ACS Biomaterials Science & Engineering
·
2019
·
IF 4.511
Lingna Deng,Fang Zhang,Yanlin Wu,Jiahao Luo,Xuhong Mao,Lingli Long,Maling Gou,Liqun Yang,David Y. B. Deng
Studies have shown that the use of proangiogenic genes can improve the prognosis of ischemic stroke by promoting angiogenesis at the injury site. For example, within this study, hypoxia-inducible factor 1-α (HIF-1α) has exhibited an angiogenic effect. Our previous study reported a more stable HIF-1α mutant form (HIF-1α-AA), which was transfected into mesenchymal stem cells to provide neuroprotective effects against ischemic stroke. The safety of nonviral gene vectors has attracted researchers’ attention. This study encapsulated the HIF-1α-AA plasmid DNA into a newly synthesized effective nonviral gene vector, a hyperbranched cationic amylopectin derivative (DMAPA-Amyp) nanocarrier. In addition, a targeting strategy was applied to select the RGD peptides and bind to the designed nanocarrier as a molecule targeting endothelial cells. The targeting strategy is used to directly deliver the nanocarriers to the vascular endothelial cells of the brain peri-infarct site. This study emphasizes the targeting ability of nanocarrier and its therapeutic effect on cerebral ischemia. The results showed that RGD-DMAPA-Amyp had good biocompatibility and a high cell uptake rate, indicating that it is a safe nonviral gene vector that can be endocytosed by human cells. In rat models of ischemic stroke, compared with the nontargeted nanocarrier group, more RGD-DMAPA-Amyp nanoparticles aggregated in vascular endothelial cells of the peri-infarct region and significantly improved the recovery of neurological function. It is indicated that the RGD-modified nanomedicine promotes the recovery of nerve function more efficiently. Further study on the mechanism of RGD-DMAPA-Amyp/HIF-1α-AA in the treatment of cerebral ischemia displayed potential to significantly promote the formation of new blood vessels in vivo. Our findings suggest that the RGD-modified nonviral gene vector containing HIF-1α-AA appears to be a safe and promising therapeutic strategy for ischemic stroke gene therapy.
研究领域:
神经科学
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分子生物学
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基因治疗
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药学
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PubMed
高影响因子
Theranostics
·
2018
·
IF 8.537
Feng Zhang,Shuai Lu,Jianlin He,Huanhuan Jin,Feixia Wang,Li Wu,Jiangjuan Shao,Anping Chen,Shizhong Zheng
Rationale: Hepatic stellate cells (HSCs) are liver-specific pericytes regulating vascular remodeling during hepatic fibrosis. Here, we investigated how ligustrazine affects HSC pericyte functions. Methods: Rat HSC-T6 and human HSC-LX2 cells were cultured, and multiple molecular experiments including real-time PCR, Western blot, flow cytometry, immunofluorescence, electrophoretic mobility shift assay and co-immunoprecipitation were used to elucidate the underlying mechanisms. Molecular simulation and site-directed mutagenesis were performed to uncover the target molecule of ligustrazine. Rats were intoxicated with CCl 4 for evaluating ligustrazine's effects in vivo . Results: Ligustrazine inhibited angiogenic cytokine production, migration, adhesion and contraction in HSCs, and activated PPARγ. Selective PPARγ inhibitor GW9662 potently abrogated ligustrazine suppression of HSC pericyte functions. Additionally, HIF-1α inhibitor PX-478 repressed HSC pericyte functions, and ligustrazine inhibited the transcription of HIF-1α, which was diminished by GW9662. Moreover, ligustrazine downregulation of HIF-1α was rescued by knockdown of SMRT, and ligustrazine increased PPARγ physical interaction with SMRT, which was abolished by GW9662. These findings collectively indicated that activation of PPARγ by ligustrazine led to transrepression of HIF-1α via a SMRT-dependent mechanism. Furthermore, molecular docking evidence revealed that ligustrazine bound to PPARγ in a unique double-molecule manner via hydrogen bonding with the residues Ser289 and Ser342. Site-directed mutation of Ser289 and/or Ser342 resulted in the loss of ligustrazine transrepression of HIF-1α in HSCs, indicating that interactions with both the residues were indispensable for ligustrazine effects. Finally, ligustrazine improved hepatic injury, angiogenesis and vascular remodeling in CCl 4 -induced liver fibrosis in rats. Conclusions: We discovered a novel ligand activation pattern for PPARγ transrepression of the target gene with therapeutic implications in HSC pericyte biology and liver fibrosis.
