ARCHIVES OF TOXICOLOGY
·
2022
·Vol. 97
·期 2
·441-456
·
IF 6.168
Xu Chi,Jiang Shuyun,Ma Xingyu,Jiang Zeyong,Pan Youguang,Li Xiang,Zhang Liying,Zhou Hao,Chen Shen,Xing Xiumei,Chen Liping,Fu Wenfan,Wang Qing,Chen Wen,Li Daochuan
Cisplatin is recommended as a first-line chemotherapeutic agent against advanced non-small cell lung cancer (NSCLC), but acquired resistance substantially limits its clinical efficacy. Recently, DNA methylation has been identified as an essential contributor to chemoresistance. However, the precise DNA methylation regulatory mechanism of cisplatin resistance remains unclear. Here, we found that nicotinamide nucleotide transhydrogenase ( NNT ) was silenced by DNA hypermethylation in cisplatin resistance A549 (A549/DDP) cells. Also, the DNA hypermethylation of NNT was positively correlated to poor prognosis in NSCLC patients. Overexpression of NNT in A549/DDP cells could reduce their cisplatin resistance, and also suppressed their tumor malignancy such as cell proliferation and clone formation. However, NNT enhanced sensitivity of A549/DDP cells to cisplatin had little to do with its function in mediating NADPH and ROS level, but was mainly because NNT could inhibit protective autophagy in A549/DDP cells. Further investigation revealed that NNT could decrease NAD + level, thereby inactivate SIRT1 and block the autophagy pathway, while re-activation of SIRT1 through NAD + precursor supplementation could antagonize this effect. In addition, targeted demethylation of NNT CpG island via CRISPR/dCas9-Tet1 system significantly reduced its DNA methylation level and inhibited the autophagy and cisplatin resistance in A549/DDP cells. Thus, our study found a novel chemoresistance target gene NNT , which played important roles in cisplatin resistance of lung cancer cells. Our findings also suggested that CRISPR-based DNA methylation editing of NNT could be a potential therapeutics method in cisplatin resistance of lung cancer.
研究领域:
肿瘤学
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分子生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2024
·
IF 5.3
Bei Jia,Jiachen He,Ying Zhang,Wenli Dang,Bin Xing,Mengru Yang,Haonan Xie,Jiawei Li,Zhidong Liu
Chronic obstructive pulmonary disease (COPD) is a prevalent lung condition characterized by airflow obstruction, disability, and high mortality rates. Magnolol (MA), known for its anti-inflammatory and antioxidant properties, holds the potential for alleviating COPD symptoms. However, MA faces challenges like poor aqueous solubility and low bioavailability. Herein MA-loaded nanostructured lipid carriers (MA-NLC) were prepared using emulsification and solvent evaporation. These carriers exhibited a particle size of (19.67 ± 0.36) nm, a polydispersity index of (0.21 ± 0.01), and a zeta potential of (−5.18 ± 0.69) mV. The fine particle fraction of MA-NLC was (68.90 ± 0.07)%, indicating minimal lung irritation and enhanced safety. Pulmonary delivery of MA-NLC via nebulizer actively targeted the diseased lung tissues, facilitated slow release, and overcame the challenges of low oral absorption and bioavailability associated with MA. This formulation prolonged the residence time of MA and optimized its therapeutic effect in pulmonary tissues. Upon pulmonary administration, MA-NLC effectively regulated inflammatory and oxidative stress markers in COPD models, demonstrating its potential as a promising therapeutic platform for COPD management.
