Frontiers in Bioscience-Landmark
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2024
·Vol. 29
·期 8
·278
·
IF 3.3
Feng Long,Hailong Li,Xujun Chen,Yiqun He,Youhai Dong
Background: Bone tissue engineering offers a new approach for the treatment of bone defects, with angiogenesis being critical to the survival and development of tissue-engineered bone. Mineralized osteoblasts (MOBs) have been reported to promote vascular formation by endothelial cells (ECs) through the secretion of exosomes containing a variety of angiogenic factors. The aim of the present study was to investigate the effect of miR-423-5p contained within exosomes derived from MOBs (MOB-Exos) on EC angiogenesis. Methods: The Cell Counting Kit-8 (CCK-8), scratch wound healing, Transwell migration, and tube formation assays were conducted to assess the in vitro effects of MOB-Exos on EC proliferation, migration, and tubule-forming capabilities. The miR-423-5p level in MOB-Exos was quantified using quantitative polymerase chain reaction (qPCR). Co-culture experiments were used to study the exosomal transport of miR-423-5p and its angiogenic effects. High-throughput sequencing was used to identify differentially expressed genes, and a dual luciferase reporter assay to determine whether CXCL10 was a direct target gene for miR-423-5p. Furthermore, the in vivo effect of MOB-Exos-derived miR-423-5p on angiogenesis was evaluated using a subcutaneous xenograft model. Results: MOB-Exos significantly promoted the in vitro proliferation, migration, and tubule formation of ECs. A high level of miR-423-5p was found in MOB-Exos and promoted the angiogenesis of ECs. The CXCL10 gene was significantly downregulated in ECs upon miR-423-5p mimic transfection. Dual luciferase reporter assay confirmed the direct binding of miR-423-5p to the CXCL10 gene. miR-423-5p derived from MOB-Exos upregulated expression of the vascular markers CD31 and vascular endothelial growth factor (VEGF) in vivo, thus underscoring its angiogenic potential. Conclusion: This study found that miR-423-5p derived from MOB-Exos could potentially enhance EC angiogenesis via the regulation of CXCL10. Therefore, exosomes are promising therapeutic candidates for clinical bone defects.
研究领域:
骨生物学
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组织工程
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分子生物学
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细胞生物学
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PubMed
高影响因子
CNS Neuroscience & Therapeutics
·
2025
·Vol. 31
·期 11
·e70655
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IF 5
Mao‐mei Song,Ting‐yan Chen,Shi‐na Song,Ying‐jie Gao,Chang‐xin Li,Sui‐yi Xu
CXCL10 activates the PI3K/AKT signaling pathway, promoting the release of inflammatory factors, including IL‐1β, IL‐6, and TNF‐α, and is thus involved in the pathogenesis of VM.
研究领域:
神经病学
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分子生物学
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免疫学
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PubMed
高影响因子
NEUROPHARMACOLOGY
·
2026
·
IF 4.7
Ruinan Ni,Shulin Bi,Zhihong Cheng,Shangqi Ni,Yang Guo,Yu Xiang,Bin Peng
Neuropathic pain (NP) remains a clinical challenge due to the limited efficacy and significant side effects of current treatments, highlighting the need for a deeper understanding of its pathogenesis. While dysfunction of GABAergic inhibitory neurons in the spinal dorsal horn is a known key driver of central sensitization, the mechanisms precipitating this neuronal injury remain obscure. In this study, using a spinal nerve ligation (SNL) model, we aimed to investigate whether the chemokine CXCL10 drives NP progression by promoting ferroptosis, a process that is associated with and ultimately leads to the loss of GABAergic neurons. We observed that mechanical hypersensitivity in post-SNL rats coincided with progressive spinal ferroptosis, characterized by iron accumulation, lipid peroxidation, and suppression of the GPX4/xCT system. Notably, CXCL10 expression mirrored the trajectory of ferroptosis. Interventional studies established CXCL10 as an upstream initiator, rather than a consequence, of the ferroptotic process. Mechanistically, we demonstrated that CXCL10 activates STAT3 through the CXCR3 receptor; activated STAT3 then acts as a transcriptional repressor to downregulate the cystine transporter xCT, thereby triggering ferroptosis. This molecular cascade resulted in a significant loss of spinal GABAergic neurons, which could be partially reversed by CXCL10 inhibition. Collectively, our findings uncover a novel mechanism of NP maintenance, wherein the CXCL10/CXCR3/STAT3 axis disrupts the spinal excitation-inhibition balance by promoting ferroptosis-mediated loss of inhibitory neurons. These results offer a fresh perspective on NP pathology and identify this signaling axis as a promising therapeutic target.
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高影响因子
Bioactive Materials
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2024
·
IF 18
Zilin Tan,Liangjie Tian,Yang Luo,Kexin Ai,Xuehua Zhang,Haitao Yuan,Jinfan Zhou,Guangyao Ye,Shuofei Yang,Ming Zhong,Gaohua Li,Yanan Wang
Colorectal cancer (CRC) recurrence post-surgery remains a major challenge. While Chimeric Antigen Receptor (CAR)-engineered natural killer (NK) cells hold immense therapeutic potential, their intratumoral infiltration ability remains limited, hampering efficacy. Building upon prior research suggesting that chemokines like C-X-C motif chemokine ligand 9 (CXCL9) and C-X-C motif chemokine ligand 10 (CXCL10) recruit CAR-NK cells, we hypothesized that tumor cell m6A methylation, regulated by Methyltransferase-like 3 (METTL3), influences chemokine secretion. This study aims to elucidate the underlying mechanisms and improve METTL3 inhibition efficiency. We designed an adhesive hemostasis hydrogel loaded with STM2457, a METTL3 inhibitor, aimed at sustained release in the acidic tumor microenvironment. In vitro, the hydrogel promoted CAR-NK cell recruitment and tumor killing via sustained METTL3 inhibition. The hydrogel's Schiff base bonds further enabled intestinal adhesion and hemostasis in an incomplete tumor resection model of CRC. Combining the hydrogel with CAR-NK cell therapy significantly reduced CRC recurrence in vivo. Overall, our study reveals the crucial role of METTL3 in CRC recurrence and proposes a promising, multimodal strategy using STM2457-loaded hydrogel and CAR-NK cells for enhanced therapeutic efficacy.
