JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Wang Xuewei,Zhang Yue,Wu Hao,Yang Zelei,Ma Sufang,Li Lihong,Guo Lixia,Yan Lili,Zhang Boye,Liu Jianfei,Diao Haipeng,Ren Guodong,Zhang Chengwu,Liu Wen
Esophageal cancer (EC) is a highly malignant tumor that poses a significant threat to patient survival. Chemotherapy, a mainstay treatment for EC, often yields unsatisfactory outcomes due to chemotherapy resistance, the low efficacy of monotherapy and off-target toxicity. Therefore, it is imperative to develop one novel therapeutic strategy capable of overcoming drug resistance, enabling tumor microenvironment-responsive drug release, and achieving multimodal synergistic therapy. Currently, treatment of chemotherapy-resistant EC (CREC) faces great challenges. To address this, a pH-responsive nanoplatform, CDs-DOX-GOX@PEG (CDG@PEG), composed of iron-doped carbon dots (Fe-CDs), doxorubicin (DOX), glucose oxidase (GOX), and polyethylene glycol (PEG), was fabricated to improve CREC treatment through synergistic and targeted therapy. The physicochemical properties of CDG@PEG were characterized using TEM, XPS, XRD, FTIR and other techniques. Its anti-tumor efficacy was assessed with DOX-resistant KYSE-30 cells and corresponding xenograft mouse models. Moreover, the underlying therapeutic mechanism was further investigated via transcriptomic, immunofluorescence and immunohistochemical analyses. Physicochemical characterization results showed that the designed nanoplatform was successfully fabricated, which was endowed with outstanding pH-responsive behavior and O₂/ROS-generation capabilities. In vitro, CDG@PEG demonstrated excellent cellular uptake and potent tumor cell-killing capacities. In vivo, it displayed superior anti-tumor efficacy with good biocompatibility. Mechanistically, CDG@PEG realized the CREC therapy by down-regulating drug-resistant genes (such as HIF-1α related genes), inducing mitochondrial dysfunction, and triggering cell apoptosis. This work opened new avenues for developing novel therapeutic strategies against chemotherapy-resistant cancers. Graphical The alternative text for this image may have been generated using AI.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
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IF 5.7
Jia Liu,Yangxian Chen,Mengyu Li,Guobao Chen,Junhui Yang,Ying Jiang,Xiao Zhang,Fang Li,Haibing Hua
Chronic atrophic gastritis (CAG) is a critical precancerous condition with limited therapeutic options to halt its progression toward gastric cancer. Targeting dysregulated metabolism and inflammation-driven transformation represents a promising yet underexplored strategy. Herein, through systematic screening of Jianwei Xiaoyan Granule (JWXYG)-derived compounds via molecular docking and surface plasmon resonance (SPR), we identified hederagenin as a potent and novel mechanistic target of rapamycin (mTOR) binder (Kd = 1.30 μM). In a rat CAG model, hederagenin administration resulted in marked histological and biochemical improvements. Histopathological evaluation revealed that hederagenin effectively restored gastric mucosal architecture, significantly attenuated characteristic glandular atrophy, and reduced the extent of intestinal metaplasia, a key precancerous lesion. Concurrently, serum analysis demonstrated that hederagenin treatment normalized critical biomarker levels, including a significant reduction in gastrin-17 (G-17) and the pro-inflammatory cytokine interleukin-6 (IL-6), alongside a notable increase in the levels of pepsinogen I (PG I) and pepsinogen II (PG II). Functionally, hederagenin exhibited potent anti-tumor properties in vitro by significantly suppressing the proliferation, migration, and invasion capabilities of premalignant gastric epithelial cells. Mechanistically, transcriptomic analyses revealed that hederagenin targeted cancer-associated metabolic reprogramming through the mTOR/hypoxia-inducible factor-1α (mTOR/HIF-1α) signaling axis. Experimental validation further confirmed that hederagenin significantly suppressed the mTOR/HIF-1α pathway. Additionally, it downregulated the expression of key rate-limiting glycolytic enzymes, including hexokinase II (HK II), pyruvate kinase M2 (PKM2), enolase 1 (ENO1), and lactate dehydrogenase A (LDHA), thereby attenuating glycolytic flux, a hallmark metabolic adaptation in precancerous lesions. Importantly, mTOR knockdown abolished hederagenin-mediated LDHA suppression and compromised its therapeutic efficacy, validating mTOR as an essential target. Our findings demonstrated that hederagenin could inhibit inflammation-cancer transformation in CAG via regulation of glycolysis through the mTOR/HIF-1α pathway, which provided new candidate compounds for regulating the transformation of CAG into cancer.