研究领域:
药理学
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细胞生物学
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分子生物学
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肝病学
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·
IF 15
Sheng Ding,Siyu Liu,Shaoyang Kang,Shuwei Wang,Nan Jiang,Yuwei Li,Chunxiao Zhou,Hantao Lou,Chuangnian Zhang,Pingsheng Huang,Wenshuai Liu,Zujian Feng,Weiwei Wang,Deling Kong,Ningbei Yin
Diabetic wound healing poses a major clinical challenge. One of the promising therapy, the flap transplantation surgery exhibited unsatisfactorily low flap survival due to the intertwined pathological barriers: impaired angiogenesis, excessive oxidative stress, and persistent inflammation, leading to poor tissue repair. While the therapeutic platforms based on extracellular vesicles (EVs) emerges as a promising treatment, its efficacy is often limited by the inadequate yield and rapid in vivo clearance. To address this challenge, this study developed a strategy centered on preconditioning human umbilical vein endothelial cells (HUVECs) with high glucose (HG) stress to produce HG-preconditioned extracellular vesicles (hEVs), which significantly improve production, enrich regenerative cargoes (e.g., HIF-1α, VEGF), and enhance homologous cellular internalization. The hEVs derived from HUVECs were encapsulated by microfluidically fabricated gelatin methacryloyl (GelMA) microgels to create GelMA@hEVs. The biodegradable and biocompatible GelMA microgels enabled a sustained hEVs release profile. Therefore, GelMA@hEVs exhibited significant efficacy improvement in promoting endothelial cell proliferation, migration, and tube formation critical for vascularization, mitigating reactive oxygen species, and modulating macrophage polarization toward a pro-reparative phenotype. Mechanistically, these therapeutic effects relied on activating the HIF-1α/VEGF pathway, a core axis for angiogenesis dysregulated in diabetes. In diabetic ischaemic flap models, GelMA@hEVs significantly improved flap survival, restored vascular perfusion, and facilitated tissue regeneration without systemic toxicity. Altogether, this work provides a generalizable strategy for diabetic ischaemic flap repair by combining engineered EVs as bioactive cargo with a microgel scaffold for sustained delivery, offering a promising in situ tissue engineering solution.
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高影响因子
ACS Applied Materials & Interfaces
·
2026
·
IF 7.8
Xin Zhang,Zutong Cui,Wenming Liang,Zihan Zhang,Jianming Sun,Liming Gao,Ming Shi,Zhiwei Liu,Kun Li,Jian Li
Phototherapy not only targets tumor cells for destruction but also triggers immunogenic cell death (ICD), thereby activating systemic immunity. Traditional photothermal therapy (PTT), however, damages adjacent normal tissues, and photodynamic therapy (PDT) creates severe hypoxia within tumor tissues, which promotes immune evasion and reduces the effectiveness of immunotherapy. In this study, we developed a biomimetic nanomodulators-cell membrane-coated gambogic acid/indocyanine green micelles loaded with HIF-1α siRNA (CM-IGM/siRNA) to achieve mild photothermal therapy (mPTT), enhance photodynamic therapy (PDT), and modulate the tumor microenvironment (TME). This platform utilizes gambogic acid (GA) to inhibit HSP90 expression and synergizes with HIF-1α siRNA to suppress HIF-1α expression, thereby ameliorating hypoxic and immunosuppressive TME. HSP90 inhibition further reduces tumor cell thermotolerance, enabling effective tumor cell ablation at mild hyperthermia temperatures (42−45 °C) characteristic of mPTT. Furthermore, we found that π–π stacking of GA with indocyanine green (ICG) enhances ICG photostability and boosts reactive oxygen species (ROS) generation. The elevated ROS production significantly improves PDT efficacy and, in combination with mPTT, potentiates the ICD of tumor cells. Overall, this strategy offers a significant advancement in cancer immunotherapy by improving the tumor microenvironment and enhancing immune activation.
