Scientific Reports
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2018
·Vol. 8
·期 1
·1-18
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IF 4.122
Du Jing,Li Xiao-Yu,Hu He,Xu Li,Yang Shi-Ping,Li Feng-Hua
Molecularly-targeted contrast enhanced ultrasound (US) imaging is a promising imaging strategy with large potential for improving diagnostic accuracy of conventional US imaging in breast cancer detection. Therefore, we constructed a novel dual-targeted nanosized US contrast agent (UCA) directed at both vascular endothelial growth factor receptor 2 (VEGFR2) and human epidermal growth factor receptor 2 (HER2) based on perfluoropropane (C 3 F 8 )-filled poly(lactic-co-glycolic acid) (PLGA) (NBs) for breast cancer detection. In vitro , single- or dual-targeted PLGA NBs showed high target specificities and better effects of target enhancement in VEGFR2 or HER2-positive cells. In vivo , US imaging signal in the murine breast cancer model was significantly higher ( P < 0.01) for dual-targeted NBs than single-targeted and non-targeted NBs. Small animal fluorescence imaging further confirmed the special affinity of the dual-targeted nanosized contrast agent to both VEGFR2 and HER2. Immunofluorescence and immunohistochemistry staining confirmed the expressions of VEGFR2 and HER2 on tumor neovasculature and tumor cells of breast cancer. In conclusions, the feasibility of using dual-targeted PLGA NBs to enhance ultrasonic images is demonstrated in vitro and in vivo . This may be a promising approach to target biomarkers of breast cancer for two site-specific US molecular imaging.
研究领域:
医学影像
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肿瘤学
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药剂学
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生物医学工程
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
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2023
·Vol. 51
·期 5
·1-16
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IF 5.4
Sheng Huan,Sumin Sun,Shilian Song,Jin Dai,Guining Zhu,Yanling Zhong,Yihao Ji,Shizhong Zheng,Guoping Yin
Liver fibrosis is an early pathological feature of hepatic diseases. Hepatic stellate cell (HSC) activation and disordered proliferation are associated with liver fibrosis. The present study identified significant differences in the expression levels of microRNA (miRNA/miR)‑29b‑3p in clinical samples and multiple miRNA databases. Subsequently, the specific antifibrotic mechanism of miR‑29b‑3p was further elucidated. Reverse transcription‑quantitative PCR, western blot, ELISA and immunofluorescence were used to detect the expression levels of target genes and proteins. Oil red O, Nile red and trypan blue staining were used to evaluate HSC activation and cell viability. A luciferase assay was used to detect the relationship between miR‑29b‑3p and VEGFA. Adhesion, wound healing, apoptosis double staining and JC‑1 assays were used to detect the effects of VEGFR1 and VEGFR2 knockdown on HSCs. Immunoprecipitation and fluorescence colocalization were used to identify interactions between the proteins. Furthermore, a rat fibrosis model was constructed to investigate the effects of dihydroartemisinin (DHA) and miR‑29b‑3p in vivo and in vitro. The results indicated that miR‑29b‑3p both inhibited the activation of HSCs and limited the proliferation of activated HSCs via lipid droplet recovery and VEGF pathway regulation. VEGFA was identified as a direct target of miR‑29b‑3p, and knockdown of VEGFA induced cell apoptosis and autophagy. Notably, VEGFR1 and VEGFR2 knockdown both promoted apoptosis; however, VEGFR1 knockdown inhibited autophagy, whereas VEGFR2 knockdown induced autophagy. Furthermore, it was revealed that VEGFR2 regulated autophagy by mediating the PI3K/AKT/mTOR/ULK1 pathway. VEGFR2 knockdown also led to ubiquitination of heat shock protein 60, ultimately inducing mitochondrial apoptosis. Finally, DHA was identified as a natural agonist of miR‑29‑3p that effectively prevented liver fibrosis in vivo and in vitro. Overall, the present study determined the molecular mechanism by which DHA inhibited HSC activation and prevented liver fibrosis.