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PHYTOMEDICINE
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2026
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IF 11.3
Jing Chen,Gejing Li,Fang Zhao,Ye Zhang,Qingrui Mu,Junlan Zhang,Xiong Cai,Yuanyuan Tang
Background Cannabidiol (CBD), a major non-psychoactive phytocannabinoid derived from Cannabis sativa L., has shown therapeutic potential in rheumatoid arthritis (RA). However, the mechanisms by which CBD modulates synovial angiogenesis remain unclear. Purpose This study aimed to investigate whether CBD attenuates RA progression by suppressing synovial angiogenesis and to elucidate the underlying molecular mechanisms. Methods An adjuvant-induced arthritis (AIA) rat model was established to evaluate the therapeutic effects of CBD in vivo using arthritis scoring, micro-CT, and histopathological, immunohistochemical, and immunofluorescence analyses. In vitro , cytotoxicity was determined using the CCK-8 assay, followed by evaluations of CBD’s direct effects on the proliferation, migration, invasion, and inflammatory responses of RA fibroblast-like synoviocytes (RA-FLS) were evaluated, alongside Cell Counting Kit-8 (CCK-8) for cytotoxicity screening. Furthermore, the paracrine regulation of angiogenesis was assessed using a conditioned medium (CM) transfer system from hypoxia-stimulated RA-FLS applied to human umbilical vein endothelial cells (HUVECs). Molecular mechanisms were analyzed via Western blotting, RT-qPCR, ELISA, co-immunoprecipitation (Co-IP), molecular docking, and targeted proteasome inhibition (MG132). Results In vivo , CBD (5 and 10 mg/kg) treatment markedly alleviated joint inflammation, synovial angiogenesis, and structural bone destruction in AIA rats. In vitro , non-cytotoxic concentrations of CBD (2.4-4.8 μM) significantly suppressed aberrant RA-FLS proliferation, migration, invasion, and pro-inflammatory cytokine secretion. Mechanistically, CBD abrogated the hypoxia-induced accumulation of hypoxia-inducible factor-1α (HIF-1α) protein in RA-FLS without significantly altering HIF1A mRNA expression. This reduction was effectively reversed by MG132. Co-IP and molecular docking analyses revealed that CBD directly enhances the polyubiquitination of HIF-1α through stable structural interactions, driving a ubiquitin-proteasome-dependent degradation mechanism. Consequently, CBD dose-dependently decreased the extracellular secretion of vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANG-2) from RA-FLS. Functionally, CM from CBD-treated RA-FLS disrupted the pro-angiogenic paracrine crosstalk—independent of direct CBD carryover—significantly impairing HUVEC migration, capillary-like tube formation, and downstream VEGFR2 (Tyr1175) phosphorylation. Conclusion CBD attenuates RA pathogenesis not only by directly suppressing RA-FLS hyperactivity but also by severing the pro-angiogenic paracrine crosstalk between RA-FLS and endothelial cells. These effects are driven by the ubiquitin-proteasome-dependent degradation of HIF-1α in RA-FLS via direct structural engagement, which depletes VEGFA/ANG-2 production and subsequent endothelial VEGFR2 activation. These findings highlight CBD as a promising disease-modifying anti-angiogenic therapeutic agent for RA. Download: Download high-res image (290KB) Download: Download full-size image
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PHYTOMEDICINE
·
2026
·
IF 11.3
Juan Zhan,JianHan Zhou,RunQiang Liu,ChaoChen Wu,YiHan Lai,Lin Jiang,Wei Wang,Meng Cheng,YiSen Shao
