Experimental Hematology & Oncology
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2025
·Vol. 14
·期 1
·1-19
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IF 13.5
Shan Guangyao,Bian Yunyi,Ren Shencheng,Hu Zhengyang,Pan Binyang,Zeng Dejun,Zheng Zhaolin,Fan Hong,Bi Guoshu,Yao Guangyu,Zhan Cheng
Background Ferroptosis, a regulated cell death driven by iron-dependent lipid peroxidation, is associated with chemoresistance in lung adenocarcinoma (LUAD). This study aims to investigate the role of sarcosine in ferroptosis and its underlying mechanisms.Methods An RSL3-induced ferroptosis model was used to screen a library of 889 human endogenous metabolites and metabolomic profiling was harnessed to identify metabolites associated with ferroptosis. Cell viability, lipid-reactive oxygen species (ROS), ferrous iron, malondialdehyde (MDA), and mitochondrial integrity were assessed to evaluate sarcosine’s effects on ferroptosis. Metabolic fate was studied using 15N-labeled sarcosine. Next, we used untargeted metabolomic profiling and next-generation sequencing to dissect metabolic and transcriptomic changes upon sarcosine supplementation. The effects of sarcosine on ferroptosis and chemotherapy were further validated in patient-derived organoids (PDOs), xenograft models, and LUAD tissues.Results Sarcosine emerged as a potent ferroptosis inducer in the metabolic library screening, which was further confirmed via cell viability, lipid-ROS, ferrous iron, and MDA measurements. Metabolic flux analysis showed limited conversion of sarcosine to other metabolites in LUAD cells, while untargeted metabolomic profiling and seahorse assays indicated a metabolic shift from glycolysis to oxidative phosphorylation. Sarcosine enhanced pyruvate dehydrogenase activity to generate more ROS by interacting with PDK4, reducing PDHA1 phosphorylation. As a co-activator of N-methyl-D-aspartate receptor (NMDAR), sarcosine also exerted its pro-ferroptosis effect via regulating ferrous export through the NMDAR/MXD3/SLC40A1 axis. Given the significance of ferroptosis in chemotherapy, we validated that sarcosine enhanced the sensitization of cisplatin by promoting ferroptosis in LUAD cells, PDOs, and xenograft models.Conclusion Sarcosine promotes ferroptosis and enhances chemosensitivity, suggesting its potential as a therapeutic agent in treating LUAD.
研究领域:
肿瘤学
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代谢组学
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细胞生物学
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DOI
PubMed
高影响因子
Research
·
2024
·
IF 8.5
Pingjun Zhu,Xi Wang,Qingfeng Wu,Jianbo Zhu,Yifan Que,Yan Wang,Yongkai Ding,Yang Yang,Jie Jin,Xin Zhang,Qian Xu,Qinge Yong,Christopher Chang,Guogang Xu,Yingzhen Du
Background: B-cell receptor-associated protein 31 (BCAP31) has protective effects against alveolar epithelial type II cells (AECII) damage by inhibiting mitochondrial injury in acute lung injury (ALI) induced by lipopolysaccharide (LPS), whereas the precise mechanism is still unclear. It is known that PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy can remove damaged mitochondria selectively, which may be involved in BCAP31 protection against mitochondrial injury. Methods: In the current study, ALI mice models were established by using surfactant protein C (Sftpc)-BCAP31 transgenic mice (BCAP31TG mice) and AECII-specific BCAP31 knockout mice (BCAP31CKO mice) treated with LPS. Results: BCAP31 expression in lung tissue and AECII were inhibited in ALI mice. Under LPS challenge, lower level of BCAP31 was found to correlate positively with pathological injury of the lung, respiratory dysfunction, mortality rates, inflammation response, and AECII damage. Further study showed that down-regulation of BCAP31 induced decreased phosphorylation of PINK1 via reduced binding to PINK1, thereby restraining PINK1/Parkin-mediated mitophagy. Down-regulation of mitophagy promoted mitochondrial injury, as shown by the increase in mitochondrial permeability transition pore opening rate, together with enhanced mitochondrial reactive oxygen species (mROS), which were accompanied by increased cellular apoptosis and reactive oxygen species (ROS). The increased cellular ROS contributed to the inflammatory response via activation of nuclear factor κB (NF-κB). In contrast, BCAP31 overexpression promoted phosphorylation of PINK1 and PINK1/Parkin-mediated mitophagy, thus blocking the mROS/ROS/NF-κB pathway, favoring a protective condition that ultimately led to the inhibition of AECII apoptosis and inflammatory response in LPS-induced ALI. Conclusion: Ultimately, BCAP31 alleviated ALI by activating PINK1/Parkin-mediated mitophagy and blocking the mROS/ROS/NF-κB pathway in AECII.
