ONCOGENE
·
2023
·Vol. 42
·期 29
·2278-2293
·
IF 8
Chen Yihuan,Dai Xiaoshuo,Chen Wei,Qiao Yan,Bai Ruihua,Duan Xiaoxuan,Zhang Kai,Chen Xinhuan,Li Xin,Mo Saijun,Cao Wenbo,Li Xiang,Liu Kangdong,Dong Ziming,Lu Jing
Cisplatin (CDDP) is the first-line drug in the clinical treatment of esophageal squamous cell carcinoma (ESCC), which has severe nephrotoxicity. Diosmetin (DIOS) can protect kidney from oxidative damage, however, its function in ESCC is unknown. This study aims to explore the effect and mechanism of DIOS on ESCC and its combined effect with CDDP. Herein, we found that DIOS significantly inhibited the progression of ESCC in vitro and in vivo. Furthermore, the anti-tumor effect of DIOS was not statistically different from that of CDDP. Mechanically, transcriptomics revealed that DIOS inhibited the E2F2/RRM2 signaling pathway. The transcriptional regulation of RRM2 by E2F2 was verified by luciferase assay. Moreover, docking model, CETSA, pull-down assay and CDK2 inhibitor assay confirmed that DIOS directly targeted CDK2, leading to significant suppression of ESCC. Additionally, the patient-derived xenografts (PDX) model showed that the combination of DIOS and CDDP significantly inhibited the growth of ESCC. Importantly, the combined treatment with DIOS and CDDP significantly reduced the mRNA expression levels of kidney injury biomarkers KIM-1 and NGAL in renal tissue, as well as the levels of blood urea nitrogen, serum creatinine and blood uric acid compared to the single treatment with CDDP. In conclusion, DIOS could be an effective drug and a potential chemotherapeutic adjuvant for ESCC treatment. Furthermore, DIOS could reduce the nephrotoxicity of CDDP to some extent.
研究领域:
肿瘤学
·
药理学
·
分子生物学
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DOI
PubMed
高影响因子
Cancer Immunology Research
·
2022
·Vol. 10
·期 4
·525-539
·
IF 12.02
Chen Yu,Cai Qiaomei,Pan Chaohu,Liu Wancheng,Li Lili,Liu Junxiao,Gao Meiling,Li Xiaorong,Wang Liguo,Rao Yu,Yang Heng,Cheng Genhong
Inhibitors of cyclin-dependent kinase-2 (CDK2) are commonly used against several solid tumors, and their primary mechanisms of action were thought to include cell proliferation arrest, induction of cancer cell apoptosis and induction of differentiation. Here, we found that CDK2 inhibition by either small molecular inhibitors or genetic Cdk2 deficiency promoted antitumor immunity in murine models of fibrosarcoma and lung carcinoma. Mechanistically, CDK2 inhibition reduced phosphorylation of RB protein and transcription of E2F-mediated DNA methyltransferase 1 (DNMT1), which resulted in increased expression of endogenous retroviral RNA and type I IFN (IFN-I) response. The increased IFN-I response subsequently promoted antitumor immunity by enhancing tumor antigen presentation and CD8 + T-cell infiltration. Our studies provide evidence that inhibition of CDK2 in cancer cells suppresses tumor growth by enhancing antitumor immune responses in the tumor microenvironment, suggesting a new mechanism to enhance antitumor immunity by CDK2 inhibitors.
研究领域:
肿瘤学
·
免疫学
·
分子生物学
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DOI
PubMed
高影响因子
FITOTERAPIA
·
2024
·
IF 2.5
Ling Jiang,Cai-Bo Tian,Rui-Han Ye,Nian Shi,Xing-Chao He,Yun-Li Zhao,Xiao-Dong Luo
Drug-induced liver injury caused acute hepatic failure and hepatitis frequently. In this investigation, kakuol and asarinin reduced the levels of serum alanine transaminase (ALT), aspartate transaminase (AST) and malondialdehyde (MDA) dramatically, and ameliorated the pathological damage of liver tissues in APAP-induced mice. Furthermore, both compounds increased the viabilities of APAP-induced L-O2 cells and extracellular glutathione (GSH) levels accompanied significantly by reducing the level of intracellular ROS in vitro . In addition, HSP90AA1/CDK2/mTOR signaling pathway and five target proteins (CDK2, HSP90AA1, HRAS, MMP1, mTOR) were proposed from network pharmacology and molecular docking prediction, and then the up-regulation of protein expression of CDK2, mTOR and down-regulation of HSP90AA1, HRAS, MMP1 by kakuol and asarinin in western blotting supported their mechanism.