Objective : Tongue squamous cell carcinoma (TSCC) is characterized by high invasiveness and early lymph node metastasis, leading to a poor prognosis.Current surgical and chemoradiotherapy regimens often cause functional impairment, drug resistance, and other drawbacks. Thus, developing highly effective, low-toxicity treatments is a key research priority. Traditional Chinese medicine (TCM) offers unique advantages via multi-target synergistic effects, enabling innovative therapeutic approaches. Method : In this study, we developed Astragaloside IV-Brucea javanica oil nanoemulsion (AS/BJO-NEs) and characterized its stability, polydispersity, and pharmacokinetic profile. The effects of AS/BJO-NEs on TSCC cells were evaluated through a series of functional assays, including CCK-8 (viability), colony formation (proliferation), and scratch wound healing (migration). Both in vitro and in vivo experiments were performed to investigate whether its mechanism involves regulation of the MTFR2–HIF-1α–EZH2/FoxM1 signaling axis. Results The optimized AS/BJO-NEs exhibited uniform spherical morphology at the nanoscale and demonstrated favorable stability. In both in vitro and in vivo models, AS/BJO-NEs significantly suppressed the malignant phenotype of TSCC cells. Mechanistic investigation further revealed that the anti-tumor effects of AS/BJO-NEs are mediated, at least in part, through targeting the MTFR2–HIF-1α–EZH2/FoxM1 signaling axis, as confirmed by establishing stable MTFR2/HIF-1α knockdown and overexpression cell models. Conclusion : This study demonstrates that AS/BJO-NEs inhibit TSCC progression by targeting the MTFR2–HIF-1α–EZH2/FoxM1 signaling axis. Our findings provide experimental evidence supporting the development of multi-target therapeutic strategies derived from traditional Chinese medicine for the treatment of TSCC.
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MATERIALS & DESIGN
·
2026
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IF 8.2
Hongbao Hou,Xu Li
Introduction Esophageal cancer (EC) is the most malignant tumor posing great threat to human health. Chemotherapy, as the first-line treatment for EC, can not yield expected outcome due to chemo-resistance, low efficacy of monotherapy and off-target toxicity. Hence, it is imperative to develop one novel therapeutic strategy that can realize anti-drug resistance, tumor microenvironment response drug release, and integrated multi-modal therapy. Objectives Currently, treatment of EC faces great challenges. One pH-responsive nanoplatform, CDs-DOX-GOx@PEG (CDG@PEG), composed of copper-doped carbon dots (Cu-CDs), doxorubicin (DOX), glucose oxidase (GOx), and polyethylene glycol (PEG), was fabricated to realize better treatment of EC via multi-modal synergistic and targeted therapy. Methods Microscopy. The physicochemical properties of CDG@PEG were determined via TEM, XPS, XRD, FTIR and so on. The anti-tumor capacity was assessed with KYSE-30 cells and xenograft mice models. Moreover, the therapeutic mechanism was assessed by transcriptome, immunofluorescence and immunohistochemical analysis. Results Physiochemical characterization results showed that as designed nanoplatform was successfully fabricated and was endowed with outstanding pH-responsive and O 2 /ROS-generation capacities. In vitro , CDG@PEG exhibited excellent cell uptake and potent tumor cell-killing effect. In vivo, CDG@PEG displayed superior anti-tumor effect accompanied by good biocompatibility. Mechanistically, CDG@PEG realized the EC therapy by down-regulating drug-resistant genes (such as HIF-1α related genes), inducing mitochondria dysfunction, triggering cell apoptosis. Conclusion One multifunctional nanoplatform, CDG@PEG, was successfully prepared and it exhibited excellent in vitro and in vivo anti-tumor effect, which open new venues for developing novel therapeutic strategies for chemo-resistance cancer.
