MOLECULAR THERAPY
·
2025
·
IF 12
Jingjing Zhang,Chao Li,Yuheng Liu,Rui Liao,Dian He,Lifeng Xu,Tingting Chen,Qin Xiao,Mingxing Luo,Yang Chen,Yali Li,Huaxing Zhu,Joseph Rosenecker,Xiaoyan Ding,Shuchen Pei,Shan Guan
The development of mucosal mRNA vaccines is promising but extremely challenging. Major efforts have been focused on optimizing delivery systems, whereas it is still unknown whether the intrinsic quality of mRNA components significantly impacts the potency of airway inoculated mRNA vaccines. Here, we systematically demonstrate mucosal mRNA vaccine requires higher standards of purification and tailor-designed sequence to fulfil its potency compared to parenteral-route inoculated counterpart. Double-stranded RNA (dsRNA) contaminants are prone to trigger innate immune response in the airway that activates the mRNA degradation mechanism, thereby diminishing the mRNA expression and subsequent antigen-specific immune responses. To address these challenges, we developed a strategy that combines optimized untranslated regions (UTRs) screened from endogenous genes of pulmonary cells with affinity chromatography-based purification which effectively removed dsRNA contaminants. The optimized mRNA administered via airway route not only demonstrated superior protein expression (30-fold increase) and reduced inflammation in the lung, but also promoted robust immunity comprising significantly elevated systemic, cellular, and mucosal immune responses, which was in stark contrast to intramuscular injected counterpart that displays less pronounced benefits. Our findings offer new insights into the development of mucosal mRNA therapeutics from an overlooked but crucial perspective of optimizing mRNA components.
研究领域:
免疫学
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分子生物学
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疫苗开发
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产品关联
DOI
PubMed
高影响因子
Nanomaterials
·
2022
·Vol. 13
·期 1
·84
·
IF 5.719
Yuan-Yuan Liu,Jie Liu,Hao Wu,Qiangqiang Zhang,Xue-Rui Tang,Dan Li,Chen-Si Li,Yuanfang Liu,Aoneng Cao,Haifang Wang
Nanoplastics, one component of plastic pollution, can enter human bodies via inhalation and thus threaten human health. However, the knowledge about the uptake and exocytosis of nanoplastics in cells of human lung organs is still very limited. Herein, we investigated the endocytosis, distribution, and exocytosis of polystyrene nanoparticles (PS NPs) of 50 nm (G50PS) and 100 nm (R100PS) in A549 cells and BEAS-2B cells. We found that both the cellular uptake of PS NPs increased positively with exposure time and dose, and A549 cells ingested more PS NPs than BEAS-2B cells did. In addition, the intracellular content of G50PS was higher than that of R100PS except at a higher dose and longer time. The ingested PS NPs were distributed mainly in lysosomes, while many G50PS appeared around the cell membrane, and R100PS also accumulated in mitochondria in BEAS-2B cells. As for the exocytosis, R100PS was more difficult to excrete than G50PS. Lysosomes in A549 cells and actin and microtubule in BEAS-2B cells were involved in the exocytosis of the PS NPs. These findings provide detailed information about the translocation of nanoplastics in lung cells, which is valuable for the safety assessment of nanoplastics in the environment.Keywords:nanoplastic;polystyrene particles;lung cells;cellular uptake;translocation;excretion
研究领域:
环境科学
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细胞生物学
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毒理学
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2021
·Vol. 12
·期 5
·1958-1972
·
IF 5.396
Zhaohui Xue,Xin Gao,Wancong Yu,Qian Zhang,Weichen Song,Shihao Li,Xu Zheng,Xiaohong Kou
Urban particulate matter (UPM), an air pollutant-absorbing toxic substance, can access alveoli, leading to pulmonary diseases. Studies have shown that the water-soluble components of UPM (WS-UPM), containing main toxic substances, can induce oxidative damage in lung cells. In this study, the UPM particle size and composition were detected via instrumental analysis. The isoflavones (biochanin A (BCA), formononetin and daidzein) from chickpeas possess biological antioxidant properties. The present study aimed to investigate the mechanism of the oxidative damage induced by WS-UPM, and the protective role of isoflavones in human alveolar basal epithelial cells. The antioxidant activity of BCA, formononetin and daidzein was investigated through the total reduction capacity, diphenylpicrylhydrazine radical (DPPH), superoxide radical, and