Pharmacognosy Magazine
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2023
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IF 0.7
Guiyuan Liu,Yinliang Bai,Guangxian Leng,Hanwei Ma,Yin Kong,Liuqing Guo,Fahong Wu,Fengxian Wei,Yi Pang,Youcheng Zhang
Background:Leakage of the alveolar epithelial barrier can lead to pulmonary oedema, leading to organ dysfunction.Objectives:Combination anthraquinone (CA) and free anthraquinone (FA) were extracted from Rhubarb, and the prevention and therapeutic effects of Rhubarb anthraquinones (RA) on lipopolysaccharide (LPS)-induced lung injury were investigated.Materials and Methods:The CA and FA were extracted from Rhubarb by water solvent extraction and ethanol solvent extraction. The extracted RA content was determined using spectrophotometry and high-performance liquid chromatography (HPLC). A mouse model of inflammatory lung injury was established by LPS induction to study the mechanism of RA activity. Inflammatory factors were measured using an enzyme-linked immunosorbent assay. Changes in alveolar epithelial leakage were assessed using a permeability assay. Changes in lung injury were evaluated by histopathological and ultrastructural observations. Tight junction (TJ) markers and Ras homolog gene family member A (RhoA)/Rho-associated protein kinase 1 (ROCK1) pathway-related proteins were measured using immunohistochemistry and Western blotting. As an agonist of RhoA/Rock signalling, U46619 was used to further verify whether RA acts through this pathway.Results:RA could inhibit pulmonary inflammation by decreasing the level of inflammatory factors. The alveolar epithelial permeability was reduced, and the pathological injury of the lung tissue was alleviated after administration with RA. Furthermore, the expression of TJ proteins was up regulated and RhoA/ROCK1 signalling was inhibited in the presence of RA. The effects of RA on TJ proteins were partially reversed by U46619.Conclusion:RA effectively protects mice against inflammatory lung injury by enhancing alveolar epithelial TJ via RhoA/ROCK1 signalling.
研究领域:
药理学
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肺病学
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免疫学
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分子生物学
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高影响因子
JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Zhi-Chao Sun,Ran Liao,Caihong Xian,Ran Lin,Liying Wang,Yifei Fang,Zhongde Zhang,Yuntao Liu,Jun Wu
Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a high-mortality disease caused by multiple disorders such as COVID-19, influenza, and sepsis. Current therapies mainly rely on the inhalation of nitric oxide or injection of pharmaceutical drugs (e.g., glucocorticoids); however, their toxicity, side effects, or administration routes limit their clinical application. In this study, pachypodol (Pac), a hydrophobic flavonol with anti-inflammatory effects, was extracted from Pogostemon cablin Benth and intercalated in liposomes (Pac@liposome, Pac-lipo) to improve its solubility, biodistribution, and bioavailability, aiming at enhanced ALI/ARDS therapy. Nanosized Pac-lipo was confirmed to have stable physical properties, good biodistribution, and reliable biocompatibility. In vitro tests proved that Pac-lipo has anti-inflammatory property and protective effects on endothelial and epithelial barriers in lipopolysaccharide (LPS)-induced macrophages and endothelial cells, respectively. Further, the roles of Pac-lipo were validated on treating LPS-induced ALI in mice. Pac-lipo showed better effects than did Pac alone on relieving ALI phenotypes: It significantly attenuated lung index, improved pulmonary functions, inhibited cytokine expression such as TNF-α, IL-6, IL-1β, and iNOS in lung tissues, alleviated lung injury shown by HE staining, reduced protein content and total cell number in bronchoalveolar lavage fluid, and repaired lung epithelial and vascular endothelial barriers. As regards the underlying mechanisms, RNA sequencing results showed that the effects of the drugs were associated with numerous immune- and inflammation-related signaling pathways. Molecular docking and western blotting demonstrated that Pac-lipo inhibited the activation of the TLR4-MyD88-NF-κB/MAPK signaling pathway. Taken together, for the first time, our new drug (Pac-lipo) ameliorates ALI via inhibition of TLR4-MyD88-NF-κB/MAPK pathway-mediated inflammation and disruption of lung barrier. These findings may provide a promising strategy for ALI treatment in the clinic.
