Biomedicines
·
2025
·Vol. 13
·期 2
·486
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IF 3.9
Chunli Zhu,Yiheng Cheng,Lei Yang,Yifu Lyu,Jingjing Li,Pengbo Zhao,Ying Zhu,Xiaofei Xin,Lifang Yin
Background and Objectives: As a key mechanism of metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis, inflammation triggered by chronic liver injury and immune cells with macrophages enables MASLD to progress to an advanced stage with irreversible processes such as fibrosis, cell necrosis, and cancer in the liver. The complexity of MASLD, including crosstalk between multiple organs and the liver, makes developing a new drug for MASLD challenging, especially in single-drug therapy. It was reported that upregulation of Notch1 is closely associated with the function of pro-inflammatory macrophages. To leverage this signaling pathway in treating MASLD, we developed a combination therapy.Materials and Methods: We chose Notch1 siRNA (siNotch1) to block the Notch pathway so that phenotypic regulation and functional recovery can be achieved in macrophages, combining with small molecule drug AMD3100. AMD3100 can cut off the migration of inflammatory cells to the liver to impede the development of inflammation and inhibit the CXCL12/CXCR4 biological axis in liver fibrosis to protect against the activation of HSCs. Then, we investigated the efficacy of the combination therapy on resolving inflammation and MASLD.Results: We demonstrated that in liver cells, siNotch1 combined with AMD3100 not only directly modulated macrophages by downregulating multiple pathways downstream of Notch, exerting anti-inflammatory, anti-migration, and switch of macrophage phenotype, but also modulated macrophage phenotypes through inhibiting NET release. The restored macrophages further regulate HSC and neutrophils. In in vivo pharmacodynamic studies, combination therapy exhibits a superior therapeutical effect over monotherapy in MASLD models.Conclusions: These results constitute an siRNA therapeutical approach combined with a small molecule drug against inflammation and liver injury in MASLD, offering a promising therapeutic intervention for MASLD.
研究领域:
医学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Inflammation Research
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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
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分子生物学
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药理学
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泌尿学
✓ 已验证
DOI
PubMed
高影响因子
CHINESE JOURNAL OF CHEMISTRY
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2023
·
IF 5.4
Xu Huan,Yi Chen,Xiaozhen Wu,Hui Wang,Ying Yang,Pengkai Wu,Tianqing Liu,Kaikai Wang,Dan Ding
Comprehensive Summary Inflammation is associated with different stages of liver disease, including acute injury, fibrosis, cirrhosis, and hepatoma. During the progression of liver inflammation, activation of hepatic stellate cells (HSCs) and extracellular matrix (ECM) deposition are critical pathologies, and thus the combined therapy using HSCs and ECM as targets represents a promising strategy in the treatment of liver injury. Here, a novel CXCR4-inhibiting nanomedicine that can simultaneously deliver AMD3100 (CXCR4 antagonist) and siPAI-1 (siRNA of plasminogen activator inhibitor-1) was designed and developed to reverse liver fibrosis by inhibiting HSCs activation and degrading ECM deposition. With this goal in mind, a Zn (II) coordinated polymeric AMD3100 named PAMD/Zn polymer with siRNA delivery and CXCR4 antagonism capabilities was synthesized. Overall, our results suggest that PAMD/Zn recruits pro-inflammatory cells for fibrogenesis and inhibits the activation of HSCs for fibrolysis at various stages of liver injury. Its use in conjunction with PAI-1 silencing achieved satisfactory therapeutic efficacy in liver injury and fibrosis. The derivative CXCR4-inhibiting nanomedicine is a versatile platform that offers valuable benefits for the treatment of liver diseases. This article is protected by copyright. All rights reserved.