研究领域:
免疫学
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肺病学
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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
International Journal of Chronic Obstructive Pulmonary Disease
·
2024
·
IF 2.7
Liguo Lu,Chengdong Zhu,Jian Xu,Yulan Hu,Juxiang Dai,Sheng Wang,Tao Wei
Introduction The Lifei Decoction (LD) is a commonly utilized Chinese medicine for the treatment of sepsis and bronchial inflammation. However, its therapeutic potential in chronic obstructive pulmonary disease (COPD) remains unknown. Therefore, the objective of this study was to investigate the therapeutic efficacy and underlying mechanism of LD in a mouse model of COPD induced by cigarette smoke (CS) combined with lipopolysaccharide (LPS).Methods Hematoxylin-eosin (H&E) staining was employed to observe the pathological alterations in lung tissue, while ELISA was utilized for the detection of levels of inflammatory factors in both lung tissue and bronchoalveolar lavage fluid (BALF). Additionally, Western blot analysis was conducted to assess the expression of p-NF-κB, GDF11, ZO-1, and Occludin-1 proteins. The changes in intestinal flora were evaluated using the viable bacteria count method.Results The administration of LD demonstrates significant efficacy in mitigating pulmonary tissue damage in a murine model, while concurrently inhibiting the activation of the inflammatory pathway NF-κB to attenuate the levels of pro-inflammatory factors. Moreover, LD exhibits the capacity to enhance the expression of intestinal functional proteins ZO-1 and Occludin-1, thereby rectifying dysbiosis within the gut microbiota.Conclusion The LD shows great promise as a potential treatment for COPD.
研究领域:
药理学
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呼吸病学
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免疫学
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微生物学
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DOI
PubMed
高影响因子
JOURNAL OF MEMBRANE SCIENCE
·
2025
·
IF 9
Bingyang Lu,Junchang Guo,Hao Yang,Xiao Han,Peng Yu,Shengjun Cheng,Zhenxu Shi,Dehui Wang,Weifeng Zhao,Jing Luo,Xu Deng
Gas exchange membranes, as the crucial components of extracorporeal membrane oxygenation (ECMO) systems, enable efficient O 2 /CO 2 exchange in blood while maintaining adequate oxygen saturation in patients. However, clinical gas exchange membranes remain prone to thrombosis complications, which severely compromise their gas exchange effectiveness. To address this, we propose a blood-repellent gas exchange membrane (BRGEM) that helps in preventing thrombosis due to its minimal solid-liquid contact areas, while significantly enhancing gas exchange through a gas-liquid direct contact diffusion strategy. Notably, the BRGEM exhibits a 22.09-fold reduction in thrombus formation without anticoagulants compared to commercial ECMO membranes, demonstrating its exceptional anti-fouling properties. Furthermore, the membrane enables rapid oxygen recovery in the acute respiratory distress syndrome rabbit model, achieving approximately 12.97-fold improvement. We anticipate this strategy will significantly advance the development of next-generation blood oxygenation membranes and artificial lung technologies, offering transformative potential for future clinical applications.
研究领域:
生物医学工程
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膜技术
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呼吸医学
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生物材料
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人工器官
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产品关联
DOI
高影响因子
CARBOHYDRATE POLYMERS
·
2017
·
IF 4.811
Suhui Ni,Yun Liu,Yue Tang,Jing Chen,Shuhan Li,Ji Pu,Lidong Han
The effect of gene silencing by survivin siRNA (siSurvivin) on the proliferation and apoptosis of lung tumor has been attracted more interest. GABA B receptor ligand-directed nanoparticles consisting of baclofen functionalized trimethyl chitosan (Bac-TMC) as polymeric carriers, tripolyphosphate (TPP) as ionic crosslinker, and siSurvivin as therapeutic genes, were designed to enhance the survivin gene silencing. GABA B receptor agonist baclofen (Bac) was initially introduced into TMC as a novel ligand. This Bac-TMC/TPP nanoparticles increased the uptake of survivin siRNA through the interaction with GABA B receptor, further resulted in efficient cell apoptosis and gene silencing. For siRNA-loaded nanoparticles pulmonary delivery, mannitol was utilized for it delivery into pressurized metered dose inhalers (pMDI). The fine particle fractions of this formulation was (45.39 ± 2.99)% indicating the appropriate deep lung deposition. These results revealed that this pMDI formulation containing Bac-TMC/TPP nanoparticles would be a promising siRNA delivery system for lung cancer treatment.
