Journal of Extracellular Vesicles
·
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.
研究领域:
癌症生物学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
MICROBIOLOGICAL RESEARCH
·
2025
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IF 6.9
Zheng Jia,Lingdi Niu,Junjie Guo,Jiaqing Wang,Hai Li,Runhang Liu,Ning Liu,Shuhe Zhang,Fang Wang,Junwei Ge
Regulation of the innate immune response may be an effective strategy to enhance Staphylococcus aureus vaccines. Based on our previous findings that the Listeria peptidoglycan skeleton (pBLP) enhances the immune response through an unknown mechanism, we hypothesized that pBLP provides protection by modulating the innate immune response via trained immunity. In vitro, pBLP increased phagocytosis and inflammatory cytokine levels and elevated the anti-inflammatory cytokine TGF-β following secondary stimulation. In an in vivo model, our findings indicate that pBLP, when administered with a vaccine, protects mice from methicillin-resistant S. aureus challenge and also provides protection against S. aureus CMCC26003 in the absence of antigens. Using an ex vivo model, we demonstrated that pBLP increases markers of trained immunity in peritoneal macrophages. Transcriptome analysis of differentially expressed genes and inhibitor experiments revealed that the trained immunity process induced by pBLP depends on mTOR-HIF-1α and hexokinase 2. This study is the first to demonstrate that pBLP can induce trained immunity. Furthermore, we show that the peptidoglycan skeleton induces a distinct trained immunity phenotype compared to β-glucan, enhancing vaccine protection. Our study provides valuable insights for the design of novel vaccines that integrate both specific and innate immune responses.
研究领域:
免疫学
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微生物学
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疫苗研发
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DOI
PubMed
高影响因子
Materials Today Bio
·
2025
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IF 10.2
Wenjin Zhong,Pengcheng Wang,Jintian Wang,Yuejia Zhu,Liquan Chen,Yilong Qian,Xiang Huang,Kai Ye
Background The immune checkpoint inhibitor (ICI) PD-1α can effectively treat Lynch syndrome (LS)-associated colorectal cancer (CRC) (LS-CRC). In some cases, LS-CRC is not sensitive to ICIs. Dendritic cell (DC)-based hybrid membrane nanoparticles have great potential to upgrade the efficacy of ICIs, which can theoretically be applied to enhance the efficacy of ICIs in treating LS-CRC. Methods MnO 2 nanomaterials with si-CTLA4 were absorbed by coating mature DCs loaded with PD-1α and liposome hybrid membranes. The morphology and physicochemical properties of DCsLipo@MnO 2 @si-CTLA4@PD-1α were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), dynamic light scattering (DLS), fluorescence resonance energy transfer (FRET), and Fourier transform infrared spectroscopy (FTIR). The activation of DCs and T cells was assessed by utilizing the detection of cell surface markers by flow cytometry. The mRNA levels of CTLA4 in T cells were measured using the qPCR method. The biosafety of DCsLipo@MnO 2 @si-CTLA4@PD-1α was proved by hemolysis test in vitro , CCK-8 assay, and live/dead cell staining. In vitro T-cell uptake experiments proved that the nanomedicine can be effectively absorbed by T cells. Cell proliferation, apoptosis, and ELISA experiments demonstrated that nanomedicine facilitated T-cell proliferation, cytokine secretion, and cancer cytotoxicity. Finally, the anti-cancer effect and immune activation ability of the nanomedicine against LS-CRC were verified by a mouse allograft model. Results The nanomedicine DCsLipo@MnO 2 @si-CTLA4@PD-1α created in this research exhibited good stability and uniform vesicle morphology. In vitro hemolysis test, CCK-8 assay, and live/dead staining experiments indicated that DCsLipo@MnO 2 @si-CTLA4@PD-1α had great biosafety. The nanoparticle loaded with si-CTLA4 effectively reduced the mRNA expression of CTLA4 in T cells. Meanwhile, the results of T cell flow analysis, cell proliferation, cytotoxicity, apoptosis, and ELISA experiments manifested that DCsLipo@MnO 2 @si-CTLA4@PD-1α effectively reinforced the proliferation and activation of T cells, and enhanced the cytotoxicity of T cells to cancer cells. The validation experiments based on the mouse allograft tumor model manifested that DCsLipo@MnO 2 @si-CTLA4@PD-1α boosted the infiltration of T cells into tumor tissues and suppressed the development of LS-CRC. Conclusion DCsLipo@MnO 2 @si-CTLA4@PD-1α can facilitate T cell activation and synergistically enhance the efficacy of ICIs, exhibiting a great inhibitory effect on LS-CRC.
