JOURNAL OF NANOBIOTECHNOLOGY
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2022
·Vol. 20
·期 1
·1-16
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IF 9.429
Liu Jie,Hu Xiaochun,Feng Lei,Lin Yun,Liang Shujing,Zhu Zhounan,Shi Shuo,Dong Chunyan
Background Non-redundant properties such as hypoxia and acidosis promote tumor metabolic adaptation and limit anti-cancer therapies. The key to the adaptation of tumor cells to hypoxia is the transcriptional and stable expression of hypoxia-inducible factor-1 alpha (HIF-1α). The phosphorylation-activated tumorigenic signal PI3K/AKT/mTOR advances the production of downstream HIF-1α to adapt to tumor hypoxia. Studies have elucidated that acid favors inhibition of mTOR signal. Nonetheless, carbonic anhydrase IX (CAIX), overexpressed on membranes of hypoxia tumor cells with pH-regulatory effects, attenuates intracellular acidity, which is unfavorable for mTOR inhibition. Herein, a drug delivery nanoplatform equipped with dual PI3K/mTOR inhibitor Dactolisib (NVP-BEZ235, BEZ235) and CAIX inhibitor 4‐(2‐aminoethyl) benzene sulfonamide (ABS) was designed to mitigate hypoxic adaptation and improve breast cancer treatment. Results ABS and PEG-NH 2 were successfully modified on the surface of hollow polydopamine (HPDA), while BEZ235 and Chlorin e6 (Ce6) were effectively loaded with the interior of HPDA to form HPDA-ABS/PEG-BEZ235/Ce6 (H-APBC) nanoparticles. The release of BEZ235 from H-APBC in acid microenvironment could mitigate PI3K/mTOR signal and resist HIF-1α-dependent tumor hypoxia adaptation. More importantly, ABS modified on the surface of H-APBC could augment intracellular acids and enhances the mTOR inhibition. The nanoplatform combined with phototherapy inhibited orthotopic breast cancer growth while reducing spontaneous lung metastasis, angiogenesis, based on altering the microenvironment adapted to hypoxia and extracellular acidosis. Conclusion Taken together, compared with free BEZ235 and ABS, the nanoplatform exhibited remarkable anti-tumor efficiency, reduced hypoxia adaptation, mitigated off-tumor toxicity of BEZ235 and solved the limited bioavailability of BEZ235 caused by weak solubility. Graphical Abstract
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Frontiers in Bioengineering and Biotechnology
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2021
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IF 5.89
Dong Wenpei,Song Zhicheng,Liu Suihong,Yu Ping,Shen Zhipeng,Yang Jianjun,Yang Dongchao,Hu Qinxi,Zhang Haiguang,Gu Yan
Application of synthetic or biological meshes is the main therapy for the repair and reconstruction of abdominal wall defects, a common disease in surgery. Currently, no ideal materials are available, and there is an urgent need to find appropriate ones to satisfy clinical needs. Electrospun scaffolds have drawn attention in soft tissue reconstruction. In this study, we developed a novel method to fabricate a composite electrospun scaffold using a thermoresponsive hydrogel, poly (N-isopropylacrylamide)-block-poly (ethylene glycol), and a biodegradable polymer, polylactic acid (PLA). This scaffold provided not only a high surface area/volume ratio and a three-dimensional fibrous matrix but also high biocompatibility and sufficient mechanical strength, and could simulate the native extracellular matrix and accelerate cell adhesion and proliferation. Furthermore, rat adipose-derived stem cells (ADSCs) were seeded in the composite electrospun scaffold to enhance the defect repair and regeneration by directionally inducing ADSCs into endothelial cells. In addition, we found early vascularization in the process was regulated by the hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway. In our study, overexpression of HIF-1α/VEGF in ADSCs using a lentivirus system promoted early vascularization in the electrospun scaffolds. Overall, we expect our composite biomimetic scaffold method will be applicable and useful in abdominal wall defect regeneration and repair in the future.
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JOURNAL OF PHARMACY AND PHARMACOLOGY
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2023
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IF 3.3
Zeng Xiangfeng,Liu Shengyao,Yang Hua,Jia Menglei,Liu Wei,Zhu Wenting
ObjectivesThe most common cause of osteosarcoma (OS) death is lung metastasis. Currently, doxorubicin is the primary chemotherapy drug used to treat OS, however, it is not effective in inhibiting metastasis, and it has obvious cardiotoxicity. The anticancer activity of ginsenoside Rg3 has been demonstrated in a variety of malignant tumours. The aim of this study was to determine the potential role of ginsenoside Rg3 and doxorubicin in OS and the possible mechanism.MethodsThe potential synergistic effects of ginsenoside Rg3 and doxorubicin on human osteosarcoma cells 143B and U2OS, human umbilical vein endothelial cells, and mice receiving 143B xenografts and lung metastases were investigated.Key findingsOur study demonstrated that the combination of ginsenoside Rg3 and doxorubicin significantly inhibited cell proliferation, metastasis and angiogenesis in vitro. Mechanically, the anti-tumour activity of ginsenoside Rg3 and doxorubicin by modulating mTOR/HIF-1α/VEGF and EMT signalling pathways. Furthermore, ginsenoside Rg3 combined with doxorubicin inhibits tumour growth and lung metastasis in 143B-derived murine osteosarcoma models. More importantly, ginsenoside Rg3 can effectively ameliorate doxorubicin-induced weight loss and cardiotoxicity in mice.ConclusionsConsequently, we concluded that the combination of ginsenoside Rg3 and doxorubicin displayed an evidently synergistic effect, which has the potential to be used as an effective and safe therapeutic approach for OS treatment.