研究领域:
药学
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肺科学
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纳米技术
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药物递送系统
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DOI
PubMed
高影响因子
Applied Biological Chemistry
·
2025
·Vol. 68
·期 1
·1-11
·
IF 2.7
Dou Yufeng,Yang Jiao,Huang Na,Lu Xiaoxiao,Yan Liping
Background Pneumonia is a serious respiratory disease that significantly impacts human health. Quercetin (QUE), a plant extract, has been shown to exert protective effects against lung injury, but its precise mechanisms remain unclear. Methods Lipopolysaccharide (LPS) was used to induce injury in embryonic lung fibroblasts. Cell viability, proliferation, and apoptosis were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, 5-ethynyl-2’-deoxyuridine (EdU) staining, and flow cytometry assay, respectively. Reactive oxygen species (ROS), malondialdehyde (MDA), and Fe 2+ levels were evaluated using corresponding assay kits. The levels of inflammatory factors were determined by enzyme-linked immunosorbent assay (ELISA). Quantitative real-time PCR (qRT-PCR) and western blot were employed to analyze the expression and correlation of related genes. Methylated RNA immunoprecipitation (MeRIP) was employed to verify the regulatory mechanism between genes. Results QUE inhibited embryonic lung fibroblast injury. Both transducin β-like 1 X-linked receptor 1 (TBL1XR1) and methyltransferase 3 (METTL3) were highly expressed in lung injury tissues and cells, which were decreased by QUE treatment. TBL1XR1 deficiency weakened LPS-induced embryonic lung fibroblast injury. Mechanistically, METTL3 mediated the N 6 -methyladenosine (m6A) methylation and stabilized the TBL1XR1 mRNA. TBL1XR1 up-regulation alleviated the retardation of METTL3 absence on embryonic lung fibroblast injury. Furthermore, METTL3 overexpression reversed the inhibition of QUE on embryonic lung fibroblast injury. Conclusion QUE inhibited embryonic lung fibroblast injury by regulating the METTL3-mediated m6A methylation of TBL1XR1 mRNA.
研究领域:
分子生物学
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药理学
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呼吸医学
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表观遗传学
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细胞生物学
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产品关联
DOI
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2021
·Vol. 31
·期 21
·2008960
·
IF 18.808
Jiandong Yang,Shanzhou Duan,Huan Ye,Chenglong Ge,Chunxian Piao,Yongbing Chen,Minhyung Lee,Lichen Yin
Pulmonary delivery of anti-inflammatory siRNA holds great potential in mitigating the cytokine storm during severe pneumonia. However, commonly utilized polycationic siRNA delivery vehicles can hardly penetrate the mucus barrier, thus greatly hurdling their therapeutic efficacy. Herein, TNF-α siRNA (siTNF-α) delivery nanocomplexes (NCs) are engineered with mucus/cytomembrane dual-penetration capabilities, realized via surface-coating of NCs with RC, an inflammation-sheddable, charge-reversal pro-peptide of RAGE-binding peptide (RBP). RC-coated dendritic poly- L -lysine/siTNF-α (DsT) NCs possess negative surface charges, and can thus efficiently penetrate the mucus layer after intratracheal administration. In the inflamed alveolar space with mild acidity, RC recovers to the cationic RBP and shed off, re-exposing the DsT NCs that efficiently transfect the alveolar macrophages and provokes TNF-α silencing. Thus, siTNF-α and RBP cooperatively alleviate the uncontrolled inflammation during acute lung injury. This study renders a unique approach for mediating trans-mucus nucleic acid delivery, and will find promising utilities for the treatment of severe pneumonia.