hydroxyl radical scavenging capacity detection. We also established cell models in vitro to further explore the BCA-protective mechanism. BCA presented a significant protection, and increased the levels of antioxidant makers including superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). The effects were also reflected as the reduction of malondialdehyde (MDA) and nitric oxide (NO). Moreover, results obtained from RT-PCR and western blot techniques revealed that MEK5/ERK5 played an indispensable role in regulating the antioxidant effect of BCA, alleviating WS-UPM-induced lung injury. Furthermore, BCA mitigated WS-UPM-exposed damage through upregulating the Nrf2 signaling pathway to enhance the antioxidase expression downstream of Nrf2. In summary, our findings indicated that the WS-UPM-induced pulmonary disease was involved in oxidative stress and the MEK5/ERK5-Nrf2 signaling pathway, and BCA regulated the WS-UPM-induced lung damage via upregulation of the MEK5/ERK5-Nrf2 pathway.
研究领域:
环境科学
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毒理学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2025
·
IF 11.3
Qianyu Zhang,Huimin Ma,Jun Li,Fei liu,Hongxing Jiang,Jinbo Huang,Bin Jiang,Jing You,Guanghui Dong,Qilu Li,Wanli Ma,Zhiqiang Yu,Gan Zhang
The potential of PM2.5 to cause lung cancer has been well established; however, evidence regarding which specific components are responsible remains limited. We investigated dissolved organic matter (DOM) in PM2.5 using high-resolution mass spectrometry (HRMS) and cellular DNA damage assays to elucidate molecular composition and sources of carcinogenic components. Our analysis revealed hundreds of genotoxic compounds, with condensed aromatic amines predominating in number, abundance, and contribution to overall genotoxicity. Notably, norharman, a heterocyclic aromatic amine, was identified as a key carcinogenic component. Genotoxicity analysis using a lung cell exposure model indicated that, based on the measured concentration ratio of norharman to benzo[a]pyrene in DOM, the genotoxicity of norharman was approximately 0.21 to 0.6 times that of benzo[a]pyrene. Compared to proinflammatory compounds, these carcinogenic compounds exhibited greater unsaturation, increased aromaticity, an augmented reduced state, and the presence of nitrogenous organic matter. Two-ring aromatic amines containing two nitrogen atoms were identified as key contributors to both inflammation and genotoxicity. Regional source apportionment revealed significant regional variability in condensed aromatic amines within PM2.5. While polycyclic aromatic hydrocarbons (PAHs) are significant, condensed aromatic amines also warrant consideration in PM2.5 management. Effective mitigation requires tailored prevention measures based on regional pollution profiles and health impacts.
研究领域:
环境毒理学
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大气污染与健康
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分子毒理学
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环境化学
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肺癌病因学
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暴露组学
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产品关联
DOI
PubMed
高影响因子
GLYCOCONJUGATE JOURNAL
·
2021
·Vol. 39
·期 3
·315-325
·
IF 2.916
Zeng Jiaxin,Meng Yuan,Chen Shi-Yi,Zhao Gaofeng,Wang Lianchun,Zhang En-Xin,Qiu Hong
Furin is one of the nine-member proprotein convertase family. Furin cleaves proteins with polybasic residues, which includes many viral glycoproteins such as SARS-Cov-2 spike protein. The cleavage is required for the activation of the proteins. Currently, the mechanisms that regulate Furin activity remain largely unknown. Here we demonstrated that Furin is a novel heparin/heparan sulfate binding protein by the use of biochemical and genetic assays. The K D is 9.78 nM based on the biolayer interferometry assay. Moreover, we found that sulfation degree, site-specific sulfation (N-sulfation and 3-O-sulfation), and iduronic acid are the major structural determinants for the binding. Furthermore, we found that heparin inhibits the enzymatic activity of Furin when pre-mixes heparin with either Furin or Furin substrate. We also found that the Furin binds with cells of different origin and the binding with the cells of lung origin is the strongest one. These data could advance our understanding of the working mechanism of Furin and will benefit the Furin based drug discovery such as inhibitors targeting the interaction between heparan sulfate and Furin for inhibition of viral infection.