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PubMed
高影响因子
Scientific Reports
·
2024
·Vol. 14
·期 1
·1-13
·
IF 3.8
Zhu Dongsheng,Chen Feng,Qiang Hongjia,Qi Han
To clarify the impact of SETD2 on macrophage function in pediatric patients with acute suppurative osteomyelitis and to elucidate the precise underlying mechanism. To gain insights into the potential functions of SETD2, a comprehensive study was conducted utilizing a co-culture model of human bone mesenchymal stem cells (hBMSCs) and bone marrow-derived macrophages (THP-1). A range of techniques were employed, including quantitative polymerase chain reaction, western blotting, ELISA, alkaline phosphatase activity assays, alizarin red S staining, luciferase reporter gene assays, and chromatin immunoprecipitation, to unravel the intricate interactions and molecular mechanisms involving SETD2 in this system. It was observed that SETD2 expression was reduced in THP-1 cells stimulated by staphylococcal protein A (SPA). Furthermore, the downregulation of SETD2 resulted in elevated M1 macrophage polarization and glycolysis, effects that were mitigated by SPA stimulation. Notably, SPA-stimulated THP-1 cells exhibited an increase in HIF-1α expression, which exhibited an inverse correlation with SETD2 levels. Moreover, it was discovered that SETD2 functioned as a catalyst for H3K36me3 and bound to the HIF-1α gene, which, in turn, regulated HIF-1α expression. Furthermore, the suppression of HIF-1α abrogated the consequences of SETD2 downregulation on glycolysis and M1 macrophage polarization. Lastly, the study demonstrated that M1 macrophage polarization serves as a mediator for BMP4’s inhibitory effect on osteogenic differentiation of hBMSCs. This research has uncovered a previously unknown role of SETD2 in macrophages during osteomyelitis, revealing its significance in the pathogenesis of this condition. These findings suggest SETD2 as a novel target for the treatment of osteomyelitis.
研究领域:
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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骨科
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DOI
PubMed
高影响因子
Food & Function
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2020
·Vol. 11
·期 7
·5815-5826
·
IF 4.171
Yi Zhao,Mu-Zi Li,Milton Talukder,Yu Luo,Yue Shen,Hao-Ran Wang,Jin-Long Li
Di(2-ethylhexyl) phthalate (DEHP) is a widespread environmental contaminant, which is mainly used as a plasticizer to improve the flexibility of products; however, its extensive use causes male reproductive damage. Lycopene (LYC) has a protective effect on male reproductive toxicity. Nevertheless, the underlying role of LYC in DEHP-induced spermatogenic cell damage remains unclear. Our study aimed to investigate the role of LYC in DEHP-induced spermatogenic cell damage and its underlying mechanism. Male ICR mice were treated with LYC (5 mg kg−1) and/or DEHP (500 mg kg−1 or 1000 mg kg−1) for 28 days. The results showed that LYC alleviated the DEHP-induced decrease in mitochondria volume density and mitochondrial membrane potential (ΔΨm). Subsequently, LYC prevented the DEHP-induced PGC-1α-mediated reduction in mitochondrial biogenesis in spermatogenic cells. LYC exhibited a potential preventive effect against DEHP-induced mitophagy caused by mitochondrial dynamics disorder in the spermatogenic cells. Meanwhile, LYC relieved DEHP-induced mitochondrial stress in the spermatogenic cells by activating UPRmt. These results proved that mitochondrial quality control may be related to the beneficial role of LYC in preventing DEHP-induced mitophagy in spermatogenic cells. This study provides new evidence of mitochondrial quality control as a target for LYC treatment, which can prevent DEHP-induced toxicity.
研究领域:
毒理学
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生殖生物学
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细胞生物学
·
环境健康
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PubMed
高影响因子
Molecular Medicine Reports
·
2019
·Vol. 19
·期 4
·2758-2766
·
IF 1.851
Ya Hou,Xiaobo Wang,Xiaorui Chen,Jing Zhang,Xiaopeng Ai,Yusheng Liang,Yangyang Yu,Yi Zhang,Xianli Meng,Tingting Kuang,Yao Hu
This study was conducted to establish a stable hypobaric hypoxia brain injury model. SD rats were randomly separated into control and model groups, and placed outside or inside of a hypobaric chamber, respectively. Subsequent to 24 h anoxic exposure, plasma superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), oxidized glutathione (GSSG) and lactate dehydrogenase (LDH) were measured using commercial biochemical kits. Hematoxylin‑eosin (H&E), Nissl's and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to observe the morphology of neurons in the hippocampus. The protein expression levels of apoptotic protease activating factor‑1 (Apaf‑1), hypoxia inducible factor‑1α (HIF‑1α), caspase‑3, cleaved caspase‑3, Bcl‑2‑associated X protein (Bax) and cytochrome c (cyto‑c) were detected using western blot and immunohistochemistry analyses. Hypoxic substantially induced morphological lesions in the hippocampus concomitant with the physical behavioral performance deficit. Furthermore, hypoxia markedly exacerbated the levels of MDA, LDH and GSSG, and restrained GSH (P<0.01) and SOD (P<0.05) levels compared with the control group. In addition, hypoxia significantly induced the protein expression of Apaf‑1, HIF‑1α, caspase‑3, cleaved caspase‑3, Bax and Cyto‑c (P<0.01) compared with the control group. Finally, a lower number and volume of Nissl bodies were verified in the hypoxic group. TUNEL results demonstrated a greater number of apoptotic cells in the hypoxic group. The present study demonstrates a model of rat hypoxic brain injuries induced by a hypobaric chamber at 9,000 m for 24 h. Furthermore, the redox enzyme, HIF‑1α and mitochondrial apoptosis‑associated protein, along with H&E and Nissl's staining, may be applied to evaluate the degree of injury.
