Frontiers in Pharmacology
·
2025
·
IF 4.8
Lingjie Meng,Huijing Lv,Anli Liu,Qian Cao,Xinyi Du,Chengjin Li,Qinggui Li,Qingqing Luo,Yi Xiao
Liver fibrosis is a common pathological feature of chronic hepatic injury that currently lacks effective therapeutic interventions. Albiflorin (ALB), a pinane-type monoterpene derived from Paeonia lactiflora Pall, has notable anti-inflammatory and hepatoprotective effects. However, the potential role of ALB against liver fibrosis is largely unknown. In this study, we discovered that ALB significantly inhibited CCl4-induced liver fibrosis in mice. This was evidenced by improvements in liver and kidney function indexes, fibrosis indicators, and histopathological findings. In vitro studies also showed that ALB inhibited TGF-β1-induced LX-2 cell activation and reduced the expression of α-SMA and collagen I. Additionally, we found that ALB mitigates inflammation and ameliorates liver fibrosis by targeting the CXCL12/CXCR4 axis, as confirmed using the CXCR4 inhibitor AMD3100 in CCl4-treated mice. Notably, combining ALB with metformin (MET) enhanced the inhibition of liver fibrosis progression. These findings highlight that ALB exerts anti-liver fibrosis effects by targeting the CXCL12/CXCR4 axis, underscoring its potential as a standalone treatment or as an adjuvant therapy.
研究领域:
药理学
·
肝脏疾病研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMACROMOLECULES
·
2017
·
IF 5.246
Feiran Zhang,Siman Gong,Jun Wu,Huipeng Li,David Oupicky,Minjie Sun
The unsatisfied results of cancer therapy are caused by many issues and metastasis of cancer cells is one of the major challenge. It has been reported that inhibiting the SDF1/CXCR4 interaction can significantly reduce the metastasis of breast cancer cells to regional lymph nodes and lung. Herein, a nanogel system equipped with the FDA-approved CXCR4 antagonist AMD3100 was developed and evaluated for its combined antimetastatic and tumor targeting effects. Briefly, a bioreducible cross-linked dextrin nanogel (DNG) coated with AMD3100 was designed to possess multiple functions, including CXCR4 chemokine targeting, inhibition of tumor metastasis, and reduction-responsive intracellular release of doxorubicin (DOX) to reduce the cells proliferation. The in vitro results confirmed that the DOX-loaded AMD3100-coated dextrin nanogel (DOX-AMD-DNG) was more effectively taken up by 4T1 breast cancer cells than DOX-DNG and was significantly more cytotoxic to 4T1 cells than DOX-DNG. In biodistribution studies, the stronger fluorescence intensity of Cy7-AMD-DNG than Cy7-DNG further confirmed that AMD3100 mediated tumor targeting in vivo. AMD3100-coated DOX-DNG also exhibited a distinct antimetastatic effect and CXCR4 antagonistic activity by inhibiting CXCR4-mediated cell invasion in 4T1 and U2OS cells. Moreover, DOX-AMD-DNG displayed superior anticancer activity and antimetastatic effects in orthotopic breast cancer-bearing Balb/C mice. In summary, the multifunctional DOX-AMD-DNG can effectively target the tumor site and dually impede cancer progression and metastasis.
研究领域:
肿瘤学
·
药剂学
·
生物材料学
✓ 已验证
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2024
·
IF 18.5
Congzheng Zhu,Jin Li,Xinru Chen,Longwen Fu,Zhiyang Zhang,Yunqing Wang,Xiaoyan Wang,Lingxin Chen
CXC chemokine receptor 4 (CXCR4) is recently regarded as a valuable biomarker for triple-negative breast cancer (TNBC) metastasis but lacks available imaging reagents. Surface-enhanced resonance Raman scattering (SERRS) with resonant dyes has emerged as a powerful tool for single-cell imaging because of the electronically enhanced vibrational fingerprint signals. However, resonant Raman signals are often overwhelmed by accompanying fluorescence backgrounds. To address this, two black hole quenchers (BHQs) are designed as visible resonance Raman reporters with absolutely nonfluorescent readouts. Ultrafast spectroscopy elucidates that the nonfluorescent mechanism of the reporters originates from the ultrafast internal conversion at the subpicosecond scale that quenches the excited states of fluorescence. SERRS nanoprobes (NPs) decorated with such reporters exhibit strong Raman enhancement (5.82 × 10 6 ), the femtomolar-level limit of detection as well as unrivaled photostability (τ s = 26516 s), outperforming that of crystal violet-decorated counterparts. When conjugation of a CXCR4 antagonist, these fluorescence-free SERRS NPs allow for photostable imaging of CXCR4 on TNBC cells at the single-cell level, and for monitoring the expression variation during combined drug treatment. To the best of the available knowledge, this is the first example of absolutely nonfluorescent Raman reporters for single-cell SERRS imaging.
