JOURNAL OF NANOBIOTECHNOLOGY
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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
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2026
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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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高影响因子
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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高影响因子
Theranostics
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2018
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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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高影响因子
BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2019
·Vol. 42
·期 6
·886-891
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IF 1.54
Yangbiao He,Xujun Lang,Dong Cheng,Zhihao Yang
Previous studies implicated the mammalian target of rapamycin (mTOR)/hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway in renal fibrosis and found that curcumin could suppress the expression of mTOR. Therefore, the aim of the present study was to investigate the therapeutic effects of curcumin against chronic renal failure (CRF) in a rat model induced by 5/6 nephrectomy through inhibition of mTOR/HIF-1α/VEGF signaling. A total of 70 male Sprague–Dawley rats were divided into seven groups: a sham group, a CRF group, and five treatment groups. Except for the sham rats, all rats underwent 5/6 nephrectomy to induce CRF. The 5/6 nephrectomized rats received treatment with curcumin vehicle, everolimus vehicle, curcumin, everolimus, or the combination of curcumin and everolimus. Everolimus, a specific inhibitor of mTOR, was used as a positive control. At the end of treatment, blood biochemical indexes, proteinuria and the kidney index were detected. Moreover, histological change was examined by hematoxylin and eosin staining, and protein expression levels were detected by Western blotting. The blood biochemical indexes, proteinuria, and kidney index were increased in the CRF group as compared to the sham group, which was accompanied by marked activation of the mTOR/HIF-1α/VEGF pathway. However, curcumin, as well as everolimus, restored or ameliorated these changes. These results indicate that activation of the mTOR/HIF-1α/VEGF signaling pathway plays an important role in the occurrence and development of CRF, and that curcumin has renoprotective effects by blocking activation of this pathway.
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PHYTOMEDICINE
·
2026
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IF 11.3
Minghui Zhao,Hongfang Mu,Qian Ji,Jiale Song,Fuyixuan Zheng,Tianlong Liu,Wenbin Li,Rong Wang
Background The effects of persistent hypoxic conditions in high-altitude regions on metabolic disorders remain poorly understood and in-depth investigation into its underlying molecular mechanisms is notably insufficient. As a metabolism-associated liver disease, the pathogenesis of non-alcoholic fatty liver disease (NAFLD) under hypoxic conditions urgently requires clarification. Previous studies have demonstrated that resveratrol (Rsv) possesses significant anti-inflammatory, antioxidant, and lipid metabolism-modulating properties, and it can act as an inhibitor of ferroptosis. Yet its precise therapeutic efficacy and mechanism in hypoxic NAFLD remain to be further explored. Objective This study aims to explore the potential mechanism by which Rsv improves the deterioration of NAFLD under hypoxia exposure. Methods Herein, we performed concurrent interventions in both in vivo and in vitro models of NAFLD, comprehensively detecting biochemical indicators (inflammatory factors, oxidative stress markers, liver function), liver histopathological changes, and nucleic acid levels to assess the effects of Rsv. By introducing ferroptosis modulators, we measured core ferroptosis parameters (mitochondrial ultrastructure, Fe²⁺, 4-HNE, LPO levels, and key protein expressions) to define disease progression patterns. By HIF-1α silencing was employed to verify its regulatory roles in ferroptosis-related factors and NAFLD pathogenesis. Co-Immunoprecipitation assays and immunofluorescence co-localization were used to explore protein interactions among ACSL4, TfR1, and HIF-1α. Conclusion Our results demonstrated that high-altitude hypoxia exacerbates NAFLD via inducing ferroptosis; HIF-1α upregulates the expression of key ferroptosis mediators (ACSL4, TfR1), and HIF-1α silencing attenuates ferroptosis. Rsv exerts therapeutic effects against hypoxia-related NAFLD by targeting the HIF-1α-mediated ferroptosis pathway. This study elucidates the pivotal role of HIF-1α-dependent ferroptosis in hypoxia-aggravated NAFLD, identifies the therapeutic targets and mechanisms of Rsv, and provides novel theoretical foundations and potential intervention strategies for clinical management of hypoxia-related NAFLD in high-altitude areas.
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International Journal of Nanomedicine
·
2025
·
IF 6.5
Dian-Chao Cao,Yan Liang,Yang Guo,Dong-Yang Wu,Na-Na Wang,Yan-Mei Li,Hong-Fang Sun,Qin Wang,Xia Zhang,Yong-Liang Chi,Pei-Pei Sun,You-Jie Li,Ran-Ran Wang,Ping-Yu Wang,Shu-Yang Xie,Ning Xie
Purpose This study aims to develop an innovative delivery system, (Q+M/MnOx)@Clip, to enhance the bioavailability and therapeutic efficacy of quercetin both in tumor treatment and pain alleviation.Methods The (Q+M/MnOx)@Clip system was evaluated to enhance the release of quercetin, investigate its ability to target cancer cells, alleviate tumor hypoxia, and improve the efficacy of chemodynamic therapy (CDT). Tumor hypoxia markers and immune response activation were assessed, along with the impact on pain relief biomarkers.Results (Q+M/MnOx)@Clip successfully mitigated tumor hypoxia, facilitated controlled Q release, and enhanced CDT in vitro and in vivo. The system demonstrated a dual therapeutic effect: anti-tumor immunity and significant cancer pain relief by reducing HIF-1α and VEGF-A levels.Conclusion The novel (Q+M/MnOx)@Clip system represents a promising advancement in nanomedicine, improving the bioavailability of quercetin and offering a more effective approach to cancer treatment by downregulation of HIF-1α and VEGF-A. This study demonstrates the potential for combining anti-tumor immunity with pain relief for triple-negative breast cancer therapy.