研究领域:
药理学
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呼吸病学
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纳米医学
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DOI
PubMed
高影响因子
FASEB JOURNAL
·
2025
·Vol. 39
·期 5
·e70420
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IF 4.2
Min Zhu,Xiaofang Fan,Nan Zhang,Hui Wang,Jianshe Ma,Xianghong Yin,Junyan Cai,Linjing Cong,Ran Chen,Junming Fan,Xiaoxia Kong,Bin Geng,Yongsheng Gong,Congkuo Du
Endothelial pyroptosis, a pro-inflammatory programmed cell death, promotes endothelial inflammation and is a pivotal process in the initial stage of acute lung injury (ALI). Hydrogen sulfide (H 2 S), a gasotransmitter primarily dependent on cystathionine γ-lyase (CSE) in the cardiovascular and respiratory systems, plays a protective role during ALI. Nonetheless, the modulatory role and precise molecular mechanism of endothelial endogenous CSE/H 2 S in the pathogenesis of ALI remain elusive. Herein, we prepared an ALI mouse model using intratracheal administration of LPS (5 mg/kg), and lung injury was assessed by evaluating pulmonary edema, inflammatory response, and endothelial pyroptosis. In this model, H 2 S production from pulmonary tissues declined in a time-dependent manner, accompanied by a compensatory elevation of CSE protein levels. Treatment with the H 2 S donor (NaHS) attenuated pulmonary edema, inflammatory cell infiltration, endothelial pyroptosis, and reduced serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Meanwhile, the inducible deletion of CSE in endothelial cells exacerbated these changes. The blocking effect of CSE/H 2 S on endothelial pyroptosis (evidenced by caspase-11 activation and GSDMD-NT formation) was also confirmed in cultured pulmonary microvascular endothelial cells (PMECs). Mechanistically, H 2 S-mediated regulation of sirtuin-1 (SIRT1) expression and activation (via sulfhydration) contributed to the modulatory process. Collectively, we uncovered that endothelial endogenous CSE/H 2 S alleviates endothelial pyroptosis by activating SIRT1, thereby preventing LPS-induced acute lung injury. Graphical In the LPS-induced ALI model, caspase-1-independent pyroptosis was activated. The expression of activated caspase-11 and GSDMD-NT was increased, accompanied by pulmonary edema and inflammatory infiltration. Endothelial CSE/H 2 S deficiency aggravated endothelial pyroptosis and acute lung injury. Mechanistically, endothelial endogenous CSE/H 2 S mediated the expression and activation of sirtuin-1 (SIRT1) via sulfhydration, one of the post-translational modifications. Activated SIRT1 inhibited the activation of caspase-11 and GSDMD-NT to inhibit endothelial pyroptosis, thereby alleviating acute lung injury.
研究领域:
医学
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分子生物学
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DOI
PubMed
高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
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2023
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IF 3.6
Zhu Xiaona,Bai Bin,Ge Xiangting,Zheng Bin,Xiao Zhongxiang,Tang Yue,Fang Letong,Tang Yelin,Dai Yuanrong,Zhang Bing,Zhang Yali
Inflammation is an important pathological process of many acute and chronic diseases, such as sepsis, arthritis, and cancer. Many factors can lead to an inflammatory state of the body, among which bacterial infection plays an important role. Bacterial infection often leads to sepsis, acute lung injury (ALI), or its more serious form of acute respiratory distress syndrome, which are the main fatal diseases in intensive care units. Costunolide has been reported to possess excellent anti-inflammatory activity; however, whether it can affect inflammation induced by gram-negative bacterial is still unclear. Lipopolysaccharide (LPS) stimulated mouse peritoneal macrophages (MPMs) to release proinflammatory cytokines was used as the cell model. The mouse model of sepsis and ALI was built through injecting intravenously and intratracheally of LPS. In the present study, costunolide inhibited LPS-induced inflammatory response through IKK/NF-κB signaling pathway in macrophages. In vivo, costunolide attenuated LPS-induced septic death in mice. Meanwhile, costunolide treatment alleviated LPS-induced lung injury and inflammation via inhibiting the infiltration of inflammatory cells and the expression of inflammatory cytokines. Taken together, these results demonstrated that costunolide could attenuate gram-negative bacterial induced inflammation and diseases and might be a potential candidate for the treatment of inflammatory diseases.
