JOURNAL OF AUTOIMMUNITY
·
2020
·
IF 6.658
Yingzhen Du,Pingjun Zhu,Xi Wang,Mi Mu,Hongxia Li,Yanhong Gao,Xuebing Qin,Yan Wang,Zhijian Zhang,Geping Qu,Guogang Xu,Christopher Chang,Tianzhi Li,Xiangqun Fang,Senyang Yu
Pirfenidone has been widely used in the treatment of idiopathic pulmonary fibrosis (IPF). However, the role of pirfenidone in LPS-induced acute lung injury (ALI) remains unclear. This study aims to investigate the protective effects of pirfenidone in ALI and to explore its underlying mechanism. Pirfenidone clearly reduces LPS-triggered ALI as indicated by significant pathological alterations, reduced oxidative stress and inflammatory responses in vivo . Furthermore, pirfenidone also blocks apoptosis of LPS-induced alveolar epithelial type II (ATII) cells through inhibition of endoplasmic reticulum (ER) stress and mitochondrial injury in vivo and in vitro . A lower expression level of BAP31, an ER transmembrane protein , was found to be associated with ALI followed LPS challenge. The reintroduction of BAP31 blunted LPS induced ER stress and mitochondrial damage and therefore alleviated ATII cell apoptosis, which correlated with pirfenidone treatment. Knockdown of BAP31 expression in pirfenidone treated ATII cells re-activated ER stress, mitochondrial damage and followed cellular apoptosis. In summary, this study confirms the beneficial effect of pirfenidone on ER stress and mitochondrial dysfunction mediated apoptosis via upregulation of BAP31. Our results demonstrated that pirfenidone may be considered as a potential agent for the treatment of ALI in the future.
研究领域:
药理学
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肺病学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2023
·
IF 5
Jingxuan Lu,Jingwen Luo,Jie Li,Shiyan Fu,Yonghong Ran,Juan Li,Yazhen Zhao,Yuhui Hao
Radiation-induced pulmonary fibrosis (RIPF) is a common adverse effect of thoracic radiation therapy. Although pirfenidone is approved for treating pulmonary fibrosis, its utility is limited by its short half-life and ability to scavenge reactive oxygen species (ROS). Thus, a nanoscale complexes of cerium(III), 10-carboxyl-pirfenidone, and 1,10-phenanthroline (NPs Ce(phen)Pirf 3 ) was developed to prevent RIPF in a mouse model. NPs Ce(phen)Pirf 3 was successfully prepared using a simple moderate solvothermal method and characterized using FTIR , electrospray ionization MS , 1H nuclear magnetic NMR, and transmission electron microscopy . The cerium(III) nanocomplexes exhibited a near-spherical shape and dissolved in water with a diameter of ∼125.2 nm , as characterized by dynamic light scattering . Compared with pirfenidone, NPs Ce(phen)Pirf 3 with blue fluorescence exhibited prolonged retention times with thoracic-specific accumulation in vivo. Mice received 15 Gy gamma-ray treatment on the thorax with or without NPs Ce(phen)Pirf 3 or pirfenidone administration. NPs Ce(phen)Pirf 3 improved lung function, alleviated radiation-induced pathological changes in the lung tissues, and reduced collagen deposition 16 weeks after radiation. Our results from in vivo and in vitro experiments demonstrated that NPs Ce(phen)Pirf 3 increased the ROS-scavenging ability. Additionally, NPs Ce(phen)Pirf 3 regulated epithelial-mesenchymal transition (EMT)-related proteins, including up-regulate E-cadherin and down-regulate N-cadherin, α-SMA, and TGF-β1 in RLE-6TN cells, which suggested NPs Ce(phen)Pirf 3 may alleviate RIPF by inhibiting EMT. Finally, NPs Ce(phen)Pirf 3 also inhibited the growth of thoracic tumor cells in mice. NPs Ce(phen)Pirf 3 had a protective role against RIPF and antitumor effects, suggesting that they are a promising therapy for thoracic radiation-induced RIPF.