研究领域:
药理学
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纳米技术
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肝病学
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分子生物学
✓ 已验证
产品关联
DOI
高影响因子
BIOMACROMOLECULES
·
2017
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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
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药剂学
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生物材料学
✓ 已验证
DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2023
·
IF 8
Aftab Ullah,Kaikai Wang,Pengkai Wu,David Oupicky,Minjie Sun
Background: Liver fibrosis is a chronic liver disease associated with an excessive accumulation of extracellualr matrix (ECM) proteins which ultimately lead to cirrohosis and hepatocellular carcinoma.Purpose: Liver fibrosis therapies that use combination approaches with the ability to affect multiple disease pathways have proven higher efficacies. This study aimed at optimizing and characterizing the co-encapsulation of pirfenidone (PF) and AMD3100 (AMD) into CXCR4-targeted combination liposomes (CTC liposome) for CXCR4 targeting, and the inhibition of major molecular culprits ie α-SMA, CXCR4, TGFβ, and P-p38 involved in liver fibrosis in-vitro.Methods: The CTC liposomes were prepared using the thin-film hydration method. The concentration of encapsulated AMD and PF was measured by HPLC and UV spectrophotometry, respectively. Tramsmission electron microscopy (TEM) was used to determine the liposomal morphology. The CXCR4 targeting ability was determined by CXCR4 redistribution assay. Confocal microscopy and flowcytometry were used to determine the CXCR4 mediated cell uptake. The apoptosis inducing and protein downreguating ability of CTC liposomes were determined by apoptosis assay and western blot analysis, respectively. In-vivo biodistribution and Hoechst staining were used to confirm the feasibility of CTC liposome for the in-vivo applications and drug targeted accumulation, respectively.Results: The TEM studies revealed that CTC liposomes were spherical in shape. The cumulative release of AMD and PF from CTC liposome was 67% and 84%, respectively, at 48 h. Compared to the free drug counterparts, encapsulated drugs displayed higher cell viability. The CXCR4 redistribution assay confirmed the CXCR4 targeting and antagonistic ability of CTC liposomes. The CTC liposomes were internalized more effectively via caveolae-mediated endocytic pathways. CTC liposomes displayed aggressive apoptosis (87.3%) in TGFβ-induced activated HSC-T6 cells suggesting a propensity to fibrosis regression. Also, CTC liposomes significantly reduced α-SMA (65%), CXCR4 (77%), TGFβ (89%), and P-p38 (66%) expressions, better than free drugs. CTC@IR780 liposomes (CTC liposomes incorporating IR780 dye) were more accumulated in fibrotic livers compared to free IR780, as judged by in-vivo imaging, biodistribution analysis, and Hoechst staining. These findings suggest that this simple and stable CTC liposomal system holds a great promise for the treatment and prevention of liver fibrosis.
研究领域:
药理学
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生物技术
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细胞生物学
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分子生物学
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治疗学
✓ 已验证
DOI
PubMed
高影响因子
Cell Communication and Signaling
·
2023
·Vol. 21
·期 1
·1-17
·
IF 8.4
Zhao Weiming,Wang Lan,Yang Juntang,Chen Xinyu,Guo Xiaoshu,Xu Kai,Wang Ningdan,Zhao Wenyu,Xia Cong,Lian Hui,Rosas Ivan,Yu Guoying
Background Matrix metalloproteinases (MMPs) play important roles in remodeling the extracellular matrix and in the pathogenesis of idiopathic pulmonary fibrosis (IPF). MMP19, which is an MMP, was significantly upregulated in hyperplastic alveolar epithelial cells in IPF lung tissues and promoted epithelial-mesenchymal transition (EMT). Recent studies have demonstrated that endothelial-to-mesenchymal transition (E(nd)MT) contributes to pulmonary fibrosis. However, the role of MMP19 in pulmonary vascular injury and repair and E(nd)MT remains unclear. Methods To determine the role of MMP19 in E(nd)MT and pulmonary fibrosis. MMP19 expressions were determined in the lung endothelial cells of IPF patients and bleomycin (BLM)-induced mice. The roles of MMP19 in E(nd)MT and endothelial barrier permeability were studied in the MMP19 cDNA-transfected primary human pulmonary microvascular endothelial cells (HPMECs) and MMP19 adenoassociated virus (MMP19-AAV)-infected mice. The regulatory mechanism of MMP19 in pulmonary fibrosis was elucidated by blocking its interacting proteins SDF1 and ET1 with AMD3100 and Bosentan, respectively. Results In this study, we found that MMP19 expression was significantly increased in the lung endothelial cells of IPF patients and BLM-induced mice compared to the control groups. MMP19 promoted E(nd)MT and the migration and permeability of HPMECs in vitro, stimulated monocyte infiltration into the alveolus, and aggravated BLM-induced pulmonary fibrosis in vivo. SDF1 and Endothelin-1 (ET1) were physically associated with MMP19 in HPMECs and colocalized with MMP19 in endothelial cells in IPF patient lung tissues. AMD3100 and bosentan alleviated the fibrosis induced by MMP19 in the BLM mouse model. Conclusion MMP19 promoted E(nd)MT by interacting with ET1 and stimulated monocyte infiltration into lung tissues via the SDF1/CXCR4 axis, thus aggravating BLM-induced pulmonary fibrosis. Vascular integrity regulated by MMP19 could be a promising therapeutic target for suppressing pulmonary fibrosis.