研究领域:
生物医学工程
·
癌症研究
·
分子影像学
✓ 已验证
产品关联
DOI
高影响因子
Journal of Inflammation Research
·
2022
·
IF 4.631
Meng Zhang,Yi Liu,Jing Chen,Lei Chen,Li Zhang,Xianguo Chen,Zongyao Hao,Chaozhao Liang
Background Chronic nonbacterial prostatitis (CNP) has a high incidence, low cure rate, and unclear pathogenesis. Here, we aimed to systematically identify effective diagnostic and therapeutic targets for CNP.Methods Prostate tissues were obtained from established mouse models and negative controls and were used for mRNA array sequencing and immunohistochemistry (IHC) staining. Predominant pathways were identified based on pathway enrichment analysis and pharmaceutical experiments. We also investigated the functional role of CXCL12 on CP, a critical factor belonging to the predominant chemotaxis pathway, and employed IHC staining to explore the influence of the CXCL12/CXCR4 axis on the activation of the NF-κB, AKT, and STAT3 signaling pathways. Serum samples derived from both CNP cases and healthy controls were used to determine the secretion level of CXCL12.Results By employing mRNA array sequencing and immunohistochemistry, we found that CXCR4, CXCL12, CD44, and OFLM4 were highly expressed in the infiltrated inflammatory T cells of the prostate tissues generated from CNP mice, while they were rarely expressed on the epithelial cells. Based on the pathway enrichment results, we applied pathway inhibitors to suppress the activity of these classic pathways. We found that targeting the CXCL12/CXCR4 axis with its specific antagonist AMD3100 remarkably alleviated inflammatory infiltration of the prostate in CNP models. Similar results were obtained when we replaced AMD3100 with adenovirus-associated virus (AAV)-shCxcl12. To clarify the potential mechanisms of how the CXCL12/CXCR4 axis influences the pathogenesis of CNP, we tested the classical downstream pathways. The results suggested that p-Akt, p-STAT3, and p-NF-κB were more highly expressed on the inflammatory cells of the prostate derived from the CNP model and were partly suppressed after applying AMD3100 or delivering AAV-shCxcl12, indicating that the CXCL12/CXCR4 axis potentially functioned through AKT/NF-κB and STAT3 signaling to influence the pathogenesis of CNP.Conclusion Our study provides potential diagnostic biomarkers and therapeutic targets for CNP.
研究领域:
免疫学
·
分子生物学
·
药理学
·
泌尿学
✓ 已验证
DOI
PubMed
高影响因子
Nanoscale
·
2020
·Vol. 12
·期 24
·12779-12789
·
IF 6.895
Yi Cao,Zhenqi Jiang,Yanying Li,Yinjie Wang,Yong Yang,Ozioma Udochukwu Akakuru,Juan Li,Aiguo Wu
Zeolitic imidazolate frameworks (ZIFs) as emerging porous materials have attracted remarkable attention for their unprecedented porosity and acidic sensitive degradation that enables high drug loading and microenvironment responsive fast payload release. However, the limited functions and disadvantages of ZIFs such as early drug release, potential cytotoxicity inducing damage to major organs, and even death of animals, impede their further biomedical application. In this work, we report the first tandem post-synthetic modification of ZIF-7 with both metal ions and organic ligands. Inspired by the benzimidazole-like inhibitors that are similar to the organic ligand of ZIF-7, a chemokine (C-X-C motif) receptor 4 (CXCR4) inhibitor AMD-070 (AMD) and magnesium ions (Mn2+) were successfully tandem exchanged to the ZIF-7 framework, forming an active-targeting framework AMD-ZIF-7(Mn) for CXCR4-overexpressed esophageal squamous cell cancer. The obtained AMD-ZIF-7(Mn) showed good biocompatibility in vitro and in vivo. Meanwhile, it exhibited an excellent T1-weighted magnetic resonance imaging performance and CXCR4 targeting ability. With 5-Fu loading, AMD-ZIF-7(Mn)/5-Fu showed a synergistic therapeutic effect in DNA damage and CXCR4 inhibition of esophageal squamous cell cancer. Therefore, we propose a structural reconstruction method to effectively explore and improve the biomedical application of ZIFs in esophageal squamous cell cancer theranostics.