研究领域:
药剂学
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纳米技术
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肺科学
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分子生物学
✓ 已验证
DOI
高影响因子
ANALYTICAL CHEMISTRY
·
2025
·
IF 6.7
Tao Dong,Guangze Sun,Wanjian Liu,Yunze Long,Aihua Liu
Acute respiratory infections (ARIs) are among the leading causes of morbidity and mortality worldwide, with Mycoplasma pneumoniae (M. pneumoniae) and Chlamydia pneumoniae (C. pneumoniae) being major pathogens responsible for community-acquired respiratory infections. Rapid and accurate diagnosis is critical for improving patient outcomes and effectively controlling disease transmission. Herein, we report a novel dual-channel lateral flow immunoassay (DC-LFIA) platform based on the Co3O4@polydopamine (PDA) nanocomposite with outstanding extinction coefficient, oxidase-like activity, and magnetic properties for the simultaneous detection of specific IgM antibodies (Ab) against these two pathogens in human serum. The magnetic properties of the Co3O4@PDA nanocomposite enable rapid enrichment of trace target Abs from large-volume serum samples, with a high extinction coefficient for direct colorimetric visualization and an excellent oxidase-like catalytic activity for signal enhancement. On the basis of the multifunctional Co3O4@PDA nanocomposite, rapid dual-mode detection of serum Abs was achieved within 12 min. By the direct colorimetric mode, the visual limit of detection (vLOD) for M. pneumoniae Ab and C. pneumoniae Ab reached 2 and 1 ng/mL, respectively, while the oxidase-like catalyzing signal amplification mode further lowered the vLODs to 0.2 and 0.1 ng/mL, accordingly. Additionally, the signal normalization using a 3D-printed device significantly enhanced assay accuracy and reproducibility. When applied to 96 clinical serum samples, compared to commercial kits, this multifunctional Co3O4@PDA-based DC-LFIA demonstrated superior performance, providing a reliable approach for simultaneous antibody detection in respiratory infection diagnosis. Overall, this work contributes a valuable diagnostic tool to the field of rapid detection of ARIs.
研究领域:
免疫学
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临床检验医学
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纳米生物技术
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传染病学
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诊断学
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转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2024
·
IF 7.1
Liu Yang,Zeyu Peng,Fanpeng Gong,WenXin Yan,Yi Shi,Hanyi Li,Chang Zhou,Hong Yao,Menglu Yuan,Fan Yu,Lei Feng,Naifu Wan,Guizhu Liu
Pulmonary hypertension (PH) is a devastating disease that lacks effective treatment options and is characterized by severe pulmonary vascular remodeling. Pulmonary arterial endothelial cell (PAEC) dysfunction drives the initiation and pathogenesis of pulmonary arterial hypertension. Canonical transient receptor potential (TRPC) channels, a family of Ca 2+ -permeable channels, play an important role in various diseases. However, the effect and mechanism of TRPCs on PH development have not been fully elucidated. Among the TRPC family members, TRPC4 expression was markedly upregulated in PAECs from hypoxia combined with SU5416 (HySu)-induced PH mice and monocrotaline (MCT)-treated PH rats, as well as in hypoxia-exposed PAECs, suggesting that TRPC4 in PAECs may participate in the occurrence and development of PH. In this study, we aimed to investigate whether TRPC4 in PAECs has an aggravating effect on PH and elucidate the molecular mechanisms. We observed that hypoxia treatment promoted PAEC apoptosis through a caspase-12/endoplasmic reticulum stress (ERS)-dependent pathway. Knockdown of TRPC4 attenuated hypoxia-induced apoptosis and caspase-3/caspase-12 activity in PAECs. Accordingly, adeno-associated virus (AAV) serotype 6-mediated pulmonary endothelial TRPC4 silencing (AAV6-Tie-shRNA-TRPC4) or TRPC4 antagonist suppressed PH progression as evidenced by reduced right ventricular systolic pressure (RVSP), pulmonary vascular remodeling, PAEC apoptosis and reactive oxygen species (ROS) production. Mechanistically, unbiased RNA sequencing (RNA-seq) suggested that TRPC4 deficiency suppressed the expression of the proapoptotic protein sushi domain containing 2 (Susd2) in hypoxia-exposed mouse PAECs. Moreover, TRPC4 activated hypoxia-induced PAEC apoptosis by promoting Susd2 expression. Therefore, inhibiting TRPC4 ameliorated PAEC apoptosis and hypoxic PH in animals by repressing Susd2 signaling, which may serve as a therapeutic target for the management of PH.
