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
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
MOLECULAR BIOLOGY REPORTS
·
2022
·Vol. 49
·期 8
·7665-7676
·
IF 2.742
Jiang Haoran,Wen Xianxin,Zhang Xue,Zhong Xianhua,Li Zhangyong,Zhang Bingyu
Background Hepatocellular carcinoma (HCC) is the main types of primary liver cancer, which shows some abnormal glycosylation, such as the increase of fucose. Lens culinaris agglutinin (LCA), a natural plant lectin that can bind to mannose and fucose, has been reported to be antiproliferative to may tumors. However, the effect of LCA on the vitality and migration ability of human hepatoma cells is not demonstrated. Therefore, the aim of this study is to investigate the effects of LCA on vitality and migration in human hepatoma cells and its potential mechanisms. Methods and results LCA had no significant effect on viability of human hepatoma cells (HCCLM3, MHCC97L and HepG2) and hepatocytes (L02) by CCK-8 kit, but it could inhibit human hepatoma cells migration significantly without affecting hepatocytes by Transwell method. Sugar inhibition assay was used to verify the possible binding site between LCA and human hepatoma cells. The result showed that Mannose- and fucose- related sites were associated with LCA inhibiting human hepatoma cells migration. Moreover, LCA could affect HCCLM3 migration by activating ERK1/2 and JNK1/2/3 signalling pathways. LCA did not affect MMP-2 and MMP-9 of HCCLM3 through gelatinase zymography. However, the results of immunofluorescence standing showed that LCA could reduce the F-actin formation in HCCLM3 via ERK1/2 and JNK1/2/3 signalling pathways. Conclusions LCA might inhibit human hepatoma cell migration by reducing the F-actin formation via the mannose and fucose-mediated ERK1/2 and JNK1/2/3 signalling pathway. This result will deepen people’s understanding on plant lectin as a drug in tumor glycobiology.
研究领域:
肿瘤生物学
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分子生物学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
FASEB JOURNAL
·
2026
·Vol. 40
·期 5
·e71641
·
IF 4.3
Xiaoxue Wang,Zexin Zhu
Rosacea is a chronic inflammatory dermatological disorder involving the activation of various signaling pathways. Imperatorin (IMP), a coumarin compound, has been documented to exhibit anti‐inflammatory properties. Nevertheless, its therapeutic efficacy in managing rosacea remains unexplored. Bioinformatics and network pharmacology approaches were utilized to elucidate potential signaling pathways and molecular targets of IMP in the context of rosacea. Subsequently, to assess the in vivo therapeutic efficacy of IMP, murine models exhibiting rosacea‐like inflammatory responses were developed. Additionally, in vitro experiments were conducted to elucidate the molecular mechanisms underlying the anti‐rosacea effects of IMP. Our findings demonstrated that both intraperitoneal and topical administration of IMP significantly attenuated skin inflammation in mice with LL37‐induced rosacea models. Mechanistic investigations, guided by bioinformatics and network pharmacology analyses, revealed an interaction between JNK1 and STAT1. IMP was found to directly bind to JNK1 and STAT1, disrupting their interaction, thereby inhibiting STAT1 phosphorylation and nuclear translocation. This inhibition resulted in decreased production of STAT1‐mediated inflammatory mediators in keratinocytes. These results suggest that IMP may serve as a promising therapeutic agent for inflammatory skin diseases by targeting the crosstalk between JNK1 and STAT1. IMP treatment disrupts the interaction between JNK1 and STAT1, thereby attenuating STAT1 activity. This interference subsequently diminishes the phosphorylation and nuclear translocation of STAT1, which ultimately results in a reduced production of inflammatory cytokines and chemokines. Consequently, this process alleviates the symptoms of rosacea.