研究领域:
生物材料学
·
癌症治疗学
·
医学影像学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2020
·
IF 7.727
Xue Yang,Fang Gao,Wenan Zhang,Huipeng Li,Xinzhi Huang,Jiajia Wei,Jiayi Bian,Ying Yang,Chenggen Qian,Minjie Sun
Invasion and metastasis of tumor cells is one of the major obstacles in cancer therapy. The process of tumor metastasis and diffusion is coordinated by multiple pathways associated with chemokine signals and migration microenvironment. In our previous work, chemokine CXC receptor 4 (CXCR4) antagonists showed significant anti-metastatic effects by blocking the CXCR4/stromal cell-derived factor-1(SDF-1) axis in pancreatic cancer and breast cancer. Here, we proposed to achieve migration chain-treatment for metastatic tumors by introducing a cell adhesion molecules CD44 inhibitor (Star miR-34a) to deprive of cell migration capability on the basis of CXCR4 antagonism (cyclam monomer , CM). Dextrin modified 1.8 k PEI with CM-end was prepared to deliver therapeutic miR-34a (named DPC/miR-34a) for efficient anti-metastasis by downregulating adhesion protein CD44 and targeting the CXCR4/SDF-1 axis. Additionally, reduced expression of the anti-apoptotic protein Bcl2 caused by miR-34a could enhance the anti-tumor efficacy of DPC/miR-34a nanoplex administration. Compared with inhibition of the CXCR4/SDF-1 axis or CD44 expression, the multidimensional therapy (DPC/miR-34a) exhibited considerable suppression of cancer cell invasion as assessed by an in vitro cell invasion assay and in vivo anti-metastasis model. Moreover, DPC/miR-34a demonstrated a superior antitumor and anti-metastatic efficacy both in lung metastatic model and orthotopic MDA-MB-231 tumor models, thus providing an efficient approach for combating metastatic tumors.
研究领域:
肿瘤学
·
分子生物学
·
药学
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
·
2024
·
IF 5.3
Jiyang Xue,Hai Zhang
Immunotherapy has become a potential treatment technique for ovarian cancer. However, its improvement is impeded by obstacles such as immunosuppression and minimal tumor penetration. Inhibiting the chemokine receptor 4 (CXCR4)/chemokine ligand 12 (CXCL12) axis to enhance tumor infiltration and alleviate the immunosuppressive microenvironment holds promise for enhancing tumor immunotherapy. We developed a targeted drug delivery system by encapsulating the chemotherapeutic drug paclitaxel (PTX) in PEGylated albumin nanoparticles (NPs) modified with the tumor-specific CXCR4 inhibitor plerixafor (AMD3100) (AMD-NP-PTX). The effects of AMD-NPs on cell uptake and migration were investigated using ID8 cells. Subsequently, an ovarian cancer-bearing mouse model was developed to assess the targeting ability of AMD-NP-PTX and its repressive result on ovarian cancer. Lastly, the prospective healing system was investigated. The CXCR4 blocker-enriched NPs showed increased tumor cell uptake in vitro and significant inhibition of CXCL12-mediated immune cell migration. Moreover, this system not only properly targets tumors using AMD3100 but also hinders tumor growth by modulating the CXCR4/CXCL12 axis, hence boosting MAPK expression and lowering PI3K expression. Immune analysis showed that the medicine shipment system upregulates CD8+ T cells as well as natural killer cells in both growth tissues and the spleen, while all at once downregulating myeloid-derived suppressor cells and regulatory T cells. This study underscores the synergistic inflection of the immunosuppressive microenvironment within the tumor, triggering a durable and appropriate antitumor immune response. These findings underscore the potential of a tailored medication delivery system to enhance immunotherapy for ovarian cancer.