研究领域:
分子生物学
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病毒学
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药理学
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产品关联
DOI
PubMed
高影响因子
CHEMOSPHERE
·
2024
·
IF 8.1
Huilin Chen,Maomao Xie,Wenjie Li,Lipin Tan,Xiaoming Cai,Mingjing Shen,Ruibin Li
The extensive use of synthetic antioxidants, notably N-(1,3-dimethylbutyl)-N′-phenyl- p -phenylenediamine (6-PPD), in rubber-related products, particularly in tire manufacturing, has induced concerns regarding their environmental impact and potential health hazards. Despite the identification of 6-PPD and its derivative, 6-PPD quinone (6-PPDQ), in various water samples and their lethal effects on certain aquatic species ( e.g. , coho salmon, rainbow trout and brook trout), the levels of airborne 6-PPD/6-PPDQ and their respiratory toxicity remain relatively unexplored. In this study, we aimed to evaluate the respiratory toxicity potential of 6-PPD and its derivatives, with a specific focus on detecting these compounds in airborne particulates and assessing their toxic effects on lung cells. Characterization of four airborne fine particulate (FP) samples revealed spherical morphologies with diameters ranging from 17.7 to 225.7 nm, displaying slight agglomeration and negative surface charge. methanol/acetonitrile extraction followed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis confirmed the presence of both 6-PPD and 6-PPDQ on the surfaces of FPs, with significant variations (0.26–1.05 μg g −1 ) in loading capacity observed among the samples. Subsequent exposure of lung cells (THP-1, BEAS-2B, and A549) to 6-PPD and 6-PPDQ revealed dose-dependent declines in mitochondrial metabolic activity induced by 6-PPD, along with severe membrane damage, ATP depletion, and pro-inflammatory cytokine release. Conversely, 6-PPDQ exhibited negligible toxicity in all tested parameters. These findings underscore the potential health risks associated with airborne 6-PPD exposure and emphasize the importance of further research into the respiratory toxicity of 6-PPD derivatives.
研究领域:
环境科学
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毒理学
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公共卫生
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2023
·
IF 13.6
Xiaoyue Wang,Jin Wang,Shanjun Liu,Mengmeng Dou,Boru Gao
The sterilization effect of photocatalysis and biotoxicity of nanomaterial catalysts have attracted high attention. In this study, the novel visible-driven defective carbon nitride (VL/DCN) system exhibits non-photoreactivation, non-toxic superior performance compared with traditional ultraviolet radiation (UV) and UV/titanium dioxide (UV/TiO 2 ). The inactivation of antibiotic-resistant bacteria (ARB) by novel VL/DCN still reached 7 log within 4 h, and the reduction rates of aminoglycoside gene strB and tetracycline gene tetA exceeded 0.8 log and 1.2 log, respectively. Further, the sterilization mechanism and nanotoxicity were contrastively and systematically analyzed among above three systems as following. Firstly, in the VL/DCN system, reactive oxygen species (ROSs) generated from photocatalytic process leads to the destruction of cell membranes, resulting in dissolving out of potassium ion (K + ), protein and cell membrane ATP content. Thus, resistant bacteria were completely inactivated and photoreactivation disappears. In contrast, the UV only acted on bacterial DNA and existed the light resurrection. The UV/TiO 2 strictly dependent on ultraviolet light and can be used in limited scenarios. Secondly, in cell viability analysis by human lung cell line BEAS-2B experiments, the 10% inhibition of cell growth when DCN was 600 mg/L much lower than 28% inhibition of cell growth when TiO 2 was only 200 mg/L. The expression of pro-inflammatory cytokines (( Interleukin, IL) -6), IL-8, IL-1β ) under the effect of DCN was 1.5-fold, 5.7-fold and 3.7-fold lower than TiO 2 , respectively. Meanwhile, DCN induced cells to produce less ROSs, malondialdehyde (MDA), and more superoxide dismutase (SOD). Above results demonstrated that DCN has far lower cytotoxicity than TiO 2 . This study provides theoretical support for the application of photocatalytic sterilization technology and the exploration of the toxicity