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
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF IMMUNOLOGY
·
2024
·
IF 3.6
Gao Along,Lin Yuhua,Chai Yiwen,Han Jugan,Wu Liting,Ye Jianmin
Chemokines play crucial roles in the regulation of immune cell migration and development. The CXCL12/CXCR4 axis has been extensively studied in mammals, but its regulatory mechanism in teleost fish remains unclear. In this study, we used Nile tilapia (Oreochromis niloticus) as a teleost model to investigate the mediation of the CXCL12/CXCR4 axis in IgM+ B cells. Our findings demonstrate that the CXCL12/CXCR4 axis exhibits chemotactic activity on IgM+ B cells and promotes the phagocytosis of IgM+ B cells. Blocking CXCR4 severely impairs the chemotaxis and phagocytosis of IgM+ B cells in vitro and reduces the percentages and numbers of IgM+ B cells that migrate to peripheral blood after pathogen infection in vivo. This reduction in migration leads to a decrease in the inflammatory response, an increase in tissue bacterial load, and a decrease in survival rate. We also discovered that the evolutionarily conserved PI3K-AKT signaling pathway and Girdin are involved in the immune response during Streptococcus agalactiae infection. Inhibitors of the PI3K-AKT signaling pathway prevent the chemotaxis and phagocytosis of IgM+ B cells, impair the expression and phosphorylation levels of related proteins in vitro, and prevent IgM+ B cells chemotaxis into the peripheral blood after pathogen infection in vivo. Furthermore, CXCR4 blocking significantly downregulates the expression of AKT and Girdin. Overall, our study reveals the regulatory mechanism of the CXCL12/CXCR4 axis on IgM+ B cells via the PI3K-AKT signaling pathway in tilapia, suggesting that the functions of the CXCL12/CXCR4 axis in B cells may be conserved between mammals and teleost fish.
研究领域:
免疫学
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分子生物学
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鱼类生理学
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病理生物学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2018
·
IF 3.457
Lifeng Qin,Jinmei Qin,Xiumei Zhen,Qian Yang,Liyi Huang
The C-X-C motif chemokine 12/C-X-C chemokine receptor type 4 (CXCL12/ CXCR4) biological axis plays an important role in the pathogenesis of liver fibrosis . Curcumin is known to have an anti-fibrosis effect, but the specific mechanism needs to be elucidated. There is currently no evidence illustrating a connection between curcumin and the CXCL12/CXCR4 axis in liver fibrosis . Here, we investigated the contribution of curcumin on CXCL12/ CXCR4 biological axis in liver fibrosis. Our results showed that curcumin remarkably improved hepatic function and liver fibrosis, and the effects are similar as silymarin . The alleviation of liver fibrosis with curcumin treatment was associated with a reduction of CXCL12, CXCR4, α-SMA and RhoA. In addition, curcumin markedly inhibited the proliferation and migration of HSC-T6 cells. This study indicates that curcumin could protect against hepatic stellate cells activation and migration by inhibiting the CXCL12/CXCR4 biological axis in liver fibrosis.
研究领域:
药理学
·
肝病学
·
分子生物学
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产品关联
DOI
PubMed
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
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分子生物学
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药理学
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泌尿学
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DOI
PubMed
高影响因子
CANCER GENE THERAPY
·
2026
·
IF 6.4
Ling Fengyu,Zhang Meibiao,Kuang Jia,Wu Shuai,Yang Zhao
This study aimed to investigate how the CXCL12/CXCR4 axis facilitates immune evasion in gastric cancer (GC) by enhancing cellular communication between cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) using single-cell transcriptome sequencing. Single-cell RNA sequencing of tumor and normal gastric tissues in a murine GC model revealed an increased macrophage population in GC, characterized by predominantly M2-polarized TAMs. The study identified that the CXCL12/CXCR4 axis potentially triggers M2 macrophage polarization through mediating communication between CAFs and TAMs. In vitro experiments confirmed that CAFs induced M2 polarization through CXCL12/CXCR4 signaling. Inhibition of the PD-L1/PD-1 axis disrupted communication between M2 macrophages and T cells, which enhanced T cell activation. In vivo experiments showed that silencing CXCR4 reduced M2 macrophages and PD-L1 expression, leading to improved T cell proliferation, reduced immune evasion, and slower tumor growth. These findings highlight the role of the CXCL12/CXCR4 axis in driving immune evasion in GC by inducing M2 polarization and PD-L1-mediated T cell suppression, and indicate a promising therapeutic target for GC immunotherapy. Schematic Molecular Mechanism Illustrating CXCL12/CXCR4 Axis-Mediated Cellular Communication between CAFs and TAMs Promoting Gastric Cancer Immune Evasion.