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PubMed
高影响因子
AGING CELL
·
2026
·Vol. 25
·期 10
·e70732
·
IF 7.7
Lixing Zhou,Ying Cheng,Wanyu Zhao,Xuelian Sun,Fengjuan Hu,Meiling Ge,Yan Zhang,Gongchang Zhang,Birong Dong,Xiaolei Liu
Cognitive impairment (CI) associated with aging and immunosenescence is linked to metabolic alterations. Microglial senescence and dysregulated autophagy have been implicated as major contributors to this process, but the underlying metabolic regulators remain unclear. This study aimed to identify key metabolic regulators of CI and elucidate their underlying mechanisms. Human cohort analyses, older and D‐galactose (D‐gal)‐induced mouse models, and microglial cell models were integrated to investigate the metabolic regulation of CI. Clinical analyses identified ghrelin as the factor most strongly associated with CI. Older and D‐gal mice exhibited CI, microglial senescence, enhanced inflammation, and elevated ghrelin. Ghrelin treatment improved cognitive function, attenuated microglial senescence, and suppressed inflammation, whereas high‐dose ghrelin induced growth hormone secretagogue receptor (GHSR) desensitization. Sex hormone‐binding globulin (SHBG) showed mainly cytoplasmic localization, was identified as a potential mediator of ghrelin signaling in microglia, and its expression was downregulated following ghrelin treatment. Transcriptomic profiling revealed significant enrichment of autophagy‐related pathways in ghrelin‐treated microglia. Ghrelin altered autophagy‐related markers, as indicated by increased Beclin1 and LC3 and decreased p62. SHBG overexpression or JNK1 inhibition attenuated the ghrelin‐induced alterations in autophagy‐related markers and anti‐senescent effects, whereas Beclin1 overexpression partially rescued these inhibitory effects caused by SHBG overexpression. In conclusion, ghrelin alleviated aging‐related CI, with mechanistic evidence indicating that the modulation of microglial autophagy‐related mechanisms through the SHBG/JNK1/Beclin1 axis may contribute to its protective effects, thereby providing a potential therapeutic strategy for aging‐related CI. This study found that aging‐related cognitive impairment is accompanied by hippocampal microglial senescence. Ghrelin suppresses microglial senescence by promoting autophagy through the SHBG/JNK1/Beclin1 axis, thereby alleviating aging‐related cognitive impairment. The graphical abstract was drawn using the Figdraw.
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DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2020
·Vol. 24
·期 17
·9667-9681
·
IF 4.486
Li-Juan Wang,Lin He,Lu Hao,Hong-Lei Guo,Xiang-Peng Zeng,Ya-Wei Bi,Guo-Tao Lu,Zhao-Shen Li,Liang-Hao Hu
Chronic pancreatitis (CP) is characterized by persistent inflammation of the pancreas that results in progressive loss of the endocrine and exocrine compartment owing to atrophy and/or replacement with fibrotic tissue. Currently, the clinical therapeutic scheme of CP is mainly symptomatic treatment including pancreatic enzyme replacement, glycaemic control and nutritional support therapy, lacking of specific therapeutic drugs for prevention and suppression of inflammation and fibrosis aggravating in CP. Here, we investigated the effect of isoliquiritigenin (ILG), a chalcone-type dietary compound derived from licorice, on pancreatic fibrosis and inflammation in a model of caerulein-induced murine CP, and the results indicated that ILG notably alleviated pancreatic fibrosis and infiltration of macrophages. Further in vitro studies in human pancreatic stellate cells (hPSCs) showed that ILG exerted significant inhibition on the proliferation and activation of hPSCs, which may be due to negative regulation of the ERK1/2 and JNK1/2 activities. Moreover, ILG significantly restrained the M1 polarization of macrophages (RAW 264.7) via attenuation of the NF-κB signalling pathway, whereas the M2 polarization was hardly affected. These findings indicated that ILG might be a potential anti-inflammatory and anti-fibrotic therapeutic agent for CP.
研究领域:
药理学
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病理学
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免疫学
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DOI
PubMed
高影响因子
Oncology Letters
·
2022
·Vol. 24
·期 5
·1-12
·
IF 3.111
Haoran Jiang,Xianxin Wen,Xue Zhang,Bingyu Zhang
Concanavalin A (Con A), the first and most typical representative of the legume lectin family, has a potent anti‑liver cancer effect by inducing cell apoptosis and autophagy. However, its function in human liver cancer cell migration remains unclear. The present study investigated the effect of Con A on the viability and migration of human liver cancer cells with different metastatic abilities. It was found that Con A could reduce the viability of human liver cancer cells (HCCLM3, MHCC97L and HepG2) and human hepatocytes (MIHA). In addition, Con A could inhibit human liver cancer cell migration specifically without affecting hepatocytes. Sugar inhibition assay showed that glucose‑related sugar binding sites played an important role in the inhibition of Con A on human liver cancer cell migration. In addition, Con A could affect HCCLM3 migration by activating ERK1/2, JNK1/2/3 and p38 signaling in the MAPK pathway. Moreover, Con A could regulate fibrous actin (F‑actin) redistribution and assembly via the MAPK signaling pathway. However, Con A had no significant effect on the activation of matrix metalloproteinase (MMP)‑2 and MMP‑9 in HCCLM3 cells. In conclusion, Con A may bind to glucose‑related receptor protein, activating ERK1/2, JNK1/2/3 and p38 signaling in the MAPK pathway, further contracting cells and reducing the content of F‑actin of single cells to inhibit HCCLM3 cell migration. These results would deepen the links between human liver cancer cell migration and related glycoproteins or signaling molecules, and may provide a new perspective for Con A as a potential anticancer agent.