研究领域:
药学科学
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纳米技术
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分子生物学
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药物递送系统
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癌症研究
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DOI
PubMed
高影响因子
MOLECULES
·
2022
·Vol. 27
·期 22
·7857
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IF 4.927
Rong Tian,Haiyan Zhu,Yan Lu,Xunlong Shi,Peng Tu,Hong Li,Hai Huang,Daofeng Chen
Qingdai-Mabo (QM), a traditional Chinese herbal formula composed of medicinal herb and fungus, has been used for treatment of cough and viral pneumonia. However, the underlying mechanism and bioactive components against anti-influenza A virus remain unclear. In the present study, ethyl acetate (EA) extract of QM decoctions was tested for its biological activity against acute lung injury (ALI) and its main components were identified using UPLC−MS/MS. In total, 18 bioactive components were identified, including 2-Methylquinaozlin-4(3H)-one (C1), which showed significant antiviral activity in vitro with an IC50of 23.8 μg/mL. Furthermore, we validated the efficacy of C1 in ameliorating ALI lesions and inflammation in influenza A virus-infected mice. The results showed that C1 significantly reduced the lung index, downregulated neuraminidase (NA) and nucleoprotein (NP), and decreased the expression of pro-inflammatory molecules IFN-α, TNF-α, MCP-1, IL-6, and IL-8; however, they enhanced levels of IL-10 and IFN-γ in lung homogenate from mice infected by influenza A virus. In addition, C1 inhibited the recruitment of macrophages. These in vitro and in vivo studies suggested that the significant anti-influenza A virus activity contributed to its curative effect on lesions and inflammation of viral pneumonia in mice. Given its potential antiviral activity against influenza A virus, C1 is determined to be a main active component in the EA extract of QM. Taken together, the antiviral activity of C1 suggests its potential as an effective treatment against viral pneumonia via the inhibition of virus replication, but the mechanism C1 on antiviral research needs to be explored further.Keywords:influenza A virus;2-Methylquinazolin-4(3H)-one;antiviral activity;acute lung injury;viral pneumonia;Qingdai-Mabo
研究领域:
药理学
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病毒学
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中医药
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DOI
PubMed
高影响因子
CELL RESEARCH
·
2020
·Vol. 30
·期 9
·794-809
·
IF 20.507
Wu Jun,Song Dingyun,Li Zhongwen,Guo Baojie,Xiao Yani,Liu Wenjing,Liang Lingmin,Feng Chunjing,Gao Tingting,Chen Yanxia,Li Ying,Wang Zai,Wen Jianyan,Yang Shengnan,Liu Peipei,Wang Lei,Wang Yukai,Peng Liang,Stacey Glyn Nigel,Hu Zheng,Feng Guihai,Li Wei,Huo Yan,Jin Ronghua,Shyh-Chang Ng,Zhou Qi,Wang Liu,Hu Baoyang,Dai Huaping,Hao Jie
Lung injury and fibrosis represent the most significant outcomes of severe and acute lung disorders, including COVID-19. However, there are still no effective drugs to treat lung injury and fibrosis. In this study, we report the generation of clinical-grade human embryonic stem cells (hESCs)-derived immunity- and matrix-regulatory cells (IMRCs) produced under good manufacturing practice requirements, that can treat lung injury and fibrosis in vivo. We generate IMRCs by sequentially differentiating hESCs with serum-free reagents. IMRCs possess a unique gene expression profile distinct from that of umbilical cord mesenchymal stem cells (UCMSCs), such as higher expression levels of proliferative, immunomodulatory and anti-fibrotic genes. Moreover, intravenous delivery of IMRCs inhibits both pulmonary inflammation and fibrosis in mouse models of lung injury, and significantly improves the survival rate of the recipient mice in a dose-dependent manner, likely through paracrine regulatory mechanisms. IMRCs are superior to both primary UCMSCs and the FDA-approved drug pirfenidone, with an excellent efficacy and safety profile in mice and monkeys. In light of public health crises involving pneumonia, acute lung injury and acute respiratory distress syndrome, our findings suggest that IMRCs are ready for clinical trials on lung disorders.
