Oncotarget
·
2015
·
IF 6.359
Libin Wei,Yuxin Zhou,Jing Yao,Chen Qiao,Ting Ni,Ruichen Guo,Qinglong Guo,Na Lu
Reprogramming energy metabolism, such as enhanced glycolysis, is an Achilles' heel in cancer treatment. Most studies have been performed on isolated cancer cells. Here, we studied the energy-transfer mechanism in inflammatory tumor microenvironment. We found that human THP-1 monocytes took up lactate secreted from tumor cells through monocarboxylate transporter 1. In THP-1 monocytes, the oxidation product of lactate, pyruvate competed with the substrate of proline hydroxylase and inhibited its activity, resulting in the stabilization of HIF-1α under normoxia. Mechanistically, activated hypoxia-inducible factor 1-α in THP-1 monocytes promoted the transcriptions of prostaglandin-endoperoxide synthase 2 and phosphoenolpyruvate carboxykinase, which were the key enzyme of prostaglandin E2 synthesis and gluconeogenesis, respectively, and promote the growth of human colon cancer HCT116 cells. Interestingly, lactate could not accelerate the growth of colon cancer directly in vivo . Instead, the human monocytic cells affected by lactate would play critical roles to ‘feed’ the colon cancer cells. Thus, recycling of lactate for glucose regeneration was reported in cancer metabolism. The anabolic metabolism of monocytes in inflammatory tumor microenvironment may be a critical event during tumor development, allowing accelerated tumor growth.
研究领域:
癌症生物学
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免疫学
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代谢
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细胞生物学
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DOI
PubMed
高影响因子
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
·
2021
·
IF 2.73
Shengyu Sun,Yourui Zou,Shaocai Hao,Zhanfeng Niu,Liang Wu
Objective Polydatin has been used in the treatment of various inflammatory diseases. However, its role in the regulation of neuroinflammation has not been reported. In this study, we designed to investigate the anti-inflammatory effects of polydatin in LPS-stimulated BV2 microglia cells.Methods Inflammatory mediators TNF-α, IL-1β, NO, and PGE2 production were measured by ELISA. The protein of signaling pathways were detected by western blot analysis.Results The results showed that polydatin significantly ameliorated the production of TNF-α, IL-1β, NO, and PGE2 up-regulated by LPS. Polydatin also blocked LPS-induced NF-κB activation. In addition, PI3K and AKT, the up-stream molecules of NF-κB signaling pathway, were inhibited by the treatment of polydatin. Also, we found the formation of lipid rafts was inhibited by polydatin through attenuating the cholesterol content. Finally, polydatin was found to increase the expression of ABCA1 and ABCG1.Conclusion In conclusion, the results of the present study suggested that polydatin exhibited its anti-inflammatory effects in BV2 cells through disrupting lipid rafts, which subsequently inhibiting PI3K/AKT signaling pathway.
研究领域:
药理学
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神经科学
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免疫学
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DOI
PubMed
高影响因子
INFLAMMATION
·
2021
·Vol. 44
·期 5
·2018-2032
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IF 4.092
Zhou Changkai,Gao Jing,Ji Hongyan,Li Wenjing,Xing Xiaomin,Liu Donghua,Guo Qie,Zhou Lihua,Jing Fanbo
Previous studies have shown that benzoylaconine (BAC), a representative monoester alkaloid, has a potential anti-inflammatory effect. This study investigated the underlying molecular mechanisms using the mode of LPS-activated RAW264.7 macrophage cells. Our findings showed that BAC significantly suppressed the release of pro-inflammatory cytokines and mediators, including IL-6, TNF-α, IL-1β, ROS, NO, and PGE 2 . BAC treatment also effectively downregulated the elevated protein levels of iNOS and COX-2 induced by LPS in a dose-dependent manner. In this study, we found that BAC inhibited LPS-induced NF-κB activation by reducing the phosphorylation and degradation of IκBα by western blotting and blocking the nuclear translocation of p65 using an immunofluorescence assay. The elevated protein levels of JNK, p38, and ERK phosphorylation after LPS stimulation were restored effectively by BAC treatment. The protein expression of Toll-like receptor 4 (TLR4) and LPS-induced phosphorylation of TAK1, which is a crucial upstream regulatory factor of TLR-induced MAPK and NF-κB signaling, were inhibited by BAC in activated RAW264.7 macrophages. Moreover, BAC decreased the levels of TAK1 phosphorylation and pro-inflammatory cytokines and mediators associated with MAPK and NF-κB activation, similar to TLR4 inhibitor TAK-242. These findings demonstrated that BAC exhibited an anti-inflammatory effect by the inhibition of TLR-induced MAPK and NF-κB pathways, indicating that it could potentially be used for treating inflammatory diseases.
