Frontiers in Pharmacology
·
2025
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IF 4.8
Qian Feng,Cai-Zhi Li,Yi-Hua Zou,Xue-Yu Wang,Xia Yang,Rong Zhang*,Zhong-Qiu Liu*,Rong-Rong Zhang
Introduction: Brain metastasis (BM) is the most common and serious complication of breast cancer (BC). There is significant interest in investigating the crosstalk between BC cells and immune cells. β-elemene is the main pharmacodynamic component of Curcumae Rhizoma, a traditional Chinese medicine that is commonly used for the clinical treatment and prevention of various tumors. However, the specific underlying mechanism of β-elemene in BC-BM is still unclear.Methods: An intracardiac (ICT) injection model was used to establish specific BC-BM cells, then an intracarotid (ICD) injection model was used to verify the inhibitory effect of β-elemene in BC-BM. Tumor-cell-conditioned media, a primary microglia co-culture model, and an in vitro recruitment experiment were used to explore crosstalk between BC cells and immune cells. TMT-based quantitative proteomic, ELISA, IF, and other molecular biotechnologies were used to investigate the mechanisms.Results: The BC-BM cells established in our study not only increased BM rates but also exhibit mesenchymal phenotype and activated the JAK–STAT signaling pathway. Microglia, particularly M2 microglia, were enriched in BM lesions and secreted high levels of both IL6 and CCL2. Hypersecretory IL6 reversed the MET process of BC cells by regulating the JAK2/STAT3 signaling pathway to promote colonization in the brain. Increased levels of CCL2 significantly recruited monocytic myeloid-derived suppressor cells (M-MDSCs) to induce an immunosuppressive brain microenvironment. β-elemene could significantly inhibit BC-BM in mice by regulating the IL6/STAT3 signaling pathway and suppressing the M-MDSC recruitment.Conclusion: Our work first demonstrated that β-elemene regulated the IL6/STAT3 axis and M-MDSC recruitment to reconstruct immunosuppressive brain microenvironment to suppress BC-BM.
研究领域:
肿瘤学
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免疫学
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药理学
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PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2023
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IF 8.2
Wang Wei,Chen Xiao-kang,Zhou Lu,Wang Feng,He Yan-ji,Lu Bing-jun,Hu Ze-gang,Li Zhu-xin,Xia Xue-wei,Wang Wei Eric,Zeng Chun-yu,Li Liang-peng
Stimulation of adult cardiomyocyte proliferation is a promising strategy for treating myocardial infarction (MI). Earlier studies have shown increased CCL2 levels in plasma and cardiac tissue both in MI patients and mouse models. In present study we investigated the role of CCL2 in cardiac regeneration and the underlying mechanisms. MI was induced in adult mice by permanent ligation of the left anterior descending artery, we showed that the serum and cardiac CCL2 levels were significantly increased in MI mice. Intramyocardial injection of recombinant CCL2 (rCCL2, 1 μg) immediately after the surgery significantly promoted cardiomyocyte proliferation, improved survival rate and cardiac function, and diminished scar sizes in post-MI mice. Alongside these beneficial effects, we observed an increased angiogenesis and decreased cardiomyocyte apoptosis in post-MI mice. Conversely, treatment with a selective CCL2 synthesis inhibitor Bindarit (30 μM) suppressed both CCL2 expression and cardiomyocyte proliferation in P1 neonatal rat ventricle myocytes (NRVMs). We demonstrated in NRVMs that the CCL2 stimulated cardiomyocyte proliferation through STAT3 signaling: treatment with rCCL2 (100 ng/mL) significantly increased the phosphorylation levels of STAT3, whereas a STAT3 phosphorylation inhibitor Stattic (30 μM) suppressed rCCL2-induced cardiomyocyte proliferation. In conclusion, this study suggests that CCL2 promotes cardiac regeneration via activation of STAT3 signaling, underscoring its potential as a therapeutic agent for managing MI and associated heart failure.