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DOI
高影响因子
Frontiers in Immunology
·
2020
·
IF 5.085
Lu Wei-Jia,Zhou Li,Gao Fan-Xiang,Zhou Yu-Lin,Li Zhi,Zhang Xiao-Juan,Wang Yang,Gui Jian-Fang
Chemokine receptor cxcr4 and its ligand cxcl12 have evolved two paralogs in the teleost lineage. In this study, we have identified four duplicated cxcr4 and cxcl12 genes from hexaploid gibel carp, Carassius gibelio, respectively. Cgcxcr4bs and Cgcxcl12as were dynamically and differentially expressed in immune-related tissues, and significantly up-regulated in head kidney and spleen after crucian carp herpesvirus (CaHV) infection. Blocking Cxcr4/Cxcl12 axis by injecting AMD3100 brought more severe bleeding symptom and lower survival rate in CaHV-infected fish. AMD3100 treatment also suppressed the up-regulation of key antiviral genes in head kidney and spleen, and resulted in more acute replication of CaHV in vivo. Consistently, the similar suppression of up-regulated expression of key antiviral genes were also observed in CAB cells treated by AMD3100 after poly(I:C) stimulation. Finally, MAPK3 and JAK/STAT were identified as the possible pathways that CgCxcr4s and CgCxcl12s participate in to promote the antiviral response in vitro.
研究领域:
分子生物学
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免疫学
·
病毒学
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鱼类遗传学
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DOI
PubMed
高影响因子
BIOMATERIALS
·
2026
·
IF 12.9
Rongguo Yu,Jiamei Xiao,Zhencheng Xiong,Xiaoyang Wu,Chaoyi Zhang,Yusheng Zhang,Kangkang Huang,Jing Sun,Hongsong Fan,Hao Liu
Cervical nerve root injury (CNRI) presents significant clinical challenges owing to complex anatomical constraints and poor intrinsic regenerative capacity. In this study, we introduce an in situ -sprayable magnetoelectric hydrogel (DG/FBD) engineered through dynamic covalent assembly and photo-triggered stabilization. The construction of critical boronate ester bonding between dopamine-modified Fe 3 O 4 @BaTiO 3 nanoparticles and phenylboronic acid-functionalized dextran endows DG/FBD with optimal viscosity (87 mPa s), rapid gelation (<2s) and robust tissue adhesion (22.11 kPa), allowing for precise deposition along tortuous nerve roots while conforming to branched cervical anatomy. We then establish a wireless magnetic actuation platform with conductivity modulation enabled spatiotemporally controllable bioelectronic interfacing. In CNRI models loading with magnetic stimulation, we found the hydrogel spray significantly promotes axonal regeneration and myelination, and importantly, improving functional recovery, including enhanced pain and temperature sensation, as well as increased grip strength. We also demonstrate accelerated neural differentiation of BMSCs and attenuated astrogliosis by in vitro studies. Mechanistically, we reveal that magnetoelectrically triggered CXCL12 upregulation drives Schwann cells remodeling through PI3K/AKT/mTOR inhibition and enhances autophagic flux, establishing a bioelectronic-metabolic bridge where the CXCL12-autophagy axis emerges as a fundamental regulatory node for neural regeneration. Collectively, our work pioneers wireless magnetoelectric regulation of chemokine-directed neural repair via an integrated sprayable hydrogel system that overcomes cervical interfacing constraints, establishing a promising platform for spatiotemporal microenvironmental reprogramming in complex neuropathies.
