DRUG DELIVERY
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2019
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IF 3.829
Weijie Li,Ruicong Yan,Yong Liu,Chuanchuan He,Xiaojuan Zhang,Yao Lu,Muhammad Waseem Khan,Chuanrui Xu,Tan Yang,Guangya Xiang
Overexpression of Bmi1 gene is an important feature of cancer stem cell in various human tumors. Therefore, Bmi1 gene can be a potential target for small interfering RNA (siRNA) mediated cancer therapy. Ursolic acid (UA) as a natural product plays a pivotal role in anti-tumor field, although its performance is limited by low bioavailability and poor hydrophilicity. A folate receptor-targeted cationic liposome system was designed for the purpose of investigating the relationship between Bmil siRNA and UA. The folate receptor-targeted cationic liposomes co-delivering UA and Bmi1 siRNA (FA-UA/siRNA-L) were fabricated by electrostatic interaction between folate UA liposome (FA-UA-L) and Bmi1 siRNA. Tumor growth is inhibited by FA-UA/siRNA-L in vitro and in vivo and this inhibition is contributed by a synergistic anti-tumor effect of UA and Bmi1 siRNA. The western blot measurement of apoptosis-protein and cancer stem cell (CSC) marked-protein demonstrated that UA led to activation-induced tumor cell death and Bmi1 siRNA resulted in inhibition of cancer stem cells. Overall, these results indicate that Bmi1 as a regulating gene for cancer stem cell is an effective target for cancer treatment using siRNA and co-delivery of UA and Bmi1 siRNA using folate-targeted liposomes is a promising strategy for improved anti-tumor effect.
研究领域:
肿瘤学
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药学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Advanced Research
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2026
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IF 17.1
Xiao-Fei Zhang,Bo-Wen Zhang,Fan Wu,Zi-Xuan Wang,Wen-Ming Pan,Chu-Yi Cao,Xin-Yu Lv,Tian-Xing Ren,Wei-Hua Xu,Hui Wang,Jin-Xiang Zhang
Introduction Osteoarthritis (OA) is the most prevalent degenerative joint disorder worldwide, characterized by impaired anabolic activity and excessive catabolic responses in chondrocytes. However, the precise mechanisms governing chondrocyte homeostasis during OA progression remain unclear. Objectives This study aimed to elucidate the role of polycomb protein BMI1 in maintaining chondrocyte homeostasis, identify its upstream transcriptional regulator and downstream signaling cascade, and evaluate its therapeutic potential in OA. Methods BMI1 expression was assessed in articular cartilage from OA patients and destabilization of the medial meniscus (DMM) mouse models. Transcriptional regulation of BMI1 by zinc finger and BTB domain–containing protein 17 (ZBTB17) was analyzed using Western blotting, chromatin immunoprecipitation and dual-luciferase reporter assays. In vivo effects of BMI1 were evaluated by intra-articular injection of rAAV6- Bmi1 . In vitro BMI1 overexpression and inhibition were achieved using Bmi1-overexpressing plasmid and PTC209, respectively. The BMI1-SMAD2 interaction was investigated using nuclear–cytoplasmic fractionation, co-immunoprecipitation, ubiquitination assays, cycloheximide chase assays, and immunofluorescence. Therapeutic efficacy of BMI1 was evaluated using a three-dimensional hydrogel-based delivery system in DMM mice. Results BMI1 expression was significantly downregulated in human and murine OA cartilage and negatively correlated with disease severity. ZBTB17 directly activated BMI1 transcription by binding to its promoter. BMI1 overexpression alleviated OA progression by enhancing chondrocyte anabolism and antioxidant capacity through upregulating SMAD2 and promoting its nuclear localization. Mechanistically, BMI1 interacted with SMAD2 to increase its stability by inhibiting SMURF2-mediated K48-linked ubiquitination while facilitating K63-linked ubiquitination at Lys157 to facilitate SMAD2 nuclear translocation. DKK1 was identified as a principal downstream target of the BMI1-SMAD2 axis. Finally, we confirmed that local delivery of BMI1 mdified stromal cells via a three-dimensional hydrogel significantly attenuated cartilage degeneration in vivo . Conclusion Our findings identify a novel ZBTB17–BMI1–SMAD2–DKK1 axis essential for chondrocyte homeostasis and highlight BMI1 as a promising therapeutic target for osteoarthritis.