of nanomaterials. Environmental Implication In this study, the novel visible-driven defective carbon nitride (VL/DCN) system exhibits non-photoreactivation, non-toxic superior performance compared with traditional ultraviolet radiation (UV) and UV/titanium dioxide (UV/TiO 2 ). The VL/DCN exhibited excellent sterilization efficiency and a high rate of reduction of the E. coli resistance gene strB. The inactivation of ARB reached 7 log within 4 h without the occurrence of photoreactivation. The reduction rates of the aminoglycoside gene strB and tetracycline gene tetA exceeded 0.8 log and 1.2 log, respectively. This study provides a valuable theoretical basis for the development of a new sustainable and environmentally friendly visible light catalytic sterilization technologies.
研究领域:
环境科学
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材料科学
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生物技术
·
毒理学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Gege Zeng,Zepeng He,Haihong Yang,Zhan Gao,Xueer Ge,Lixin Liu,Zhijia Liu,Yongming Chen
Much of current clinical interest has focused on mRNA therapeutics for the treatment of lung-associated diseases, such as infections, genetic disorders, and cancers. However, the safe and efficient delivery of mRNA therapeutics to the lungs, especially to different pulmonary cell types, is still a formidable challenge. In this paper, we proposed a cationic lipid pair (CLP) strategy, which utilized the liver-targeted ionizable lipid and its derived quaternary ammonium lipid as the CLP to improve liver-to-lung tropism of four-component lipid nanoparticles (LNPs) for in vivo mRNA delivery. Interestingly, the structure–activity investigation identified that using liver-targeted ionizable lipids with higher mRNA delivery performance and their derived lipid counterparts is the optimal CLP design for improving lung-targeted mRNA delivery. The CLP strategy was also verified to be universal and suitable for clinically available ionizable lipids such as SM-102 and ALC-0315 to develop lung-targeted LNP delivery systems. Moreover, we demonstrated that CLP-based LNPs were safe and exhibited potent mRNA transfection in pulmonary endothelial and epithelial cells. As a result, we provided a powerful CLP strategy for shifting the mRNA delivery preference of LNPs from the liver to the lungs, exhibiting great potential for broadening the application scenario of mRNA-based therapy.
研究领域:
药学
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纳米技术
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分子生物学
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治疗学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2022
·
IF 5.062
Zimin Cai,Qin Wang,Jinzhuan Xu,Jia Zhou,Zhaohui Jiang,Di Pan,Yanyan Zhang,Ling Tao,Jianqing Peng,Yi Chen,Xiangchun Shen
Emphysema is a type of chronic obstructive pulmonary disease (COPD) usually leading to difficulty breathing. It is highly in need of effective interventions to prevent airspace damage and stretch. Herein, we studied the protective effect of 1,8-cineole (CIN) on porcine pancreatic elastase (PPE)-induced emphysema in mice via quantitative pulmonary administration. To overcome the volatility, instability and poor water solubility of CIN that limits its pharmacological activities in vivo , a hyaluronic acid (HA)-coated liposome was prepared to encapsulate CIN (Lipo/ [email protected] ), which facilitated the delivery of CIN to lung tissue and improved its therapeutic effect for emphysema. A Microsprayer Ⓡ aerosolizer was used to deliver free CIN and its liposomal preparations every other day for four weeks and evaluate the therapeutic effects on emphysema in mice. The results clearly showed that CIN significantly reduced the level of inflammation and oxidative stress, resulting in less lung cell apoptosis. Compared with the free CIN and Lipo/CIN, Lipo/ [email protected] exhibited superior protective effects on mice to prevent the PPE-induced emphysema. Furthermore, the therapeutic mechanisms were verified to be mainly mediated by Nrf2/NQO1 and NF-κB/IκBα pathways. In conclusion, quantitative pulmonary administration of CIN could alleviate the progression of emphysema and the therapeutic effects were further improved by the HA-coated liposome carrier.