研究领域:
肿瘤学
·
药剂学
·
免疫学
✓ 已验证
产品关联
DOI
高影响因子
STEM CELLS AND DEVELOPMENT
·
2021
·Vol. 30
·期 10
·526-536
·
IF 3.272
Chaoqun Hu,Yun He,Daijiang Liu,Li Zhao,Shuyu Fang,Bin Tan,Shifang Dong,Yi Wang,Tongchuan He,Yang Bi
Our previous studies reported that urine-derived stem cells (USCs) possess a strong self-renewal ability and multidirectional differentiation potential and thus are an ideal candidate cell source for hepatocellular transplantation. USC transplantation may repair the pathological changes of chronic liver injury to a certain extent, and hypoxia pretreatment may improve the recovery efficiency of USCs. Therefore, the present study aimed to investigate the possible mechanism of the improved recovery efficiency of hypoxia-pretreated USCs. A chronic liver injury model was established by intraperitoneal injection of carbon tetrachloride into nude mice. USCs were transplanted via caudal vein injection. Hematoxylin and eosin staining and Masson's staining were performed to determine the pathology of the liver. Immunofluorescence and frozen section biopsy were performed to determine differentiation and cell fusion in vivo. Cell coculture was used to detect cell fusion in vitro. The proliferative ability of USCs was evaluated using cell viability and colony formation assays, and the migratory functions of USCs were evaluated using wound healing and transwell assays. The degeneration of hepatocytes and the level of fibrosis in the hypoxia transplantation group were improved compared with the normoxia transplantation group. It was found that exogenous USCs may be differentiated into functional hepatocytes or fused with hepatocytes in vivo. C-X-C motif chemokine (CXC) ligand 12 (CXCL12) expression levels in liver tissue of the chronic liver injury model were upregulated compared with those in the control group. The expression of CXC receptor 4 (CXCR4) in hypoxia-pretreated USCs was also significantly upregulated. The results suggested that USCs fused with different types of liver cells and that hypoxia treatment promoted the fusion rate in vitro by upregulating CXCR4 signaling. Furthermore, hypoxia pretreatment promoted cell proliferation, migration, and cell fusion by inducing CXCR4 signaling, leading to USC-elicited liver tissue recovery following injury in vivo.
研究领域:
干细胞生物学
·
肝病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2024
·
IF 6.6
Wenlu Li,Yaolin Gong,Jing Zhang,Jiong Liu,Jiali Li,Shaozhi Fu,Wen Xiu Ren,Jian Shu
Introduction Targeting, imaging, and treating tumors represent major clinical challenges. Developing effective theranostic agents to address these issues is an urgent need.Methods We introduce an “all-in-one” tumor-targeted theranostic platform using CuFeSe2-based composite nanoparticles (CuFeSe2@PA) for magnetic resonance (MR) and computed tomography (CT) dual model imaging-guided hyperthermia tumor ablation. Plerixafor (AMD3100) is bonded to the surface of CuFeSe2 as a targeting unit. Due to the robust interaction between AMD3100 and the overexpressed Chemokine CXC type receptor 4 (CXCR4) on the membrane of 4T1 cancer cells, CuFeSe2@PA specifically recognizes 4T1 cancer cells, enriching the tumor region.Results CuFeSe2@PA serves as a contrast agent for T2-weighted MR imaging (relaxivity value of 1.61 mM−1 s−1) and CT imaging. Moreover, it effectively suppresses tumor growth through photothermal therapy (PTT) owing to its high photothermal conversion capability and stability, with minimized side effects demonstrated both in vitro and in vivo.Discussion CuFeSe2@PA nanoparticles show potential as dual-mode imaging contrast agents for MR and CT and provide an effective means of tumor treatment through photothermal therapy. The surface modification with Plerixafor enhances the targeting ability of the nanoparticles, performing more significant efficacy and biocompatibility in the 4T1 cancer cell model. The study demonstrates that CuFeSe2@PA is a promising multifunctional theranostic platform with clinical application potential.
研究领域:
肿瘤学
·
医学影像学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2019
·Vol. 38
·期 1
·1-18
·
IF 5.646
Zheng Ning,Liu Weiqun,Li Bifei,Nie Huifang,Liu Jian,Cheng Yunlong,Wang Jichuang,Dong Haiyan,Jia Lee
Background Sorafenib is approved as a standard therapy for advanced hepatocellular carcinoma (HCC), but its clinical application is limited due to moderate therapeutic efficacy and high incidence of acquired resistance resulted from elevated levels of SDF-1/CXCR4 axis induced by prolonged sorafenib treatment. We previously demonstrated metapristone (RU486 metabolite) as a cancer metastatic chemopreventive agent targeting SDF-1/CXCR4 axis. Therefore, we hypothesized that combining sorafenib with metapristone could synergistically suppress cell proliferation, enhance anti-cancer activity and repress potential drug resistance. Methods Changes in cellular CXCR4 expression by metapristone were analyzed by RT-PCR and western blotting. Effect of combining sorafenib with metapristone on cell viability was examined by MTT assay; combination index value was calculated to evaluate the synergistic effect of combined therapy. To overcome poor pharmacokinetics and reduce off-target toxicity, CXCR4-targeted nanoparticles (NPs) were developed to co-deliver sorafenib and metapristone into CXCR4-expressing HCC in vitro and in vivo; cell proliferation, colony formation and apoptosis assays were conducted; nude mice bearing HCC xenograft were used to examine effects of this therapeutic approach on HCC progression. Results Here we showed metapristone significantly reduced CXCR4 expression in HCC. Combinatory chemotherapy of sorafenib with metapristone synergistically suppressed HCC proliferation and resistance. CXCR4-targeted PEGylated poly (lactic-co-glycolic acid) NPs conjugated with LFC131 (a peptide inhibitor of CXCR4), could deliver more sorafenib and metapristone into HCC via specific recognition and binding with transmembrane CXCR4, and resulted in the enhanced cytotoxicity, colony inhibition and apoptosis by regulating more Akt/ERK/p38 MAPK/caspase signaling pathways. Co-delivery of sorafenib with metapristone by the LFC131-conjugated NPs showed prolonged circulation and target accumulation at tumor sites, and thus suppressed tumor growth in a tumor xenograft model. Conclusions In conclusion, co-delivery of sorafenib and metapristone via the CXCR4-targeted NPs displays a synergistic therapy against HCC. Our results suggest combinational treatment of chemotherapeutics offer an effective strategy for enhancing the therapeutic efficacy on carcinoma, and highlight the potential application of ligand-modified tumor-targeting nanocarriers in delivering drugs as a promising cancer therapeutic approach.