研究领域:
干细胞生物学
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肺病学
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再生医学
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免疫学
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药理学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2019
·
IF 3.845
Ma Xiaoyao,Liu Aina,Liu Wenjuan,Wang Zhihua,Chang Nianwei,Li Suyun,Li Jiansheng,Hou Yuanyuan,Bai Gang
Chronic obstructive pulmonary disease (COPD) has been a major public health problem and is still a formidable challenge for clinicians. It is urgent to find new compounds for minimizing the risk of disease progression and exacerbation especially in the early phase of COPD. A traditional Chinese medicine (TCM) formula, Chuan Bei Pi Pa dropping pills (CBPP), was tested in this study to investigate its potential mechanisms in preventing the exacerbation of COPD. Phosphoproteomics analysis for a smog stimulated early stage COPD mice model was employed to detect the underlying molecular mechanisms of CBPP. In addition, protein–protein interaction (PPI) and bioinformatics analyses were included to analyze the key proteins and predict the key bioactive compounds. The results indicated that peiminine (PEI) target epidermal growth factor receptor (EGFR) prevented the exacerbation of COPD by inhibiting the EGFR signaling pathway, and ursolic acid (UA) can alleviate inflammation disorders via inhibition of CASP3 on mitogen-activated protein kinase (MAPK) signaling pathway. After in vivo and in vitro evaluations, we revealed that PEI from CBPP, as a lead compound, can improve lung function and alleviate pulmonary fibrosis by acting on the EGFR and MLC2 signaling pathways. Furthermore, the approach described here is an effective way to analyze and identify the bioactive ingredients from a mixture by functional proteomics analysis.
研究领域:
药理学
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呼吸病学
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蛋白质组学
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传统中药
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产品关联
DOI
PubMed
高影响因子
Journal of Advanced Research
·
2025
·
IF 13
Lin-Tao Xu,Qing-Tong Han,Zhen-Peng Xu,Xiao-Ning Wang,Hua Zhang,Tao Shen
Introduction Chronic obstructive pulmonary disease (COPD) represents a significant global health challenge, characterized by substantial morbidity and mortality rates. In traditional Chinese medicine (TCM), Farfarae Flos (FF) has been widely utilized as a therapeutic agent for COPD. However, its specific bioactive compounds and the underlying mechanisms are unclear. Objectives This study aims to identify bioactive constituent of FF against COPD and illustrate its therapeutic target and mechanism. Methods and Results In this research, a high-throughput screening on constituents of FF was conducted, leading to the identification of a potent anti-COPD lead, tussilagone (TUS). Utilizing biotin-labeling approach, Kelch-like ECH-associated protein 1 (KEAP1), the ubiquitin E3 ligase of nuclear factor erythroid 2-related factor 2 (Nrf2), was identified to be the direct target of TUS. Mechanistically, TUS activated KEAP1-Nrf2 axis by covalent modification of cysteine 434 (Cys434), a novel high-reactivity cysteine of KEAP1. TUS-mediated Nrf2 activation further suppressed the activation of nuclear factor kappa-B (NF-κB) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome, consequently attenuating lung inflammation in COPD. Conclusion TUS was identified as the bioactive constituent of FF against COPD, which directly targeted Cys434 of KEAP1. KEAP1 was proven to be a pharmacological target for the treatment of COPD, and Cys434 was identified to be the first highly reactive cysteine in Kelch domain of KEAP1. TUS inhibits lung inflammation by regulating Nrf2 and NF-κB/NLRP3, which is the mechanism of FF against COPD
研究领域:
药理学
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分子生物学
·
呼吸医学
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民族药理学
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生物化学
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免疫学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Xiangyan Meng,Junfeng Li,Qianying Lu,Jianfeng Zhang,Yi Zheng,Ziquan Liu,Mengjun Ji,Zihan Kou,Linlin Li,Haojun Fan
Primary blast lung injury (PBLI) manifests as respiratory distress and hemoptysis syndrome resulting from exposure to blast waves, yet its pathogenesis remains incompletely understood, leading to a dearth of effective treatment options. Neutrophil extracellular traps (NETs) may play important roles in acute lung injury. However, the role of NETs in PBLI was unclear. Therefore, the objective of the present study was to investigate the role of NETs in PBLI. Our study found that, compared to the Con group, blast wave induced the destruction of lung tissue structure, the increase of lung inflammatory factors, coagulation-related factors, and endothelial injury markers, as well as the release of NETs. Further research showed that the levels of inflammatory factors, coagulation-related factors, and endothelial injury markers of pulmonary microvascular endothelial cells (PMVEC) were up-regulated after co-culturing with neutrophils extracted from the blood of PBLI rats, compared to the Con group. The damaging effect of NETs on the lung tissue of rats and PMVEC was reversed after DNase I was applied. Our work revealed that blast exposure induces lung tissue inflammation and coagulation disorders in PBLI rats by mediating PMVEC dysfunction, thereby accelerating the development of PBLI. Moreover, NETs are the key factors causing inflammation and coagulation disorders of PBLI, and the elimination of NETs may become a new target for PBLI therapy.