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Journal of Agriculture and Food Research
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2026
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IF 7.2
Yizhu Chen,Yi Liu,Yurong Fang,Huixue Huang,Zhihong Long,Bomi Ryu,Haisheng Xie,Zhong-Ji Qian
Age related macular degeneration (AMD) is one of the main causes of blindness in. elderly patients, and its treatment methods include intraocular injection and oral. administration, requiring long-term treatment and suboptimal efficacy. Tilapia skin-derived oligopeptides, characterized by high safety and bioactivity, emerge as a promising source of functional food ingredients. Here, we investigated the protective mechanism of TBP-1 (Ser-Val-Val-Ala-Ile), a pentapeptide isolated from tilapia skin, against hypoxia-induced damage in retinal pigment epithelial (ARPE-19) cells and angiogenesis in human umbilical vein endothelial cells (HUVECs). In the functional evaluation, TBP-1 notably attenuated ROS overproduction in CoCl 2 -induced ARPE-19 cells, simultaneously suppressing the stabilization of hypoxia-inducible factor-1α (HIF-1α), which was associated with reduced vascular endothelial growth factor (VEGF) transcription, diminished inflammatory factor levels, and restoration of normal autophagic flux. To validate the ROS-dependent nature of this regulatory pathway, we performed a rescue experiment using N-acetylcysteine (NAC), a well-characterized ROS scavenger. In HUVECs activated by VEGF, TBP-1 decreased the phosphorylation of VEGFR-2 and dampened the activation of the MAPK signaling pathway, resulting in dose-dependent inhibition of cell migration, invasion, and the formation of capillary-like tubular structures. Molecular docking and quantum chemical analyses suggested that the bioactivity of TBP-1 may rely on the electron-donating property of the Ser residue and hydrophobic interactions mediated by Ile, both of which are critical for its ROS scavenging ability and predicted interaction with HIF-1α. Collectively, these findings suggest that TBP-1 is a multi-target functional food supplement for preventing AMD by targeting the ROS/HIF-1α/VEGF axis, providing a theoretical basis for the high-value utilization of tilapia skin.
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Acta Biomaterialia
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2022
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IF 10.633
Yifan Li,Qiangwei Liang,Liyue Zhou,Yongjing Cao,Jiayu Yang,Juan Li,Jinxia Liu,Jiawei Bi,Yanhua Liu
The signaling cascade between nuclear factor-kappa B (NF-κB) and hypoxia-inducible factor-1α (HIF-1α) can be activated by proinflammatory M1 macrophages in rheumatoid arthritis (RA), which produces reactive oxygen species (ROS) and enhances M1 macrophage polarization, thus aggravating the development of RA. Therefore, an ROS-responsive artesunate prodrug micellar nanosystem for co-delivery of dexamethasone (DEX/HA-TK-ART micelles , abbreviated as DEX/HTA) was developed for synergistic inhibition of the HIF-1α/NF-κB cascade to regulate ROS scavenging and macrophage repolarization in RA combination therapy. DEX/HTA micelles displayed prolonged circulation in blood and efficiently co-delivered ART&DEX in the inflamed joints of adjuvant-induced arthritis (AIA) rats; moreover, they were specifically recognized and internalized into M1 macrophages through CD44 receptor-mediated endocytosis . ROS-responsive co-released ART&DEX then exerted a synergistic action to efficiently perform ROS scavenging and repolarization of M1 to M2 macrophages by inhibition of the HIF-1α/NF-κB cascade. The intravenous administration of DEX/HTA micelles into AIA rat models significantly alleviated inflammatory cell infiltration and repaired cartilage injury in the joint. Collectively, our study highlights the therapeutic potential of DEX/HTA micelles for treating RA through synergistic inhibition of the HIF-1α/NF-κB signaling cascade to regulate ROS scavenging and macrophage repolarization. Statement of significance An ROS-responsive artesunate (ART) prodrug micellar nanosystem for co-delivering dexamethasone (DEX), abbreviated as DEX/HA-TK-ART micelle, was developed for synergistic cascade regulation of the HIF-1α/NF-κB pathway on ROS scavenging and macrophage repolarization in combination therapy for rheumatoid arthritis. The well-designed nanosystem showed prolonged circulation in blood and superior ART&DEX accumulation in the inflamed joints of AIA rats; moreover, the micelles were specifically internalized into M1 macrophages and co-released ART&DEX, subsequently leading to inhibition of the HIF-1α/NF-κB pathway for ROS scavenging and macrophage repolarization, thus generating synergistic anti-inflammatory effects in RAW 264.7 cells and AIA rats. The HIF-1α/NF-κB cascade regulation on ROS scavenging and macrophage repolarization based on ART&DEX combination with smart nanotechnology could serve as a promising approach for rheumatoid arthritis therapy.
