PHYTOTHERAPY RESEARCH
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2025
·
IF 6.3
Yichao Du,Junjie Bai,Tingting Ma,Ziming Wu,Pengru Wang,Xiaolin Zhong,Wenguang Fu,Shuixiang He
Liver fibrosis, a pivotal pathological feature in the progression of chronic liver injury, currently lacks effective therapies. Sinomenine (SIN), a bioactive alkaloid derived from traditional Chinese medicine, demonstrates diverse pharmacological properties. However, its therapeutic potential and mechanisms in liver fibrosis remain inadequately characterized. This study investigates the anti-fibrotic effects of SIN and its underlying molecular mechanisms. The anti-fibrotic efficacy of SIN was evaluated in two murine models of liver fibrosis induced by carbon tetrachloride (CCl 4 ) or bile duct ligation (BDL), along with transforming growth factor-beta 1 (TGF-β1)-stimulated rat hepatic stellate cells (HSC-T6). Serum biochemical markers, histopathological analyses (Hematoxylin–Eosin, Sirius red, and Masson's trichrome staining), immunofluorescence, and immunohistochemistry were employed to assess hepatic injury and collagen deposition. Western blotting elucidated molecular mechanisms. SIN administration significantly attenuated hepatic injury in CCl 4 - or BDL-induced mice, as evidenced by reduced transaminase levels and improved histopathological features. In both in vivo and in vitro models, SIN suppressed fibrogenesis by decreasing collagen deposition and downregulating expression of α-smooth muscle actin (α-SMA), matrix metalloproteinase 2 (MMP2), and collagen I. Mechanistically, SIN inhibited the TGF-β/SMAD pathway through reduced phosphorylation of SMAD2/3 and attenuated c-JUN signaling via diminished phosphorylated c-JUN levels. Pretreatment with TP0427736 (a SMAD2/3 inhibitor) or SP600125 (a c-JUN inhibitor) synergistically enhanced SIN-mediated α-SMA suppression in HSC-T6 cells. SIN ameliorates liver fibrosis through inhibition of TGF-β/SMAD and c-JUN signaling pathways. These findings position SIN as a promising therapeutic candidate for liver fibrotic disorders.
研究领域:
药理学
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肝脏病学
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DOI
PubMed
高影响因子
Journal of Pharmaceutical Analysis
·
2024
·
IF 6.1
Xin Yang,Guang-Yuan Ma,Xiao-Qiang Li,Na Tang,Yang Sun,Xiao-Wei Hao,Ke-Han Wu,Yu-Bo Wang,Wen Tian,Xin Fan,Zezhi Li,Caixia Feng,Xu Chao,Yu-Fan Wang,Yao Liu,Di Li,Wei Cao
Hepatocellular carcinoma (HCC) expresses abundant glycolytic enzymes and displays comprehensive glucose metabolism reprogramming. Aldolase A (ALDOA) plays a prominent role in glycolysis; however, little is known about its role in HCC development. In the present study, we aim to explore how ALDOA is involved in HCC proliferation. HCC proliferation was markedly suppressed both in vitro and in vivo following ALDOA knockout, which is consistent with ALDOA overexpression encouraging HCC proliferation. Mechanistically, ALDOA knockout partially limits the glycolytic flux in HCC cells. Meanwhile, ALDOA translocated to nuclei and directly interacted with c-Jun to facilitate its Thr93 phosphorylation by P21-activated protein kinase; ALDOA knockout markedly diminished c-Jun Thr93 phosphorylation and then dampened c-Jun transcription function. A crucial site Y364 mutation in ALDOA disrupted its interaction with c-Jun, and Y364S ALDOA expression failed to rescue cell proliferation in ALDOA deletion cells. In HCC patients, the expression level of ALDOA was correlated with the phosphorylation level of c-Jun (Thr93) and poor prognosis. Remarkably, hepatic ALDOA was significantly upregulated in the promotion and progression stages of diethylnitrosamine-induced HCC models, and the knockdown of ALDOA strikingly decreased HCC development in vivo . Our study demonstrated that ALDOA is a vital driver for HCC development by activating c-Jun-mediated oncogene transcription, opening additional avenues for anti-cancer therapies.
