jun to the promoters of the core stem cell genes. Moreover, IL33 recruited macrophages into the cancer microenvironment and stimulated them to produce prostaglandin E 2 , which supported colon cancer stemness and tumor growth. Clinically, tumor IL33 expression associated with poor survival in patients with metastatic colon cancer. Thus, IL33 dually targets tumor cells and macrophages and endows stem-like qualities to colon cancer cells to promote carcinogenesis. Collectively, our work reveals an immune-associated mechanism that extrinsically confers cancer cell stemness properties. Targeting the IL33 signaling pathway may offer an opportunity to treat patients with metastatic cancer. Cancer Res; 77(10); 2735–45. ©2017 AACR .
研究领域:
肿瘤学
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免疫学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Journal of Cancer
·
2026
·Vol. 17
·期 5
·1094
·
IF 3.4
Yu Rim Cho,Ke Huang,Zhibin Liu,Hyeonjin Kim,Chae Yeon Kim,Lei Ma,Nangwon Yee,Chae Rim Kim,Geun Hye Park,Jiaxi Zhang,Zae Young Ryoo,Sung Hyun Kim,Myoung Ok Kim
Background Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and remains one of the leading contributors to cancer-related mortality worldwide, primarily due to the disease's therapeutic resistance and marked tumor heterogeneity. Among the molecular mechanisms implicated in HCC progression, the dysregulation of the JNK and PI3K/AKT signaling pathways plays a critical role in tumor initiation, cell proliferation, and cell survival. Vemurafenib, a clinically approved inhibitor of mutant BRAF kinase, has shown robust antitumor activity across multiple malignancies. However, its therapeutic utility in HCC remains largely unexplored. Methods We investigated the anticancer effects of vemurafenib in two human HCC cell lines. Results Vemurafenib treatments led to significant declines in cell viability and colony formation, accompanied by marked reductions in the migratory and invasive behaviors of HCC cells. Mechanistically, vemurafenib enhanced JNK pathway activation while suppressing AKT phosphorylation. Conclusion Vemurafenib markedly inhibited HCC cell proliferation and metastasis, which was accompanied by a pronounced induction of apoptosis and G0/G1 phase cell-cycle arrest. At the signaling level, these cellular responses were linked to enhanced JNK activation and the suppression of AKT phosphorylation, suggesting that vemurafenib may serve as a potential therapeutic agent for HCC.
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PubMed
高影响因子
Frontiers of Medicine
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2025
·
IF 3.5
Li Fengchan,Ni Haofu,Tang Fan,Lyu Jiaxin,Wu Lili,Ren Lijie,Lu Qiongyu,Zhao Shouming,Tang Chaojun,Zhu Li
Atherosclerosis is a chronic inflammatory disease driven by pathological processes such as macrophage foam cell formation. Semaphorin 7A (SEMA7A) is an immunoregulatory signaling molecule known to modulate immune responses and cellular adhesion. However, the contribution of macrophage-derived SEMA7A to atherogenesis has yet to be fully elucidated. In this study, we analyzed gene expression profiles of human mononuclear cells from the Gene Expression Omnibus (GEO) database and revealed highly expressed SEMA7A and its receptor integrin β1 in macrophages. The upregulation of SEMA7A and integrin β1 was also observed during the differentiation of THP-1 monocytes into macrophages. Mice with macrophage-specific deletion of Sema7a showed a 57.2% reduction in atherosclerotic lesion size and improved plaque stability in atherosclerosis mouse model compared to control mice. Mechanistically, macrophage SEMA7A promoted the expression of macrophage scavenger receptor 1 (MSR1) and lipid uptake mediated by integrin β1 and downstream JNK signaling pathway in macrophages. Notably, pharmacological inhibition of integrin β1 with integrin receptor antagonist GLPG0187 effectively suppressed atherosclerosis progression. These findings identify macrophage-derived SEMA7A as a key driver of atherosclerosis through a novel integrin β1/JNK/MSR1 axis, providing potential targets for the prevention and treatment of atherosclerosis.