研究领域:
肿瘤学
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药理学
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纳米医学
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
·
IF 15
Lv Nanning,Dong He,Sun Haifu,Shi Jing,Wu Xinhui,Chen Xiaofan,Li Hongye,Feng Xiaoxiao,Guo Xuran,Dong Xieping,Hu Ying,Zheng Longpo,Liu Mingming
Diabetic bone defects are difficult to repair because chronic hyperglycemia disrupts local immunometabolic and vascular homeostasis, leading to persistent inflammation, poor angiogenesis, and impaired osteogenesis. Here we report a piezoelectrically driven hierarchical biomimetic architecture that promotes diabetic bone defect repair through spatially bidirectional regulation of HIF-1α. The system comprises an ultrasound-responsive PLLA/ZnO/DFO biomimetic periosteum and a conductive GelMA/MXene/Ce-MOF@Arg defect-filling hydrogel. Under ultrasound stimulation, the upper layer generates piezoelectric microcurrents and releases deferoxamine, which is associated with activation of endothelial HIF-1α/VEGF signaling and angiogenic responses, whereas the lower layer relays electrical cues into the defect core and is associated with reduced macrophage HIF-1α expression and glycolytic activity in parallel with arginine delivery and Ce-MOF nanozyme-mediated redox regulation. This design promotes recovery toward a more favorable immunometabolic-vascular state by coupling superficial pro-angiogenic activation with deep anti-inflammatory metabolic remodeling. The scaffold shows favorable piezoelectric, conductive, mechanical, degradation, and release properties, promotes endothelial migration, drives macrophage polarization toward a reparative phenotype, enhances osteogenic-angiogenic coupling, and substantially accelerates critical-sized calvarial defect healing in diabetic rats. Our findings provide an electroactive and spatially coordinated strategy for diabetic bone regeneration.
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Biomaterials Science
·
2021
·Vol. 9
·期 19
·6403-6415
·
IF 6.843
Li-Jun Zhang,Rui Huang,Yi-Wen Shen,Jie Liu,Ye Wu,Jin-Mei Jin,Hong Zhang,Yun Sun,Hong-Zhuan Chen,Xin Luan
Tumor hypoxic stress after photodynamic therapy (PDT) will be inevitably exacerbated by the vascular blocking effects and oxygen consumption in the tumor microenvironment (TME) which usually leads to compromised efficacy and clinical performance. Increasing evidence links the hypoxia induced up-regulation of hypoxia inducible factor 1α (HIF-1α) with immunosuppressive TME, including the polarization of M2 phenotype tumor associated macrophages (TAMs), which promote the recurrence and metastasis. Here, we reported NIR-triggered core-satellite upconverting nanoparticles (CSNPs) with curcumin (Cur) embedded as a difunctional photosensitizer, which could realize PDT in deep tumors with long excitation wavelength (980 nm) and reverse the immunosuppressive TME induced by up-regulated HIF-1α at the same time. This Cur-loaded CSNPs (Cur–CSNPs)-mediated PDT could successfully induce the immunogenic cell death (ICD) of triple negative breast cancer (TNBC) cell lines (4T1 and MDA-MB-231) in vitro and repolarize the 4T1 cells co-cultured TAMs from pro-tumor M2 to the anti-tumor M1 phenotype. Furthermore, Cur–CSNPs-mediated PDT could suppress the 4T1 tumor growth in primary and distant sites through the synergistic immunotherapeutic effects in vivo by priming M1 type TAMs and CD4+/CD8+ T cells’ infiltration. Our data highlight the novel application of CSNPs-embedded Cur as a difunctional photosensitizer to enhance the anti-tumor efficacy of PDT.