研究领域:
肿瘤学
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分子生物学
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免疫疗法
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生物医学工程
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DOI
PubMed
高影响因子
Neuroscience Bulletin
·
2017
·Vol. 34
·期 1
·54-63
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IF 2.624
Jing Peng-Bo,Cao De-Li,Li Si-Si,Zhu Meixuan,Bai Xue-Qiang,Wu Xiao-Bo,Gao Yong-Jing
Recent studies have shown that the chemokine receptor CXCR3 and its ligand CXCL10 in the dorsal root ganglion mediate itch in experimental allergic contact dermatitis (ACD). CXCR3 in the spinal cord also contributes to the maintenance of neuropathic pain. However, whether spinal CXCR3 is involved in acute or chronic itch remains unclear. Here, we report that Cxcr3
−/− mice showed normal scratching in acute itch models but reduced scratching in chronic itch models of dry skin and ACD. In contrast, both formalin-induced acute pain and complete Freund’s adjuvant-induced chronic inflammatory pain were reduced in Cxcr3
−/− mice. In addition, the expression of CXCR3 and CXCL10 was increased in the spinal cord in the dry skin model induced by acetone and diethyl ether followed by water (AEW). Intrathecal injection of a CXCR3 antagonist alleviated AEW-induced itch. Furthermore, touch-elicited itch (alloknesis) after compound 48/80 or AEW treatment was suppressed in Cxcr3
−/− mice. Finally, AEW-induced astrocyte activation was inhibited in Cxcr3
−/− mice. Taken together, these data suggest that spinal CXCR3 mediates chronic itch and alloknesis, and targeting CXCR3 may provide effective treatment for chronic pruritus.
研究领域:
神经科学
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免疫学
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疼痛研究
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皮肤科
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Heng Wang,Guojiang Zhang,Cai Zhao,Youan Xue,Di Zhu,Yan Chang
While interferon-alpha (IFN-α) demonstrates potent antineoplastic activity against hepatocellular carcinoma (HCC), but many patients have a low response rate and may even develop resistance to it. It is necessary to find new strategies to reduce IFN-α resistance and improve its efficacy. RAR-related orphan receptor gamma t (RORγt) agonists exhibit dual immunomodulatory functions, demonstrating both immunosuppression-reducing and immune-activating properties. In this study, we demonstrated that the combination of the RORγt agonist-LYC-55716 and IFN-α significantly promoted cytotoxic T cell 17 (Tc17 cell) differentiation and interleukin-17a (I1-17a) expression through activation of the Akt/Stat3 signal pathway. The combination therapy markedly enhanced the tumoricidal activity of differentiated Tc17 cells against hepatoma carcinoma cells. Moreover, this therapeutic strategy showed superior antitumor efficacy in multiple HCC models while maintaining a favorable safety profile compared to single-agent treatment. Importantly, our findings revealed that the combination treatment significantly enhanced CD8 + T cells infiltration into tumor tissues. Moreover, our mechanistic studies revealed that the observed synergistic antitumor effect was mediated by enhanced CD8 + T cell tumor infiltration, which was facilitated by the C-X-C motif chemokine ligand 10 (Cxcl10)- C-X-C motif chemokine receptor 3 (Cxcr3) interaction. Collectively, these findings support a novel immunoregulatory strategy that leverages RORγt agonists to enhance the efficacy of IFN-α in HCC therapy
研究领域:
肿瘤免疫学
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肝脏疾病
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分子生物学
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药物开发
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DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2024
·
IF 3.3
Miao Yang,Kanmin Mao,Xin Cao,Hongjuan Liu,Weifeng Mao,Liping Hao
Benzo[ a ]pyrene (BaP) is a ubiquitous environmental pollutant posing various toxicity effects on organisms. Previous studies demonstrated that BaP could induce hepatotoxicity, while the underlying mechanism remains incompletely elucidated. In this study, a comprehensive strategy including network toxicology, transcriptomics and gut microbiomics was applied to investigate the hepatotoxicity and the associated mechanism of BaP exposure in mice. The results showed that BaP induced liver damage, liver oxidative stress and hepatic lipid metabolism disorder. Mechanistically, BaP may disrupt hepatic lipid metabolism through increasing the uptake of free fatty acid (FFA), promoting the synthesis of FA and triglyceride (TG) in the liver and suppressing lipid synthesis in white adipose tissue. Moreover, integrated network toxicology and hepatic transcriptomics revealed that BaP induced hepatotoxicity by acting on several core targets, such as signal transducer and activator of transcription 1 (STAT1), C-X-C motif chemokine ligand 10 (CXCL10) and toll-like receptor 2 (TLR2). Further analysis suggested that BaP inhibited JAK2-STAT3 signaling pathway, as supported by molecular docking and western blot. The 16S rRNA sequencing showed that BaP changed the composition of gut microbiota which may link to the hepatotoxicity based on the correlation analysis. Taken together, this study demonstrated that BaP caused liver injury, hepatic lipid metabolism disorder and gut microbiota dysbiosis, providing novel insights into the hepatotoxic mechanism induced by BaP exposure.
研究领域:
毒理学
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分子生物学
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基因组学
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微生物组学
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DOI
PubMed
高影响因子
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