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
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2021
·
IF 5.279
Yaozhong Hu,Jiaxin Gu,Yi Wang,Jing Lin,Huaning Yu,Feier Yang,Sihao Wu,Jia Yin,Huan Lv,Xuemeng Ji,Shuo Wang
Tea polyphenol of epigallocatechin-3-gallate (EGCG) has been verified to possess multiple biological activities. Interleukin-23 (IL-23) is a heterodimeric cytokine consisting of two subunits of IL-23p19 and IL-12p40, with the functionality in regulating the production of cytokines under physiological or pathological conditions. By serendipity, the raised expression of IL-23 was observed after treating cells with EGCG, whereas the detailed mechanism remains poorly understood. This study was proposed to investigate the signaling related to EGCG-induced IL-23. The raised expression of IL-23 was confirmed primarily by intraperitoneally injecting with different concentrations of EGCG (0, 20, 50, 80 mg/kg) into BALB/c mice, and the raised expression was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Results from enzyme-linked immunosorbent assay (ELISA) revealed the increase of IL-23 in serum from 116.09 to 153.90 pg/mL after treating with EGCG. The same results were also observed in RAW264.7 and peritoneal macrophages after treating with EGCG (0, 1, 5, 10, 25 μM) with the increased tendency of IL-23 in cultural medium (7.98 to 25.38 pg/mL for RAW264.7; 3.64 to 260.93 pg/mL for peritoneal macrophages). After preliminary exploration of the signaling related to the increased IL-23, the classical signaling pathways and key transcription factors, such as nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK) signaling pathways, and interferon regulatory factor 5 (IRF5), were demonstrated with no relevant contribution. A further study revealed the involvement of the key transcription factor of BATF2, which could antagonistically modulate the transcription and translation of IL-23. The signaling of STAT3-BATF2-c-JUN/ATF2-IL-23 has been further verified in RAW264.7 macrophages using the STAT3 inhibitor of AG490 and the activator of Colivelin TFA. The results indicated that EGCG inhibits the phosphorylation of STAT3 to facilitate the decreased level of BATF2, which contributed to the increased level of IL-23 by the enhancing heterodimerization of c-JUN and ATF2.
研究领域:
免疫学
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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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产品关联
DOI
PubMed
高影响因子
iScience
·
2023
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IF 5.8
Zhijie Zhang,Jiangzhou Shi,Qifang Wu,Zijian Zhang,Xiaoyan Liu,Anqi Ren,Guanlin Zhao,Ge Dong,Han Wu,Jiaxuan Zhao,Yuan Zhao,Jia Hu,Hui Li,Tongcun Zhang,Fuling Zhou,Haichuan Zhu
Dexamethasone (Dex) plays a critical role in T-ALL treatment, but the mechanisms of Dex resistance are poorly understood. Here, we demonstrated that the expression of JUN was regulated in Dex-resistant T-ALL cell lines and patient samples. JUN knockdown increased the sensitivity to Dex. Moreover, the survival data showed that high expression of JUN related to poor prognosis of T-ALL patients. Then, we generated dexamethasone-resistant clones and conducted RNA-seq and ATAC-seq. We demonstrated that the upregulation of JUN was most significant and regulated by JNK pathway in Dex-resistant cells. High-throughput screening showed that HIF1α inhibitors synergized with Dex could enhance Dex resistance cells death in vitro and in vivo. Additionally, JUN combined and stabilized HIF1α in Dex resistance cells. These results reveal a new mechanism of Dex resistance in T-ALL and provide experimental evidence for the potential therapeutic benefit of targeting the JNK-JUN-HIF1α axis for T-ALL treatment.
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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DOI
PubMed
高影响因子
Communications Biology
·
2023
·Vol. 6
·期 1
·1-10
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IF 5.9
Jiao Fuxin,Hu Xiaoming,Yin Hanrui,Yuan Feixiang,Zhou Ziheng,Wu Wei,Chen Shanghai,Liu Zhanju,Guo Feifan
Psychiatric disorders, such as anxiety, are associated with inflammatory bowel disease (IBD), however, the neural mechanisms regulating this comorbidity are unknown. Here, we show that hypothalamic agouti-related protein (AgRP) neuronal activity is suppressed under chronic restraint stress (CRS), a condition known to increase anxiety and colitis susceptibility. Consistently, chemogenic activation or inhibition of AgRP neurons reverses or mimics CRS-induced increase of anxiety-like behaviors and colitis susceptibility, respectively. Furthermore, CRS inhibits AgRP neuronal activity by suppressing the expression of c-Jun. Moreover, overexpression of c-Jun in these neurons protects against the CRS-induced effects, and knockdown of c-Jun in AgRP neurons ( c-Jun ∆AgRP ) promotes anxiety and colitis susceptibility. Finally, the levels of secreted protein thrombospondin 1 (THBS1) are negatively associated with increased anxiety and colitis, and supplementing recombinant THBS1 rescues colitis susceptibility in c-Jun ∆AgRP mice. Taken together, these results reveal critical roles of hypothalamic AgRP neuron-derived c-Jun in orchestrating stress-induced anxiety and colitis susceptibility.