研究领域:
免疫学
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药理学
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细胞生物学
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炎症研究
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
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IF 6.8
Zhiyuan Cheng,Yao Zhang,Limin Du,Wei Wang,Xiaolei Chai,Mengxian He,Hankun Zhang,Deyan Wu,Jian Lu,Sen Zhang,Bo Feng,Linlin Yang,Mingyao Liu,Weiqiang Lu
The development of dual prostaglandin E2 receptors 2/4 (EP2/EP4) antagonists represents an attractive strategy for cancer immunotherapy. Herein, a series of 4,7-dihydro-5H-thieno[2,3-c]pyran derivatives with potent EP2/EP4 dual antagonism were discovered by fine-tuned structural modifications. The biphenyl side chain was found to be the key pharmacophore for the transition from EP4 antagonism to EP2/EP4 dual antagonism. The introduction of large sterically hindered segments posed challenges on obtaining EP2 potency, while having minimal impact on EP4 potency. Molecular dynamics simulations verified that the EP2 pocket is relatively narrow compared to EP4, and the key residues surrounding the EP2 pocket impose spatial restrictions on the entry of antagonists. Representative compound 29 (CZY-1068) significantly reduced PGE2-induced expression of immunosuppression-related genes in macrophages. Notably, compound 29 elicited robust antitumor efficacy in the syngeneic MC38 tumor model. Taken together, this study provides a proof-of-concept for obtaining novel potent dual EP2/EP4 antagonists based on rational structural modifications.
研究领域:
药物化学
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癌症研究
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免疫学
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药物研发
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2026
·
IF 15
Zhang Yiling,Li Yu,Lu Jiayu,Qin Xin,Wang Zixin,Cai Aojie,Fan Ling,Jin Ronghua,Xie Yandong
To address the therapeutic limitations and metabolic toxicity associated with conventional nanocarriers, a nanostructure using an “MOF-in-MOF” strategy was engineered. The comprises an olsalazine (Olsa)-based copper metal-organic framework (Olsa-MOF) that integrates intrinsic anti-inflammatory properties and enhanced chemodynamic performance. This Olsa-MOF template is integrally enveloped by a tumor microenvironment-responsive TK-based Cu-MOF layer, which demonstrates exceptional photothermal properties. Subsequent surface functionalization with dopamine-grafted hyaluronic acid (DOPA-HA) endows active targeting ability, yielding the final nanocomposite termed Olsa@TK-Cu@HA. Olsa@TK-Cu@HA not only overcomes the limitations of conventional nanocarriers but also offers a novel strategy to enhance the therapeutic efficacy of photothermal therapy (PTT) and chemodynamic therapy (CDT) through targeted modulation of the COX-2/PGE2 inflammatory axis. The Olsa@TK-Cu@HA demonstrates a superior photothermal conversion efficiency (26.8%) and robust reactive oxygen species (ROS) generation, along with pH-responsive release of Olsa. In vitro evaluation demonstrated that Olsa@TK-Cu@HA exerts tumor-selective cytotoxicity, showing 3.5-fold higher potency against cancer cell. Moreover, Olsa@TK-Cu@HA effectively induces immunogenic cell death (ICD), as evidenced by increased extracellular ATP efflux (5.06-fold elevation) and CRT exposure. Concurrently, it downregulates the COX‑2/PGE2 axis to relieve immunosuppression in the tumor microenvironment and suppresses PD‑L1 expression. This coordinated action amplifies ICD‑mediated antitumor immunity, leading to a tumor regression rate of 84.0% in vivo. By integrating precision targeting, stimulus-responsive drug release, and immunometabolic reprogramming, this work moves beyond conventional treatment paradigms and establishes an innovative platform for next‑generation cancer therapy. Graphical The alternative text for this image may have been generated using AI.