研究领域:
心血管研究
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免疫学
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分子生物学
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炎症
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DOI
PubMed
高影响因子
Frontiers in Cell and Developmental Biology
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2021
·
IF 6.684
Sheng Xiao,Zhu Yuedan,Zhou Juanyu,Yan La,Du Gang,Liu Zhiming,Chen Haiyang
The dysfunction or exhaustion of adult stem cells during aging is closely linked to tissue aging and age-related diseases. Circumventing this aging-related exhaustion of adult stem cells could significantly alleviate the functional decline of organs. Therefore, identifying small molecular compounds that could prevent the age-related decline of stem cell function is a primary goal in anti-aging research. Caffeic acid (CA), a phenolic compound synthesized in plants, offers substantial health benefits for multiple age-related diseases and aging. However, the effects of CA on adult stem cells remain largely unknown. Using the Drosophila midgut as a model, this study showed that oral administration with CA significantly delayed age-associated Drosophila gut dysplasia caused by the dysregulation of intestinal stem cells (ISCs) upon aging. Moreover, administering CA retarded the decline of intestinal functions in aged Drosophila and prevented hyperproliferation of age-associated ISC by suppressing oxidative stress-associated JNK signaling. On the other hand, CA supplementation significantly ameliorated the gut hyperplasia defect and reduced environmentally induced mortality, revealing the positive effects of CA on tolerance to stress responses. Taken together, our findings report a crucial role of CA in delaying age-related changes in ISCs of Drosophila.
研究领域:
衰老研究
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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
BIOMEDICINE & PHARMACOTHERAPY
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2021
·
IF 6.53
Huqun Li,Chongshu Wang,Jiefang Zhao,Cuilian Guo
Aims c-jun N-terminal kinase (JNK) plays pivotal roles in many physiological processes, including inflammation and glucose metabolism. However, the effects of JNK on olanzapine-induced insulin resistance and the underlying mechanisms have not been fully elucidated. The aim of our study was to explore the role of JNK in olanzapine-induced insulin resistance and the underlying mechanisms. Methods We studied glucose metabolism in olanzapine-treated female C57B/J mice and mice with adeno-associated virus (AAV)-mediated downregulation of JNK1 in epididymal white adipose tissue (eWAT). 3T3-L1 adipocytes were used to investigate the mechanism of JNK1 regulating insulin signaling after olanzapine treatment. Results JNK was activated in eWAT after olanzapine treatment. JNK1 downregulation in eWAT ameliorated the insulin resistance and adipose tissue inflammation in olanzapine-treated mice. Furthermore, overexpression of JNK1 in adipocytes exacerbated the glucose disorder while JNK1 knockdown alleviated the impaired insulin signaling on olanzapine challenge, which was likely mediated by the reduced inflammation and insulin receptor substrate 1 (IRS1) phosphorylation. Moreover, the effect of JNK1 was attenuated by downregulation of IRS1 in adipocytes. Finally, the JNK1-IRS1 interaction and IRS1 S307 phosphorylation were required for JNK1-regulated olanzapine-induced insulin resistance in adipocytes. Conclusions Our results demonstrated that JNK1 activation by olanzapine induced insulin resistance by promoting IRS1 Ser307 phosphorylation and inflammation in eWAT. These results highlighted the importance of JNK1 in eWAT as a promising drug target for olanzapine-induced insulin resistance.
研究领域:
药理学
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内分泌学
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代谢
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炎症
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DOI
PubMed
高影响因子
Biomedical Materials
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2025
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IF 3.7
Jun Yao,Sunfang Chen,Zaihua Zhu,Jianjiang Chen,Jiajie Xia,Bin Fang,Jingjing Guo,Bing Wu,Gaoxiang Ma
Osteoarthritis has become a common degenerative joint disease, lacking clinical means to alleviate this disease. Melittin, taken from natural honeybee venom, possesses outstanding anti-inflammatory properties and has great potential to treat OA. However, its high toxicity and hemolytic properties limit its application. In this work, a biocompatible hydrogel was prepared from extracellular matrix of rib cartilage, possessing fibrous mesh structure characteristics, which was beneficial for melittin loading. It was found that the use of extracellular matrix hydrogel loaded with melittin can reduce the intrinsic toxicity of melittin and prolong the release behavior, simultaneously. The in vitro study demonstrated that melittin-hydrogel could effectively inhibit phosphorylation-ERK/JNK, prevent the exacerbation of TNF-α-induced apoptosis in ATDC5 cells, and reduce their inflammatory markers, effectively alleviating osteoarthritis and preventing cartilage degradation.
Subsequently, in vivo studies have demonstrated that injecting melittin-hydrogel into the joint cavity of OA mice can effectively reduce cartilage degeneration. These findings suggest that melittin-hydrogel plays a critical role in the development of osteoarthritis and may provide a therapeutic option for the treatment of OA disease.
