Cancer Communications
·
2023
·Vol. 43
·期 5
·562-581
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IF 16.2
Zhaowei Wen,Huiying Sun,Zhihua Zhang,Yannan Zheng,Siting Zheng,Jianping Bin,Yulin Liao,Min Shi,Rui Zhou,Wangjun Liao
Background Several clinical studies have uncovered a negative correlation between baseline tumor burden and the efficacy of immune checkpoint inhibitor (ICI) treatment. This study aimed to uncover the specific mechanisms underlying the difference in sensitivity to ICI treatment between tumors with high (HTB) and low (LTB) tumor burden. Methods For in vivo studies, several mouse models of subcutaneous tumors were established, and transcriptome sequencing, immunohistochemistry, and flow cytometry assays were used to detect the immune status in these subcutaneous tumors. For in vitro experiments, co-culture models, cytokine antibody arrays, western blotting, flow cytometry, and enzyme-linked immunosorbent assays were used to explore the underlying molecular mechanisms Results We found that MC38 or B16 subcutaneous tumors from the HTB group did not show any response to anti-programmed cell death protein-1 (PD-1) therapy. Through flow cytometry assays, we found that the infiltration with CD8 + T cells was significantly decreased whereas M2-like macrophages were enriched in subcutaneous tumors of HTB groups compared with those of LTB group. These changes were not affected by the initial number of injected tumor cells or tumor age, nor could they be reversed by surgical tumor reduction. Intraperitoneal colony-stimulating factor 1 receptor (CSF-1R) inhibitor PLX3397 injection at different time points of tumor growth only had an effect when administered in the early tumor stage to maintain the “heat” of the tumor microenvironment during the process of tumor growth, thereby achieving a response to ICI treatment when the tumor grew to a large size. Mechanistically, we found that insulin-like growth factor binding protein 2 (IGFBP2) expression levels were significantly elevated in HTB tumor tissues. IGFBP2 promoted the programmed death-ligand 1 (PD-L1) expression in M2-like macrophages by activating signal transducer and activator of transcription 3 (STAT3), and PD-L1 + M2-like macrophages exerted an immunosuppressive effect by inhibiting the proliferation and activation of CD8 + T cells in a PD-L1-dependent fashion. Conclusions This study suggested that the low efficacy of ICI treatment in HTB tumors is mainly attributed to the intratumoral accumulation of PD-L1 + M2-like macrophages via the IGFBP2-STAT3-PD-L1 signaling pathway and their substantial inhibitory effects on T cell proliferation and activation.
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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PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2022
·
IF 10.753
Chenxi Zhao,Ruihui Xie,Qiuhui Qian,Jin Yan,Huili Wang,Xuedong Wang
As a broad-spectrum antibacterial agent, triclosan (TCS) has been confirmed to possess potential immunotoxicity to organisms, but the underlying mechanisms remains unclear. Herein, with the aid of transgenic zebrafish strains Tg ( coro 1A: EGFP) and Tg ( rag 2: DsRed), we intuitively observed acute TCS exposure caused the drastic differentiation, abnormal development and distribution of innate immune cells, as well as barriers to formation of adaptive immune T cells. These abnormalities implied occurrence of the cytokine storm, which was further evidenced by expression changes of immune-related genes, and functional biomarkers. Based on transcriptome deep sequencing, target gene prediction and dual luciferase validation, the highly conservative and up-regulated miR-19a was chosen as the research target. Under TCS exposure, miR-19a up-regulation triggered down-regulation of its target gene socs3b , and simultaneously activated the downstream IL-6/STAT3 signaling pathway. Artificial over-expression and knock-down of miR-19a was realized by microinjecting agomir and antagomir, respectively, in 1–2-cell embryos. The miR-19a up-regulation inhibited socs3b expression to activate IL-6/STAT3 pathway, and yielded abnormal changes in the functional cytokine biomarkers, along with the sharp activation of immune responses. These findings disclose the molecular mechanisms regarding TCS-induced immunotoxicity, and offer important theoretical guidance for healthy safety evaluation and disease early warning from TCS pollution.