研究领域:
分子生物学
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药理学
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肝病学
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细胞生物学
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DOI
PubMed
高影响因子
Journal of Orthopaedic Translation
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2021
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IF 5.191
Wen-Xiang Cheng,Yan-Zhi Liu,Xiang-Bo Meng,Zheng-Tan Zheng,Ling-Li Li,Li-Qing Ke,Ling Li,Cui-Shan Huang,Guo-Yuan Zhu,Hu-Dan Pan,Ling Qin,Xin-Luan Wang,Peng Zhang
Objectives Vascularization is an essential step in successful bone tissue engineering. The induction of angiogenesis in bone tissue engineering can be enhanced through the delivery of therapeutic agents that stimulate vessel and bone formation. In this study, we show that cucurbitacin B (CuB), a tetracyclic terpene derived from Cucurbitaceae family plants, facilitates the induction of angiogenesis in vitro. Methods We incorporated CuB into a biodegradable poly (lactide-co-glycolide) (PLGA) and β-tricalcium phosphate (β-TCP) biomaterial scaffold (PT/CuB) Using 3D low-temperature rapid prototyping (LT-RP) technology. A rat skull defect model was used to verify whether the drug-incorporated scaffold has the effects of angiogenesis and osteogenesis in vivo for the regeneration of bone defect. Cytotoxicity assay was performed to determine the safe dose range of the CuB. Tube formation assay and western blot assay were used to analyze the angiogenesis effect of CuB. Results PT/CuB scaffold possessed well-designed bio-mimic structure and improved mechanical properties. CuB was linear release from the composite scaffold without affecting pH value. The results demonstrated that the PT/CuB scaffold significantly enhanced neovascularization and bone regeneration in a rat critical size calvarial defect model compared to the scaffold implants without CuB. Furthermore, CuB stimulated angiogenic signaling via up-regulating VEGFR2 and VEGFR-related signaling pathways. Conclusion CuB can serve as promising candidate compound for promoting neovascularization and osteogenesis, especially in tissue engineering for repair of bone defects. The translational potential of this article This study highlights the potential use of CuB as a therapeutic agent and strongly support its adoption as a component of composite scaffolds for tissue-engineering of bone repair.
研究领域:
生物医学工程
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组织工程
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药理学
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再生医学
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DOI
PubMed
高影响因子
MOLECULAR MEDICINE
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2023
·Vol. 29
·期 1
·1-21
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IF 5.7
Bai Tao,Li Mingxing,Liu Yuanfeng,Qiao Zhentao,Zhang Xusheng,Wang Yafeng,Wang Zhiwei
Background Diabetes-related limb ischemia is a challenge for lower extremity amputation. Aurora Kinase A (AURKA) is an essential serine/threonine kinase for mitosis, while its role in limb ischemia remains unclear. Method Human microvascular endothelial cells (HMEC-1) were cultured in high glucose (HG, 25 mmol/L d -glucose) and no additional growth factors (ND) medium to mimic diabetes and low growth factors deprivation as in vitro model. Diabetic C57BL/6 mice were induced by streptozotocin (STZ) administration. After seven days, ischemia was surgically performed by left unilateral femoral artery ligation on diabetic mice. The vector of adenovirus was utilized to overexpress AURKA in vitro and in vivo. Results In our study, HG and ND-mediated downregulation of AURKA impaired the cell cycle progression, proliferation, migration, and tube formation ability of HMEC-1, which were rescued by overexpressed AURKA. Increased expression of vascular endothelial growth factor A (VEGFA) induced by overexpressed AURKA were likely regulatory molecules that coordinate these events. Mice with AURKA overexpression exhibited improved angiogenesis in response to VEGF in Matrigel plug assay, with increased capillary density and hemoglobin content. In diabetic limb ischemia mice, AURKA overexpression rescued blood perfusion and motor deficits, accompanied by the recovery of gastrocnemius muscles observed by H&E staining and positive Desmin staining. Moreover, AURKA overexpression rescued diabetes-related impairment of angiogenesis, arteriogenesis, and functional recovery in the ischemic limb. Signal pathway results revealed that VEGFR2/PI3K/AKT pathway might be involved in AURKA triggered angiogenesis procedure. In addition, AURKA overexpression impeded oxidative stress and subsequent following lipid peroxidation both in vitro and in vivo, indicating another protective mechanism of AURKA function in diabetic limb ischemia. The changes in lipid peroxidation biomarkers (lipid ROS, GPX4, SLC7A11, ALOX5, and ASLC4) in in vitro and in vivo were suggestive of the possible involvement of ferroptosis and interaction between AUKRA and ferroptosis in diabetic limb ischemia, which need further investigation. Conclusions These results implicated a potent role of AURKA in diabetes-related impairment of ischemia-mediated angiogenesis and implied a potential therapeutic target for ischemic diseases of diabetes.