研究领域:
心脏病学
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分子生物学
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再生医学
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PubMed
高影响因子
International Journal of Medical Sciences
·
2025
·Vol. 22
·期 4
·856-872
·
IF 3.2
Li Bowei,Yang Jingyuan,Wang Zhixing,He Mingzhu,Chen Xujing,Chen Yixuan,Shen Baoying,Chen Junru,Yang Chunqi,Li Tian,Lai Chengcai,Gao Yue,Cai Hong
Introduction: Solar dermatitis, a condition triggered by excessive exposure to ultraviolet B (UVB) radiation, results in inflammatory skin damage marked by erythema, edema, and epidermal injury. Portulaca oleracea (PO) and Patrinia scabiosaefolia (PS) have been traditionally used in dermatological treatments, though their mechanistic pathways in UVB-induced skin injury are not fully understood.Methods: In this study, a mouse model of UVB-induced solar dermatitis was employed to evaluate the therapeutic potential of combined PO and PS (POPS) extracts. After UVB irradiation, POPS extracts were administered, and their bioactive compounds were identified through ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Network pharmacology, molecular docking, and pathway analysis were performed to identify key targets, focusing on the IL-17/CCL2 pathway and oxidative stress reduction.Results: Treatment with POPS extracts significantly diminished UVB-induced inflammation, erythema, and epidermal thickening in a dose-dependent manner. Network pharmacology and docking studies identified curvularin and olmesartan medoxomil as bioactive components with high affinity for IL-17 and IL-17RA targets, modulating the IL-17/CCL2 axis. In vivo experiments demonstrated that POPS extracts suppressed the expression of IL-17 and CCL2, reduced macrophage infiltration, and alleviated oxidative stress, effectively mitigating the symptoms of solar dermatitis.Conclusion: This study provides insight into the anti-inflammatory and protective properties of POPS extracts in solar dermatitis, highlighting their potential as a treatment through IL-17/CCL2 pathway modulation and oxidative stress reduction.
研究领域:
药理学
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皮肤病学
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分子生物学
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PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2023
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IF 3.1
Chan-juan Chai,Yao Sun,Rui-fang Chi,Hui-yu Yang,Bin Yang,Bao Li
Cardiac remodeling (CR), characterized by cardiac hypertrophy and fibrosis, leads to the development and progression of heart failure (HF). Nowadays, emerging evidence implicated that inflammation plays a vital role in the pathogenesis of CR and HF. Astragaloside IV (AS-IV), an effective component of Astragalus membranaceus , exerts cardio-protective and anti-inflammatory effects, but the underlying mechanism remains not fully elucidated. This present study aimed to investigate the effects of AS-IV on cardiac hypertrophy and fibrosis in cultured H9C2 cells stimulated with LPS, as well as explore its underlying mechanisms. As a result, we found AS-IV could reduce the cell surface size, ameliorate cardiac hypertrophy and fibrosis in LPS-induced H9C2 cells. To specify which molecules or signaling pathways play key roles in the process, RNA-seq analysis was performed. After analyzing the transcriptome data, CCL2 has captured our attention, of which expression was sharply increased in model group and reversed by AS-IV treatment. The results also indicated that AS-IV could ameliorate the inflammatory response by down-regulating NF-κB signaling pathway. Additionally, a classical inhibitor of CCL2 (bindarit) were used to further explore whether the anti-inflammatory effect of AS-IV was dependent on this chemokine . Our results indicated that AS-IV could exert a potent inhibitory effect on CCL2 expression and down-regulated NF-κB signaling pathway in a CCL2-dependent manner. These findings provided a scientific basis for promoting the treatment of HF with AS-IV.
研究领域:
心脏病学
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药理学
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炎症
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分子生物学
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PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
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IF 13.3
Yuxiao Wang,Guichun Wang,Jiaxin Li,Maomao Tang,Baoqing Jia,Zixuan Shu,Yang Ding,Chengjun Peng,Shuangying Gui,Jian Guo
Periodontitis is a chronic inflammatory disease caused by pathogenic biofilms and over-activated host immune response, leading to sustained damage to periodontal supporting tissue and even tooth loss. A key therapeutic challenge in recurrence of periodontitis is persistent existence of infiltrating monocytes and macrophages in periodontal tissues. Particularly, C-C motif ligand 2 (CCL2) is vital for monocyte recruitment and macrophage polarization in periodontitis. In this study, we developed biomimetic caffeic acid phenethyl ester-loaded nanoparticles (M−CNPs) as nanodecoys by macrophage membrane encapsulation to block CCL2-mediated inflammatory response and tissue damage. M−CNPs were distributed in the thermosensitive gel matrix (M−CNPs@Gel) to improve the retention time and sustained-release in the periodontal pocket. Our study demonstrated that M−CNPs@Gel exhibited a significant nanodecoy effect by competitively binding to CCL2 in periodontium, which inhibited monocyte/macrophages recruitment. Additionally, biomimetic nanodecoy system could reprogram macrophages phenotype through multi-step blocking CCL-CCR2-PI3K pathway and ROS elimination . M−CNPs@Gel effectively reduced the infiltration of monocytes and macrophages, and promote alveolar bone regeneration by regulating the ratio of M1/M2 macrophages in vivo . This study develops a novel CCL2-scavenging biomimetic nanodecoy hydrogel that remodel monocytes recruitment and macrophages polarization for effective periodontitis treatment.