研究领域:
药理学
·
分子生物学
·
毒理学
·
肝病学
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DOI
PubMed
高影响因子
Cell Death Discovery
·
2023
·Vol. 9
·期 1
·1-10
·
IF 7
Wang Xianzhe,Shi Wei,Wang Xumei,Lu Jin-Jian,He Ping,Zhang Hongjie,Chen Xiuping
Though palbociclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor has been approved for treating breast cancer, two major clinical challenges remain: (i) Triple-negative breast cancer (TNBC) appears to be more resistant to palbociclib, and (ii) Palbociclib-induced senescence-associated secretory phenotype (SASP) has a pro-tumorigenic function. Here we report that combining palbociclib with the STAT3 inhibitor nifuroxazide uncouples SASP production from senescence-associated cell cycle exit. Moreover, we identified nifuroxazide as a CDK2 inhibitor that synergistically promotes palbociclib-induced growth arrest and senescence in TNBC cells. In vitro, the combination of nifuroxazide with palbociclib further inhibited the TNBC cell proliferation and enhanced palbociclib-induced cell cycle arrest and senescence. The modulation of palbociclib-induced SASP by nifuroxazide was associated with the reduction of phosphorylated-STAT3. Nifuroxazide also blocks SASP-dependent cancer cell migration. Furthermore, thermal shift assay and molecular docking of nifuroxazide with STAT3 and CDK2 revealed that it binds to their active sites and acts as a potent dual inhibitor. In vivo, the combination of nifuroxazide with palbociclib suppressed 4T1 tumor growth and lung metastasis. Our data suggest that nifuroxazide enhances the anticancer effects of palbociclib in TNBC by uncoupling SASP production from senescence-associated cell cycle exit and inhibiting CDK2 to promote tumor senescence.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
·
药理学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Abudureyimu Alimujiang,Yutong Kang,Wenjing Wei,Zehua Zhang,Yipeng Bai,Yong Zhu,Shixia Huo,Dengqiu Xu,Zhijian Li
Background Psoriasis is a long-lasting inflammatory skin condition marked by unusual growth of keratinocytes and infiltration of immune cells in the dermis and epidermis. Dijincao (DJC), a key component of Qing Xue Wan (QXW), is traditionally used to treat psoriasis. Although its clinical efficacy is well-recognized, the absence of pharmacological and mechanistic studies limits the validation of DJC as an effective and scientifically substantiated treatment for psoriasis. Purpose This study aimed to investigate the anti-psoriasis activity of QXW and DJC, identify their most effective constituents, and elucidate the underlying mechanisms of action. Methods Mice with imiquimod (IMQ)-induced psoriasis were treated with QXW or DJC, and the therapeutic effects were evaluated using the Psoriasis Area and Severity Index (PASI), histological analysis, immunohistochemistry, immunofluorescence, RT-PCR, and ELISA. Additionally, UPLC-QTOF/MS technology and lipopolysaccharide (LPS)-induced human keratinocytes (HaCaT) cells were employed to identify the main active components of DJC. Mechanistic insights were gained through RNA sequencing, Western blotting, cell cycle analysis, and luciferase assays. Results Treatment with QXW and DJC resulted in a significant reduction of the PASI score, skin thickness, spleen index, and inflammatory cell infiltration. Moreover, both QXW and DJC reduced serum levels of pro-inflammatory cytokines. DJC alleviated psoriasis by inhibiting keratinocyte hyperproliferation and the inflammatory response. UPLC-QTOF/MS analysis and LPS-induced HaCaT cell studies identified Apigenin as the principal active compound of DJC. Transcriptomic analysis, along with WB, cell cycle, and luciferase assays, revealed that Apigenin mitigates keratinocyte hyperproliferation and the inflammatory response by modulating the CDK2/E2F2-mediated cell cycle and IL-17 signaling pathway. Conclusion This study represents the first comprehensive comparison of the anti-psoriatic effects of QXW, DJC, and Apigenin. The findings suggest that the therapeutic effects of QXW and DJC are primarily attributed to Apigenin, which exerts anti-proliferative properties by inhibiting the CDK2/E2F2 signaling pathway.