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产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2024
·Vol. 16
·期 12
·1516
·
IF 4.9
Cailian Chen,Jinying Liu,Hongbo Zhang,Hongrui Zhang,Yanhui Liang,Qilian Ye,Wei Shen,Haibin Luo,Ling Guo
Background: Lung cancer is an aggressive disease with rapid progression and a high rate of metastasis, leading to a significantly poor prognosis for many patients. While chemotherapy continues to serve as a cornerstone treatment for a large proportion of lung cancer patients, expanding preclinical and clinical evidence indicates that chemotherapy may promote tumor metastasis and cause side effects.Methods: We develop an injectable bait-and-hook hydrogel (BH-gel) for targeted tumor cell eradication, which embedded doxorubicin liposomes as cytotoxic agents and CXCL12 as a chemoattractant to capture and kill tumor cells. The hydrogel backbone was formed through covalent cross-linking between PVA and borax. In vitro, we investigated tumor recruitment and the antitumor effects in A549 cells. In vivo, we explored the anti-metastatic and antitumor activities against lung cancer.Results: BH-gel retained CXCL12 within its three-dimensional porous architecture for gradual release, effectively recruiting tumor cells. In contrast, blank hydrogel failed to achieve this. After encapsulation in BH-gel, the therapeutic efficacy of doxorubicin liposomes for tumor eradication was markedly improved, significantly reducing metastatic tumor presence to near-undetectable levels, while also resulting in notable reductions in cardiotoxicity and hepatotoxicity. Notably, BH-gel adhered well to tissues and exhibited exceptional electrical conductivity, which may be further developed into a real-time tumor monitoring system, facilitating timely therapeutic adjustments.Conclusions: BH-gel utilizes CXCL12 as a bait to recruit and entrap tumor cells in a three-dimensional porous matrix and subsequently kill them with embedded doxorubicin liposomes, thereby tackling the issue of metastatic spread. This bait-and-hook strategy has significant implications for the field of anti-metastasis medicine and shows considerable potential for clinical application.
研究领域:
肿瘤学
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药学
·
生物医学工程
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癌症研究
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产品关联
DOI
PubMed
高影响因子
Biomedicines
·
2025
·Vol. 13
·期 2
·486
·
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
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产品关联
DOI
PubMed
高影响因子
Cell Death Discovery
·
2024
·Vol. 10
·期 1
·1-14
·
IF 6.1
Sun Bao-Ye,Wang Zhu-Tao,Chen Ke-Zhu,Song Yang,Wu Jing-Fang,Zhang Dai,Sun Guo-Qiang,Zhou Jian,Fan Jia,Hu Bo,Yi Yong,Qiu Shuang-Jian
Lymph node metastasis (LNM) facilitates distant tumor colonization and leads to the high mortality in patients with intrahepatic cholangiocarcinoma (ICC). However, it remains elusive how ICC cells subvert immune surveillance within the primary tumor immune microenvironment (TIME) and subsequently metastasize to lymph nodes (LNs). In this study, scRNA-seq and bulk RNA-seq analyses identified decreased infiltration of dendritic cells (DCs) into primary tumor sites of ICC with LNM, which was further validated via dual-color immunofluorescence staining of 219 surgically resected ICC samples. Tumor-infiltrating DCs correlated with increased CD8 + T cell infiltration and better prognoses in ICC patients. Mechanistically, β-catenin-mediated CXCL12 suppression accounted for the impaired DC recruitment in ICC with LNM. Two mouse ICC cell lines MuCCA1 and mIC-23 cells were established from AKT/NICD or AKT/YAP-induced murine ICCs respectively and were utilized to construct the footpad tumor LNM model. We found that expansion and activation of conventional DCs (cDCs) by combined Flt3L and poly(I:C) (FL-pIC) therapy markedly suppressed the metastasis of mIC-23 cells to popliteal LNs. Moreover, β-catenin inhibition restored the defective DC infiltration into primary tumor sites and reduced the incidence of LNM in ICC. Collectively, our findings identify tumor cell intrinsic β-catenin activation as a key mechanism for subverting DC-mediated anti-tumor immunity in ICC with LNM. FL-pIC therapy or β-catenin inhibitor could merit exploration as a potential regimen for mitigating ICC cell metastasis to LNs and achieving effective tumor immune control.