研究领域:
神经科学
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免疫学
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精神病学
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
Cell Reports Medicine
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2025
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IF 10.6
Yong Liu,Zefan Du,Lindi Li,Junbin Huang,Su Liu,Bo Lu,Yifei Duan,Yucai Cheng,Tianwen Li,Jing Zhang,Jiani Mo,Yalin Yang,Wengqing Wang,Hailin Zou,Tianqi Liang,Meng Jiang,Mo Yang,Yun Chen,Cheng Ouyang,Chun Chen
T cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous disease characterized by a high relapse rate. By single-cell transcriptome analysis, we characterize the bone marrow immune microenvironment in patients with T-ALL, identifying 13 major cell clusters. These patients exhibited abnormally expanded hematopoietic stem cells (HSCs) and granulocyte-monocyte progenitors (GMPs), immunosuppressive traits in CD4 + T, CD8 + T, and natural killer (NK) cells. Subdividing CD4 + T cells reveal two subsets transitioning between T helper (Th)1/Th2, Annexin-A1 (ANXA1) − GATA3 − CD4 + T, and ANXA1 + GATA3 + CD4 + T. Additionally, NK cells demonstrate exhaustion in the tumor microenvironment of patients with relapsed T-ALL, with JUN identified as a critical factor. Additionally, JUN is also highly expressed in T-ALL and is crucial for maintaining its proliferation. The JUN inhibitor exhibited successful lethality toward leukemia cells and ameliorated NK cell exhaustion in relapsed T-ALL cell line, as well as in cell-derived tumor xenograft (CDX), patient-derived tumor xenograft (PDX), and NOTCH1-mutant mouse models. In summary, our findings enhance the understanding of T-ALL relapse mechanisms and support the development of innovative immunotherapies for patients with relapsed T-ALL.
研究领域:
血液学
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肿瘤学
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免疫学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PARENTERAL AND ENTERAL NUTRITION
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2021
·Vol. 46
·期 6
·1353-1360
·
IF 4.016
Kaiming He,Chun Cao,Xiangrong Xu,Zhenyu Ye,Xiaoming Ma,Wei Chen,Peng Du
Background Acute liver injury (ALI) is an essential component of sepsis associated with poor outcomes. Octanoic acid (OA), a medium-chain fatty acid, has a protective effect on sepsis-induced organ damage, and autophagy is an adaptive response to sepsis. However, the underlying mechanism by which OA prevents ALI remains unknown. Therefore, we investigated whether OA-rich enteral nutrition (EN) prevented lipopolysaccharide (LPS)-induced ALI through the c-Jun N-terminal kinase (JNK)-dependent autophagy. Methods Firstly, Sprague Dawley rats were randomly divided into four groups (sham, LPS, LPS + EN, and LPS + EN + OA) to detect the effect of OA-rich EN on LPS-induced ALI. Then, rats were randomly divided into five groups (sham, LPS, LPS + EN + OA, LPS + EN + OA + anisomycin (AN), and LPS + SP600125) to explore the mechanism by which OA-rich EN prevented ALI. EN and OA-rich EN were conducted through gastric tubes for 3 days. The liver protective effects were measured by liver histopathological changes, enzymes, inflammatory cytokines of serum and liver, the levels of autophagy, and JNK activity. Results OA-rich EN inhibited JNK activity, up-regulated autophagy and prevented LPS-induced ALI. Inhibition of JNK activity conferred by SP promoted autophagy and prevented LPS-induced ALI. Moreover, the protective effect of autophagy and inhibition of JNK activity conferred by OA-rich EN on ALI was counteracted by AN. Conclusion OA-rich EN prevented LPS-induced ALI through JNK-dependent autophagy. This result suggested that OA-rich EN may be a therapeutic potential for ALI in patients with sepsis.