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DOI
PubMed
高影响因子
Theranostics
·
2023
·
IF 12.4
Mingrui Xiong,Hong Chen,Yu Fan,Muchuan Jin,Dong Yang,Yuchen Chen,Yu Zhang,Robert B. Petersen,Hua Su,Anlin Peng,Congyi Wang,Ling Zheng,Kun Huang
Rationale: Ischemia-reperfusion injury (I/R) is a common cause of acute kidney injury (AKI). Post-ischemic recovery of renal blood supply plays an important role in attenuating injury. Exogenous application of elabela (ELA) peptides has been demonstrated by us and others to alleviate AKI, partly through its receptor APJ. However, the endogenous role of ELA in renal I/R remains unclear. Methods: Renal tubule specific ELA knockout ( Apela Ksp KO) mice challenged with bilateral or unilateral I/R were used to investigate the role of endogenous ELA in renal I/R. RNA-sequencing analysis was performed to unbiasedly investigate altered genes in kidneys of Apela Ksp KO mice. Injured mice were treated with ELA32 peptide, Nω-hydroxy-nor-L-arginine (nor-NOHA), prostaglandin E2 (PGE2), Paricalcitol, ML221 or respective vehicles, individually or in combination. Results: ELA is mostly expressed in renal tubules. Aggravated pathological injury and further reduction of renal microvascular blood flow were observed in Apela Ksp KO mice during AKI and the following transition to chronic kidney disease (AKI-CKD). RNA-seq analysis suggested that two blood flow regulators, arginine metabolizing enzyme arginase 2 (ARG2) and PGE2 metabolizing enzyme carbonyl reductases 1 and 3 (CBR1/3), were altered in injured Apela Ksp KO mice. Notably, combination application of an ARG2 inhibitor nor-NOHA, and Paricalcitol, a clinically used activator for PGE2 synthesis, alleviated injury-induced AKI/AKI-CKD stages and eliminated the worst outcomes observed in Apela Ksp KO mice. Moreover, while the APJ inhibitor ML221 blocked the beneficial effects of ELA32 peptide on AKI, it showed no effect on combination treatment of nor-NOHA and Paricalcitol. Conclusions: An endogenous tubular ELA-APJ axis regulates renal microvascular blood flow that plays a pivotal role in I/R-induced AKI. Furthermore, improving renal blood flow by inhibiting ARG2 and activating PGE2 is an effective treatment for AKI and prevents the subsequent AKI-CKD transition.
研究领域:
肾病学
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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
JOURNAL OF FOOD BIOCHEMISTRY
·
2022
·Vol. 46
·期 12
·e14460
·
IF 3.654
Jing Guo,Jian-Kai Tang,Bai-Fang Wang,Wen-Rui Yan,Ting Li,Xue-Jian Guo,Lei Zhang,Tao Wang,Qian-Yun Sun,Li-Wei Zhang
Forsythia suspensa (Thunb.) Vahl (Oleaceae) leaves are valuable sources of phillygenin. This study aimed to isolate phillygenin from F. suspensa leaves and examine its analgesic and anti-inflammatory effects. Phillygenin was successfully extracted and isolated from F. suspensa leaves after fermentation. Phillygenin significantly reduced the number of writhing induced by acetic acid, prolonged the latency period in the hot plate test, and inhibited the xylene-induced ear edema and carrageenan-induced paw edema in mice. IL-6, TNF-α, IL-1β, NO, and PGE 2 levels in the carrageenan-induced paw edema were notably reduced after pretreatment with phillygenin. Phillygenin significantly decreased the iNOS and COX-2 protein expressions and the IκB-α and NF-κB p65 phosphorylation. This study demonstrated that phillygenin is a potential therapeutic candidate for managing pain and inflammation-mediated disorders. The study contributes to the comprehensive development and utilization of F. suspensa leaves for economic and health care. Practical applications Phillygenin is one of the major active ingredients in Forsythia suspensa . But the content of phillygenin in F. suspensa is very low which limits its application. Phillygenin has potential pharmacological activity and anti-inflammatory properties. However, the potential effects of phillygenin on analgesic activity have not been clarified. Furthermore, the data on its anti-inflammatory activity in vivo are relatively limited. This study evaluated the analgesic activity for the first time and the acute anti-inflammatory effect of phillygenin from F. suspensa leaves by fermentation, which indicated phillygenin is a potential therapeutic candidate for managing pain and inflammation-mediated disorders.