研究领域:
放射肿瘤学
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药学
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材料科学
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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
高影响因子
Acta Biomaterialia
·
2025
·
IF 9.6
Xinrui Zhang,Ruibing Yu,Xusheng Duan,Tenghan Zhang,Fanyu Cheng,Shan Pan,Dongfang Zhou,Juhong Zhu,Yue Cai,Xuanrong Sun
Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease marked by epithelial-mesenchymal transition (EMT) and overactivation of the transforming growth factor-β (TGF-β) signaling pathway, leading to collagen accumulation and macrophage infiltration in the lungs. Here, a bioinspired inhalable nanoplatform (PCMΦ@PPT) was designed and prepared for delivering therapy agents by penetrating the excessive physiological barrier deposited in the lesions and reversing established fibrotic foci in IPF. The nanoplatform was composed of two components: a pirfenidone (PFD) and tetrandrine (TET) co-loaded poly(lactic-co-glycolic acid) (PLGA) core (PPT), as well as a collagen-binding peptide and collagenase functionalized macrophage membrane (PCMΦ) shell. Following inhalation, PCMΦ@PPT has been shown to possess the capacity to target and penetrate the dense collagen barrier with the assistance of functional groups present on PCMΦ. The coating of PCMΦ enables PCMΦ@PPT to evade phagocytosis by macrophages that accumulate at the site of lesions. Meanwhile, the precise co-delivery of PFD and TET to the lesion site not only blocks the TGF-β signaling pathway but also promotes the recovery of damaged autophagy in fibroblasts, thereby alleviating the progression of IPF and partially improved lung function parameters in mice. In summary, this study proposes a novel nano-inhalation formulation for the treatment of IPF. Statement of significance The biomimetic nanoparticle PCMΦ@PPT was designed to recognize and degrade overexpressed extracellular matrix proteins. It is composed of two components: a poly(lactic-co-glycolic acid) core co-loaded with pirfenidone (PFD) and tetrandrine (TET), as well as a collagen-binding peptide and collagenase-functionalized macrophage membrane shell (PCMΦ). Following inhalation, PCMΦ@PPT has been shown to target and penetrate the dense collagen barrier while evading phagocytosis by macrophages, promoting drug retention in the focus. Finally, co-delivery of PFD and TET blocks the TGF-β signaling pathway, promoting recovery of damaged autophagy in fibroblasts and alleviating IPF progression and restoring lung function.
研究领域:
纳米医学
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肺部药理学
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药物递送系统
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生物医学工程
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呼吸系统疾病
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2026
·Vol. 27
·期 9
·4061
·
IF 5.6
Yuelu Lan,Sijia Li,Shuangli Zhu,Can Pan,Kai Fu,Xueping Wang,Liwu Fu,Fang Wang
Chronic liver injury is characterized by sustained activation of transforming growth factor-β (TGF-β) signaling within the fibrotic microenvironment, yet the contribution of TGF-β-associated metabolic remodeling to hepatic stellate cell (HSC) activation remains incompletely understood. Here, we investigated whether TGF-β signaling is associated with lipid metabolic remodeling in HSCs and whether pirfenidone (PFD) interferes with this process. We found that TGF-β1 was spatially associated with lipid accumulation in fibrotic liver tissue and that TGF-β1/2 promoted HSC proliferation. In vitro, TGF-β1/2 coordinately upregulated sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN), accompanied by increased intracellular lipid accumulation and enhanced oleic acid (OA)-associated lipid responses. Low-dose OA further activated AKT/ERK/p70 S6K signaling in HSCs, whereas PFD attenuated these signaling events. In parallel, PFD suppressed TGF-β-associated lipid accumulation in vitro, reduced SREBP1/FASN expression in activated HSC-rich regions in vivo, and alleviated CCl 4 -induced liver fibrosis. Together, these findings support a model in which TGF-β-associated lipogenic remodeling contributes to HSC activation and suggest that interference with this metabolic state may represent one component of the antifibrotic action of pirfenidone.
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DOI
PubMed
高影响因子
DRUG DELIVERY
·
2021
·
IF 6.419
Caiqing Wu,Ping Wai Or,Jones Iok Tong Chong,Isuru K. K. Pathirage Don,Ching Hymn Christopher Lee,Kaili Wu,Minbin Yu,David C. C. Lam,Yangfan Yang
To increase the amount of pirfenidone (PFD) loaded in polyvinyl alcohol (PVA) film embedded soft contact lens (SCL), and evaluate its function of sustaining delivery of drug in vitro and in vivo. Drug loading efficiency within PVA film and SCLs, drug release from SCLs in vitro, and the effects of parameters of SCLs and external environment on drug release in vitro were evaluated by ultraviolet–visible spectrophotometer at 312 nm. Safety of SCLs was evaluated in vitro by transformed human corneal epithelial cell. Safety in vivo was determined by optical coherence tomography and histology of anterior segment of rabbits. Drug release study in tear fluid and aqueous humor were measured by ultra-performance liquid chromatography. SCLs had smooth surface and were fit for experimental rabbits. Amount of PFD in PVA film and SCLs were 153.515 μg ± 12.508 and 127.438 μg ± 19.674, respectively, PFD in PVA film was significantly higher than SCLs (p=.006) and closed to 150 μg (targeting amount of PFD to be loaded). Thickness of SCLs, molecular weight of PVA, and amount of PVA used in SCLs affected drug release in vitro significantly. Thickness of PVA film and amount of drug in SCLs had no effect on drug release rate in vitro. SCLs were safe in vitro and in vivo, PFD released from SCLs could be detected around 12 hours in tears and aqueous humor, and the concentration of drug was higher than eye drop at all detected time points while amount of PFD in SCLs was lower than eye drop. Drug loaded PVA film embedded SCLs may be a promising ocular drug delivery system.