研究领域:
肝病学
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免疫学
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营养学
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分子生物学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2023
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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
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药物化学
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肺科学
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2021
·
IF 6.4
Qi Liu,Pingping Xiang,Mingyao Chen,Yi Luo,Yun Zhao,Jinyun Zhu,Wangwei Jing,Hong Yu
Purpose: The deposition of hydroxyapatite (HAp) crystals plays an important role in the development of vascular calcification (VC). This study aimed to demonstrate the effects of nanosized HAp (nHAp) on vascular smooth muscle cells (VSMCs) and VC progression.Methods: Transmission electron microscopy (TEM) was used to examine cellular uptake of nHAp. Cell viability was determined using CCK-8 assay kit. Mitochondrial impairment and reactive oxygen species were detected by TEM and fluorescence dye staining, respectively. Cell apoptosis was detected by Western blot analysis and Annexin V staining. Mouse model of VC was built via applying nHAp on the surface of abdominal aorta. Calcification was visualized by Alizarin red and von Kossa staining.Results: We found that nHAp could promote osteogenic transformation of VSMCs by elevating expression of runt-related factor 2 (Runx2), osteopontin (OPN) and alkaline phosphatase (ALP), impairing function and morphology of mitochondria and inducing apoptosis of VSMCs. More phosphorylation of c-Jun N-terminal protein kinase/c-JUN (JNK/c-JUN) in VSMCs was detected after mixing nHAp with VSMCs. HAp-induced osteogenic transformation of VSMCs was blocked by JNK inhibitor SP600125, resulted in decreased ALP activity, less Runx2 and OPN expressions. SP600125 also inhibited apoptosis of VSMCs. Application of nHAp to outside of aorta induced osteogenic transformation and apoptosis of VSMCs, and significant deposition of calcium on the vessel walls of mice, which can be effectively attenuated by SP600125.Conclusion: JNK/c-JUN signaling pathway is critical for nHAp-induced calcification, which could be a potential therapeutic target for controlling the progression of VC.
研究领域:
心血管研究
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Jia Li,Ying Zhang,Zhe Su,Tangxiaoxiao He,Ze Chen,Zhiwei Pan,Chao Ding,Zhichao Yu,Lei Bi
Ethnopharmacological relevance With a prevalence reaching 80% in terminal cancer patients,Cancer cachexia (CC) manifests as irreversible skeletal muscle wasting. Presently, there exists no effective therapeutic strategy for managing cancer cachexia. Traditional Chinese medicine (TCM) contributes significantly to the management of CC, enhancing quality of life and potentially prolonging survival in affected patients. Bu-zhong-yi-qi decoction (BYD), a classical Chinese formulation, demonstrates therapeutic potential for tumor-associated conditions and muscle-related disorders. However, its precise pharmacological mechanisms remain to be fully elucidated. Aim of the study To systematically investigate the therapeutic effects and underlying mechanisms of BYD on muscle atrophy caused by CC through an integrated approach combining network pharmacology analysis with comprehensive in vivo and in vitro experimental validation. Materials and methods Network pharmacology analysis was employed to recognize bioactive components, potential therapeutic targets, and associated pathways of BYD. Molecular docking simulations were subsequently performed to evaluate the binding affinity between BYD constituents and key target proteins. The skeletal muscle atrophy model of CC in vivo was established by subcutaneous injection of Lewis lung cancer (LLC) cells. The therapeutic efficacy of BYD was systematically evaluated through a comprehensive assessment of multiple parameters, including carcass weight, gastrocnemius muscle mass, histopathological alterations, the cross-sectional area (CSA) of muscle fibers and inflammatory markers. The muscle atrophy model in vitro was established by C2C12 mouse myoblasts and LLC cells to investigate the underlying mechanisms of BYD. qRT-PCR and Western blot analysis were employed to evaluate the regulatory effects of BYD on both mRNA and protein expression levels of MuRF-1, Atrogin-1 and key molecular components of the JNK/c-JUN signaling pathway. Results Network pharmacology analysis identified 146 bioactive components and 331 corresponding potential targets of BYD. KEGG pathway enrichment analysis revealed significant enrichment of BYD component targets in the MAPK signaling pathway. Molecular docking simulations revealed strong binding affinities between BYD's bioactive components and JUN protein. Experiments in vivo demonstrated that BYD could increase the carcass weight, gastrocnemius muscle mass and CSA of muscle fibers in mice with cachexia. Meanwhile, it could increase C2C12 myotube diameters in vitro . Additionally, BYD down-regulated the mRNA and protein expressions of MuRF-1, Atrogin-1 and JNK/c-JUN signaling pathway in vivo . Conclusions BYD might contribute to ameliorate muscle atrophy induced by CC through suppression of JNK/c-JUN signaling pathway and downregulation of muscle atrophy markers MuRF-1 and Atrogin-1. These findings suggested BYD as a potential therapeutic intervention for CC.