研究领域:
毒理学
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分子生物学
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免疫学
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环境科学
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PubMed
高影响因子
PHARMACEUTICAL BIOLOGY
·
2021
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IF 3.503
Rubin Cheng,Yilan Huang,Yun Fang,Qirui Wang,Meixiu Yan,Yuqing Ge
Context A portion of patients with chronic myeloid leukaemia (CML) develop resistance to the Bcr-Abl tyrosine kinase inhibitors (TKIs), limiting the clinical applications. Previous results have demonstrated the synergistic effects between cryptotanshinone (CPT) and imatinib on apoptosis of CML cells in vitro.Objective To determine the antileukemia effects of CPT and TKIs on the resistant CML cells, and further investigate the effect of combined treatment of CPT and imatinib on tumour growth and apoptosis in the xenograft model and clarify its regulatory mechanisms.Materials and methods The combination effects of CPT and second-generation TKIs were evaluated in resistant CML cells K562-R. CPT and imatinib were orally administered once daily for 21 days on K562-R xenografts in nude mice (6 per group). Tumour proliferation and apoptosis were examined by Ki-67, PCNA and TUNEL staining. The expression levels of apoptotic markers and activities of STAT3 and eIF4E pathways were determined via immunohistochemistry staining and western blotting analysis.Results CPT significantly enhanced the antiproliferative effects of TKIs, via triggering cleavages of caspase proteins, and inhibiting activities of STAT3 and eIF4E pathways. The administration of CPT and imatinib dramatically inhibited the tumour growth of xenografts and achieved a suppression of 60.2%, which is 2.6-fold higher than that of single imatinib group. Furthermore, CPT and imatinib increased the apoptotic rates and markedly decreased the phosphorylation levels of STAT3 and eIF4E.Conclusions Our results demonstrated that CPT could significantly enhance the antileukemia efficacy of TKIs, suggesting the therapeutic potential of CPT to overcome CML resistance.
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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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
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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
Frontiers in Immunology
·
2025
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IF 5.9
Lingdi Niu,Haoyuan Duan,Jiaqing Wang,Zheng Jia,Hai Li,Junjie Guo,Shuhe Zhang,Ning Liu,Yaxin Miao,Junwei Ge,Fang Wang
Trained immunity refers to the ability of trained innate immune cells to generate an immune memory that produces rapid, broad-spectrum, and long-lasting protection against heterologous stimuli. Based on the rapid and broad-spectrum protection that the peptidoglycan backbone from lactic acid bacteria, bacterium-like particles (BLPs), offers, we hypothesized that BLPs enhance protection through trained immunity. Here, we found that combining BLP with a vaccine significantly improves protective efficacy against methicillin-resistant Staphylococcus aureus (MRSA) infection, accompanied by changes in trained immunity markers. We demonstrate that BLP-induced trained immunity macrophages exhibit increased cytokine secretion and phagocytic activity in vitro. In an in vivo model, BLP confers protection against S. aureus 26003 even without specific antigens. In an ex vivo model, BLP induces increased markers of trained immunity. Transcriptome analysis suggests that BLP may induce trained immunity by activating the IL-6-JAK-STAT3 pathway through TLR2 receptor activation, thereby modulating macrophage metabolic reprogramming and function. In summary, our study establishes that BLP induction of trained immunity, along with regulated metabolic reprogramming and macrophage function, may contribute to enhancing vaccine efficacy. Our findings elucidate a novel mechanism for BLP-mediated immune enhancement, critical for the application of BLP as a vaccine vector to construct a vaccine that combines specific immune response with innate immune response.