研究领域:
神经科学
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药理学
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分子生物学
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PubMed
高影响因子
TOXICOLOGY LETTERS
·
2021
·
IF 4.374
Jiayi Gu,Ling Tong,Xin Lin,Yuming Chen,Hao Wu,Xueling Wang,Dehong Yu
The ototoxic mechanisms of cisplatin on the organ of Corti and spiral ganglion neurons have been extensively studied, while few studies have been focused on the stria vascularis (SV). Herein, we verified the functional and morphological impairment in SV induced by a single injection of cisplatin (12 mg/kg, I.P.), represented by a reduction in Endocochlear Potentials (EP) and strial atrophy, and explored underlying mechanisms. Our results revealed increased extravasation of chromatic tracers (Evans blue dye and FITC-dextran) around microvessels after cisplatin exposure. The increased vascular permeability could be attributed to changes of pericytes (PCs) and perivascular-resident macrophage-like melanocytes (PVM/Ms) in number or morphology, as well as the enhanced level of HIF-1α and downstream VEGF. This capillary leakage led to a high accumulation of cisplatin in the perivascular space in SV, and disrupted the integrity of blood-labyrinth barrier (BLB). Also, tight junction (ZO-1) loosening and Na + , K + -ATPase damage was considered to be other critical contributors of BLB breakdown, which resulted in EP drop and consequent hearing loss. This study explored the role of stria vascularis in cisplatin-induced ototoxicity in terms of BLB hyperpermeability and pointed to a novel therapeutic target for the prevention of cisplatin-related hearing loss.
研究领域:
耳鼻喉科学
·
药理学
·
毒理学
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PubMed
高影响因子
International Journal of Bioprinting
·
2023
·
IF 8.4
Jianpeng Gao,Hufei Wang,Ming Li,Zhongyang Liu,Junyao Cheng,Xiao Liu,Jianheng Liu,Xing Wang,Licheng Zhang
Intramembranous ossification (IMO) and endochondral ossification (ECO) are two pathways of bone regeneration. The regeneration of most bone, such as limb bone, trunk bone, and skull base bone, mainly occurs in the form of endochondral ossification, which has also become one of the effective ways for bone tissue engineering. In this work, we prepared a well-structured and biocompatible methacrylated gelatin/polymethacrylic acid (GelMA/PMAA) hydrogel by digital light processing (DLP) printing technology, which could effectively chelate iron ions and continuously activate the hypoxia-inducible factor-1 alpha (HIF-1α) signaling pathway to promote the process of endochondral ossification and angiogenesis. The incorporation of PMAA endowed the hydrogel with remarkable viscoelasticity and high efficacy in chelation of iron ions, giving rise to the activation of HIF-1α signaling pathway, improving chondrogenic differentiation in the early stage, and facilitating vascularization in the later stage and bone remodeling. Therefore, the findings have significant implications on DLP printing technology of endochondral osteogenesis induced by the iron-chelating property of biological scaffold, which will provide an effective way in the development of novel bone regeneration.