研究领域:
癌症生物学
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细胞生物学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Chen Mingjun,Feng Yang,Luo Dan,Zhang Chen,Zhou Jing,Dai Hengheng,Lin Mingxiong,Tong ZhanQi
Purpose: Wuwei Kushen Changrong capsule (Composite Sophora Colon-soluble Capsule, CSCC) is a Chinese patent medicine developed to treat ulcerative colitis. Studies highlight CSCC potential efficacy for ulcerative colitis (UC) but unclear mechanism limits its widely treatment for patients. We aimed to investigate the anti-colitis efficacy of CSCC and explore the mechanism by which GPR43 inhibits the NLRP3/STAT3 signaling pathway, thereby mediating the protective effects of CSCC on the intestinal barrier.Methods: The protective effects of CSCC were evaluated in a murine ulcerative colitis model induced by 3% DSS. Assessments included body weight, Disease Activity Index (DAI) score, colon length, and histopathological score. Colon tissue, cell function, and immune-inflammatory status were evaluated using immunohistochemistry, immunofluorescence, ELISA, and real-time fluorescence quantitative PCR (RT-PCR). Protein expression levels of relevant pathways and receptors were measured using Western blot. All experiments were repeated.Results: CSCC protected mice from DSS-induced colitis by upregulating Gpr43, promoting the expression of ZO-1 and Occludin tight junction proteins. Mechanistically, CSCC inhibits the MEK4/JNK1/STAT3 activation pathway, consequently suppressing the STAT3/NLRP3/IL-1β pathway and inhibiting the production of inflammatory factors such as IL-17A.Conclusion: The mechanisms through which CSCC protects against DSS-induced colitis may include upregulating Gpr43, inhibiting the STAT3/NLRP3 pathway, and suppressing inflammation factors like IL-17A. These findings highlight the mechanisms underlying CSCC’s anti-colitis effects and suggest its potential as a therapeutic candidate for managing the progression of UC.
研究领域:
药理学
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免疫学
·
胃肠病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2018
·Vol. 8
·期 1
·1-11
·
IF 4.122
Wu Chuanhong,Zhao Wenwen,Yu Jie,Li Shaojing,Lin Ligen,Chen Xiuping
Neurodegenerative diseases (NDD) are typically associated with neuron loss in nervous system areas. Interventions with related death mechanisms may ameliorate NDD progression. Oxidative stress plays an important role in NDD cell death routines. However, tert-butylhydroperoxide (t-BHP), a widely used oxidative stress stimulus, induces neural cell death through a mechanism that remains elusive. In our study, the ferroptosis marker events occurred after co-treatment with 100 μM t-BHP for 1 h, all of which were reversed in the presence of the ferroptosis inhibitor ferrostatin-1 (Fer-1) and the iron chelator deferoxamine, implying the occurrence of ferroptosis. Moreover, mitochondrial dysfunction accompanied by a decreased in membrane potential and ATP production, increased mitochondrial ROS generation. Furthermore, this mitochondrial dysfunction could be reversed by Fer-1. In addition, JNK1/2 and ERK1/2 were activated upstream of the ferroptosis and mitochondrial dysfunction. In summary, these data suggest that ferroptosis, coupled with mitochondrial dysfunction, was involved in t-BHP-induced PC12 death. JNK1/2 and ERK1/2 played important roles in t-BHP-induced cell death. Overall, this study might provide clues to the oxidative stress-based strategies for cell protection in NDD.