研究领域:
药学
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眼科
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产品关联
DOI
PubMed
高影响因子
Molecular Therapy-Nucleic Acids
·
2023
·
IF 8.8
Xin Chang,Chang Liu,Yu-Mo Han,Qiu-Ling Li,Bin Guo,Hu-Lin Jiang
Pulmonary fibrosis (PF) is an interstitial lung disease with complex pathological mechanism, and there is currently a lack of therapeutics that can heal it completely. Using gene therapy with drugs provides promising therapeutic strategies for synergistically reversing PF. However, improving the intracellular accumulation and transfection efficiency of therapeutic nucleic acids is still a critical issue that urgently needs to be addressed. Herein, we developed lipid nanoparticles (PEDPs) with high transfection efficiency coloaded with pDNA of nuclear factor erythroid 2-related factor 2 (pNrf2) and pirfenidone (PFD) for PF therapy. PEDPs can penetrate biological barriers, accumulate at the target, and exert therapeutic effects, eventually alleviating the oxidative stress imbalance in type II alveolar epithelial cells (AECs II) and inhibiting myofibroblast overactivation through the synergistic effects of Nrf2 combined with PFD, thus reversing PF. In addition, we systematically engineered various liposomes (LNPs), demonstrated that reducing the polyethylene glycol (PEG) proportion could significantly improve the uptake and transfection efficiency of the LNPs, and proposed a possible mechanism for this influence. This study clearly reveals that controlling the composition ratio of PEG in PEDPs can efficiently deliver therapeutics into AECs II, improve pNrf2 transfection, and synergize with PFD in a prospective strategy to reverse PF.
研究领域:
药理学
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分子生物学
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基因治疗
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肺科学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2023
·
IF 15.1
Yin Zhang,Ranran Yu,Cheng Zhao,Jiawei Liang,Yixuan Zhang,Haochen Su,Jing Zhao,Hao Wu,Shijin Xu,Ziying Zhang,Lei Wang,Xiaoping Zou,Yun Zhu,Shu Zhang,Ying Lv
BRD4 is a member of the BET protein family involved in chromatin remodeling and transcriptional regulation. Several BET inhibitors (BETi) have entered clinical trials, demonstrating potential in inducing cancer cell apoptosis and tumor regression. However, resistance to BETi is common in solid tumors. In pancreatic cancer, it is found that cancer-associated fibroblasts (CAFs) in the tumor microenvironment reduce the BET inhibitor JQ1 sensitivity by inducing BRD4 expression. Moreover, CAFs play a crucial role in the formation of a dense stromal barrier. Therefore, targeting CAFs in the tumor microenvironment of pancreatic cancer not only enhances cancer cells sensitivity to JQ1 but also increases drug perfusion and improves oxygen supply, thus reducing glycolysis and limiting energy supply. To address this challenge, a homologous targeting mechanism utilizing activated fibroblast membrane-coated liposomes is proposed for specific drug precise target to CAFs-rich pancreatic cancer. Additionally, TAT peptides enable liposomes penetration, delivering PFD for targeted anti-fibrotic therapy, reducing extracellular matrix generation and glycolysis, and enhancing JQ1 delivery and sensitivity. In conclusion, the findings indicate the tremendous potential of this CAFs-targeting liposomal delivery system in pancreatic cancer.