研究领域:
免疫学
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药理学
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炎症研究
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分子生物学
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DOI
PubMed
高影响因子
Journal of Functional Foods
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2025
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IF 4
Rui Ge,Qikai Su,Jian Liang,Lu Zheng,Qing-shan Li,Li Tang
The identification of natural compounds with therapeutic efficacy for acute lung injury has consistently represented a critical area of research. Dulcitol, a natural product isolated from plants, is extensively used in the food and medical industries as a sweetener. Herein, we investigated whether dulcitol exerts an anti-inflammatory effect on LPS-induced acute lung injury (ALI) in mice. In our study, ICR mice were pretreated with dulcitol at dose of 6, 12 and 24 mg/kg for seven consecutive days, followed by intratracheally instilled with LPS (10 mg/kg) to induce acute lung injury. In vitro, RAW264.7 and A549 cells were incubated with LPS in the presence of dulcitol to investigate the anti-inflammatory activity and mechanism. The results demonstrated that dulcitol effectively inhibited the infiltration of inflammatory cells and reduced the excessive production of pro-inflammatory cytokines triggered by LPS to ameliorates acute lung injury in mice. Additionally, in vitro experiments indicated that dulcitol suppressed the release of NO, IL-6 and TNF-α while reducing mRNA expression levels of IL-1β, IL-6, COX-2, iNOS and TNF-α in RAW264.7 and A549 cells in a dose-dependent manner. Furthermore, dulcitol significantly decreased TLR4, MyD88, and TRIF levels and inhibited the translocation of NF-κB from the cytoplasm to the nucleus. Our finding suggested that dulcitol could serve as a protective agent against LPS-induced acute lung injury by inhibiting the TLR-4/NF-κB signaling pathway.
研究领域:
免疫学
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药理学
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分子生物学
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高影响因子
PHYTOMEDICINE
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2025
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IF 8.3
Yixu Wang,Jin Zhang,Sihan Xu,Junjie Li,Wenjuan Liu,Min Jiang,Gang Bai
Background Acute lung injury (ALI) is a critical pathophysiological response in various respiratory diseases characterized by alveolar damage and excessive inflammation. It can progress to acute respiratory distress syndrome, with current treatments showing limited efficacy and considerable side effects. Psoralen (Pso), derived from Psoralea corylifolia L., has anti-inflammatory properties, but its role in ALI remains fully elucidated. Purpose This study aimed to investigate the therapeutic effects of Pso on ALI, and to explore its therapeutic targets and mechanisms. Methods The therapeutic potential of Pso was assessed using a model of ALI induced by lipopolysaccharide (LPS). The direct target was investigated using alkynyl-Psoralen (A-Pso) for chemical proteomic analysis, and a series of molecular biology methods were used to explore the underlying mechanism. Results Pso treatment significantly alleviated LPS-induced lung injury in mice, targeted macrophages, and inhibited the LPS-induced activation of macrophages. Target-fishing experiments identified high-mobility group box-1 (HMGB1) as a direct target of Pso in macrophages. FTS and CETSA confirmed Pso binding to HMGB1, and LC-MS/MS analysis indicated a covalent interaction between Pso and Cys106 of HMGB1. Furthermore, Pso covalently targeted Cys106, affecting HMGB1 binding to TLR4 and downregulating the phosphorylation of NF-κB, indicating the inhibition of the TLR4/NF-κB signaling pathway both in macrophages and in lung tissues of ALI mice. These findings suggest that Pso exerts its therapeutic effects by covalently targeting HMGB1 in macrophages and modulating the TLR4/NF-κB signaling pathway. Conclusion This study not only found that Pso improves LPS-induced ALI inflammation by targeting macrophages, but also verified that this mechanism of action is mainly caused by Pso covalently targeting Cys106 of HMGB1, inhibiting the HMGB1-TLR4 interaction, and thereby suppressing cytokine storm generation. As the first naturally derived HMGB1 covalent inhibitor with a clear binding site, Pso plays an important role in HMGB1 induced inflammatory diseases and is an active precursor for the development of new HMGB1 covalent inhibitors.