研究领域:
肿瘤学
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免疫学
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生物医学工程
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Oncology
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2022
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IF 4.501
Hongliang You,Dao Wang,Linlin Wei,Jiao Chen,Huanhuan Li,Yufeng Liu
Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer, with a feature of easy to induce multidrug resistance and relapse. Abundant studies have proved that iron overload strengthens the growth and metastasis of tumor cells. Herein, we found that deferoxamine (DFO) effectively decreased the concentration of intracellular iron in ALL cells. DFO inhibited proliferation, induced apoptosis, and obstructed cell cycle of ALL cells, whereas DFO and dextriferron (Dex) used in combination significantly decreased the sensitivity of ALL cells to DFO. Reactive oxygen species (ROS) level was reduced in ALL cells treated with DFO, and the combination of DFO and Dex reversed the effects of DFO. In vivo, DFO inhibited mouse tumor growth. Besides, cyclinD1, β-catenin, c-Myc, hypoxia inducible factor 1 (HIF-1), p-p38MAPK, and p-ERK1/2 protein levels were significantly downregulated, and the levels of prolyl hydroxylase-2 (PHD-2) were upregulated after treated with DFO, whereas Dex treatment reversed those in vivo and in vitro. In conclusion, DFO inhibited the proliferation and ALL xenograft tumor growth, obstructed the cell cycle, and induced apoptosis of ALL cells, probably via inactivating the ROS/HIF-1α, Wnt/β-catenin, and p38MAPK/ERK signaling.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
FREE RADICAL RESEARCH
·
2023
·
IF 3.3
Yangying Li,Yuda Zhu,Shiyi Li,Yuman Dong,Chengyu Wan,Xiuxian Yu,Guang Xin,Zeliang Wei,Fan Li,Yilan Wang,Kun Zhang,Qingqiu Chen,Cuicui Zhang,E. Wen,Hai Niu,Wen Huang
Severe acute pancreatitis (SAP) is an inflammatory disorder of the exocrine pancreas associated with high morbidity and mortality. SAP has been proven to trigger mitochondria dysfunction in the pancreas. We found that Deoxyarbutin (dA) recovered impaired mitochondrial function. High-temperature requirement protein A2 (HtrA2), a mitochondrial serine protease upstream of PGC-1α, is charge of quality control in mitochondrial homeostasis. The molecular docking study indicated that there was a potential interaction between dA and HtrA2. However, whether the protective effect of dA against SAP is regulated by HtrA2/PGC-1α remains unknown. Our study in vitro showed that dA significantly reduced the necrosis of primary acinar cells and reactive oxygen species (ROS) accumulation, recovered mitochondrial membrane potential (ΔΨm) and ATP exhaustion, while UCF-101 (HtrA2 inhibitor), and SR-18292 (PGC-1α inhibitor) eliminated the protective effect of dA. Moreover, HtrA2 siRNA transfection efficiently blocked the protective of dA on HtrA2/PGC-1α pathway in 266-6 acinar cells. Meanwhile, dA also decreased LC3II/I ration, as well as p62, and increased Parkin expression, while UCF-101 and Bafilomycin A1 (autophagy inhibitor) reversed the protective effect of dA. Our study in vivo confirmed that dA effectively alleviated severity of SAP by reducing pancreatic edema, plasma amylase, and lipase levels and improved the HtrA2/PGC-1α pathway. Therefore, this is the first study to identify that dA inhibits pancreatic injury caused by oxidative stress, mitochondrial dysfunction, and impaired autophagy in a HtrA2/PGC-1α dependent manner.
