JOURNAL OF PATHOLOGY
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2025
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IF 5.2
Fang Liu,Qingchun Liang,Li Li,Yuan Gong,Mingxi Li,Liyun Feng,An Chen,Yuanzhi Ye,Zirong Lan,Yining Li,Jing-Song Ou,Lihe Lu,Jianyun Yan
Vascular calcification is an important risk factor related to all-cause mortality of cardiovascular events in patients with chronic kidney disease (CKD). Vascular extracellular matrix (ECM) proteins have been demonstrated to regulate vascular calcification. ECM protein thrombospondin 1 (THBS1/TSP-1) plays a critical role in the regulation of vascular diseases. However, whether THBS1 is involved in vascular calcification in CKD patients remains unclear. In this study, RNA sequencing datasets from the Gene Expression Omnibus (GEO) database GSE146638 showed that THBS1 was upregulated in the aortas of CKD rats. Enzyme-linked immunosorbent assay (elisa) revealed that serum THBS1 levels were increased in CKD patients with thoracic calcification. Western blotting and immunofluorescence analysis showed that THBS1 expression was increased in calcified vascular smooth muscle cells (VSMCs) and arteries. THBS1 knockdown exacerbated rat VSMC calcification induced by high phosphorus and calcium, as shown by Alizarin red staining and calcium content assays. Conversely, THBS1 overexpression attenuated VSMC calcification and abdominal aortic calcification in rats with CKD. Moreover, addition of recombinant THBS1 protein inhibited calcification of VSMC S and human arterial rings. Smooth muscle cell-specific knockout of THBS1 mice treated with vitamin D3 displayed aggravated aortic calcification. Mechanistically, the protein–protein interaction database STRING ( http://string-db.org/ ) analysis and coimmunoprecipitation assays revealed THBS1 bound to integrin β3. Reduction of integrin β3 levels abrogated the protective effect of THBS1 on vascular calcification. RNA-seq analysis revealed that THBS1 overexpression modulated the nuclear factor-kappa B (NF-κB) signaling pathway. Of note, the inhibitory effect of THBS1 overexpression on the NF-κB signal was abolished by knockdown of integrin β3. In conclusion, THBS1 interacts with integrin β3 to inhibit vascular calcification through suppression of NF-κB signal, suggesting a promising therapeutic target for vascular calcification in CKD. © 2025 The Pathological Society of Great Britain and Ireland.
研究领域:
医学
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分子生物学
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心血管研究
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2022
·Vol. 11
·期 20
·2200938
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IF 11.092
Lei Zhou,Haifeng Liang,Yuxiang Ge,Wang Ding,Qing Chen,Taiwei Zhang,Lan Xiao,Yulin Li,Jian Dong,Xiaowen He,Fengfeng Xue,Libo Jiang
Although immune checkpoint inhibitors (ICIs) have been widely applied to treat non-small cell lung cancer (NSCLC), a significant proportion of patients, especially those with spinal metastasis (NSCLC-SM), are insensitive to anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) ICIs. A drug delivery nano-controller of PD-L1 that targets NSCLC-SM can solve this problem, however, none have been developed to date. In this study, it is shown that integrin β 3 ( β 3-int) is strongly upregulated in NSCLC-SM. Its inhibitor RGDyK promotes PD-L1 ubiquitination, indicating the potential application of RGDyK as a new PD-L1 inhibitor in nano-controller and a targeting peptide for NSCLC-SM treatment. According to the synergistic effect of photodynamic therapy and ICIs on T-cell activation through the release of tumor antigens, RGDyK-modified and zinc protoporphyrin (ZnPP)-loaded mesoporous silicon nanoparticles (ZnPP@MSN-RGDyK) are fabricated. The ZnPP@MSN-RGDyK nanoparticles precisely target β 3-int to inhibit PD-L1, exhibiting high photodynamic therapy efficiency, and excellent immunotherapeutic effects in an NSCLC-SM mouse model. Collectively, the findings indicate that ZnPP@MSN-RGDyK is a promising immunotherapeutic agent for treating NSCLC-SM.
研究领域:
肿瘤学
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纳米技术
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免疫学
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癌症治疗
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2023
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IF 15.1
Bingyang Dai,Yuwei Zhu,Xu Li,Zuru Liang,Shunxiang Xu,Shian Zhang,Zhe Zhang,Shanshan Bai,Wenxue Tong,Mingde Cao,Ye Li,Xiaobo Zhu,Wei Liu,Yuantao Zhang,Liang Chang,Patrick Shu-hang Yung,Kevin Ki-wai Ho,Jiankun Xu,To Ngai,Ling Qin
The knowledge of osteoarthritis (OA) has nowadays been extended from a focalized cartilage disorder to a multifactorial disease. Although recent investigations have reported that infrapatellar fat pad (IPFP) can trigger inflammation in the knee joint, the mechanisms behind the role of IPFP on knee OA progression remain to be defined. Here, dysregulated osteopontin (OPN) and integrin β 3 signaling are found in the OA specimens of both human and mice. It is further demonstrated that IPFP-derived OPN participates in OA progression, including activated matrix metallopeptidase 9 in chondrocyte hypertrophy and integrin β 3 in IPFP fibrosis. Motivated by these findings, an injectable nanogel is fabricated to provide sustained release of siRNA Cd61 ( RGD− Nanogel/siRNA Cd61 ) that targets integrins. The RGD− Nanogel possesses excellent biocompatibility and desired targeting abilities both in vitro and in vivo. Local injection of RGD− Nanogel/siRNA Cd61 robustly alleviates the cartilage degeneration, suppresses the advancement of tidemark, and reduces the subchondral trabecular bone mass in OA mice. Taken together, this study provides an avenue for developing RGD− Nanogel/siRNA Cd61 therapy to mitigate OA progression via blocking OPN-integrin β 3 signaling in IPFP.
研究领域:
骨科
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分子生物学
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纳米技术
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风湿病学
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DOI
PubMed
高影响因子
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