研究领域:
牙科学
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药学
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生物医学工程
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免疫学
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高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Ningchao Luo,Lisha Ma,Ninghui Ma,Jiale Wei,Hongyan Zhang,Wanyu Jin,Yujie Li,Jingbin Shi,Yang Xiong
Triple negative breast cancer (TNBC) represents a heterogeneous subtype of breast cancer characterized by an unfavorable prognosis due to its aggressive biology. Cancer-associated adipocytes (CAAs) play an active role in tumor development, invasion and metastasis, and response to treatment by secreting various cytokines. CAAs secrete CCL2 and ADPN which significantly affect the efficacy of aPD-1 in treating breast cancer. Our recent research has demonstrated that Hesperidin, a natural phenolic compound, significantly inhibits CCL2, elevates ADPN secreted by CAAs in vitro and in vivo, remodels the immune microenvironment, and potentiates the efficacy of aPD-1 in triple-negative breast cancer. We used Oil red staining, Bodipy 493/503 staining and quantitative real-time PCR to verify the formation of CAAs. ELISA was used to detect levels of CCL2, ADPN secreted by CAAs. Changes in the number of immune cells in mouse tumor tissues were detected using flow cytometry and immunofluorescence. Our data suggest that Hesperidin PLGA nanoparticles significantly reduced CCL2 and increased ADPN secreted by CAAs, which concurrently decreased the recruitment of M2 macrophages, Tregs and MDSCs while increased the infiltration of CD8 + T cells, M1 macrophages and DCs into tumor, thus significantly potentiated the efficacy of aPD-1 in vivo. This study provides a new combined strategy for the clinical treatment of triple-negative breast cancer by interfering with CCL2, ADPN secreted by CAAs to enhance the efficacy of immunotherapy.
研究领域:
肿瘤学
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免疫学
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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
CANCER IMMUNOLOGY IMMUNOTHERAPY
·
2025
·Vol. 74
·期 3
·1-17
·
IF 5.1
Han Tianci,Guo Xiaoqi,Xie Junwei,Tong Wei,Zhang Liang
Objective Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors with a high metastasis rate and a poor prognosis. ETS variant transcription factor 1 (ETV1) plays an important role in multiple malignancies. However, its function in ESCC progression and tumor microenvironment (TME) remains to be explored. In this study, we characterized the role of ETV1 in ESCC process and TME. Methods Gene expression and immune infiltration in ESCC samples from the Cancer Genome Atlas (TCGA) were analyzed. The expression of ETV1 in clinical samples was detected by real-time PCR, western blot and immunohistochemistry staining. Cell growth was detected by CCK-8 and colony formation assays. Macrophage phenotypes were determined using flow cytometry. Immunofluorescence double staining was used to detect the tumor-associated macrophage (TAM) infiltration. The tumor volume was recorded and weighed. Transcriptional activity was measured using dual-luciferase assay, chromatin immunoprecipitation (ChIP) assay and DNA pull-down assay. Results In this study, through analysis of ESCC samples from TCGA database and the clinic, we noticed that ETV1 was highly expressed in ESCC tumor tissues and was associated with TAM infiltration. Overexpression of ETV1 promoted ESCC cell proliferation in vitro and xenograft tumor growth in nude mice, while ETV1 knockdown elicited the opposite effects. Furthermore, ETV1 upregulation in tumor tissues was found to drive M2 macrophage infiltration both in vitro (transwell assays) and in vivo (xenograft tumor models). C–C motif chemokine ligand 2 (CCL2), a key factor inducing M2 macrophage polarization, was also found to be elevated in ESCC tumor tissues. Mechanism study demonstrated that ETV1 facilitated M2 macrophage infiltration via the transcriptional modulation of CCL2. In addition, the cause of the changes in ETV1 activity and expression was investigated. The E2 small ubiquitin-like modifier (SUMO) binding enzyme UBC9 increased ETV1 activity and expression, indicating the presence of SUMO modification in ETV1. Conclusions Our data deciphered the mechanism of ETV1-mediated M2 macrophage infiltration in the TME of ESCC, which has important implications for the development of novel prognostic and therapeutic targets to optimize current therapies against ESCC.