研究领域:
胃肠病学
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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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DOI
PubMed
高影响因子
ACS Applied Bio Materials
·
2024
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IF 4.6
Jingyu Li,Zhuoting Lu,Liwang Xu,Jing Wang,Shaojie Qian,Qinglian Hu,Yunfen Ge
Hindlimb ischemia is a common disease worldwide featured by the sudden decrease in limb perfusion, which usually causes a potential threat to limb viability and even amputation or death. Revascularization has been defined as the gold-standard therapy for hindlimb ischemia. Considering that vascular injury recovery requires cellular adaptation to the hypoxia, hypoxia-inducible factor 1 α (HIF-1α) is a potential gene for tissue restoration and angiogenesis. In this manuscript, effective gene delivery vector PEI-β-CD (PC) was reported for the first application in the hindlimb ischemia treatment to deliver HIF-1α plasmid in vitro and in vivo. Our in vitro finding demonstrated that PC/HIF-1α-pDNA could be successfully entered into the cells and mediated efficient gene transfection with good biocompatibility. More importantly, under hypoxic conditions, PC/HIF-1α-pDNA could up-regulate the HUEVC cell viability. In addition, the mRNA levels of VEGF, Ang-1, and PDGF were upregulated, and transcriptome results also demonstrated that the cell-related function of response to hypoxia was enhanced. The therapeutic effect of PC/HIF-1α-pDNA was further estimated in a murine acute hindlimb ischemia model, which demonstrated that intramuscular injection of PC/HIF-1α-pDNA resulted in significantly increased blood perfusion and alleviation in tissue damage, such as tissue fibrosis and inflammation. The results provide a rationale that HIF-1α-mediated gene therapy might be a practical strategy for the treatment of limb ischemia.
研究领域:
生物医学工程
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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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产品关联
DOI
PubMed
高影响因子
Clinical and Experimental Otorhinolaryngology
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2023
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IF 3
Kunyu Liu,Yu Xu
Objectives. Hypoxia-inducible factor 1α (HIF1α) and Tet methylcytosine dioxygenase 2 (TET2) have been reported to mediate nasal polypogenesis through the epithelial-to-mesenchymal transition (EMT). Additionally, HIF1α can regulate the expression and function of TET2. However, the precise mechanism of how TET2 regulates the EMT through HIF1α mediation in nasal epithelial cells is still poorly understood. Methods. Nasal tissue samples were collected from patients with chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), CRS without nasal polyps (CRSsNP), and controls. The expression of HIF1α and TET2 was detected using Western blotting and immunohistochemistry. EMT markers (E-cadherin and vimentin) were also evaluated by immunohistochemistry. Primary human nasal epithelial cells (hNECs) were stimulated with CoCl 2 to mimic hypoxia. Vitamin C (VC), a TET2 non-specific activator, and small interfering RNA (siRNA) transfection of TET2 were used to further determine the role of TET2 in hypoxia-induced EMT. Finally, reactive oxygen species (ROS) and Nrf2 were measured to explore the downstream consequences of TET2 in hypoxic hNECs. Results. TET2 levels were lower in the nasal epithelium of CRSwNP patients and were positively correlated with E-cadherin but negatively correlated with vimentin in CRS. However, HIF1α exhibited the opposite pattern and was negatively correlated with TET2 expression. CoCl 2 -simulated hypoxia led to EMT and increased HIF1α in hNECs in vitro , with simultaneous downregulation of TET2 expression. Addition of VC activated TET2 expression in hNECs, but inhibited EMT and HIF1α expression. Furthermore, siRNA knockdown of TET2 contributed to the EMT in CoCl 2 -simulated hNECs despite the addition of VC. Finally, TET2 regulated the EMT in hypoxic hNECs through Nrf2 expression and ROS generation. Conclusion. TET2 was negatively correlated with HIF1α and EMT in vivo . TET2 was downregulated by HIF1α, resulting in the EMT in CoCl 2 -hypoxic hNECs via regulation of oxidative stress in vitro . Hence, TET2 might provide a new therapeutic approach for CRSwNP
研究领域:
免疫学
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耳鼻喉科学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
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IF 5.6
Pingchuan Wang,Tianming Li,Changping Niu,Siyu Sun,Dongyan Liu
Reactive oxygen species (ROS) damage to the intestinal barrier is a side effect of prolonged hyperoxia therapy in neonates, which impairs growth and development of the intestine and promotes intestinal diseases. However, the research on clinical prevention and treatment is lacking. Therefore, we investigated the molecular mechanisms of the neonate intestinal response against hyperoxia-derived ROS to find targets for intestinal barrier damage prevention. Human intestinal epithelial cells were incubated under hyperoxia (85% oxygen) to build an in vitro model. ROS and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway were inhibited to detect the MAPK/ERK pathway, nuclear factor erythroid factor 2-related factor 2 (Nrf2), hypoxia-inducible factor-1α (Hif-1α), and interleukin-17D (IL-17D) expression. Nrf2 was inhibited to detect Hif-1α and IL-17D expression. Hif-1α was inhibited to detect Nrf2, IL-17D, and tight junction proteins expression and apoptosis. Cells were treated with human recombinant IL-17D to detect TNF-α, IL-1β, IL-10, and tight junction proteins expression. ROS, Nrf2, Hif-1α, and IL-17D were upregulated and the MAPK/ERK pathway was activated under hyperoxia. But ROS inhibition downregulated the MAPK/ERK pathway, Nrf2, Hif-1α, and IL-17D. MAPK/ERK pathway inhibition downregulated Nrf2, Hif-1α, and IL-17D. Nrf2 inhibition downregulated Hif-1α and IL-17D. Hif-1α inhibition downregulated Nrf2, IL-17D, tight junction proteins, and exacerbated apoptosis. The recombinant IL-17D downregulated TNF-α, IL-1β, but upregulated IL-10 and tight junction proteins. We concluded that Hyperoxia-generated ROS activated the MAPK/ERK pathway to regulate Nrf2, Hif-1α, and IL-17D expression. Nrf2 and Hif-1α were interdependent and promoted IL-17D. Importantly, Hif-1α and IL-17D expression protected the intestinal epithelial barrier.