研究领域:
心血管疾病
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细胞生物学
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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
Nano Today
·
2024
·
IF 13.2
Beiduo Wang,Yanping Xu,Qigu Yao,Liang Song,Min Liang,Hongcui Cao,Changyou Gao
Selective modulation of the types of reactive oxygen species (ROS) for the treatment of acute lung injury (ALI) has not been tackled, whereas the usually applied hydrophobic nanoparticles (NPs) are easily excreted and metabolized. Herein, a zwitterionic-segment containing polyurethane was synthesized to formulate into Pazopanib (Pazo)-loaded NPs (PUSB@Pazo NPs), which had the ability to selectively enhance the expression of H 2 O 2 but suppress other types of ROS, and achieved long retention in lung and thereby improved treatment efficacy. The zwitterionic group of PUSB effectively decreased the clearance rate of PUSB@Pazo NPs in vivo , and prolonged their resident time in lung post inhalation up to 48 h. The increase of local H 2 O 2 concentration decreased the permeability of lung epithelial cells, accompanied by the significantly reduced tissue edema and inflammatory cell recruitment. The system also reduced the expression of various inflammatory factors, revealing its effective and promising treatment for ALI.
研究领域:
药学
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材料科学
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肺病学
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产品关联
DOI
高影响因子
CHEMISTRY & BIODIVERSITY
·
2025
·
IF 2.5
xiaoli wen,Fangyan Cai,Biting Cheng,Min Tan,Xiang Zhang,Ziheng Yao,Rumei Huang,Ge Zhang,Ling Liu,Hongning Liu
Qingzao Jiufei Decoction (QD) is a renowned prescription for nourishing lung Yin to treat lung related diseases in ancient and modern times. It has been reported that QD can effectively inhibit the growth of lung cancer, but the material basis and mechanism of its treatment of LC remain to be further studied. In this experiment, we combined serum pharmacochemistry and proteomics to study the pharmacodynamic material basis and mechanism of QD against lung cancer. The results showed that In vitro a total of 121 compounds were identified. A total of 33 prototype chemical components were identified in vivo, which may be effective active ingredients for QD treatment of LC. Proteomic experiments have shown that compared with the model group, 113 DEPs in LC tissues were significantly changed after QD treatment, among which 57 proteins were significantly up-regulated and 56 proteins were significantly down-regulated (p < 0.05), GO and KEGG enrichment analysis was performed on these DEPs. A total of 205 pathways were enriched, and the PI3K-Akt signaling pathway was experimentally verified. The results showed that QD can be used to treat lung cancer by inhibiting the activation of the PI3K/Akt/mTOR signaling pathway.
研究领域:
药理学
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肿瘤学
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蛋白质组学
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中医药
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生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2019
·
IF 3.973
Kaiyu Wang,Yiteng Lei,Donglin Xia,Peipei Xu,Tao Zhu,Zhongying Jiang,Yuqiang Ma
Natural cellular membranes, with the outstanding qualities of biocompatibility and specificity, have gained growing attentions in the system of drug delivery. Nanoparticles coated with cellular membranes are starting to be applied as drug-loaded-vehicles to target tumors. Here, neutrophil membranes were selected to apply in the treatment of inflammation because neutrophils can participate in various inflammatory responses and accumulate at inflammatory sites to eliminate pathogens. Through extracting neutrophil membranes from natural neutrophils without affecting their biological properties, nanoparticles loaded with sparfloxacin (SPX) were coated with these membranes and disguised as neutrophils. Compared with traditional nano-medicines, the neutrophil membrane-coated nanoparticles (NM-NP-SPX) possessed precise targeting ability just like the neutrophils could accumulate at inflammatory sites when inflammation burst. In addition, NM-NP-SPX could prolong the circulation time and had the property of controlled-release. Through in vivo experiments, we found that the concentration of three representative inflammatory cytokines in blood, bacteria and inflammatory cells in lungs of the mice with pneumonia reduced significantly in the initial 24 h after the injection of NM-NP-SPX, which meant that NM-NP-SPX could greatly reduce the risk of death for the patients with inflammation. Moreover, the infected lungs could recover rapidly without any side effects to other organs due to the low cytotoxicity of NM-NP-SPX against normal cells. Therefore, our developed drug delivery system has enormous advantages in treating inflammations. Not only that, this kind of bionic method may have greater value and application prospects in curing the inflammations arisen from cancers.