研究领域:
分子生物学
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细胞生物学
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糖尿病研究
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血管生物学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2014
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IF 5.9
Yanyu Huang,Yi Luo,Wenjie Zheng,Tianfeng Chen
Radiotherapy displays curative potential for cervical cancer management, but radioresistance occurs during long-term therapy. To overcome this limitation, tumor-targeted nanotechnology has been proposed to enhance the radiosensitivity of solid tumors. Herein, we used biocompatible bovine serum albumin nanoparticles (BSANPs) as carriers of organic selenocompound (PSeD) with folate (FA) as the targeting ligand to fabricate a cancer-targeted nanosystem. The combination of PSeD and BSANPs endowed the nanosystem with higher light absorption and reactive oxygen species (ROS) generation owing to their properties of surface plasmon resonance (SPR) effect, heavy metal effect, high refractive index and nanoparticulate interfacial effect. The combined treatment drastically increased the ROS overproduction, VEGF/VEGFR2 inactivation and inhibition of XRCC-1-mediated repair of DNA damage, thus triggering G2/M phase arrest and apoptosis. Taken together, our findings demonstrate the utility of FA-BSANPs as a promising radiosensitizer to improve cancer radiotherapy.
研究领域:
肿瘤学
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放射生物学
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纳米技术
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药学
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产品关联
DOI
PubMed
高影响因子
Journal of Orthopaedic Surgery and Research
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2023
·Vol. 18
·期 1
·1-15
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IF 2.6
Sun Kai,Xue Yuman,Zhang Xin,Li Xiaodong,Zhao Jun,Xu Xilin,Zhang Xiaofeng,Yang Fubiao
Background The impaired blood supply to the bones is an important pathological feature of steroid-induced osteonecrosis of the femoral head (SIONFH). Danshen is a Chinese herb that shows therapeutic effects on SIONFH, but the effects of one of its major bioactive constituents, Tanshinone I (TsI), on SIONFH remain unknown. Here, we evaluated the effects of TsI on SIONFH, particularly focusing on its effects on angiogenesis, in in vivo and in vitro research. Methods SIONFH was induced in Sprague–Dawley rats by an intramuscular injection of methylprednisolone (40 mg/kg) in combination with an intraperitoneal injection of lipopolysaccharide (20 μg/kg). Morphological alterations of the femoral head were observed by dual-energy X-ray absorptiometry and HE staining. Western blot, qRT-PCR, and immunohistochemical/immunofluorescence staining were used to determine gene expression. Results TsI (10 mg/kg) alleviated bone loss and rescued the expression of angiogenesis-related molecules (CD31, VWF, VEGF, and VEGFR2) in the femoral heads of SIONFH rats. Notably, TsI rescued the down-regulated expression of SRY-box transcription factor 11 (SOX11) in CD31 + endothelial cells in the femoral heads of SIONFH rats. In vitro studies showed that TsI preserved the dexamethasone-harmed angiogenic property (migration and tube formation) of human umbilical vein cells (EA.hy926), suppressed dexamethasone-induced cell apoptosis, reduced pro-apoptotic proteins (cytosolic cytochrome C, Bax, and caspase 3/9) and increased anti-apoptotic protein Bcl-2, whereas silencing of SOX11 reversed these beneficial effects. Conclusions This study demonstrates that TsI alleviates SIONFH and promotes angiogenesis by regulating SOX11 expression. Our work would provide new evidence for the application of TsI to treat SIONFH. Graphical Abstract
研究领域:
药理学
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骨科
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
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2019
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IF 5.808
Yan Chen,Chen Chen,Xiaojuan Zhang,Chuanchuan He,Pengxuan Zhao,Minsi Li,Ting Fan,Ruicong Yan,Yao Lu,Robert J. Lee,Muhammad Waseem Khan,Muhammad Sarfraz,Xiang Ma,Tan Yang,Guangya Xiang
Platinum-based chemotherapy is used for non-small cell lung cancer (NSCLC). However, it has side effects and minimum efficacy against lung cancer metastasis. In this study, platinum–curcumin complexes were loaded into pH and redox dual-responsive nanoparticles (denoted as Pt– [email protected] ) to facilitate intracellular release and synergistic anti-cancer effects. Pt– [email protected] was prepared by a nano-precipitation method and had a diameter of ∼100 nm. The nanoparticles showed increased anti-cancer effects both in vivo and in vitro . In addition, Pt– [email protected] blocked PI3K/AKT signal transduction pathway and inhibited MMP2 and VEGFR2, resulting in enhanced anti-metastatic activity. Furthermore, reduced side effects were also observed. In conclusion, Pt– [email protected] provided a novel and attractive therapeutic strategy for NSCLC.