研究领域:
肿瘤学
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免疫学
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转录调控
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癌症生物学
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DOI
PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
·
2021
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IF 2.63
Xubin Bao,Cai Chen,Liyong Yuan
Triptolide (T10) is a common anti-inflammatory and analgesic drug. However, the activation of microglia and elimination of the corresponding inflammatory response are new targets for the treatment of neuropathic pain. Chemokine CCL (CCL2) is a key mediator for activating microglia. In this study, the effects of triptolide on the activation and polarization of microglia cells and CCL2 and its corresponding receptor, chemokine receptor 2 (CCR2), were mainly discussed. Microglia were stimulated with 1 μg/mL lipopolysaccharide (LPS) and pretreated with 10, 20, and 40 nM T10 and CCR2 antagonist (RS102895), respectively. The quantitative polymerase chain reaction (QPCR) and western blot results showed that T10 could obviously inhibit the upregulation of CCL2 and CCR2 induced by LPS stimulation in microglia cells, inhibit the fluorescence intensity of glial fibrillary acidic protein (GFAP) and inducible nitric oxide synthase (iNOS) antibody immunostaining in cells, and upregulate the fluorescence intensity of arginase 1 antibody in cells. The expression of interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) was inhibited in a dose-dependent manner. RS102895 can significantly reverse the activation and M2 polarization of microglia pretreated with 40 nM T10 and weaken the anti-inflammatory effect of T10. The addition of CCL2 did not extremely affect the function of RS102895. T10 may inhibit microglia activation and M1 polarization by inhibiting the expression of CCL2 and CCR2, promoting M2 polarization, reducing the level of inflammatory factors in cells, and exerting its analgesic effect, which is worthy of clinical promotion as a drug for neuropathic pain.
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
Frontiers in Immunology
·
2022
·
IF 8.786
Zhang Nan,Gao Xiaochen,Zhang Weijia,Xiong Junyao,Cao Xiaojian,Fu Zhen F.,Cui Min
Japanese encephalitis virus (JEV) is one of the most important members of the flavivirus family. It is a typical zoonotic pathogen that has caused substantial social and economic losses worldwide. The relation between JEV-induced immunosuppression and inflammatory responses has not been thoroughly investigated. In this study, cells infiltrating the brain tissue of JEV-infected mice were mainly identified as monocytic myeloid-derived suppressor cells (M-MDSCs), which subsequently differentiated into CD3+ macrophages. Co-culture with T cells showed that both splenic M-MDSCs and brain infiltrated M-MDSCs isolated from JEV-infected mice inhibited T cell proliferation through ARG1 and iNOS. The splenectomy model revealed that JEV-induced M-MDSCs were mainly derived from bone marrow and migrated to the spleen and central nervous system (CNS). The results of the transcriptome analysis and IRF7-deficient mice indicated that the ZBP1-IRF7 signaling pathway stimulated by JEV RNA played a central role in the induction of M-MDSCs. M-MDSCs migrated into the CNS through the chemokine CCL2/N-CCL2 derived from astrocytes and brain infiltrated M-MDSCs differentiated into CD3+ macrophages through a mechanism mediated by M-CSF, IL-6 and IFN-γ in the brain microenvironment. These findings provide evidence for the mechanism that JEV regulates the differentiation of M-MDSCs and thereby exacerbates pathogenicity, which represents a potential therapeutic target for Japanese encephalitis (JE).
研究领域:
免疫学
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神经病毒学
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病毒学
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致病机制
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PubMed
高影响因子
INTERNATIONAL DENTAL JOURNAL
·
2025
·
IF 3.7
Xiyuan Qin,Kai Kang,Bowen Zhu,Yujie Shi,Shoushan Bu
Introduction and aims Oral squamous cell carcinoma (OSCC), frequently observed in the head and neck region, possesses mechanisms that have yet to be thoroughly clarified. Poor prognosis in OSCC is closely linked to the polarization of macrophages toward the M2 phenotype. Complement component 1q subcomponent-binding protein (C1QBP), a versatile protein commonly dysregulated in OSCC, has an unclear association with M2 macrophages. Methods Immunohistochemical (IHC) staining was conducted to determine the relationship between C1QBP expression and M2 macrophage infiltration. Flow cytometry (FC) and enzyme-linked immunosorbent assay (ELISA) were employed to explore the functional role of C1QBP in macrophages polarization. Furthermore, RNA sequencing combined with quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting (WB) were utilized to verify the increased expression of TNF receptor-associated factor 2 (TRAF2) and C-C motif chemokine 2 (CCL2). Additional validation of these findings was performed through in vivo experiments. Results A negative correlation was identified between C1QBP expression and CD206, a representative marker of M2 macrophages. Decreased levels of C1QBP in OSCC cells enhanced macrophage polarization toward the M2 phenotype and facilitated tumor progression by activating pivotal elements of the tumor necrosis factor (TNF) signaling pathway, notably TRAF2 and CCL2. Conclusion These findings suggest that C1QBP modulates the polarization of macrophages toward the M2 phenotype via the TRAF2-CCL2 signaling axis, thus contributing to OSCC malignancy progression. Consequently, targeting C1QBP to regulate M2 macrophage polarization may provide a promising therapeutic avenue for OSCC management.