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高影响因子
GLIA
·
2025
·
IF 5.1
Xinrui Ma,Jingmin Liu,Jiale Cai,Huqian Zheng,Ye He,Shuyi Xu,Haowen Zhang,Jinkun Wen,Xianghai Wang,Jiasong Guo
RhoA is well known as a key molecular switch for cytoskeleton remodeling, and previous studies reveal RhoA plays a pivotal role in Schwann cell myelination which is highly dependent on the dynamics regulation of the actin and microtubule cytoskeleton. Existing evidence indicates RhoA modulates myelination and other biofunctions by targeting actin filament turnover; however, the role of RhoA in microtubule dynamics remains unknown. Herein, Bulk mRNA sequencing and bioinformatic analysis enriched microtubule dynamics-related ontology terms in RhoA knockout Schwann cells, and identified that microtubules contribute to RhoA deficiency-caused hypomyelination. Both in vivo and in vitro experiments demonstrated that genetic ablation or pharmacological inhibition of RhoA attenuates microtubule dynamics in Schwann cells, whereas activated RhoA overexpression or RhoA agonist enhances the microtubule dynamics. RhoA conditional knockout (cKO) in Schwann cells led to hypomyelination, dysmyelination and nerve functional deficits in mice. Mechanistically, the present study identified CDK2 as a crucial mediating molecule for RhoA regulating microtubule dynamics. CDK2 overexpression could reverse the reduced microtubule dynamics, hypomyelination and motor deficits in RhoA cKO mice. Furthermore, RhoA modulating CDK2 is dependent on YAP/TEAD signaling, and the ASPM/p60-Katanin axis mediates the role of CDK2 in controlling microtubule dynamics. Collectively, this study uncovered a novel RhoA/YAP1/TEAD3/CDK2/ASPM/p60-Katanin axis in regulating microtubule dynamics during Schwann cell myelination, which indicates that this pathway may be utilized as new targets for repairing congenital hypomyelination/dysmyelination neuropathy or peripheral nerve injury.
研究领域:
神经科学
·
细胞生物学
·
分子生物学
·
周围神经系统疾病
·
信号转导
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PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2025
·
IF 6.2
Shenye Qu,Yihang Liu,Jietao Liu,Xiaohu Wu,Pengfei Li,Qing Yu,Gaoxue Wang,Fei Ling
Aquaculture is a rapidly growing sector of global food production, playing a vital role in poverty alleviation, food security, and income generation. However, it faces substantial challenges, particularly due to infections caused by the protozoan Ichthyophthirius multifiliis, leading to reduced yields and economic losses. In this study, two classes of magnolol derivatives (M1–M26) were synthesized and evaluated for their parasiticidal activity against I. multifiliis theronts and tomonts. Based on the determined EC50 values, two significant convolutional neural networks (CNNs) and pharmacophore models were developed, guiding the design and synthesis of three new compounds. Among these, compound new-1 exhibited superior parasiticidal efficacy both in vitro and in vivo compared to magnolol and the commercial parasiticide methylene blue, with EC50 values of 0.197 and 0.252 mg/L, respectively. Toxicity assays demonstrated that compound new-1 showed no significant harmful effects on goldfish and zebrafish embryos at effective concentrations. Further, in silico and experimental analyses identified CDK2 as a molecular target for compound new-1, which disrupted the reproduction and exerts parasiticidal activity against I. multifiliis. Additionally, compound new-1 exhibited antifungal activity against Aspergillus flavus with a MIC of ∼0.8 mg/mL, suggesting its potential application in food preservation. This study provides valuable insights into the development of magnolol-based agents for aquaculture.