研究领域:
药理学
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肿瘤学
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纳米技术
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化疗
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产品关联
DOI
PubMed
高影响因子
Small
·
2025
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IF 12.1
Jiajie Chen,Yitong Wang,Zhibo Yang,Kai Tang,Xinchun Liu,Hongshi Ma,Huamao Ye,Chengtie Wu,Yufang Zhu
Emerging evidence demonstrates that inducing ferroptosis, a nonapoptotic programmed cell death mode, holds significant potential for tumor treatment. However, current ferroptosis strategies utilizing exogenous Fenton-type heavy metal species or introducing glutathione (GSH)/glutathione peroxidase 4 (GPX4) suppressants are hampered by latent adverse effects toward organisms, while utilizing endogenous iron may cause undesirable tumor angiogenesis through specific signaling pathways. Here, a ferric ion (Fe 3+ )-responsive and DNAzyme-delivered coordination nanosystem (ZDD) is developed to achieve a novel scheme of synergistic tumor-specific ferroptosis and gene therapy, which modulates and harnesses the endogenous iron in tumors for inducing ferroptosis while intercepting tumor angiogenesis to enhance therapeutic efficacy. Profiting from the characteristic coordination structure and components, ZDD can not only specifically capture tumor endogenous Fe 3+ into the tumor cells to promote the catalytic generation of hydroxyl radicals (·OH) and superoxide anions (O 2 · − ) under acidic environment and the catalytic GSH oxidation, arousing potent ferroptotic cell death, but also effectively deliver specific DNAzyme and release abundant zinc ion (Zn 2+ ) as a powerful cofactor to activate the biocatalytic cleavage of vascular endothelial growth factor receptor 2 (VEGFR2) gene for angiogenesis suppression. Ultimately, the ZDD-enabled synergistic therapy prominently inhibited tumor growth and prevented metastasis, representing a promising nanotherapeutic formula for safe and efficient tumor therapy.
研究领域:
肿瘤学
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纳米医学
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分子生物学
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癌症治疗
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产品关联
DOI
PubMed
高影响因子
BIOMEDICAL MICRODEVICES
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2023
·Vol. 25
·期 1
·1-13
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IF 2.8
Zhu Yuntian,Shi Zhengdi,Ding Weiping,Li Chengpan
Renal tubule chips have emerged as a promising platform for drug nephrotoxicity testing. However, the reported renal tubule chips hardly replicate the unique structure of renal tubules with thick proximal and distal tubules and a thin loop of Henle. In this study, we developed a fully structured scaffold-free vascularized renal tubule on a microfluidic chip. On the chip, the renal epithelial cell-laden hollow calcium-polymerized alginate tube with thick segments at both ends and a thin middle segment was U-shaped embedded in collagen hydrogel, parallel to the endothelial cell-laden hollow calcium-polymerized alginate tube with uniform tube diameter. After the alginate tubes were on-chip degraded, the renal epithelial cells and endothelial cells automatically attached to the collagen hydrogel and proliferated to form the renal tubule with proximal tubule, loop of Henle and distal tubule as well as peritubular blood vessel. We evaluated the viability of cells on the hollow alginate tubes, characterized the distribution and morphology of cells before and after the degradation of the alginate tube, and confirmed the proliferation of cells and the metabolic function of cells in terms of ATP synthesis, fibronectin secretion and VEGFR2 expression on the chip. The enhanced metabolic functions of renal epithelial cells and endothelial cells were preliminarily demonstrated. This study provides new insights into designing a more biomimetic renal tubule on a microfluidic chip.