研究领域:
生物材料学
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药理学
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骨科医学
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DOI
PubMed
高影响因子
Cell and Bioscience
·
2021
·Vol. 11
·期 1
·1-13
·
IF 7.133
Tang Ying,Zhou Mengchun,Huang Rongrong,Shen Ling,Yang Li,Zhou Zhongqiu,Ren Hui,Bai Ying
Background Astrocytes participate in innate inflammatory responses within the mammalian central nervous system (CNS). HECT domain E3 ubiquitin protein ligase 1 (HECTD1) functions during microglial activation, suggesting a connection with neuroinflammation. However, the potential role of HECTD1 in astrocytes remains largely unknown. Results Here, we demonstrated that HECTD1 was upregulated in primary mouse astrocytes after 100 ng/ml lipopolysaccharide (LPS) treatment. Genetic knockdown of HECTD1 in vitro or astrocyte-specific knockdown of HECTD1 in vivo suppressed LPS-induced astrocyte activation, whereas overexpression of HECTD1 in vitro facilitated LPS-induced astrocyte activation. Mechanistically, we established that LPS activated σ-1R-JNK/p38 pathway, and σ-1R antagonist BD1047, JNK inhibitor SP600125, or p38 inhibitor SB203580 reversed LPS-induced expression of HECTD1, thus restored LPS-induced astrocyte activation. In addition, FOXJ2 functioned as a transcription factor of HECTD1, and pretreatment of primary mouse astrocytes with BD1047, SB203580, and SP600125 significantly inhibited LPS-mediated translocation of FOXJ2 into the nucleus. Conclusions Overall, our present findings suggest that HECTD1 participates in LPS-induced astrocyte activation by activation of σ-1R-JNK/p38-FOXJ2 pathway and provide a potential therapeutic strategy for neuroinflammation induced by LPS or any other neuroinflammatory disorders.
研究领域:
神经科学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
Biology Direct
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2026
·
IF 5.5
Du Shengwei,Zheng Peisen,Li Wen,Chen Guorong,Chen Hanbin
Hepatocellular carcinoma (HCC) remains a highly aggressive malignancy with a dismal prognosis, largely due to the limited effectiveness of current therapeutic interventions. Although Motesanib (MOT) is a clinically studied VEGFR-centered inhibitor, VEGFR-targeted strategies remain limited by innate or acquired resistance. In this study, we explored a novel pharmacological strategy combining MOT with Auranofin (AF) to enhance therapeutic outcomes in HCC. Our data demonstrate that this dual-targeting approach yields robust synergistic anticancer activity across diverse experimental models. Mechanistically, we discovered that TrxR1 inhibition is critical for this sensitization, which is closely associated with autophagy-related reactive oxygen species (ROS) accumulation. Specifically, genetic depletion of Atg5 effectively suppressed ROS accumulation and attenuated cytotoxicity, suggesting that autophagy contributes to the synergistic oxidative damage. This orchestrated stress response subsequently led to sustained endoplasmic reticulum (ER) stress and JNK pathway activation, culminating in DNA damage, impaired proliferation, and reduced cell viability. Taken together, our results identify the combination of MOT and AF as a promising and mechanistically grounded treatment regimen for advanced HCC (Graphical ). Graphical
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PubMed
高影响因子
VETERINARY MICROBIOLOGY
·
2026
·
IF 2.8
Jian Liang,Yu Song,Yingyu Liu,Wanting Kou,Xin Wang,Xuelin Wang,Guixue Hu,Yuhang Jiang,Qinglong Gong,Jianming Li,Kun Shi,Chao Xu,Xue Leng,Rui Du
AMDV induces apoptosis via the mitochondrial pathway without activating extrinsic pathways. • AMDV promotes its replication by downregulating host JNK protein. • JNK acts as a protective factor by mitigating AMDV-induced apoptosis and G1 cell cycle arrest. • Enhancing JNK activity suppresses AMDV production in a dose-dependent manner. • Targeting the JNK pathway offers a novel strategy for controlling AMDV. Aleutian mink disease virus (AMDV) is a pathogen that causes severe illness in minks, leading to substantial economic losses in the mink farming industry. This study investigated the influence of c-Jun N-terminal kinase (JNK), a host cell protein, on the pathological effects of AMDV in infected cells. AMDV infection caused extrinsic apoptotic pathway with Bax translocation, Cytochrome C release, and caspase-9/3 activation. Proteomic and Western blot analyses confirmed that JNK protein was downregulated after infection. JNK mRNA expression was unaffected at 12–48 h post-infection, whereas cycloheximide chase assays（CHX) showed faster JNK protein loss in infected cells. Because MG132 restored JNK levels while chloroquine had no effect, this degradation is proteasome-dependent. Phosphorylation of JNK and c-Jun also decreased during infection. Overexpressing JNK attenuated apoptosis and G1 arrest, reversed p53 and p21 induction, restored CDK4, and suppressed viral titers and genome copynumbers; JNK silencing had the opposite apoptotic effect. Together, these results show that JNK restricts AMDV in F81 cells and that the virus impairs thispathway by accelerating JNK proteasomal degradation.
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高影响因子
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