研究领域:
神经科学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 6.7
Hewen Qian,Yuanqing Ding,Xingyu Deng,Weiwei Huang,Zhenzhen Li,Fengling Liu,Jie Zhang,Lihui Wang,Junping Liu,Yaxia Yuan,Shurong Hou,Xiabin Chen,Lei Ma
Idiopathic pulmonary fibrosis (IPF) is a severe and progressive lung disease with poor prognosis and limited treatment options. The c -Jun N-Terminal Kinase 1 (JNK1), a key component of the MAPK pathway, has been implicated in the pathogenesis of IPF and represents a potential therapeutic target. However, the development of JNK1 inhibitors has been slowed, partly due to synthetic complexity in medicinal chemistry modification. Here, we report a synthesis-accessibility-oriented strategy for designing JNK1 inhibitors based on computational prediction of synthetic feasibility and fragment-based molecule generation. This strategy led to the discovery of several potent JNK1 inhibitors, such as compound C6 (IC 50 = 33.5 nM), which exhibited comparable activity to the clinical candidate CC-90001 (IC 50 = 24.4 nM). The anti-fibrotic effect of C6 was further confirmed in animal model of pulmonary fibrosis . Moreover, compound C6 could be synthesized in only two steps, compared to nine steps for CC-90001 . Our findings suggest that compound C6 is a promising lead for further optimization and development as a novel anti-fibrotic agent targeting JNK1. In addition, the discovery of C6 also demonstrates the feasibility of synthesis-accessibility-oriented strategy in lead discovery.
研究领域:
药理学
·
药物化学
·
肺科学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
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
·
药物化学
·
肺科学
·
药物发现
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产品关联
DOI
PubMed
高影响因子
Regenerative Biomaterials
·
2016
·Vol. 3
·期 5
·299-307
·
IF 0
Sun Hong-Ji,Wang Yan,Hao Tong,Wang Chang-Yong,Wang Qi-Yu,Jiang Xiao-Xia
Glutathione (GSH) depletion has been an important contributor to the dysfunction of dopamine neurons. Polyamidoamine-GSH (PAMAM-GSH) was synthesized and the delivery effect of GSH into PC12 cells was tested. MTT assessment for cytotoxicity and reactive oxygen species (ROS) as well as nitrite oxide (NO) and intracelluar superoxide dismutase (SOD) detection for antioxidative ability were performed. Furthermore, the antiapoptotic ability was analysed by assessing caspase-3, JNK1/2 and Erk1/2 expression. Our data indicated that PAMAM-GSH is an effective agent to replenish GSH into PC12 cells. PAMAM-GSH developed its antioxidative and protective ability for 1-methyl-4-phenylpyridinium (MPP)-induced PC12 cells by reducing the intracellular levels of ROS and SOD activity as well as decreasing the release of NO. Meanwhile, PAMAM-GSH could inhibit caspase-3 activation and might show its antiapoptotic ability to MPP-induced PC12 cells through JNK2/Erk1/2 pathway. In summary, these studies suggest that PAMAM-GSH conjugate has an intrinsic ability to penetrate PC12 cells and deliver GSH into these cells which may provide a new strategy for clinical applications in the treatment of Parkinson’s disease.
研究领域:
神经科学
·
药理学
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细胞生物学
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疾病模型
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产品关联
DOI
PubMed
BIOCHEMICAL PHARMACOLOGY
·
2022
·
IF 6.1
Yanbei Tu,Lihua Tan,Tao Lu,Kai Wang,Haiyong Wang,Bing Han,Yuxin Zhao,Hanbin Chen,Yanfang Li,Haixia Chen,Meiwan Chen,Chengwei He
The roots of Glycine tabacina are used to treat rheumatoid arthritis (RA) and joint infection in folk medicine. Glytabastan B (GlyB), a newly reported coumestan isolated from this species, was found to significantly attenuate IL-1β-induced inflammation in SW982 human synovial cells at 3 and 6 μM, as evidenced by the decreased levels of pro-inflammatory mediators and matrix metalloproteinases (MMPs). GlyB also suppressed RANKL-induced osteoclastogenesis, decreased the expression of osteoclastogenic markers (NFATc1, CTSK , MMP-9) and osteoclast-mediated bone resorption. Further, GlyB administration (12.5 and 25 mg/kg) significantly inhibited inflammation, osteoclast formation and disease progression in collagen-induced arthritis (CIA) mice. Integration of network pharmacology , quantitative phosphoproteomic and experimental pharmacology results revealed that these beneficial actions were closely associated with the blockade of GlyB on the activation of MAPK , PI3K/AKT and their downstream signals including NF-κB and GSK3β/NFATc1. Drug affinity responsive target stability (DARTS) assay, cellular thermal shift (CETSA) assay and molecular docking analysis confirmed that there were direct interactions between GlyB and its target proteins ERK2 , JNK1 and class Ⅰ PI3K catalytic subunit p110 (α, β, δ and γ), which significantly contributed to the inhibition of activation of MAPK and PI3K/AKT pathways. In conclusion, these results strongly suggest GlyB is a promising multiple-target candidate for the development of agents for the prevention and treatment of RA.
研究领域:
药理学
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免疫学
·
风湿病学
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生物化学
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分子生物学
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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）