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Biosensors-Basel
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2026
·Vol. 16
·期 5
·261
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IF 6.2
Ziyi Li,Yingxin Tian,Gefei Ren,Yingshu Guo
The overexpression of hypoxia-inducible factor-1α (HIF-1α) suppresses STING signaling and modulates lipid metabolism in tumor cells, leading to abnormal lipid droplet (LD) accumulation. Herein, we constructed a manganese dioxide (MnO2)-based nanomotor (HMIP@A). HMIP@A depletes intracellular hydrogen peroxide (H2O2) and glutathione (GSH) to generate oxygen (O2), reactive oxygen species (ROS), and manganese (Mn2+). A dual strategy of “oxygen supplementation” and “small-molecule inhibition” synergistically downregulates HIF-1α, thereby suppressing LD biogenesis. This process sensitizes tumor cells to ROS, leading to severe DNA damage. Released Mn2+and damaged DNA synergistically activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. In vitro, HMIP@A markedly increases ROS production, lipid peroxidation (LPO), and DNA damage, thereby inducing tumor cell death, immunogenic cell death (ICD), and dendritic cell (DC) maturation. Furthermore, HMIP@A exhibits excellent penetration in tumor spheroids. Overall, this study provides a theoretical basis for the design of nanomedicines through a strategy integrating metabolic intervention, oxidative damage sensitization, and immune activation.
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PHYTOMEDICINE
·
2023
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IF 7.9
Chao Ma,Chunran Zhu,Yajun Zhang,Mei Yu,Yizhi Song,Yulong Chong,Yan Yang,Chan Zhu,Yucui Jiang,Changming Wang,Shuo Cheng,Keke Jia,Guang Yu,Jia Li,Zongxiang Tang
Background Increasing evidence highlights the involvement of metabolic disorder and calcium influx mediated by transient receptor potential channels in migraine; however, the relationship between these factors in the pathophysiology of migraine remains unknown. Gastrodin is the major component of the traditional Chinese medicine Tianma, which is extensively used in migraine therapy. Purpose Our work aimed to explore the analgesic action of gastrodin and its regulatory mechanisms from a metabolic perspective. Methods/results After being treated with gastrodin, the mice were given nitroglycerin (NTG) to induce migraine. Gastrodin treatment significantly raised the threshold of sensitivity in response to both mechanical and thermal stimulus evidenced by von Frey and hot plate tests, respectively, and decreased total contact numbers in orofacial operant behavioral assessment. We found that the expression of transient receptor potential melastatin 2 (TRPM2) channel was increased in the trigeminal ganglion (TG) of NTG-induced mice, resulting in a sustained Ca 2+ influx to trigger migraine pain. The content of succinate, a metabolic biomarker, was elevated in blood samples of migraineurs, as well as in the serum and TG tissue from NTG-induced migraine mice. Calcium imaging assay indicated that succinate insult elevated TRPM2-mediated calcium flux signal in TG neurons. Mechanistically, accumulated succinate upregulated hypoxia inducible factor-1α (HIF-1α) expression and promoted its translocation into nucleus, where HIF-1α enhanced TRPM2 expression through transcriptional induction in TG neurons, evidenced by luciferase reporter measurement. Gastrodin treatment inhibited TRPM2 expression and TRPM2-dependent Ca 2+ influx by attenuating succinate accumulation and downstream HIF-1α signaling, and thereby exhibited analgesic effect. Conclusion This work revealed that succinate was a critical metabolic signaling molecule and the key mediator of migraine pain through triggering TRPM2-mediated calcium overload. Gastrodin alleviated NTG-induced migraine-like pain via inhibiting succinate/HIF-1α/TRPM2 signaling pathway in TG neurons. These findings uncovered the anti-migraine effect of gastrodin and its regulatory mechanisms from a metabolic perspective and provided a novel theoretical basis for the analgesic action of gastrodin.