研究领域:
免疫学
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创伤医学
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分子生物学
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呼吸病学
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转化医学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
·
2023
·
IF 4.9
Dongli Qi,Bei Jia,Hui Peng,Jiachen He,Jiaxin Pi,Pan Guo,Ying Zhang,Xiuping Deng,Jiawei Li,Zhidong Liu
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal lung disease caused by multiple factors. Currently, safe, and effective drugs for the treatment of IPF have been extremely scarce. Baicalin (BA) is used to treat pulmonary fibrosis, IPF, chronic obstructive pulmonary disease, and other lung diseases. Ambroxol hydrochloride (AH), a respiratory tract lubricant and expectorant, is often used to treat chronic respiratory diseases, such as bronchial asthma, emphysema, tuberculosis, and cough. The combination of BA and AH can relieve cough and phlegm, improve lung function, and potentially treat IPF and its symptoms. However, given the extremely low solubility of BA, its bioavailability for oral absorptions is also low. AH, on the other hand, has been associated with certain side effects, such as gastrointestinal tract and acute allergic reactions, which limit its applicability. Therefore, an efficient drug delivery system is urgently needed to address the mentioned problems. This study combined BA and AH as model drugs with L-leucine (L-leu) as the excipient to prepare BA/AH dry powder inhalations (BA/AH DPIs) using the co-spray drying method. We the performed modern pharmaceutical evaluation, which includes particle size, differential scanning calorimetry analysis, X-ray diffraction, scanning electron microscope, hygroscopicity, in vitro aerodynamic analysis, pharmacokinetics, and pharmacodynamics. Notably, BA/AH DPIs were found to be advantageous over BA and AH in treating IPF and had better efficacy in improving lung function than did the positive drug pirfenidone. The BA/AH DPI is a promising preparation for the treatment of IPF given its lung targeting, rapid efficacy, and high lung bioavailability.
研究领域:
药剂学
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肺病学
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药物递送系统
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药理学
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2022
·
IF 7.033
Nan Liu,Yi Guan,Chunling Zhou,Yongheng Wang,Zhanfei Ma,Sanqiao Yao
Purpose The main objective of this study was to clarify the biodistribution and in vivo toxicological effects of indium-tin oxide nanoparticles (Nano-ITO) in male rats.Methods Dose-response (three divided doses) and time-course studies (six exposure durations) were performed to examine Nano‑ITO-induced pulmonary and systemic toxicity. At the end of the experiment, hematology and serum biochemical parameters were determined, and cytokines levels and oxidative stress were analyzed in the bronchoalveolar lavage fluid. In addition, indium biodistribution following Nano‑ITO exposure was determined using inductively coupled plasma mass spectrometer to measure indium concentration in the lung, spleen, brain, liver, kidney, and testis. Rat lung tissues were also harvested for staining with hematoxylin and eosin, periodic acid Schiff stain, Masson’s trichrome, and Sirius red.Results Relative lung weights were significantly increased in all Nano-ITO-exposed groups. All organs exhibited a statistically significant difference in indium levels. Rat exposure to Nano‑ITO resulted in a dose-response increase in acute systemic inflammation and injury. BALF analysis revealed significantly elevated levels of lung oxidative stress, pulmonary injury, and inflammatory markers across most groups. Serum biochemistry results showed that Nano-ITO could affect the liver and renal functions of rats when exposed for 3 days. Compared with the control group, significant inflammatory responses or pathological changes were observed in the liver, kidney, and testis of rats at different sampling times and three doses examined. Histopathologically, foci of slight-to-severe pulmonary inflammatory response along with acute inflammatory, pulmonary fibrosis and alveolar proteinosis were detected, and the severity of these lesions worsened in a dose- and time-dependent manner.Discussion These findings provide novel evidence that enhanced progressive massive pulmonary fibrosis, diffuse interstitial fibrosis, and collagen accumulation play a role in the development of pulmonary alveolar proteinosis following Nano-ITO exposure.
研究领域:
纳米技术
·
毒理学
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肺病学
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病理学
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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）