研究领域:
免疫学
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微生物学
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疫苗学
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分子生物学
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传染病学
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PubMed
高影响因子
JOURNAL OF IMMUNOLOGY
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2024
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IF 3.6
Zhu Yiqiang,Zhou Lu,Mo Lengshan,Hong Cansheng,Pan Lingxia,Lin Jie,Qi Yanwei,Tan Simin,Qian Manhongtian,Hu Tengfei,Zhao Yi,Qiu Huaina,Lin Peibin,Ma Xiancai,Yang Quan
Myeloid-derived suppressor cells (MDSCs), the negative immune regulators, have been demonstrated to be involved in immune responses to a variety of pathological conditions, such as tumors, chronic inflammation, and infectious diseases. However, the roles and mechanisms underlying the expansion of MDSCs in malaria remain unclear. In this study, the phenotypic and functional characteristics of splenic MDSCs during Plasmodium yoelii NSM infection are described. Furthermore, we provide compelling evidence that the sera from P. yoelii–infected C57BL/6 mice containing excess IL-6 and granulocyte-macrophage colony-stimulating factor promote the accumulation of MDSCs by inducing Bcl2 expression. Serum-induced MDSCs exert more potent suppressive effects on T cell responses than control MDSCs within both in vivo P. yoelii infection and in vitro serum-treated bone marrow cells experiments. Serum treatment increases the MDSC inhibitory effect, which is dependent on Arg1 expression. Moreover, mechanistic studies reveal that the serum effects are mediated by JAK/STAT3 signaling. By inhibiting STAT3 phosphorylation with the JAK inhibitor JSI-124, effects of serum on MDSCs are almost eliminated. In vivo depletion of MDSCs with anti–Gr-1 or 5-fluorouracil significantly reduces the parasitemia and promotes Th1 immune response in P. yoelii–infected C57BL/6 mice by upregulating IFN-γ expression. In summary, this study indicates that P. yoelii infection facilitates the accumulation and function of MDSCs by upregulating the expression of Bcl2 and Arg1 via JAK/STAT3 signaling pathway in vivo and in vitro. Manipulating the JAK/STAT3 signaling pathway or depleting MDSCs could be promising therapeutic interventions to treat malaria.
研究领域:
免疫学
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传染病学
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细胞生物学
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疟疾
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-24
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IF 12.6
Yu Yang,Kong Liang,Guo Rui-bo,Zhang Ya-ni,Li Shu-tong,Zhang Feng-yuan,Wang Xin,Liu Yang,Li Xiu-Ying,Li Xue-tao
Background The imbalance of macrophage polarization plays a pivotal role in the progression of rheumatoid arthritis (RA). Reprogramming macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype is considered a promising therapeutic strategy. Methods To address this challenge, Panax notoginseng polysaccharides (PNP) with varying molecular weights were chemically conjugated with deoxycholic acid (DC) to obtain amphiphilic conjugates (PNP-DC), which self-assembled into micelles (PNP-Ms). After screening for optimal molecular weight, folic acid (FA) was introduced onto the micelle surface, and Polyphyllin I (PPI) was encapsulated to form FA-modified, PPI-loaded micelles (FA-PPI-Ms) with macrophage-targeting capability. Results FA-PPI-Ms showed enhanced cellular uptake via FA receptor–mediated endocytosis and effectively eliminated reactive oxygen species (ROS), reduced inflammatory cytokine production, and exhibited good biosafety. In vivo, FA-PPI-Ms significantly alleviated joint swelling and inflammation in RA rat models. Mechanistic studies based on RNA sequencing and experimental validation revealed that FA-PPI-Ms suppressed the JAK2/STAT3 signaling pathway, thereby promoting M2 macrophage polarization and restoring the M1/M2 balance. Conclusion This study presents a novel FA-PPI-Ms delivery system for targeted macrophages. By modulating polarization through inhibition of JAK2/STAT3 signaling, the system offers a promising therapeutic strategy for RA and potentially other inflammatory diseases.
研究领域:
药理学
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免疫学
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纳米医学
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分子生物学
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炎症性疾病
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药物递送系统
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DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2023
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IF 7.4
Yuan Hu,Miao Zhang,Bihan Liu,Yingying Tang,Zhuo Wang,Tao Wang,Jiaxin Zheng,Junjian Zhang
Alzheimer's Dementia (AD) and Vascular Dementia (VaD) are two main types of dementias for which no specific treatment is available. Chronic Cerebral Hypoperfusion (CCH) is a pathogenesis underlying AD and VaD that promotes neuroinflammatory responses and oxidative stress . Honokiol (HNK) is a natural compound isolated from magnolia leaves that can easily cross blood brain barrier and has anti-inflammatory and antioxidant effects. In the present study, the effects of HNK on astrocyte polarization and neurological damage in in vivo and in vitro models of chronic cerebral hypoperfusion were explored. We found that HNK was able to inhibit the phosphorylation and nuclear translocation of STAT3 , A1 polarization, and reduce conditioned medium's neuronal toxicity of astrocyte under chronic hypoxia induced by cobalt chloride ; STAT3 phosphorylation inhibitor C188-9 was able to mimic the above effects of HNK, suggesting that HNK may inhibit chronic hypoxia-induced A1 polarization in astrocytes via STAT3. SIRT3 inhibitor 3-TYP reversed, while Sirt3 overexpression mimicked the inhibitory effects of HNK on oxidative stress, STAT3 phosphorylation and nuclear translocation, A1 polarization and neuronal toxicity of astrocyte under chronic hypoxic conditions. For in vivo research, continuous intraperitoneal injection of HNK (1 mg/kg) for 21 days ameliorated the decrease in SIRT3 activity and oxidative stress, inhibited astrocytic STAT3 nuclear translocation and A1 polarization, and prevented neuron and synaptic loss in the hippocampal of CCH rats. Besides, HNK application improved the spatial memory impairment of CCH rats, as assessed with Morris Water Maze . In conclusion, these results suggest that the phytochemical HNK can inhibit astrocyte A1 polarization via regulating SIRT3-STAT3 axis, thus improving CCH-induced neurological damage. These results highlight HNK as novel treatment for dementia with underlying vascular mechanisms.