研究领域:
分子生物学
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细胞生物学
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儿科
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肠道生理学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2019
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IF 2.705
Ying Li,Beili Hao,Ishfaq Muhammad,Yuanyuan Zhang,Yang Yang,Chenxi Shi,Yicong Chang,Rui Li,Changwen Li,Fangping Liu
The role of hepatic nuclear factor 1α (HNF-1α) and its response element in the expression of glutathione S-transferase A1 (GSTA1) was investigated in hepatocytes cells injury induced by acetaminophen (APAP). Treatment of hepatocytes with C2-ceramide exacerbated cells injury with GSTA1 mRNA level reducing. Contrastingly, administration of oltipraz alleviated cells damage with GSTA1 mRNA level elevating relative to hepatotoxicity induced by APAP. Western blot analysis showed that C2-ceramide decreased the translocation of HNF-1α and expression of GSTA1 protein, while oltipraz increased nuclear HNF-1α level and transactivation of GSTA1. The role of HNF-1α on GSTA1 expression was confirmed by transfection experiment and dual-luciferase reporter assay system. In the cells transfected with pGSTA1-1298-LUC vector in which HNF-1 response element (HRE) was contained, the luciferase activity decreased with reduction of nuclear HNF-1α and increased with elevation of nuclear HNF-1α. However, the luciferase activity had no change with the variation of nuclear HNF-1α when the cells transfected with the plasmid of pGSTA1-ΔHNF1-LUC in which the HRE was mutated. In conclusion, HNF-1α could affect the transcription of GSTA1 and HNF-1 response element in the GSTA1 promoter region, which is functionally active for the GSTA1 transcription.
研究领域:
毒理学
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分子生物学
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肝脏病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2024
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IF 5.7
Yu-Chen Jiang,Jia-Yi Dou,Mei-Yan Xuan,Chong Gao,Zhao-Xu Li,Li-Hua Lian,Zhen-Yu Cui,Ji-Xing Nan,Yan-Ling Wu
Hepatic fibrosis is a compensatory response to chronic liver injury and inflammation, and dietary intervention is recommended as one of the fundamental prevention strategies. Raspberry ketone (RK) is an aromatic compound first isolated from raspberry and widely used to prepare food flavors. The current study investigated the hepatoprotection and potential mechanism of RK against hepatic fibrosis. In vitro, hepatic stellate cell (HSC) activation was stimulated with TGF-β and cultured with RK, farnesoid X receptor (FXR), or peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) agonist or inhibitor, respectively. In vivo, C57BL/6 mice were injected intraperitoneally with thioacetamide (TAA) at 100/200 mg/kg from the first to the fifth week. Mice were intragastrically administrated with RK or Cur once a day from the second to the fifth week. In activated HSCs, RK inhibited extracellular matrix (ECM) accumulation, inflammation, and epithelial–mesenchymal transition (EMT) process. RK both activated FXR/PGC-1α and regulated their crosstalk, which were verified by their inhibitors and agonists. Deficiency of FXR or PGC-1α also attenuated the effect of RK on the reverse of activated HSCs. RK also decreased serum ALT/AST levels, liver histopathological change, ECM accumulation, inflammation, and EMT in mice caused by TAA. Double activation of FXR/PGC-1α might be the key targets for RK against hepatic fibrosis. Above all, these discoveries supported the potential of RK as a novel candidate for the dietary intervention of hepatic fibrosis.