研究领域:
药理学
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免疫学
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呼吸病学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Zong-hui Xu,Man Li,Lin Liu,Shu-jing Wu,Ruo-an Wei,Mpofu Uphakeme Inobubele Sitholumusa,Xiao-ping Zhao,Jun-qiu Liu,Guo-yin Kai
Astragaloside IV (AS-IV), derived from Astragalus membranaceus , exhibits significant anti-inflammatory properties in a variety of diseases. However, the specific anti-inflammatory mechanism of AS-IV depends on the different organs and doses. Its protective effect is still unknown in acute lung injury (ALI). This study aims to investigate the potential anti-inflammatory mechanism of AS-IV in ALI. Lipopolysaccharide (LPS) and adenosine triphosphate (ATP) were utilized to form pyroptosis models in MH-S and RAW264.7 cells. Mouse model of ALI was induced by intranasal LPS administration. In addition, the anti-pyroptosis effect of AS-IV was evaluated by using the C5aR1 agonists BM-213, the C5aR1 overexpression plasmids and C5aR1 siRNA. AS-IV significantly reduced pulmonary edema, improved histopathological injury, and decreased inflammatory factors. Meanwhile, AS-IV reduced ROS level and the amount of NLRP3 and GSDMD-N in vitro and in vivo . Inhibiting C5aR1 can effectively and significantly alleviate the pyroptosis of alveolar macrophages. Further studies found that BM-213 and C5aR1 overexpression plasmids partially reversed the anti-pyroptosis effect of AS-IV. The anti-pyroptosis effect of AS-IV was significantly inhibited when C5aR1 was knocked down. Our study demonstrate that AS-IV has anti-inflammatory protective effects on LPS-induced ALI, indicating that AS-IV may be a potential therapeutic agent for the treatment of ALI. This effect may be achieved by reducing the content of C5a, lowering the expression of C5aR1, and inhibiting cell pyroptosis.
研究领域:
药理学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
CELLULAR IMMUNOLOGY
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2025
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IF 2.9
Yiqi Wang,Xiuhua Zhang,Jiannan Zhang,Mingbo Zhao,Yang Chong,Quankuan Gu,Xianglin Meng,Mingyan Zhao
Acute lung injury (ALI) is a respiratory disease induced by uncontrolled inflammatory responses in the lungs. The pathological features of ALI include alveolar structural damage and pulmonary edema, which ultimately leads to pulmonary dysfunction. ANAPC5 (Anaphase-promoting complex subunit 5) is an E3 ubiquitin ligase known for its anti-inflammatory properties. This study aims to investigate the effects of ANAPC5 on ALI and its underlying molecular mechanism. In the lung tissue of an ALI mouse model induced by lipopolysaccharide (LPS) administration, we observed downregulation of ANAPC5. Through both in vivo and in vitro experiments, we assessed the effect of ANAPC5 on lung injury by conducting pathological analysis and molecular biological detection. ANAPC5 overexpression alleviated inflammatory cell infiltration, reduced alveolar wall thickening, suppressed pulmonary inflammation, and decreased the levels of inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and lung tissue of the ALI model. Moreover, ANAPC5 inhibited M1 polarization and promoted M2 polarization of macrophages both in vitro and in vivo . We also found that ANAPC5 significantly suppressed the activation and expression of the epidermal growth factor receptor (EGFR) through inducing its ubiquitination in macrophages. In LPS-induced M1 macrophages, the presence of EGFR significantly decreased CD24 expression, followed by reversing the inhibitory effects of ANAPC5 on inflammatory responses and macrophage polarization. Collectively, our findings suggest that ANAPC5 serves as a therapeutic molecular target that mitigates ALI through regulating macrophage M1/M2 polarization via the EGFR/CD24 axis.