研究领域:
药理学
·
肺病学
·
药物递送系统
·
分子生物学
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产品关联
DOI
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2023
·
IF 6.8
Qingyun He,Wuduo Zhao,Peiru Luo,Lingyun Wang,Qiannan Sun,Wenfen Zhang,Dan Yin,Yanhao Zhang,Zongwei Cai
As one of the most important transportation hubs and industrial bases in China, Zhengzhou has suffered from serious PM 2.5 pollution for a long time. However, the investigation of contamination status and possible exposure risks of environmentally persistent free radicals (EPFRs) in PM 2.5 from Zhengzhou is rare. In this work, a comprehensive study of pollution levels, seasonal variations, sources, and potential health risks of PM 2.5 -bound EPFRs in Zhengzhou was conducted for the first time. The atmospheric concentrations of EPFRs in PM 2.5 from Zhengzhou ranged from 1.732 × 10 12 spin m −3 to 7.182 × 10 14 spin m −3 between 2019 and 2020. Relatively serious contamination was noticed in winter and spring. Primary fossil fuel combustion and Fe-mediated secondary formation were apportioned as possible sources of PM 2.5 -bound EPFRs in Zhengzhou. Moreover, to avert the bias of the toxicity assessment induced by utilization of incompletely extracted EPFRs from sample filter, simulatively generated EPFRs were applied to toxicological evaluations (cell viability and reactive oxygen species assays). Corresponding experimental dosages were based on the estimated adults’ annual exposure amounts of EPFRs in real PM 2.5 samples. The results elucidated that EPFRs might cause growth inhibition and oxidative stress of human lung cells, suggesting the possible exposure-induced health concerns for local people in Zhengzhou. This study provides practical information of real contamination status of PM 2.5 -bound EPFRs in Zhengzhou, which is favorable to local air pollution control and reduction of exposure risks on public health in central China.
研究领域:
环境科学
·
公共卫生
·
毒理学
·
空气污染
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产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2024
·
IF 7.5
Yiheng Mao,Ying Chen,Yuan Li,Longda Ma,Xi Wang,Qi Wang,An He,Xi Liu,Tianyi Dong,Weina Gao,Yanfen Xu,Liang Liu,Liang Ren,Qian Liu,Peng Zhou,Ben Hu,Yiwu Zhou,Ruijun Tian,Zheng-Li Shi
As a primary target of severe acute respiratory syndrome coronavirus 2, lung exhibits heterogeneous histopathological changes following infection. However, comprehensive insight into their protein basis with spatial resolution remains deficient, which hinders further understanding of coronavirus disease 2019 (COVID-19)-related pulmonary injury. Here, we generate a region-resolved proteomic atlas of hallmark pathological pulmonary structures by integrating histological examination, laser microdissection, and ultrasensitive proteomics. Over 10,000 proteins are quantified across 71 post-mortem specimens. We identify a spectrum of pathway dysregulations in alveolar epithelium, bronchial epithelium, and blood vessels compared with non-COVID-19 controls, providing evidence for transitional-state pneumocyte hyperplasia. Additionally, our data reveal the region-specific enrichment of functional markers in bronchiole mucus plugs, pulmonary fibrosis, airspace inflammation, and alveolar type 2 cells, uncovering their distinctive features. Furthermore, we detect increased protein expression associated with viral entry and inflammatory response across multiple regions, suggesting potential therapeutic targets. Collectively, this study provides a distinct perspective for deciphering COVID-19-caused pulmonary dysfunction by spatial proteomics.
研究领域:
蛋白质组学
·
肺科学
·
病理学
·
病毒学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）