研究领域:
神经科学
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药理学
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神经退行性疾病
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分子生物学
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植物化学
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DOI
PubMed
高影响因子
Bioactive Materials
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2025
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IF 20.3
Meng Zeng,Ping Deng,Qian Yang,Jie Hu,Jixiang Li,Qi Tang,Xiaoyan Pu,Liangke Zhang
Excessive accumulation of reactive oxygen and nitrogen species (RONS) exacerbates inflammatory responses and contributes to the progression of psoriasis. In particular, ROS activate the STAT3 pathway, inducing abnormal proliferation of keratinocytes and aggravating local inflammation. Moreover, interactions between macrophages and keratinocytes can further exacerbate disease progression. However, current therapeutic strategies have limited efficacy due to poor transdermal permeability and insufficient target specificity. To address these limitations, we have developed a machine learning (ML)-guided framework that integrates virtual screening, experimental validation, and mechanistic analysis into the design of transdermal ionic liquids (ILs). Using this approach, we successfully identified highly efficient transdermal ILs and developed a composite ionic liquids (CIL) delivery system capable of releasing H 2 S. This CIL platform enables the co-delivery of the APTSTAT3-9R peptide and catalase (CAT) directly to psoriatic lesions, implementing a dual therapeutic strategy: (1) inhibition of STAT3 phosphorylation to suppress keratinocyte hyperproliferation, and (2) regulation of redox homeostasis and macrophage polarization via local release of H 2 S and CAT. In vivo studies have shown that CIL@CA can effectively alleviate IMQ-induced psoriasis symptoms in mice. In this study, a novel ML-driven ILs-based drug delivery system was developed, offering a promising strategy for the treatment of inflammatory skin diseases.
研究领域:
皮肤病学
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药物递送系统
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分子生物学
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免疫调节
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纳米医学
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转化医学
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药剂学
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产品关联
DOI
PubMed
高影响因子
CHEMISTRY & BIODIVERSITY
·
2018
·Vol. 15
·期 4
·e1800024
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IF 1.617
Qi-Zhe Gong,Di Xiao,Feng Feng,Xiao-Dong Wen,Wei Qu
ent -Sauchinone, a lignan isolated from Saururus chinensis ( Lour .) Baill ., was reported that it could modulate the expression of signal transducer and activator of transcription 3 (STAT3). Since STAT3 plays a key role in invasion, migration, and metastasis of cancer, we investigated whether ent -sauchinone could exert promising inhibitory effects on the invasion and migration of the metastatic human liver cancer cell line SMMC-7721 in the present study. ent -Sauchinone was extracted from dried herbs of Saururus chinensis ( Lour .) Baill . Human liver cancer cell lines SMMC-7721 and HCCLM3 were used to test the effect of ent -sauchinone on cell viability. The IC 50 values and time-dependent effect of ent -sauchinone were determined by MTT assay. Cell migration and invasion of SMMC-7721 were evaluated by the wound healing test and transwell assay respectively, the known anti-metastasis agent curcumin was used as a positive control. Western blotting assay was used to investigate relevant molecular mechanisms of cell invasion and migration. Though ent -sauchinone didn't show high cytotoxicity, the wound healing assay and transwell migration assay revealed a profound impairment in the metastatic potential of SMMC-7721 cells due to down-regulation of N-cadherin, MMP-2, and MMP-9 proteins induced by inhibiting the phosphorylation of STAT3. These findings suggest that ent -sauchinone could be used as a promising agent to treat cancer metastasis.