研究领域:
肿瘤学
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免疫学
·
分子生物学
·
癌症免疫治疗
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DOI
高影响因子
Nano Today
·
2024
·
IF 13.2
Hui Yan,Danping Wang,Chengyin Tian,Long Zhao,Yong Wang,Guoqing Long,Bingjun Sun,Jingming Jia,Anhua Wang
Darutigenol (DL) is an active diterpenoid extracted from the traditional Chinese medicine Sigesbeckia glabrescens (Makino) Makino, widely employed in the treatment of rheumatoid arthritis (RA) for centuries in China. However, the anti-inflammatory mechanism of DL requires further exploration. In this study, we discovered that DL could scavenge reactive oxygen species (ROS) and nitric oxide (NO), and reduce the secretion of proinflammatory cytokines, inducing the M1-to-M2 polarization of macrophages in vitro . In vivo , DL was demonstrated to exert an anti-inflammatory effect via the JAK1, 3/STAT3 and MAPK pathways. It also showed efficacy in repairing cartilage damage via downregulating the proteins MMP2/MMP9 and inhibiting angiogenesis through the CXCL12/CXCR7 system in synovial tissues. However, the application and therapeutic effect of DL was constrained by its poor water solubility and low bioavailability. To address these limitations, ROS-responsive prodrug nanoassemblies were employed, which could be passively transported to the joint inflammation site and decomposed in the inflammatory environment to release DL. The therapeutic effect of prodrug nanoassemblies was superior to that of DL, with negligible toxicity to organs. In summary, we clarified the anti-RA mechanism of DL and constructed an efficient and safe drug delivery system, which provided a strategy for the further application and development of active compounds in traditional Chinese medicine.
研究领域:
药理学
·
纳米技术
·
免疫学
·
传统中药
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药物递送系统
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炎症
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产品关联
DOI
高影响因子
JOURNAL OF BONE AND MINERAL RESEARCH
·
2024
·
IF 5.1
Tan Zhijia,Chen Peikai,Zhang Jianan,Shek Hiu Tung,Li Zeluan,Zhou Xinlin,Zhou Yapeng,Yin Shijie,Dong Lina,Feng Lin,Wong Janus Siu Him,Gao Bo,Tsun To Michael Kai
Osteogenesis imperfecta (OI) is a group of severe genetic bone disorders characterized by congenital low bone mass, deformity and frequent fractures. Type XV OI is a moderate to severe form of skeletal dysplasia caused by WNT1 variants. In this cohort study from southern China, we summarized the clinical phenotypes of patients with WNT1 variants and found that the proportion of type XV patients was around 10.3% (25 out of 243) with a diverse spectrum of phenotypes. Functional assays indicated that variants of WNT1 significantly impaired its secretion and effective activity, leading to moderate to severe clinical manifestations, porous bone structure and enhanced osteoclastic activities. Analysis of proteomic data from human skeleton indicated that the expression of SOST was dramatically reduced in type XV patients when comparing to the patients with COL1A1 quantitative variants. Single-cell transcriptome data generated from the human tibia samples of patients diagnosed with type XV OI and leg-length-discrepancy respectively, revealed aberrant differentiation trajectory of skeletal progenitors and impaired maturation of osteocytes with loss of WNT1, resulting in excessive CXCL12+ progenitors, fewer mature osteocytes and existence of abnormal cell populations with adipogenic characteristics. The integration of multi-omics data from human skeleton delineates how WNT1 regulates the differentiation and maturation of skeletal progenitors, which will provide a new direction for the treatment strategy of type XV osteogenesis imperfecta and relative low bone mass diseases such as early onset osteoporosis.
研究领域:
遗传学
·
骨生物学
·
医学遗传学
·
蛋白质组学
·
转录组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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