研究领域:
药理学
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炎症
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疼痛管理
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天然产物
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传统中药
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
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2026
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IF 13.6
Dandan Mi,Tiantian Liu,Lan Zou,Yuyu Wei,Jun Zeng,Chunxiao Nie,Yi Zeng,Rujing Wang,Mengnan Zhao,Sanjun Shi
Surgical resection combined with chemotherapy remains the standard clinical intervention for triple-negative breast cancer (TNBC). However, the elevated expression of COX-2/PGE 2 , often exacerbated by chemotherapeutic agents, is significantly associated with high postoperative recurrence and metastasis. Tailored for the TNBC postoperative setting, we developed a photopolymerizable, dual-asymmetric hemostatic Janus hydrogel patch (DJ-Patch) based on the synergistic pharmacodynamic rationale of gambogic acid (GA) and celecoxib (CXB) pairing. The DJ-Patch exhibits a stratified bilayer configuration comprising a rapid-release layer (5% GelMA) encapsulating GA, juxtaposed with an extended-release layer (10% GelMA/2.5% PEGNB) containing the selective COX-2 inhibitor CXB. In vitro study corroborated this differential release modality, revealing asymmetric kinetics wherein GA achieved ∼20% release at 8 h escalating to greater than 60% by day 3, whereas CXB demonstrated ∼10% release at 8 h and ∼30% by day 3. In vivo release profiles further substantiated these findings, demonstrating that CXB exhibited a 2-fold prolonged release duration relative to GA. The asymmetric adhesive design, featuring a high-adhesion interface manifesting adhesion strength 12.5-fold superior to GelMA alone, facilitated rapid intraoperative hemostasis with clotting time reduced to 160 s versus 440 s in untreated controls, and effected efficacious wound sealing as validated in a mouse liver laceration model. In an orthotopic 4T1-Luc TNBC resection model, the DJ-Patch achieved 86% survival, complete tumor clearance by day 7, and suppressed lung metastasis through sustained COX-2/PGE 2 axis inhibition, Treg cell reduction, and remodeled the immunosuppressive tumor microenvironment (TME). Collectively, this integrated platform offers a promising strategy for comprehensive TNBC postsurgical management.
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DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2025
·Vol. 44
·期 1
·321
·
IF 12.8
Lei Yu,Bai Yaowei,Bai Xiatong,Sun Bo,Zhu Licheng,Wu Wenlong,Su Yang,Zhang Hongsen,Wang Yingliang,Zheng Chuansheng
Background and aims Radiofrequency ablation (RFA) is an effective treatment for hepatocellular carcinoma (HCC), but incomplete ablation and recurrence of residual tumors remain significant challenges, partly due to local inflammation and elevated COX-2 levels in the tumor microenvironment. This study aims to investigate the potential of combining celecoxib, a COX-2 inhibitor, with anti-PD-1 monoclonal antibody (αPD-1) to enhance anti-tumor efficacy and activate immune responses. Methods In vitro, ELISA was used to assess the effects of radiofrequency heat treatment and celecoxib on PGE 2 secretion by Hepa1-6 cells. Scanning electron microscopy, flow cytometry, and CCK-8 assays were employed to evaluate the function and cytotoxic activity of NK92 cells against Hepa1-6 cells. In vivo, orthotopic HCC mice were divided into five groups to evaluate tumor volume, pathology, and survival. The role of celecoxib in the COX-2/PGE 2 /NK cell axis and its impact on NK cell immune function were investigated. Results In vitro experiments showed that celecoxib reversed PGE 2 -mediated suppression of NK cell function and cytotoxic activity against HCC cells by inhibiting PGE 2 secretion. In vivo, orthotopic HCC mice treated with celecoxib and αPD-1 exhibited significantly reduced tumor volumes, attenuated the infiltration and activation of NK cells, and prolonged survival compared to control groups. The combination therapy also demonstrated a notable abscopal-like effect, inhibiting metastatic tumor growth and activating systemic immunity. Conclusions Taken together, these findings suggest that celecoxib combined with αPD-1 represents a promising strategy for treating residual HCC after RFA, with enhanced anti-tumor effects and good safety. Graphical abstract
研究领域:
肿瘤学
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免疫治疗
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分子生物学
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癌症免疫学
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转化医学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 7.3
Zhiyuan Cheng,Yijie Wang,Yao Zhang,Chan Zhang,Mengru Wang,Wei Wang,Jiacheng He,Yang Wang,Hankun Zhang,Qiansen Zhang,Chunyong Ding,Deyan Wu,Linlin Yang,Mingyao Liu,Weiqiang Lu
Nowadays, small-molecule drugs have become an indispensable part of tumor immunotherapy. Accumulating evidence has indicated that specifically blocking PGE2/EP4 signaling to induce robust antitumor immune response represents an attractive immunotherapy strategy. Herein, a 2H-indazole-3-carboxamide containing compound 1 was identified as a EP4 antagonist hit by screening our in-house small-molecule library. Systematic structure–activity relationship exploration leads to the discovery of compound 14, which displayed single-nanomolar EP4 antagonistic activity in a panel of cell functional assays, high subtype selectivity, and favorable drug-like profiles. Moreover, compound 14 profoundly inhibited the up-regulation of multiple immunosuppression-related genes in macrophages. Oral administration of compound 14, either as monotherapy or in combination with an anti-PD-1 antibody, significantly impaired tumor growth via enhancing cytotoxic CD8+ T cell-mediated antitumor immunity in a syngeneic colon cancer model. Thus, these results demonstrate the potential of compound 14 as a candidate for developing novel EP4 antagonists for tumor immunotherapy.