研究领域:
药学
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纳米技术
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炎症研究
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Jing Tang,Jianming Li,Guo Li,Haitao Zhang,Ling Wang,Dai Li,Jinsong Ding
Idiopathic pulmonary fibrosis is a progressive, fatal lung disease with poor survival. The advances made in deciphering this disease have led to the approval of different antifibrotic molecules, such as pirfenidone and nintedanib. An increasing number of studies with particles (liposomes, nanoparticles [NPs], microspheres, nanopolymersomes, and nanoliposomes) modified with different functional groups have demonstrated improvement in lung-targeted drug delivery. In the present study, we prepared, characterized, and evaluated spermidine (Spd)-modified poly(lactic-co-glycolic acid) (PLGA) NPs as carriers for fluorofenidone (AKF) to improve the antifibrotic efficacy of this drug in the lung. Spd-AKF-PLGA NPs were prepared and functionalized by modified solvent evaporation with Spd and polyethylene glycol (PEG)-PLGA groups. The size of Spd-AKF-PLGA NPs was 172.5±4.3 nm. AKF release from NPs was shown to fit the Higuchi model. A549 cellular uptake of an Spd–coumarin (Cou)-6-PLGA NP group was found to be almost twice as high as that of the Cou-6-PLGA NP group. Free Spd and difluoromethylornithine (DFMO) were preincubated in A549 cells to prove uptake of Spd-Cou-6-PLGA NPs via a polyamine-transport system. As a result, the uptake of Spd-Cou-6-PLGA NPs significantly decreased with increased Spd concentrations in incubation. At higher Spd concentrations of 50 and 500 µM, uptake of Spd-Cou-6-PLGA NPs reduced 0.34- and 0.49-fold from that without Spd pretreatment. After pretreatment with DFMO for 36 hours, cellular uptake of Spd-Cou-6-PLGA NPs reached 1.26-fold compared to the untreated DFMO group. In a biodistribution study, the drug-targeting index of Spd-AKF-PLGA NPs in the lung was 3.62- and 4.66-fold that of AKF-PLGA NPs and AKF solution, respectively. This suggested that Spd-AKF-PLGA NPs accumulated effectively in the lung. Lung-histopathology changes and collagen deposition were observed by H&E staining and Masson staining in an efficacy study. In the Spd-AKF-PLGA NP group, damage was further improved compared to the AKF-PLGA NP group and AKF-solution group. The results indicated that Spd-AKF-PLGA NPs are able to be effective nanocarriers for anti–pulmonary fibrosis therapy.
研究领域:
药学
·
肺病学
·
纳米技术
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2023
·
IF 4.9
Shengnan Qiu,Xianglei Fu,Yanbin Shi,Hengchang Zang,Yunpeng Zhao,Zhilong Qin,Guimei Lin,Xiaogang Zhao
Idiopathic pulmonary fibrosis (IPF) causes worsening pulmonary function, and no effective treatment for the disease etiology is available now. Recombinant Human Relaxin-2 (RLX), a peptide agent with anti-remodeling and anti-fibrotic effects, is a promising biotherapeutic candidate for musculoskeletal fibrosis. However, due to its short circulating half-life, optimal efficacy requires continuous infusion or repeated injections. Here, we developed the porous microspheres loading RLX (RLX@PMs) and evaluated their therapeutic potential on IPF by aerosol inhalation. RLX@PMs have a large geometric diameter as RLX reservoirs for a long-term drug release, but smaller aerodynamic diameter due to their porous structures, which were beneficial for higher deposition in the deeper lungs. The results showed a prolonged release over 24 days, and the released drug maintained its peptide structure and activity. RLX@PMs protected mice from excessive collagen deposition, architectural distortion, and decreased compliance after a single inhalation administration in the bleomycin-induced pulmonary fibrosis model. Moreover, RLX@PMs showed better safety than frequent gavage administration of pirfenidone. We also found RLX-ameliorated human myofibroblast-induced collagen gel contraction and suppressed macrophage polarization to the M2 type, which may be the reason for reversing fibrosis. Hence, RLX@PMs represent a novel strategy for the treatment of IPF and suggest clinical translational potential.