研究领域:
水产养殖
·
药物化学
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计算生物学
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分子生物学
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DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2026
·
IF 3.2
Yang Yan,Yongfei Gu
Gastric cancer (GC) is a primary epithelial malignancy originating in the stomach. This research explored the influence and mechanism of Orientin on cellular senescence in GC. Orientin was predicted to regulate multiple cell cycle-related pathways, including cyclin-dependent protein kinase activity. Orientin docked with cyclin dependent kinase 2 (CDK2), cyclin A2 (CCNA2), cyclin E1 (CCNE1), and cyclin E2 (CCNE2) with binding energies of -9.1, -7.5, -7.2, and -8.3 kcal/mol, respectively. The IC 50 values of Orientin for AGS and HGC-27 cells were 24.33 μM and 39.28 μM, respectively. Orientin dose-dependently inhibited GC cell proliferation, promoted G0/G1 phase arrest, as well as downregulated CDK2, CCNA2, CCNE1, and CCNE2 expression. It enhanced senescence-associated β-galactosidase staining intensity, upregulated p16 and p21, and downregulated phosphorylated retinoblastoma (p-Rb). In vivo , Orientin also suppressed tumor progression, promoted p16 and p21 expression, and inhibited CCNE/CCNA-CDK2 signaling. Orientin exerts anti-cancer effects in GC through triggering cellular senescence and cell cycle arrest, likely via activating p16/p21-Rb signaling axis and inhibiting the CCNE/CCNA-CDK2 pathway. Download: Download high-res image (282KB) Download: Download full-size image
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高影响因子
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
·
2021
·Vol. 105
·期 23
·8823-8835
·
IF 4.813
Hong Yi,Zhou Zhou,Yu Lingzi,Jiang Keyang,Xia Jiamiao,Mi Yuling,Zhang Caiqiao,Li Jian
Previously, we found that Lactobacillus salivarius , Lactobacillus agilis , and Lactobacillus aviarius were associated with excellent egg nutrition in native chicken. Next, the optimal Lactobacillus combination is worth studying. Here, a total of 120 HyLine hens (30 hens per group contained 3 replicate cells, 10 hens/cell) in the laying peak period were randomly divided into (1) control, (2) L. salivarius + L. agilis , (3) L. salivarius + L. aviarius , and (4) L. agilis + L. aviarius groups, fed with diet only or with corresponding Lactobacilli (10 8 colony-forming units/hen/day) for 30 days. As a result, L. salivarius + L. agilis feeding could (1) improve egg-laying rate, egg weight, and albumen’s amino acid levels; (2) increase Lactobacillus abundance, decrease Escherichia coli abundance, upregulate the tryptophan metabolism pathway-related molecules, and downregulate the primary bile acid biosynthesis pathway-related molecules in intestinal contents; and (3) upregulate oxidative-phosphorylation pathway-related genes, reactive oxygen species levels, and mRNA abundance of Wnt3a , Dll1 , Lgr5 , CCDN1 , and CDK2 in the crypt. Collectively, L. salivarius + L. agilis feeding in hens could improve intestinal microflora and metabolism profile, promote crypt’s local energy metabolism and reactive oxygen species levels, and thus enhance Paneth cells and intestinal stem cells activity.
Key points
• Lactobacilli co-feeding could improve laying performance and egg nutrition. • Lactobacilli co-feeding could improve intestinal microflora and metabolism profile. • Lactobacilli co-feeding could enhance Paneth cells and intestinal stem cells activity.
研究领域:
动物科学
·
微生物学
·
营养学
·
分子生物学
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DOI
PubMed
高影响因子
IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL
·
2022
·Vol. 58
·期 2
·96-108
·
IF 2.723
Sun Xiaogang,Hou Zhiyun,Li Ning,Zhang Shuangwei
Hepatocellular carcinoma (HCC) is the most common primary liver cancer with high incidence and mortality. MiR-597-5p is downregulated in tumor tissues of HCC compared with non-tumor tissues. However, its role in HCC is still unknown. This study aims to assess the function of miR-597-5p in HCC development and investigate the underlying mechanism. To perform gain- and loss-of-function studies, SK-HEP-1 cells and Huh-7 cells were transfected with miR-597-5p mimics and inhibitor, respectively. MiR-597-5p markedly reduced the cell viability and the expression of Ki-67 in HCC cells. MiR-597-5p also repressed the cell cycle progression of HCC cells and the protein levels of cyclin D1 and CDK2. Moreover, miR597-5p inhibited the migration and invasion of HCC cells and decreased MMP2 and MMP9 levels. Transcriptional enhancer associate domain transcription factor 1 (TEAD1) was identified as a target of miR-597-5p by luciferase reporter assay. TEAD1 and its downstream target genes, CTGF and CYR61, were downregulated by miR-597-5p in HCC cells. Furthermore, miR-597-5p was demonstrated to function in HCC progression by targeting TEAD1 via TEAD1 expression gain and loss. Our study demonstrates that miR-597-5p represses the proliferation, migration, and invasion of HCC cells through targeting TEAD1, which provides a therapeutic target for HCC treatment.