研究领域:
免疫学
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呼吸病学
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分子生物学
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炎症反应调控
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转化医学
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PubMed
高影响因子
Chemical Biology & Drug Design
·
2015
·Vol. 86
·期 4
·753-763
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IF 2.485
Jianpeng Feng,Bing Xiao,Wenbo Chen,Ting Ding,Lingfeng Chen,Pengtian Yu,Fengli Xu,Huajie Zhang,Zhiguo Liu,Guang Liang
We previously reported a symmetric monocarbonyl analog of curcumin (MACs), C66, which demonstrated potential anti-inflammatory activity and low toxicity. In continuation of our ongoing research, we designed and synthesized 34 asymmetric MACs based on C66 as a lead molecule. A majority of the C66 analogs effectively inhibited LPS induction of TNF- α and IL-6 expression. Additionally, a preliminary SAR was conducted. Furthermore, active compounds 4a11 and 4a16 were found to effectively reduce the W/D ratio in the lungs and the protein concentration in the bronchoalveolar lavage fluid (BALF). Meanwhile, a histopathological examination indicated that these two analogs significantly attenuate tissue injury in the lungs with LPS-induced ALI rats. 4a11 and 4a16 also inhibited mRNA expression of several inflammatory cytokines, including TNF- α , IL-6, IL-1 β , COX-2, ICAM-1 and VCAM-1, in the Beas-2B cells after LPS challenge. Altogether, the data exhibit a series of new C66 analogs as promising anti-inflammatory agents for the treatment of LPS-induced ALI.
研究领域:
药理学
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合成化学
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免疫学
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DOI
PubMed
高影响因子
Molecular Medicine Reports
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2025
·Vol. 32
·期 1
·1-15
·
IF 3.5
Zhenfei Mo,Chengcheng Su,Jinxia Liu,Jiabo Ren,Lu Liu,Yueming Wang,Yanqin Li,Chunsun Li,Zhen Yang,Xiuqing Ma,Liangan Chen
The oncogene lung cancer metastasis‑related protein 1 (LCMR1) is associated with neoplastic diseases and LCMR1 conditional knockout affects cell homeostasis. In the present study, the role of LCMR1 in lipopolysaccharide (LPS)‑induced acute lung injury (ALI) was investigated. Firstly, wild‑type C57BL/6 mice were used to establish an LPS‑induced ALI model via intratracheal injection of LPS, and the expression of LCMR1 was examined at 24, 48, 72 and 96 h after injury. The LPS‑induced lung injury model was subsequently constructed in mice with conditional knockout of LCMR1 in type II alveolar epithelial cells (AEC‑II). Subsequently, histopathological analysis, lung wet/dry weight ratio comparisons and lung function tests were performed; survival rates after LPS challenge of the conditional knockout mice were measured; bronchoalveolar lavage fluid (BALF) was collected, and the concentrations of protein and inflammatory cytokines in BALF were measured; and transmission electron microscopy of lung tissue was conducted to evaluate the degree of lung injury. To further investigate the mechanism, a lung‑on‑a‑chip model with overexpression or knockdown of LCMR1 was constructed to simulate the alveolar environment under LPS treatment. The expression levels of E‑cadherin and pro‑pulmonary surfactant C precursor (proSP‑C) in the chips were determined by immunofluorescence, and the integrity of the air‑blood barrier was analyzed using a permeability assay. In the mouse model, LCMR1 expression was downregulated in wild‑type mice with LPS‑induced lung injury. LCMR1 conditional knockout in AEC‑II caused increased mortality, impaired lung function, aggravated pathological damage and increased the inflammatory response in mice with LPS‑induced ALI. Furthermore, in the lung‑on‑a‑chip model, LCMR1 knockdown reduced the expression of E‑cadherin and proSP‑C, and impaired the air‑blood barrier function, whereas LCMR1 overexpression attenuated these effects, which may be related to cell differentiation dysfunction and enhanced apoptosis. In conclusion, the present study revealed that LCMR1 deficiency may exacerbate LPS‑induced ALI and could be considered a novel target for intervention in ALI.