Video abstract
研究领域:
呼吸病学
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细胞生物学
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分子生物学
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病理学
✓ 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
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免疫学
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炎症
·
化学
✓ 已验证
DOI
高影响因子
Nanomedicine-Nanotechnology Biology and Medicine
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2022
·
IF 6.458
Zhang Ye,Lun Gao,Jiayang Cai,Yixuan Wang,Yong Li,Shiao Tong,Tengfeng Yan,Qian Sun,Yangzhi Qi,Yang Xu,Hongxiang Jiang,Si Zhang,Linyao Zhao,Shenqi Zhang,Qianxue Chen
Glioblastoma multiforme (GBM) is the intracranial malignancy with the highest rates of morbidity and mortality. Chemotherapy is often ineffective against GBM due to the presence of the blood–brain barrier (BBB); however, the application of nanotechnology is expected to overcome this limitation. Poly(lactic-co-glycolic acid) (PLGA) is a degradable and nontoxic functional polymer with good biocompatibility that is widely used in the pharmaceutical industry. Previous studies have shown that the ability of PLGA nanoparticles (NPs) to penetrate the BBB is largely determined by their size; however, determination of the optimal PLGA NP size requires further research. Here, we report a tandutinib-based prodrug (proTan), which responds to the GBM microenvironment , that was combined with NPs to overcome the BBB. AMD3100-PLGA NPs loaded with proTan inhibited tumor growth and effectively prolonged the survival of tumor-bearing mice.
研究领域:
药学
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纳米技术
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肿瘤学
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神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Today
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2022
·
IF 18.962
Di Liu,Hongliang He,Fei Kong,Yixiang Cao,Fengchao Zang,Ming Ma,Ning Gu,Yu Zhang
Currently, multimodal synergistic nanoplatform emerges as an important cancer therapy paradigm, however, multimodal synergistic theranostic nanoplatform remains to be developed. Herein, using the mouse model of breast cancer, a versatile multimodal synergistic theranostic nanoplatform is rationally designed and synthesized for enhancing chemodynamic therapy (CDT), overcoming immunosuppression within tumor microenvironment , and inhibiting metastasis as well as tracking tumor. To fulfill our design, a composite Fe/Mn magnetic nanoparticle is first synthesized by loading with Fe 3 O 4 and BMS-202 (PD-L1 inhibitor) within a poly(lactide-co-glycolide)-based nanoparticle core, which are further modified with in situ synthesis of MnO 2 layer. Then, the composite metal-organic nanoparticle is coated with two targeting moieties hyaluronic acid (HA) and AMD3100 (CXCR4 antagonist), respectively, to achieve the multimodal synergistic theranostic nanoplatform ( [email protected] +AMD). With surface targeting modification, [email protected] +AMD exhibits enhanced tumor accumulation, where it effectively consumes endogenous glutathione to generate Mn 2+ allowing for the enhanced CDT effect, alleviates tumor hypoxia by O 2 generation and reverses the tumor immunosuppression. [email protected] +AMD blocks CXCR4 receptor on cancer cells, thus suppressing the CXCR4-mediated cancer metastasis and invasion. Additionally, [email protected] +AMD would synchronously be achieving tumor tracking by T 1 -T 2 dual-mode magnetic resonance imaging. Collectively, this strategy holds a novel multimodal synergistic theranostics for effective cancer management.
研究领域:
纳米技术
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癌症治疗
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医学成像
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免疫疗法
·
药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）