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CHEMICO-BIOLOGICAL INTERACTIONS
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2023
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IF 5.1
Huijuan Ma,Qi Shu,Peiyao Wang,Ruilin Qin,Sijia Li,Huan Xu
Exposure to formaldehyde (FA) has been indicated to be positively correlated with increased incidence of allergic asthma in many epidemiological and experimental studies. However, few studies have ever addressed the molecular basis of the correlation. In the present study, it was found that inhaling 2.0 mg/m 3 FA for 2 weeks could exacerbate the pulmonary inflammation and mucus over-accumulation in OVA-induced murine asthmatic model. The pro-inflammatory cytokines, such as IL-1β, TNF-α, IL-6 and IL-8, were increased in lung and serum of FA-exposed asthmatic mice. The contribution of HIF-1α signaling in FA-exacerbated allergic asthma was confirmed by bioinformatic analysis. HIF-1α and its downstream proteins, which are known as mediators of glycolysis, were found to be upregulated by 50 μM FA, and the FA-enhanced of glycolysis was reversed by inhibition of HIF-1α with PX-478 in vitro and YC-1 in vivo . Furthermore, it was confirmed that inhibition of HIF-1α signaling could restrain the macrophagic inflammatory responses and asthma exacerbation induced by FA. Collectively, these results revealed that FA could exacerbate asthma through the potentiation of HIF-1α-mediated inflammatory responses in macrophages, which also indicated the universal roles of FA-triggered macrophage metabolic and functional alterations in inflammatory or allergic diseases.
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FOOD AND CHEMICAL TOXICOLOGY
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2023
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IF 4.3
Xin Xie,Yan Zhu,Huimin Cheng,Haili Li,Yadi Zhang,Rong Wang,Wenyong Li,Fengrui Wu
Long-term exposure to bisphenol A (BPA) in humans may promote ovarian cancer development. In present study, the mechanisms by which BPA mediates the aggression metastatic behavior of ovarian cancer were investigated in vitro/in vivo . The results showed that BPA (10 μM) significantly promoted the proliferation, migration and invasion of human ovarian cancer cells (ES-2 and OVCAR-3 cells); moreover, it promoted ES-2 and OVCAR-3 cell glucose uptake, lactic acid release and intracellular ATP synthesis. After administration of 5 μg/kg/day BPA, tumor volume was increased compared with that in control group. KEGG and GO enrichment analyses showed that the genes from ES-2 cell in 10 μM BPA-treated group were enriched mainly in central carbon metabolism and PI3K-AKT signaling pathway. Then, qRT‒PCR and western blotting results showed that BPA (10 μM) increased the mRNA and protein expression levels of glycolysis-related genes and mTOR, p-AKT HIF-1α and ERα in vitro/vivo ; whereas this effect was reduced after treatment with the ERα inhibitor methyl-piperidino-pyrazole. Furthermore, coimmunoprecipitation and mass spectrometry showed that BPA promoted the direct interaction of ERα with lactate dehydrogenase A. These results show that BPA directly promoted the proliferation, migration and invasion of ovarian cancer cells through the ERα/AKT/mTOR/HIF-1α signaling axis to enhance glycolysis.
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Journal of Extracellular Vesicles
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2023
·Vol. 12
·期 2
·e12310
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IF 16
Xiaoning Wang,Ruoyi Wu,Peisong Zhai,Zheqi Liu,Ronghui Xia,Zhen Zhang,Xing Qin,Chuwen Li,Wantao Chen,Jiang Li,Jianjun Zhang
Tumour cells under hypoxia tend to modulate the number and contents of extracellular vesicles (EVs) to regulate the tumour microenvironment (TME) and thus promote tumour progression. However, the mechanism of how hypoxia influences the secretion of EVs remains to be elucidated. Here, we confirm the increased production of EVs in head and neck squamous cell carcinoma (HNSCC) cells under hypoxia, where endosome-derived EVs are the main subtype affected by insufficient O 2 . The accumulation of hypoxia-inducible factor-1α (HIF-1α) under hypoxia directly downregulates the expression of ATP6V1A, which is pivotal to maintain the homeostasis of lysosomes. Subsequently, impaired lysosomal degradation contributes to the reduced fusion of multivesicular bodies (MVBs) with lysosomes and enables the secretion of intraluminal vesicles (ILVs) as EVs. These findings establish a HIF-1α-regulated lysosomal dysfunction-EV release axis and provide an exquisite framework to better understand EV biogenesis.