研究领域:
肿瘤学
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免疫学
·
药理学
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DOI
PubMed
高影响因子
RSC Medicinal Chemistry
·
2024
·
IF 4.1
Die Zhang,Wenping Wang,Huiping Ou,Jinhua Ning,Yingxun Zhou,Jin Ke,Anguo Hou,Lingyun Chen,Peng Li,Yunshu Ma,Wenbin Jin
To develop new anti-inflammatory agents with improved pharmaceutical profiles, a series of novel chalcone analogues were designed and synthesized. In vitro anti-inflammatory activity of these compounds has been evaluated by screening inhibitory effects of the NO production in RAW264.7 cell lines. The most promising compounds 3h and 3l were selected to further investigated by assessment of their dose-dependent inhibitory activity against cytokines such as TNF-α, IL-1β, IL-6, and PGE2 release. The further study also indicated that 3h and 3l could significantly suppress expressions of iNOS and COX-2 through NF-κB/JNK signaling pathway. Furthermore, compounds 3h and 3l could also remarkably inhibit the mRNAs expressions of inflammation-related genes. Docking simulation was conducted to position compounds 3h and 3l into the iNOS binding site to predict the probable binding mode. In conclusion, a series of chalcone analogues with reasonable drug-likeness obtained by in silico rapid prediction could be used as promising lead candidates.
研究领域:
药理学
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炎症研究
·
药物发现
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DOI
PubMed
高影响因子
Frontiers in Bioscience-Landmark
·
2023
·Vol. 28
·期 8
·177
·
IF 3.1
Pingping Lv,Huirong Zhang,Meiling Tai,Biao Che,Dan Yu,Ying Zhang,Haodong Li,Xianyao Meng,Miaomiao Guo,Li Li
Background: Propionibacterium acnes causes upregulation of inflammatory factors, such as cycloxygenase-2, prostaglandin E2, interleukin-1β, and tumor necrosis factor-alpha, increased levels of reactive oxygen species (ROS) and inward flow of calcium ions. This causes increased levels of the antimicrobial peptide LL-37 and inflammation of the skin, leading to redness, swelling, itching and other symptoms. Schisandra chinensis fruit oil (SCO) is rich in lignan active ingredients with various antioxidant and anti-inflammatory properties. Methods: In this study, SCO is obtained by supercritical CO2 fluid extraction. SCO’s anti-inflammatory actions were investigated using P. acnes-induced inflammation HaCaT cells model. A method based on reversed-phase high-pressure liquid chromatography with a diode array detector was developed and validated for the simultaneous detection of five lignan components. Levels of inflammatory factors and LL-37 were measured by ELISA kit and western blot respectively. Ca2+ and ROS levels detected by flow cytometry. Results: The experimental results show that the contents of schisanol A, schisanol B, schisanin A, schisanin B, and schisanin C were 33.89 ± 0.24, 14.89 ± 0.45, 8.92 ± 0.02, 29.14 ± 0.67, and 4.74 ± 0.09 mg/g, respectively. Studies have demonstrated that SCO can alleviate skin inflammation by inhibiting the COX-2/PGE2 and NF-κB signalling pathway. In addition, SCO can inhibit ROS production, significantly block inward Ca2+ flow, alleviate cell damage, and modulate the content of the antimicrobial peptide LL-37. Conclusions: In summary, our study elucidated the anti-inflammatory activity of SCO in a cell model and provided a scientific basis for its application as a raw material in skin care.
研究领域:
药理学
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皮肤科
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细胞生物学
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生物化学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）