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Cell Death & Disease
·
2024
·Vol. 15
·期 10
·1-15
·
IF 8.1
Chen Zi-Xiong,Mu Mao-Yuan,Yang Guang,Qi Han,Fu Xiao-Bo,Wang Gui-Song,Jiang Wei-Wei,Huang Bi-Jun,Gao Fei
Denticleless E3 ubiquitin protein ligase homolog (DTL), the substrate receptor of the CRL4A complex, plays a central role in genome stability. Even though the oncogenic function of DTL has been investigated in several cancers, its specific role in hepatocellular carcinoma (HCC) still needs further elucidation. Data from a clinical cohort ( n = 209), RNA-sequencing, and public database (TCGA and GEO) were analyzed, indicating that DTL is closely related to patient prognosis and could serve as a promising prognostic indicator in HCC. Functionally, DTL promoted the proliferation, metastasis, and sorafenib resistance of HCC in vitro. In the orthotopic tumor transplantation and tail vein injection model, DTL promoted the growth and metastasis of HCC in vivo. Mechanically, we revealed for the first time that DTL was transcriptionally activated by hypoxia-inducible factor 1α (HIF-1α) under hypoxia and functioned as a downstream effector molecule of HIF-1α. DTL promotes the ubiquitination of SAFB-like transcription modulator (SLTM) and subsequently relieves the transcriptional repression of Notch1. These results suggested that DTL may be a potential biomarker and therapeutic target for HCC.
研究领域:
肿瘤学
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分子生物学
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癌症遗传学
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JOURNAL OF MOLECULAR MEDICINE-JMM
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2024
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IF 4.8
Su Qi,Chen Kun,Ren Jiayan,Zhang Yu,Han Xu,Leong Sze Wei,Wang Jingjing,Wu Qing,Tu Kaihui,Sarwar Ammar,Zhang Yanmin
Abstract Non-small cell lung cancer (NSCLC) is a highly malignant tumor with a poor prognosis. Hypoxia conditions affect multiple cellular processes promoting the adaptation and progression of cancer cells via the activation of hypoxia-inducible factors (HIF) and subsequent transcription activation of their target genes. Preliminary studies have suggested that estrogen receptor β (ERβ) might play a promoting role in the progression of NSCLC. However, the precise mechanisms, particularly its connection to HIF-1α-mediated modulation under hypoxia, remain unclear. Our findings demonstrated that the overexpression of ERβ, not ERα, increased cell proliferation and inhibition of apoptosis in NSCLC cells and xenografts. Tissue microarray staining revealed a strong correlation between the protein expression of HIF-1α and ERβ. HIF-1α induced ERβ gene transcription and protein expression in CoCl 2 -induced hypoxia, 1% O 2 incubation, or HIF-1α overexpressing cells. ChIP identified HIF-1α binding to a hypoxia response element in the ESR2 promoter. The suppression of HIF-1α and ERβ both in vitro and in vivo effectively reduced the tumor growth, thus emphasizing the promising prospects of targeting HIF-1α and ERβ as a therapeutic approach for the treatment of NSCLC. Key messages
ERβ, not ERα, increases cell proliferation and inhibition of apoptosis in NSCLC cells and xenografts.
A strong correlation exists between the protein expression of HIF-1α and ERβ.
HIF-1α induced ERβ gene transcription and protein expression in hypoxic cells via binding to HRE in the ESR2 promoter.
The suppression of HIF-1α and ERβ both in vitro and in vivo effectively reduced the NSCLC tumor growth.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
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IF 4.7
Sen Chen,Hui Lin,Haodi Gu,Xinrou Yu,Junjie Xiang,Lili Xu,Gang Ye,Yue Shan,Yun Wang
Introduction Sepsis-induced cardiomyopathy (SIC) is a rapidly advancing condition associated with a poor prognosis due to the lack of effective treatments. Neutrophil extracellular traps (NETs), however, act as a double-edged sword in the innate immune response during sepsis. N-formyl methionine (fMet) has been documented to induce NETs in inflammatory conditions, yet its clinical significance and biological function in SIC remain unclear. In this study, we investigated whether fMet induces excessive NETs, thereby promoting SIC. Methods and results Clinically, serum fMet levels were quantified using ELISA, revealing a significant elevation in patients with SIC compared to non-sepsis patients and healthy controls. The fMet levels were positively correlated with the NETs-related markers myeloperoxidase (MPO) and double-stranded DNA (dsDNA) in patients with SIC. Treatment with lipopolysaccharide and fMet increased NET formation in human neutrophils and upregulated the expression of formyl peptide receptor 1 (FPR1) and hypoxia-inducible factor 1-alpha (HIF-1α). Furthermore, bone marrow-derived neutrophils (BMDNs) were isolated from global FPR1 knockout mice, and FPR1 deficiency in BMDNs was found to suppress NETosis. The cecal ligation and puncture (CLP) model was employed to induce SIC in mice and we found knockout of FPR1 improved outcomes in CLP mice, as evidenced by survival benefit, increased cardiac function, attenuated cytokine storm, reduced neutrophil infiltration, improved mitochondrial function and suppressed NETosis, compared with those of wild-type (WT) mice. In addition, treatment with FPR1 inhibitor HCH6–1 improved cardiac outcome and inhibits NETosis in CLP mice. Conclusion These data reveal the role of fMet-mediated FPR1/HIF-1α activation in promoting SIC through the NETosis, indicating novel therapeutic strategy for SIC.
研究领域:
免疫学
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心血管病学
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分子生物学
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重症医学
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炎症与感染
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信号转导
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转化医学
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高影响因子
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