研究领域:
肿瘤学
·
药学
·
纳米技术
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Meng-xiao Wang,Ke-ke Luo,Meng-yao Tian,Wen-ya Gao,Shan Jiang,Yan Zhang,Jian Yang,Nan Si,Shi-lan Ding,Xiao-lu Wei,Yu-yang Liu,Bao-lin Bian,Yan-yan Zhou,Hong-jie Wang
The diagnosis and treatment of chronic glomerulonephritis (CGN) during childhood pose distinct challenges. Acteoside (ACT) is the primary active ingredient extracted from the leaves of Rehmannia glutinosa by our research group, accounting for 2.15 %, which possess multiple biological activities, especially for nephropathy treatment. However, its mechanism intervention on CGN in children remains obscure. In this study, we established a model of purinomycin aminonucleoside (PAN)-induced CGN in childhood rats to assess the potential therapeutic effect and underlying mechanisms of ACT. Leveraging network pharmacology and multi-omics technology, we delved into the effects and mechanisms of ACT intervention on CGN. And these findings were further corroborated through qRT-PCR, western blot and targeted metabolomics. Our results demonstrated that ACT had significantly efficient in the treatment of CGN in childhood rats by improving the key indicators and pathological changes. Further, ACT could significantly regulate differences in endogenous small molecules and genes based on non-target metabolomics and transcriptomics. Meanwhile, target capture analysis found the crucial targets of ACT treatment in CGN. Integrated analysis of multi-omics study indicated that PI3K/Akt signaling pathway and its downstream amino acid metabolism were significantly enriched, hinting at the essential regulatory pathway for ACT in treating of CGN. Finally, through qRT-PCR, western blot and targeted metabolomics, it was verified that ACT could ameliorate CGN through Cxcr4-PI3K-Akt-eNOS signaling pathway, thereby regulating amino acid metabolism. The collective results were consistent with those of multi-omics analysis. Our study illuminated that ACT had notable curative effect on CGN rats, and preliminarily elucidated its mechanism of action. Our research will provide solid basis for the treatment of chronic glomerulonephritis in children with ACT and developing it into innovative traditional Chinese medicine.
研究领域:
药理学
·
分子生物学
·
肾脏病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
European Journal of Medicinal Chemistry Reports
·
2024
·
IF 4
Xiaoying Jiang,Liuxin Lu,Jiahui Wang,Meng Yu,Rui Wu,Rui Zhao,Hao Wen,Renren Bai
The CXCR4/CXCL12 chemokine axis demonstrates significant potential in the treatment of inflammatory bowel disease (IBD) due to its crucial roles in inflammatory and immune responses. Modulating the CXCR4/CXCL12 pathway can be an effective therapeutic approach to ameliorate the inflammatory state of IBD. In this study, a novel series of meta -dibenzyl amide derivatives were designed and synthesized based on the lead compound AMD3100 and its structurally modified derivatives. Both in vitro and in vivo assays conclusively established that these compounds exhibited potent CXCR4 antagonism and anti-inflammatory activity. Compound 5t demonstrated superior inhibitory rates of binding affinity and chemotaxis of CXCR4 + cells compared to AMD3100. Furthermore, compound 5t notably reduced swelling volume and tissue thickness in the carrageenan-induced mouse paw edema model. Most importantly, in the dextran sodium sulfate (DSS)-induced colitis model, compound 5t significantly mitigated colonic inflammation on both macroscopic and microscopic levels, while suppressing the expression of inflammatory factors and myeloperoxidase (MPO). These findings unequivocally establish the immense potential of compound 5t in the treatment of IBD.
研究领域:
药理学
·
免疫学
·
炎症
·
化学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）