研究领域:
呼吸病学
·
药学
·
生物技术
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2023
·
IF 5.6
E. Sun,Xiangqi Meng,Zhaoxia Kang,Huimin Gu,Mingyu Li,Xiaobin Tan,Liang Feng,Xiaobin Jia
Lung cancer is a common malignant tumor in clinical practice, and its morbidity and mortality are in the forefront of malignant tumors. Radiotherapy, chemotherapy, and surgical treatment play an important role in the treatment of lung cancer, however, radiotherapy has many complications and even causes partial loss of function, the recurrence rate after surgical resection is high, and the toxic and side effects of chemotherapy drugs are strong. Traditional Chinese medicine has played a huge role in the prognosis and improvement of lung cancer, among them, Zengshengping (ZSP) has the effect of preventing and treating lung cancer. Based on the “gut-lung axis” and from the perspective of “treating the lung from the intestine”, the purpose of this study was to research the effect of Zengshengping on the intestinal physical, biological, and immune barriers, and explore its role in the prevention and treatment of lung cancer. The Lewis lung cancer and urethane-induced lung cancer models were established in C57BL/6 mice. The tumor, spleen, and thymus were weighed, and the inhibition rate, splenic and thymus indexes analyzed. Inflammatory factors and immunological indexes were detected by enzyme-linked immunosorbent assay. Collecting lung and colon tissues, hematoxylin and eosin staining was performed on lung, colon tissues to observe histopathological damage. Immunohistochemistry and Western blotting were carried out to detect tight junction protein expression in colon tissues and expression of Ki67 and p53 proteins in tumor tissues. Finally, the feces of mice were collected to investigate the changes in intestinal microbiota using 16SrDNA high-throughput sequencing technology. ZSP significantly reduced tumor weight and increased the splenic and thymus indexes. It decreased expression of Ki67 protein and increased expression of p53 protein. Compared with Model group, ZSP group reduced the serum levels of interleukin (IL)-1β, IL-6, tumor necrosis factor α (TNF-α), and ZSP group increased the concentration of secretory immunoglobulin A (sIgA) in the colon and the bronchoalveolar lavage fluid (BALF). ZSPH significantly increased the level of tight junction proteins such as ZO-1, Occludin and Claudin-1. Model group significantly reduced the relative abundance of Akkermansia ( p < 0.05) and significantly promoted the amount of norank_f_ Muribaculaceae, norank_f_ Lachnospiraceae ( p < 0.05) compared with that in the Normal group. However, ZSP groups increased in probiotic strains ( Akkermansia ) and decreased in pathogens ( norank_f_ Muribaculaceae, norank_f_ Lachnospiraceae). Compared with the urethane-induced lung cancer mice, the results showed that ZSP significantly increased the diversity and richness of the intestinal microbiota in the Lewis lung cancer mice. ZSP played an important role in the prevention and treatment of lung cancer by enhancing immunity, protecting the intestinal mucosa and regulating the intestinal microbiota.
研究领域:
肿瘤学
·
药理学
·
免疫学
·
微生物学
·
分子生物学
✓ 已验证
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）