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DOI
PubMed
高影响因子
Cellular and Molecular Gastroenterology and Hepatology
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2022
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IF 8.797
Shihong Wu,Haoxiang Zhang,Chenggang Gao,Jiaoshun Chen,Hehe Li,Zibo Meng,Jianwei Bai,Qiang Shen,Heshui Wu,Tao Yin
Background & Aims Accumulating evidence strongly suggests that hyperglycemia promotes the progression of pancreatic cancer (PC). Approximately 80% of patients with PC are intolerant to hyperglycemic conditions. In this study, we define the role of Bmi1, a stemness-related oncogene, in controlling the Warburg effect, and immune suppression under hyperglycemia conditions. Methods The diabetes mellitus model was established by intraperitoneal injection of streptozotocin. The role of the hyperglycemia-Bmi1-HK2 axis in glycolysis-related immunosuppression was examined in both orthotopic and xenograft in vivo models. Evaluation of immune infiltrates was carried out by flow cytometry. Human PC cell lines, SW1990, BxPC-3, and CFPAC-1, were used for mechanistic in vitro studies. Results Through bioinformatics analysis, we found that hyperglycemia was strongly related to aerobic glycolysis, immunosuppression, and cancer cell stemness. High glucose condition in the tumor microenvironment promotes immune suppression by upregulating glycolysis in PC cells, which can be rescued via knockdown Bmi1 expression or after 2-deoxy-D-glucose treatment. Through gain-/loss-of-function assessments, we found that Bmi1 upregulated the expression of UPF1, which enhanced the stability of HK2 mRNA and thereby increased the expression of HK2. The role of the hyperglycemia-Bmi-HK2 pathway in the inhibition of antitumor immunity was further verified via the immune-competent and immunodeficient mice model. We also demonstrated that hyperglycemia promotes the expression of Bmi1 by elevating the intracellular acetyl-CoA levels and histone H4 acetylation levels. Conclusions Our results suggest that the previously unreported Bmi1-UPF1-HK2 pathway contributes to PC progression and immunosuppression, which may bring in new targets for developing effective therapies to treat patients with PC.
研究领域:
肿瘤学
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免疫学
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分子生物学
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细胞生物学
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代谢
✓ 已验证
DOI
PubMed
高影响因子
POULTRY SCIENCE
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2020
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IF 2.659
Lingzi Yu,Xiaochen Xie,Keyang Jiang,Yi Hong,Zhou Zhou,Yuling Mi,Caiqiao Zhang,Jian Li
The rapid renewal and repair of the intestinal mucosa are based on intestinal stem cells ( ISC ), which are located at the crypt bottom. Paneth cells are an essential component in the crypt, which served as the niche for ISC development. However, in the chicken, how the function of Paneth cells changes during intestinal inflammation is unclear and is the key to understand the mechanism of mucosal repair. In the present study, 36 HyLine White chickens (7 d of age, n = 6) were randomly divided into 1 control and 5 lipopolysaccharide ( LPS ) injection groups. The chickens were injected (i.p.) with PBS in the control group, however, were injected (i.p.) with LPS (10 mg/kg BW) in the LPS injection groups, which would be sampled at 5 time points (1 h postinjection [ hpi ], 2 hpi, 4 hpi, 6 hpi, and 8 hpi). Results showed that tumor necrosis factor-α mRNA transcription in duodenal tissue increased gradually since 1 hpi, peaked at 4 hpi, and then reduced remarkably, indicating that 4 hpi of LPS was the early stage of intestinal inflammation. Meanwhile, the MUC2 expression in duodenal tissue was dramatically reduced since 1 hpi of LPS. The ISC marker, Lgr5 and Bmi1 , in the duodenal crypt were reduced from 1 hpi to 4 hpi and elevated later. Accordingly, the hydroethidine staining showed that the reactive oxygen species level, which drives the differentiation of ISC, in the duodenal crypt reduced obviously at 1 hpi and recovered gradually since 4 hpi. The analysis of Paneth cells showed that many swollen mitochondria appeared in Paneth cells at 4 hpi of LPS. Meanwhile, the Lysozyme transcription in the duodenal crypt was substantially decreased since 1 hpi of LPS. However, the Wnt3a and Dll1 in duodenal crypt decreased at 1 hpi of LPS, then increased gradually. In conclusion, Paneth cells were impaired at the early stage of intestinal inflammation, then recovered rapidly. Thus, the ISC activity was reduced at first and recovery soon.
研究领域:
免疫学
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胃肠病学
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动物科学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
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IF 10.2
Yiwen Chen,Zhen Qin,Yujia Wang,Baoxin Gu,Jing Wang,Yunfei Zheng,Yuting Niu,Lingfei Jia
Cancer stem cells (CSCs) play critical roles in tumor growth, metastasis, and chemoresistance. Although several small-molecule inhibitors designed to inhibit CSCs have been investigated in clinical trials, their inadequate tumor targeting and potential off-target side effects have led to poor outcomes. A CD44-targeted virus-mimicking nanomedicine encapsulating the BMI1 inhibitor PTC209 (PTC209@VNP-HA) was designed to treat head and neck squamous cell carcinoma (HNSCC). We used a dendritic mesoporous silica nanoparticle (MSN) as the core for virus-mimicking nanoparticle (VNP) formation after adding shell particles to the MSN surface. The VNP surface was then modified with hyaluronic acid (HA), and PTC209 was adsorbed by mesopores to form PTC209@VNP-HA. In this system, HA is used to target CD44 + CSCs. The rough surface of VNP-HA provided better drug delivery efficiency than smooth nanoparticles modified with HA. VNP-HA enhanced the cancer inhibitory effect of PTC209 12-fold compared to the administration of free PTC209, leading to significantly higher bioavailability of PTC209. Both in vitro and in vivo assays showed that PTC209@VNP-HA inhibited cancer stemness, proliferation, and metastasis in HNSCC. Mechanistically, this inhibitory effect is closely associated with DNA damage/apoptosis signaling. Using a series of preclinical models in murine systems, we confirmed that PTC209@VNP-HA eliminated BMI1 + CSCs, and greatly inhibited the proliferation and metastasis of HNSCC when combined with cisplatin.This study investigated PTC209@VNP-HA as a novel and potentially transformative HNSCC treatment option that eliminates CSCs, prevents metastasis, and overcomes cisplatin resistance.
研究领域:
肿瘤学
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纳米医学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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