研究领域:
药理学
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肝病学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION
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2025
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IF 3.5
Liang Yongchao,Huo Hongjin,Wei Wei,Wang Dongxuan,Lu Jingjing,Yi Wenjie,Jiang Fei
Purpose Perfluorooctane sulfonic acid (PFOS) is a representative persistent organic pollutant that has been shown to impair male reproductive function. Epidemiological studies and animal models suggest that vitamin D may modify male reproductive function. However, whether 1α,25(OH) 2 D 3 could mitigate the PFOS-induced damage of Sertoli cells, and the underlying mechanisms remain poorly defined. Methods Mouse Sertoli cell line TM4 were pretreated with or without 10 nM or 100 nM 1α,25(OH) 2 D 3 for 6 h, followed by 100 µM or 200 µM PFOS for 24 h. Cell viability was assessed using the CCK8 assay. Reactive oxygen species (ROS) were detected by fluorescent staining, while malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) levels were measured using commercial kits. siRNA transfection, quantitative real-time PCR (qRT‒PCR), and Western blotting were performed to elucidate the underlying mechanisms. Molecular docking studies were conducted to explore the potential binding of PFOS to Keap1. Results PFOS increased MDA contents, decreased GSH levels, and induced cytotoxicity in mouse Sertoli cells. Mechanistically, PFOS might directly bind to Keap1, facilitating its degradation, leading to persistent activation of the Nrf2-ARE pathway. Conversely, 1α,25(OH) 2 D 3 attenuated PFOS-induced cytotoxicity by alleviating the Nrf2-ARE pathway, a protective effect which was abolished by vitamin D receptor (VDR) knockdown. Conclusion PFOS induces cytotoxicity in Sertoli cells by binding to Keap1 and persistently activating the Nrf2-ARE pathway. 1α,25(OH) 2 D 3 emerges as a promising candidate for mitigating PFOS-induced testicular dysfunction. Graphical abstract
研究领域:
毒理学
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分子生物学
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内分泌学
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生殖生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Wenjia CHEN,Chu ZHANG,Mingzhu XU,Tao LI,Xin LI,Peihao LI,Xun GONG,Yang QU,Chunling ZHOU,Xia MAO,Na LIN,Wei LIU,Quan JIANG,Haiyu XU,Yanqiong ZHANG
Background : Specific treatment for rheumatoid arthritis (RA) is still an unmet need. Yu-Xue-Bi (YXB) capsule effectively treats RA with blood stasis syndrome (BS). However, its mechanism remains unclear. Purpose : Exploring and elucidating the therapeutic effect and pharmacological mechanism of YXB capsule in treating RA. Methods : This study identified differentially expressed genes (DEGs) in patients with RA and BS compared to healthy controls using clinical transcriptomics data. Clinical symptoms of RA and BS, and the related genes were collected from the SoFDA and HPO databases. Candidate bioactive constituents in YXB were identified via UPLC-QTOF/MS and evaluated using ADMET rules. Putative targets were predicted, and a network linking disease-related DEGs and drug targets was constructed. Key targets were screened utilizing random walk-with-restart (RWR) algorithms and verified through experiments using rat models of collagen-induced arthritis with BS (CIA-BS model) in vivo . Results : We found 1220 DEGs along with 976 clinical symptom-related genes, as RA with BS-related genes. Chemical profiling identified 193 YXB constituents, with 98 meeting optimal ADMET criteria. We predicted 459 putative targets for these constituents. Network calculations screened 209 key targets, 129 RA with BS-related genes and 92 YXB targets involved in immune inflammation, blood stagnation, and hyperalgesia imbalance. Notably, the SUCNR1/HIF-1α/TRPV1 axis was enriched by YXB targets against RA with BS. Experimentally, YXB inhibited inflamed joint deterioration, including synovial inflammation, cartilage damage and bone erosion, relieving mechanical and cold allodynia hyperglasia. It reversed hemorrheology and vascular function in CIA-BS rats, restoring SDHB and eNOS expression, preventing SDHA, SUCNR1 and HIF-1α activation, reducing SUCN, TNF-1α and IL-1β production, and TRPV1 and TRPA1 expression. Conclusion : Our data support YXB's therapeutic effects on aggressive RA-BS by modulating the SUCNR1/HIF-1α/TRPV1 axis.
研究领域:
药理学
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分子生物学
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风湿病学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）