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JOURNAL OF MEDICINAL CHEMISTRY
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2024
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IF 6.8
Yan Chen,Ming Zhang,Zhifang Liu,Ning Zhang,Qingpeng Wang
Tumor microenvironment (TME) is a pivotal factor driving the tumor metastasis and leading to the failure of tumor therapy. Here, a series of ursodeoxycholic acid platinum(IV) conjugates with potency in remodeling the TME through suppressing JAK2/STAT3 signaling was developed. A candidate was screened out, which displayed potent antiproliferative and antimetastatic performance both in vitro and in vivo. It displayed superior pharmacokinetic properties compared to cisplatin. Serious DNA injury was induced, and then mitochondria-mediated apoptosis was initiated through the Bcl-2/Bax/Caspase3 pathway. The JAK2/STAT3 and TGF-β1 signaling pathways were remarkably inhibited, and pro-death autophagy was subsequently promoted. The inflammatory and hypoxic TME was suppressed by downregulating COX-2, MMP9, and HIF-1α, which resulted in inhibited angiogenesis in tumors by inhibiting the HIF-1α/VEGFA axis. Additionally, the immunosuppressive TME was reversed by blocking the immune checkpoint PD-L1, further improving the density of CD3+ and CD8+ tumor-infiltrating lymphocytes, and promoting macrophage polarization from M2- to M1-type.
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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癌症治疗
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MICROCHIMICA ACTA
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2019
·Vol. 187
·期 1
·1-11
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IF 5.479
Wang Qian-Long,Huang Wei-Xue,Zhang Pu-Juan,Chen Li,Lio Chon-Kit,Zhou Hua,Qing Lin-Sen,Luo Pei
An ultra-sensitive method is described here for the determination of HIF-1α (an early biomarker for myocardial infarction) in circulating exosomes in serum. Gold nanospheres were functionalized with a HIF-1α-binding aptamer via sulfydryl chemistry. The apt-AuNP-coated gold seeds were grown by seed-mediated growth, and this significantly increased the peroxidase-mimicking property the nanoparticles. A chromogenic system composed of 3,3′5,5′-tetramethylbenzidine and hydrogen peroxide was used. Absorbance at 652 nm increases linearly in the 0.3 to 200 ng L −1 HIF-1α concentration range, and the limit of detection is 0.2 ng L −1 . The method was tested by analyzing rat serum from isoproterenol (ISO)-induced myocardial infarction. It allows HIF-1α to be directly determined in a 25 μL sample without preconcentration. The assay is not interfered by the polydispersity of exosomes released under either health and disease conditions.
Gold nanospheres were functionalized with a HIF-1α-binding aptamer via sulfydryl chemistry. Nanosized gold seed particles were then modified with the functionalized gold nanospheres, and this strongly increases the peroxidase-mimicking activity of the nanomaterial. By using the tetramethylbenzidine/H 2 O 2 chromogenic system, the absorbance at 652 nm increases linearly in the 0.3 to 200 ng L -1 HIF-1α concentration range.
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Heliyon
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2024
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IF 3.4
Chongchong Liu,Jiangyan Sun,Xiaoming Shen,Shefang Li,Sha Luo,Na Chen,Yunke Zhang
Epilepsy is a chronic neurological disorder. Drug-resistant epilepsy (DRE) accounts for about one-third of epilepsy patients worldwide. Peimine, a main active component of Fritillaria, has been reported to show anti-inflammatory effects. However, its potential therapeutic role in DRE is not yet fully understood. In this work, a DRE rat model was established by injecting 1 μg kainic acid (KA), followed by a 250 mg/kg administration of valproic acid (VPA) from day 4–31. Rats were treated with different doses of peimine (2.5 mg/kg, 5 mg/kg and 10 mg/kg) daily from day 32–62. In vitro, BV-2 microglia were exposed to different doses of peimine (7.5 μg/ml, 15 μg/ml, and 30 μg/ml) in presence of LPS. The aim of this study was to investigate the potential therapeutic effects of peimine on DRE. The results showed that peimine efficiently suppressed the KA-induced epileptic behaviors of rats in a dose-dependent manner, as recorded by electroencephalography. Furthermore, peimine ameliorated hippocampal neuron injury in DRE rats, and promoted an M1-to-M2 microglial phenotype shift in a dose-dependent manner. Mechanistically, peimine inhibited the TLR4/NF-κB/HIF-1α signaling pathway both in vivo and in vitro. Additionally, peimine suppressed the apoptosis of primary neurons induced by LPS-treated microglia. In conclusion, peimine augments the microglial polarization towards an M2 phenotype by inhibiting the TLR4/NF-κB/HIF-1α signaling pathway, thereby attenuating DRE.
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