研究领域:
医学
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分子生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
Food & Function
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2018
·Vol. 9
·期 11
·5880-5890
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IF 3.289
Xiuling Tang,Huanhuan Zhao,Wei Jiang,Song Zhang,Shun Guo,Xiaobo Gao,Peng Yang,Lei Shi,Linna Liu
Dry citrus peel (Chenpi) is not only consumed as a dietary supplement, but also used for the treatment of respiratory diseases. Pinelliae Rhizoma Praeparatum (Banxia) is always used with Chenpi for the treatment of respiratory diseases, but β-sitosterol, the main active component in Banxia, as a food additive, shows no respiratory system activity. In the present study, the pharmacokinetic characters showed that the absorption of the active components of Chenpi was accelerated under pathological conditions combined with Banxia. Although the bioavailability of active components did not significantly change, the distribution of active components in tissues increased, particularly in the target organ. These results are consistent with the combination of Chenpi with β-sitosterol. Furthermore, the pharmacodynamics result also indicated that Chenpi combined with Banxia or β-sitosterol was able to ameliorate histopathologic damage and decrease the levels of inflammatory factors. The results suggest that pharmacokinetic interactions improve the pharmacological activity of Chenpi in respiratory diseases.
研究领域:
药理学
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中药学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2022
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IF 3.322
Yelin Tang,Wenxin Zhang,Liqin Wu,Bin Bai,Bin Zheng,Mengying Li,Yue Tang,Xiaona Zhu,Yali Zhang,Yi Wang,Bing Zhang
Purpose Acute lung injury (ALI) is a fatal acute inflammatory illness with restricted therapeutic choices clinically. Piperlongumine (PL) is recognized as an alkaloid separated from Piper longum L, which was suggested to exhibit multiple pharmacological activities (e.g., anti-inflammatory activity). However, the effects of PL on LPS-triggered ALI and its anti-inflammatory target remain unclear. This paper intended to assess the roles of PL in LPS-triggered ALI, as well as its underlying mechanism and target. Methods In vivo, ALI was induced by intratracheal injection of LPS to evaluate protective effects of PL and assessed by the changes of histopathological. In vitro, the anti-inflammatory activity and mechanism of PL were investigated by ELISA, RT-qPCR, transcription factor enrichment analysis, Western blotting and Immunofluorescence assay. The binding affinity of PL to MD2 was analyzed using computer docking, surface plasmon resonance , ELISA and immunoprecipitation assay. Results It was reported here that PL treatment alleviated LPS-induced pulmonary damage, inflammatory cells infiltration and inflammatory response in mice. In culture cells, PCR array showed that PL significantly inhibited LPS-induced inflammatory cytokines, chemokines , and type I IFNs genetic expression, along with the inhibition of TAK1 and TBK1 pathway. It is noteworthy that PL is capable of straightly binding to MD2 and inhibiting MD2/TLR4 complex formation and TLR4 dimerization . Conclusions As revealed from this study, PL directly binding to MD2 to block cytokines expression by inhibiting the activation of TAK1 and TBK1 pathway, which then exerted its pulmonary protective activity. Accordingly, PL may act as an underlying candidate for treating LPS-triggered ALI.
研究领域:
药理学
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免疫学
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肺医学
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DOI
PubMed
高影响因子
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