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高影响因子
Small
·
2026
·
IF 11.8
Jitong Zhou,Boyu Su,Ching Kang,Yujun Pei,Keke Zhang,Wenwen He,Jiao Qi,Tao Sun,Jiaqi Meng,Xiangjia Zhu
High myopia (HM), a major cause of global blindness, also significantly elevates anxiety risk via a newly discovered eye-brain inflammatory axis. We identified C-C motif chemokine ligand 2 (CCL2) as the key driver: HM visual stimuli trigger retinal CCL2 upsurge, promoting monocyte/macrophage infiltration into eyes and brain, disrupting blood-brain (BBB) and blood-ocular (BOB) barriers, and inducing anxiety. To shatter this vicious cycle, unmet by traditional CCL2 blockers (poor targeting, non-selectivity, no barrier repair), we engineered a revolutionary ROS-responsive nanocomplex, TK-F-PEI/siR@A. This system synergistically integrates: (1) Surface CCL2 aptamers for targeted lesion homing and CCL2 neutralization; (2) A fluorinated, thioketal-crosslinked low-MW PEI core enabling inflammation-triggered release; (3) Encapsulated MMP9 siRNA to restore barrier integrity. TK-F-PEI/siR@A demonstrated excellent ROS responsiveness, low cytotoxicity, and effective MMP9 silencing, enhancing tight junctions. Guided by aptamers, it achieved superior accumulation in inflamed ocular/brain regions of HM mice, with high biosafety. Critically, it delivered a dual-action strike: significantly reducing CCL2 levels, suppressing systemic/local monocyte/macrophage infiltration, and robustly repairing BBB/BOB integrity. This synergistic blockade of inflammation and barrier restoration reversed anxiety-like behaviors. We pioneer the first nanocomplex specifically co-targeting the eye-brain axis, establishing a potent dual-pronged strategy against HM-related anxiety and offering a new paradigm for inter-organ crosstalk disorders.
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PubMed
高影响因子
Chinese Medicine
·
2026
·Vol. 21
·期 1
·96
·
IF 7.4
Xu Yu,Cai Jing,Fan Yuan-Ming,Qi Lian-Wen,Zhang Lei
Background Zhen-Wu-Tang (ZWT), a classic herbal formula from Treatise on Febrile and Miscellaneous Diseases, is commonly used for heart and kidney-related diseases. Despite its widespread application, research on the active components of ZWT and their mechanisms in heart–kidney cross-organ regulation remains underexplored. Aim of the study This study aimed to elucidate the therapeutic mechanisms of ZWT in uremic cardiomyopathy (UC) focusing on its modulation of the heart–kidney inflammatory axis. Materials and methods A UC model was established via 5/6 nephrectomy in mice, followed by 8 weeks of ZWT treatment. Functional assessments included serum creatinine, blood urea nitrogen, cardiac ejection fraction, and left ventricular metrics. Proteomic analysis using Olink technology exerts its therapeutic effects by suppressing systemic inflammation. UHPLC-Q/TOF–MS were employed to identify prototype components and blood-entering components in ZWT. Cellular experiments using a three-step co-culture system were conducted to evaluate the regulatory effects of ZWT active components on HK-2 and AC16 cells and to explore their underlying molecular mechanisms. Results ZWT significantly improved renal and cardiac functions. Proteomics revealed ZWT suppressed pro-inflammatory cytokines TNFα, IL-6, IL-1β and chemokines. The bioactive constituents of ZWT, including benzoylaconine, paeoniflorin, and atractylenolide III, inhibited NF-κB activation, thereby reducing CCL2 synthesis and subsequent macrophage recruitment via the CCR2 axis. This attenuated systemic inflammation and cardiomyocyte injury. Conclusions ZWT exerts therapeutic effects on UC by targeting the kidney-heart inflammatory axis and suppressing CCL2/CCR2-mediated macrophage activation. This study provides new insights into the molecular mechanisms underlying ZWT's efficacy in treating heart–kidney disorders.
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高影响因子
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