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Bioengineered
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2022
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IF 6.832
Xiao-Yi Chen,Qian-Long Wang,Wei-Xue Huang,Long-Wei Li,Lan-Cong Liu,Yi Yang,You-Jiao Wu,Shan-Shan Song,Hao Ma,Hua Zhou,Pei Luo
Bacterial peritonitis is a severe disease that diagnosis remains challenging for clinicians. Measuring biomarkers might be a rapid diagnostic method. The objective of this study was to analyze and evaluate the dynamic changes in HIF-1α concentration in serum exosomes during bacterial peritonitis. The pre-clinical application value of serum exosomal HIF-1α was evaluated via imipenem and cilastatin sodium (ICS) intervention in the bacterial peritonitis model. The new colorimetric method to quantitate dynamic expression changes of HIF-1α in serum exosomes during bacterial peritonitis was established by our team via using the gold seed-coated with aptamer-functionalized Au @ Au core-shell peroxidase mimic. The typical inflammatory cytokines of bacterial peritonitis were also measured. Following intramuscular administration with ICS, In-Vivo Xtreme imaging system was used to visualize abdominal infection extent. Meanwhile, HIF-1α concentration in rat serum exosomes and pro-inflammatory factors levels in serum were detected. The serum typical inflammatory cytokines levels were elevated in GFP-labeled E.coli induced bacterial peritonitis. The serum exosomal HIF-1α levels clearly increased at 12 h, reached the peak during 24–48 h, and then gradually decreased at 72 h. Following intramuscular administration with ICS, the abdominal infection extent, HIF-1α concentration in serum exosomes, and the serum pro-inflammatory factors levels were reduced at 24 h in GFP-labeled E. coli induced bacterial peritonitis model. The serum exosomal HIF-1α can be used as a biomarker in the early stage of bacterial peritonitis, which might provide the basic research in the pre-clinical for further predicting and monitoring the pathological process of bacterial peritonitis.
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Applied Materials Today
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2020
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IF 8.352
Yanxin Chen,Mengqi Ye,Liwan Song,Junwen Zhang,Yao Yang,Sha Luo,Minjie Lin,Qianwen Zhang,Shengyu Li,Yajiao Zhou,Anqi Chen,Ying An,Wen Huang,Tengxiao Xuan,Yugui Gu,Huacheng He,Jiang Wu,Xiaokun Li
Skin wounds, especially chronic wounds such as pressure and diabetic ulcers, are posing a huge threat to healthcare systems worldwide. Thus, novel strategies to realize effective wound therapy are nowadays extremely needed. Herein, we are the first to report a combination therapy of electric stimulation and heat for wound healing just using a facile piezoelectric and photothermal dual functional film. The film, name as [email protected] , is simply fabricated by coating polydopamine on a chitosan film. [email protected] generates electric voltages under mechanical pressure and shows photothermal effect with irradiation of near-infra red (NIR) light. In vivo experiment with rat full-thickness wound model validates that [email protected] with NIR can effectively promote wound regeneration due to the generation of electric stimulation and heat on wounds. The healing mechanism of [email protected] is further investigated, and the result demonstrates that [email protected] enhances wound healing through a pathway in which heat shock protein 90 (Hsp90) and hypoxia-inducible factor 1α (HIF-1α) participate. These results indicate that [email protected] is a promising wound dressing candidate for clinical application in the future.
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