研究领域:
中药学
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肿瘤学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
American Journal of Translational Research
·
2023
·
IF 2.2
Ting Xie,Xunshan Ren,Huangming Zhuang,Fuze Jiang,Yuelong Zhang,Panghu Zhou
Objective: Osteoarthritis (OA) is the most common degenerative joint disease leading to disability worldwide. Cellular senescence is considered to be a fundamental pathogenic mechanism in the development of OA and has attracted increasing attention. However, regulatory mechanisms underlying chondrocyte senescence in OA remain unclear. Methods: Bioinformatic methods were used to screen key genes. Immunohistochemistry and the quantitative reverse transcription polymerase chain reaction were used to evaluate gene expression. RNA intervention experiments were performed to explore the functions of key genes. Results: We used 494 aging-associated genes provided by the Aging Atlas to identify the co-expression modules associated with age and OA. Thirty age-associated differentially expressed genes (ASDEGs) were identified. Using cytoHubba in Cytoscape, we identified Jun as the hub-ASDEG for OA chondrocytes. We confirmed the downregulation of Jun in OA rats and senescent chondrocytes by immunohistochemistry and quantitative reverse transcription polymerase chain reaction, respectively. Inhibition of proliferation and accelerated senescence were observed in chondrocytes treated with siRNA against Jun. Mechanistically, we observed micronuclei formation and reduced expression of H3K9me3 and heterochromatin protein 1gamma in siRNA-Jun-treated chondrocytes, indicating that destabilization of chromatin occurred during this treatment. Conclusion: Jun plays a crucial role in OA development and causes senescence by destabilizing chromatin in chondrocytes. These findings provide new insights into OA progression and suggest promising therapeutic targets.
研究领域:
风湿病学
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分子生物学
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细胞生物学
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老年学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2021
·
IF 5.34
Xiaohan Wei,Baoping Zhang,Xiao Liang,Changshun Liu,Ting Xia,Yingjie Xie,Xue Deng,Xiaomei Tan
ABSTRACT Background Allergic rhinitis (AR) is an inflammatory, immunoglobulin E (IgE)-mediated disease characterized by the typical symptoms of sneezing, rhinorrhea , nasal itching , and congestion. Higenamine (HG) is a plant-based alkaloid, possesses a wide range of activities, including vascular and tracheal relaxation, antioxidative, antiapoptotic , anti-inflammatory, and immunomodulatory activities. So far, the effect and the underlying mechanism of HG on AR have not been studied. Hypothesis/Purpose The purpose of this study was to evaluate the effects of HG on AR and investigate its underlying mechanism. Methods The effects of HG on AR were evaluated in an ovalbumin-induced AR mouse model. Network pharmacology-based methods such as target prediction, protein-protein interaction (PPI) network analysis, pathway analysis, and molecular docking were used to identify the likely HG targets. Finally, we validated the mechanism of action of HG through its effects on these targets in human nasal epithelial cells (HNEpCs). Results Oral administration of 30, 60, and 120 mg/kg HG significantly alleviated rubbing and sneezing in AR mice and attenuated histopathological changes in the lung and nasal tissues . Additionally, HG reduced the levels of IgE, histamine, and IL-4 in the serum of AR mice, and regulated imbalance in Th1/Th2 cells. Using network pharmacology-based methods, we identified 29 HG targets related to AR. These targets are mainly involved in the PD-L1, relaxin, estrogen, HIF-1, Th1 and Th2 cell differentiation , T cell receptor , and the Th17 cell differentiation signaling pathways . Molecular docking showed that HG may well be suited to the receptor binding pockets of key target AKT1 , EGFR, c-Jun, NOS2 , and JAK2 . In HNEpCs, HG inhibited the histamine-induced mRNA expression and secretion of interleukin (IL)-6, and IL-8, as well as the expression of MUC5AC and the phosphorylation of NF-κB. Moreover, HG affected the changes of AKT1, EGFR, c-Jun, iNOS, and JAK2 induced by histamine. Conclusion Overall, our results suggest that HG may alleviate AR by activating AKT1 and suppressing the EGFR/JAK2/c-JUN signaling. HG, therefore, has great potential as a therapeutic agent for the treatment of AR.
研究领域:
免疫学
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药理学
·
分子生物学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
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