研究领域:
生物医学工程
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组织工程
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微流控技术
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
American Journal of Cancer Research
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2022
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IF 5.942
Shan-Mei Chen,Jun-Nan Feng,Chuan-Ke Zhao,Li-Cheng Yao,Li-Xin Wang,Lin Meng,Shao-Qing Cai,Cai-Yun Liu,Li-Ke Qu,Yan-Xing Jia,Cheng-Chao Shou
Cancer is one of the main causes of death in humans worldwide, the development of more effective anticancer drugs that can inhibit the malignant progression of cancer cells is of great significance. Aiphanol is a natural product identified from the seeds of Arecaceae and the rhizome of Smilax glabra Roxb . Our preliminary studies revealed that it had potential antiangiogenic and antilymphangiogenic activity by directly targeting VEGFR2/3 and COX2 in endothelial cells. However, the influence of aiphanol on cancer cells per se remains largely undefined. In this study, the effects and related mechanisms of aiphanol on cancer growth and metastasis were evaluated in vitro and in vivo . Acute toxicity assay and pharmacokinetic analysis were utilized to investigate the safety profile and metabolism characteristics of aiphanol. We revealed that aiphanol inhibited the proliferation of various types of cancer cells and the growth of xenograft tumors in mice and zebrafish models. The possible mechanism was associated with the inactivation of multiple kinases, including FAK, AKT and ERK, and the upregulation of BAX and cleaved caspase-3 to promote cancer cell apoptosis. Aiphanol significantly inhibited cancer cell migration and invasion, which was related to the inhibition of epithelial-mesenchymal transition (EMT) and F-actin aggregation. Aiphanol effectively attenuated the metastasis of several types of cancer cells in vivo . In addition, aiphanol exerted no significant toxicity and had fast metabolism. Collectively, we demonstrated the anticancer effects of aiphanol and suggested that aiphanol has potential as a safe and effective therapeutic agent to treat cancer.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
FOLIA HISTOCHEMICA ET CYTOBIOLOGICA
·
2022
·Vol. 60
·期 3
·260-270
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IF 1.49
Ying Wang Yu Wang Yao Chen Qianqian Gao Lihui Hou Xiaoling Feng
Introduction. Abnormal ovarian angiogenesis is a common feature of polycystic ovary syndrome (PCOS), a typical endocrine disorder affecting women of reproductive age. Histone deacetylase 5 (HDAC5) has been documented as a suppressor of angiogenesis. The aim of this study was to explore the effect of HDAC5 on ovarian angiogenesis in a PCOS mouse model. Material and methods. PCOS was induced in female C57BL/6 mice by 20-day administration of dehydroepiandrosterone (DHEA). HDAC5 was over-expressed in PCOS mice by corresponding adenovirus injection. In total, 120 mice were used in this study. Western-blotting, real-time PCR, hematoxylin and eosin staining, enzyme-linked immunosorbent assay (ELISA), immunohistochemical staining, flow cytometry, and co-immunoprecipitation were respectively used to evaluate the effect of HDAC5 on PCOS mice. Results. PCOS ovaries showed a compensatory increase in HDAC5 expression, while HDAC5 over-expression alleviated abnormalities in ovarian morphology and serum hormone levels after PCOS modeling. HDAC5 inhibited ovarian angiogenesis in PCOS mice by regulating angiogenesis-related factors, such as VEGFA, platelet-derived growth factors B and D (PDGFB/D), and angiopoietins 1 and 2 (ANGPT1/2) and CD31. HDAC5 over-expression decreased levels of reactive oxygen species (ROS) and malondialdehyde, while promoting activities of catalase and superoxide dismutase in ovaries of PCOS mice, suggesting its suppressive effects on oxidative stress, an inducer of uncontrolled angiogenesis. Moreover, HDAC5 suppressed activation of angiogenesis-related HIF-1α/VEGFA/VEGFR2 signaling in PCOS ovaries partly via inhibiting VEGFR2 acetylation. Conclusions. This study reveals the protective role of HDAC5 in PCOS by inhibiting ovarian angiogenesis and provides a molecular candidate for PCOS therapy in the future.
研究领域:
内分泌学
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生殖生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Oncotarget
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2017
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IF 5.168
Yan Lou,Wenqi Qiu,Zhe Wu,Qian Wang,Yunqing Qiu,Su Zeng
We previously showed that BZG is a novel multitarget kinase inhibitor, which inhibited hepatocellular carcinoma in vivo and in vitro . In the present study, we used ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) to characterize BZG and its metabolites generated in vivo . The probable metabolic mechanism was further confirmed by analysis of Phase I and Phase II metabolism in liver microsomes and with recombinant enzymes. In addition, the binding affinities of BZG metabolites to vascular endothelial growth factor receptor 2 (VEGFR2) were predicted using electronic high throughput screening (eHiTS). The results showed that BZG underwent phase I and phase II metabolism. We detected 11 BZG metabolites and identified hydroxylation, glucuronation, acetylation, sulfonation and degradation as the major metabolic processes in vivo and in vitro . Five of the eleven metabolites showed highly favorable eHiTS energy scores that were lower than sorafenib. Knowledge of the in vivo metabolic pathways of BZG and its binding affinities to VEGFR2 will be beneficial for further clinical development of BZG.
研究领域:
药理学
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癌症研究
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药物代谢
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）