研究领域:
组织工程
·
生物材料
·
再生医学
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PubMed
高影响因子
Theranostics
·
2023
·
IF 12.4
Lianxia Guo,Haobin Cen,Jiaxian Weng,Yiting He,Xiaocao Guo,Di He,Kaisheng Liu,Shuyi Duan,Jing Yang,Xiaojian Zhang,Zifei Qin,Yong Wan,Zhiyong Chen,Baojian Wu
Rationale: The role of circadian clock in pituitary tumorigenesis remains elusive. Here we investigate whether and how circadian clock modulates the development of pituitary adenomas. Methods and Results: We found altered expression of pituitary clock genes in patients with pituitary adenomas. In particular, PER2 is prominently upregulated. Further, jetlagged mice with PER2 upregulation have accelerated growth of GH3 xenograft tumor. Conversely, loss of Per2 protects mice against developing estrogen-induced pituitary adenoma. Similar antitumor effect is observed for SR8278, a chemical that can decrease pituitary PER2 expression. RNA-seq analysis suggests involvement of cell cycle disturbance in PER2 regulation of pituitary adenoma. Subsequent in vivo and cell-based experiments validate that PER2 induces pituitary expression of Ccnb2 , Cdc20 and Espl1 (three cell cycle genes) to facilitate cell cycle progression and inhibit apoptosis, thereby promoting pituitary tumorigenesis. Mechanistically, PER2 regulates the transcription of Ccnb2 , Cdc20 and Espl1 through enhancing the transcriptional activity of HIF-1α. HIF-1α trans-activates Ccnb2 , Cdc20 and Espl1 via direct binding to its specific response element in the gene promoters. Conclusion: PER2 integrates circadian disruption and pituitary tumorigenesis. These findings advance our understanding of crosstalk between circadian clock and pituitary adenomas and highlight the relevance of clock-based approaches in disease management.
研究领域:
肿瘤学
·
内分泌学
·
分子生物学
·
昼夜节律
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高影响因子
TROPICAL JOURNAL OF PHARMACEUTICAL RESEARCH
·
2022
·Vol. 21
·期 10
·2139-2146
·
IF 0.523
Limei Du,Xinglan Huo,Ying Liu
Purpose: To study the influence of resveratrol on chronic obstruction in Aspergillus fumigatus infection-induced chronic lung disease (COPD) in rats, and the process involved.
Methods: Seventy-five Sprague Dawley SD) rats were assigned to blank control, COPD model, Aspergillus fumigatus-infected COPD model, low (100 mg/kg) and high-dose (200 mg/kg) resveratrol groups, with 15 rats in each group. Enzyme-linked immunosorbent assay (ELISA) was used to assay IL-6, IL-8 and TNF-α in bronchoalveolar lavage fluid (BALF), while lung protein concentrations of AMPK and PGC-1α were assayed by immunoblotting.
Results: In low- and high-dose resveratrol groups, inflammatory factor levels were significantly lower than the corresponding levels in COPD model and Aspergillus fumigatus-infected COPD model (p < 0.05), while lung tissue proteins of AMPK, PGC-1α, and AQP5 of the rats given high-dose resveratrol were significantly raised, relative to corresponding levels in rats given low-dose resveratrol (p < 0.05).
Conclusion: Resveratrol modulates expression levels of secretory factors and surface markers in alveolar macrophages in COPD model rats infected with Aspergillus fumigatus. Resveratrol exerts this effect through the regulation of AMPK/PGC-1α signaling pathway.
研究领域:
药理学
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免疫学
·
呼吸医学
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DOI
高影响因子
Frontiers in Pharmacology
·
2023
·
IF 5.6
Chen Zhenzhen,Liu Zhihong,Zhang Qian,Huang Sheng,Zhang Zaizhong,Feng Xianquan,Zeng Lingjun,Lin Ding,Wang Lie,Song Hongtao
Drug resistance is a huge hurdle in tumor therapy. Tumor hypoxia contributes to chemotherapy resistance by inducing the hypoxia-inducible factor-1α (HIF-1α) pathway. To reduce tumor hypoxia, novel approaches have been devised, providing significant importance to reverse therapeutic resistance and improve the effectiveness of antitumor therapies. Herein, the nanosystem of bovine serum albumin (BSA)-templated manganese dioxide (MnO2) nanoparticles (BSA/MnO2 NPs) loaded with doxorubicin (DOX) (DOX-BSA/MnO2 NPs) developed in our previous report was further explored for their physicochemical properties and capacity to reverse DOX resistance because of their excellent photothermal and tumor microenvironment (TME) response effects. The DOX-BSA/MnO2 NPs showed good biocompatibility and hemocompatibility. Meanwhile, DOX-BSA/MnO2 NPs could greatly affect DOX pharmacokinetic properties, with prolonged circulation time and reduced cardiotoxicity, besides enhancing accumulation at tumor sites. DOX-BSA/MnO2 NPs can interact with H2O2 and H+ in TME to form oxygen and exhibit excellent photothermal effect to further alleviate hypoxia due to MnO2, reversing DOX resistance by down-regulating HIF-1α expression and significantly improving the antitumor efficiency in DOX-resistant human breast carcinoma cell line (MCF-7/ADR) tumor model. The hypoxia-ameliorated photothermal MnO2 platform is a promising strategy for revering DOX resistance.
研究领域:
癌症治疗
·
纳米技术
·
药理学
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DOI
PubMed
高影响因子
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