研究领域:
肿瘤学
·
分子生物学
·
癌症研究
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DOI
PubMed
高影响因子
FUNCTIONAL & INTEGRATIVE GENOMICS
·
2021
·Vol. 21
·期 5
·557-570
·
IF 3.41
Sun Shouxiang,Cao Xiaojuan,Castro L. Filipe C.,Monroig Óscar,Gao Jian
Obesity is a rapidly growing health pandemic, underlying a wide variety of disease conditions leading to increases in global mortality. It is known that the phosphorylation of various proteins regulates sterol regulatory element-binding transcription factors 1 ( srebf1 ), a key lipogenic transcription factor, to cause the development of obesity. To detect the key protein kinases for regulating srebf1 in lipid deposition, we established the srebf1 knockout model in zebrafish (KO, srebf1 −/− ) by CRISPR/Cas9. The KO zebrafish exhibited a significant reduction of total free fatty acid content (fell 60.5%) and lipid deposition decrease compared with wild-type (WT) zebrafish. Meanwhile, srebf1 deletion in zebrafish eliminated lipid deposition induced by high-fat diet feeding. Compared with WT zebrafish, a total of 697 differentially expressed proteins and 316 differentially expressed phosphoproteins with 439 sites were identified in KO by differential proteomic and phosphoproteomic analyses. A significant number of proteins identified were involved in lipid and glucose metabolism. Moreover, some protein kinases critical for regulating srebf1 in lipid deposition, including Cdk2, Pkc, Prkceb, mTORC1, Mapk12, and Wnk1, were determined by network analyses. An in vitro study was performed to verify the network analysis results. Our findings provide potential targets (kinases) for human obesity treatments.
研究领域:
分子生物学
·
遗传学
·
蛋白质组学
·
代谢
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营养学
·
肥胖研究
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DOI
PubMed
高影响因子
Metallomics
·
2019
·Vol. 12
·期 2
·173-182
·
IF 3.571
Lv Xiaoguang,Zheng Qiaoqiao,Li Ming,Huang Zhiwei,Peng Min,Sun Jing,Shi Ping
Clioquinol is recently considered to be the most promising drug for treating cancer and neurodegenerative diseases. However, its mode of action varies from different disease models. In this study, we found that clioquinol inhibited cell growth in human neurotypic SHSY-5Y cells, which was attributed to both S-phase cell-cycle arrest and autophagic cell death. Clioquinol increased the intracellular contents of iron and zinc as well as calcium as measured by ICP-AES. Staining of Fluo-3 confirmed an increase in the level of calcium. Analysis of the metal-binding ability of clioquinol showed that it was not a chelating agent of calcium ions and the elevation of intracellular calcium content is not achieved by clioquinol as an ionophore. CaCl2 could simulate or even aggravate the cytotoxicity of clioquinol and it increased S-phase cell cycle arrest induced by clioquinol in a concentration dependent manner. Staining of acridine orange demonstrated that autophagy induced by clioquinol was not affected by addition of calcium ions. In contrast, the intracellular calcium ion chelator BAPTA-am abolished the clioquinol-induced S phase arrest and reduced the cell death caused by clioquinol. The WB assay of cell cycle-related proteins (CDK2, p21 and p27) further confirmed that S phase arrest is positively correlated with intracellular calcium elevation, which was due to the alterations of the mRNA and protein levels of calcium pumps (SERCA and SPCA). Taken together, these data indicate that clioquinol regulates the level of intracellular calcium ions to induce S-phase cell cycle arrest in human SH-SY5Y cells. Our results demonstrate for the first time that an increase of intracellular calcium content is one of the mechanisms of clioquinol in the inhibition of human neurotypic SHSY-5Y cells.
研究领域:
肿瘤学
·
神经科学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
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