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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分子生物学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2024
·
IF 4.2
Zhenyuan Qian,Wenfa Lin,Xufan Cai,Jianzhang Wu,Kun Ke,Zaiyuan Ye,Fang Wu
Background Gastric cancer (GC) is regarded as a major health burden all over the world. WYC-209 inhibits the growth and metastasis of tumor-repopulating cells (TRCs). However, its effectiveness on GC was unexplored. Herein, this study aims to investigate the effect of WYC-209 on GC and elucidate its underlying mechanism. Methods We examined the effects of WYC-209 on cell survival, migration, invasion, and colony-forming capacities of two GC cell lines (AGS and HGC-27). Subsequently, RNA-seq and enrichment analyses were performed to screen the differentially expressed genes (DEGs) and the enriched signaling pathways. To further explore the underlying mechanism, loss- and gain-function experiments, Chromatin immunoprecipitation, and luciferase reporter were conducted. Finally, xenograft models were constructed to examine the effects of WYC-209 in vivo . Results WYC-209 significantly inhibited cell motility in vitro and tumor growth in vivo . RNA-seq performed in AGS cells after WYC-209 treatment revealed that the inhibition effect of WYC-209 on GCs may be associated with the down-regulation of fibroblast growth factor-18 (FGF18), and pleasantly, FGF18 overexpression abrogated the suppression effect of the drug. In addition, we found that WYC-209 attenuated the activation of the Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway, and impeded the FGF18 levels expressed in GCs. Importantly, the WYC-209 treatment circumvented the binding of STAT3 to the FGF18 promoter, suggested that WYC-209 down-regulated FGF18 expression via the STAT3 signaling pathway. Conclusion Together, our findings presented the promise of WYC-209 in suppressing GC by down-regulating FGF18 expression through inactivating the STAT3 signaling pathway.
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
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2019
·Vol. 38
·期 1
·1-15
·
IF 5.646
Li Zizhuo,Chen Yaodong,An Tingting,Liu Pengfei,Zhu Jiyuan,Yang Haichao,Zhang Wei,Dong Tianxiu,Jiang Jian,Zhang Yu,Jiang Maitao,Yang Xiuhua
Background Nuciferine (NF), extracted from the leaves of N. nucifera Gaertn, has been shown to exhibit anti-tumor and anti-viral pharmacological properties. It can also penetrate the blood brain barrier (BBB). However, the mechanism by which NF inhibits glioblastoma (GBM) progression is not well understood. We aimed to determine the anti-tumor effect of NF on GBM cell lines and clarify the potential molecular mechanism involved.Methods U87MG and U251 cell lines were used in vitro to assess the anti-tumor efficacy of NF. Cytotoxicity, viability, and proliferation were evaluated by MTT and colony formation assay. After Annexin V-FITC and PI staining, flow cytometry was performed to evaluate apoptosis and cell cycle changes in NF-treated GBM cells. Wound healing and Transwell assays were used to assess migration and invasion of GBM cells. Western blot analysis, immunofluorescence staining, immunohistochemistry, and bioinformatics were used to gain insights into the molecular mechanisms. Preclinical therapeutic efficacy was mainly estimated by ultrasound and MRI in xenograft nude mouse models.Results NF inhibited the proliferation, mobility, stemness, angiogenesis, and epithelial-to-mesenchymal transition (EMT) of GBM cells. Additionally, NF induced apoptosis and G2 cell cycle arrest. Slug expression was also decreased by NF via the AKT and STAT3 signaling pathways. Interestingly, we discovered that NF affected GBM cells partly by targeting SOX2, which may be upstream of the AKT and STAT3 pathways. Finally, NF led to significant tumor control in GBM xenograft models.Conclusion sNF inhibited the progression of GBM via the SOX2-AKT/STAT3-Slug signaling pathway. SOX2-targeting with NF may offer a novel therapeutic approach for GBM treatment.
研究领域:
肿瘤学
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药理学
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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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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）