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 10
·8682
·
IF 5.6
Zijiao Zhang,Juhan Song,Seung-Hee Kwon,Zhao Wang,Suk-Gyun Park,Xianyu Piao,Je-Hwang Ryu,Nacksung Kim,Ok-Su Kim,Sun-Hun Kim,Jeong-Tae Koh
There has been increasing interest in adjunctive use of anti-inflammatory drugs to control periodontitis. This study was performed to examine the effects of pirfenidone (PFD) on alveolar bone loss in ligature-induced periodontitis in mice and identify the relevant mechanisms. Experimental periodontitis was established by ligating the unilateral maxillary second molar for 7 days in mice (n = 8 per group), and PFD was administered daily via intraperitoneal injection. The micro-computed tomography and histology analyses were performed to determine changes in the alveolar bone following the PFD administration. For in vitro analysis, bone marrow macrophages (BMMs) were isolated from mice and cultured with PFD in the presence of RANKL or LPS. The effectiveness of PFD on osteoclastogenesis, inflammatory cytokine expression, and NF-κB activation was determined with RT-PCR, Western blot, and immunofluorescence analyses. PFD treatment significantly inhibited the ligature-induced alveolar bone loss, with decreases in TRAP-positive osteoclasts and expression of inflammatory cytokines in mice. In cultured BMM cells, PFD also inhibited RANKL-induced osteoclast differentiation and LPS-induced proinflammatory cytokine (IL-1β, IL-6, TNF-a) expression via suppressing the NF-κB signal pathway. These results suggest that PFD can suppress periodontitis progression by inhibiting osteoclastogenesis and inflammatory cytokine production via inhibiting the NF-κB signal pathway, and it may be a promising candidate for controlling periodontitis.Keywords:pirfenidone;periodontitis;osteoclast differentiation;alveolar bone loss;inflammation;NF-κB pathway
研究领域:
牙科学
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药理学
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免疫学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2021
·
IF 3.575
Xiaobo Zhang,Jie Zhang,Yun Liu,Dongming Zhu,Dong Chen,Zhen Zhang,Yu Sun
Objective This present study aims to assess the effect of pirfenidone (PFD) on inhibiting fibroblast proliferation, migration or adhesion in vitro and reducing laminectomy-induced epidural fibrosis in vivo. Methods The effect of PFD on proliferation inhibition was evaluated with flow cytometry, CCK-8, EdU and western-blotting assays. Altered properties in migration and adhesion were confirmed by wound-scratch, transwell, immunofluorescence (IF), cell adhesion and western-blotting assays. Additionally, fifty male healthy Sprague-Dawley rats were subjected to laminectomy and then treated with various concentrations of PFD. After 4 weeks, the degree of epidural fibrosis was evaluated by histological analysis. Results In vitro, the results of flow cytometry, CCK-8, EdU and western-blotting assays showed that PFD reduced fibroblast proliferation by a dose-dependent manner. And the results of wound-scratch, transwell, IF, cell adhesion and western-blotting assays showed that the migration and adhesion of fibroblasts could be inhibited and the cytoskeleton could also be altered in a dose-dependent manner. And the inhibitory effect of PFD could be partially reversed in the PI3K overexpression experiment, which indicated that the capability of PFD to inhibit fibroblast proliferation, migration and adhesion might be through the PI3K/AKT signaling pathway . In vivo, an obvious reduction in epidural fibrosis was observed in groups topically treated with PFD. Conclusions Topical PFD application obviously suppressed laminectomy-induced epidural fibrosis, possibly by inhibiting fibroblast proliferation, migration and adhesion via the PI3K/AKT signaling pathway. PFD may be a safe and effective pharmaceutical to reduce clinical epidural fibrosis.
研究领域:
药理学
·
神经外科
·
细胞生物学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2022
·
IF 7.129
Qiong Tang,Chen Xing,Ming Li,Qiang Jia,Cunxiang Bo,Zhenling Zhang
Macrophages play an important role in causing silicosis eventually becoming an irreversible fibrotic disease, and there are no specific drugs for silicosis in the clinic so far. Pirfenidone has consistently been shown to have anti-inflammatory and anti-fibrotic effects, but the specific mechanism by which it ameliorates fibrosis in silicosis is unclear. A rat silicosis model was established in this study, and lung tissues and serum were collected by batch execution at 14, 28, and 56 days. Also, the effects of Pirfenidone on macrophage polarization and pulmonary fibrosis were evaluated in silicosis with early intervention and late treatment by histological examination, Enzyme-linked immunosorbent assay, Hydroxyproline assay, Western blot and Quantitative reverse transcription polymerase chain reaction. The results showed that Pirfenidone significantly reduced pulmonary fibrosis in rats with silicosis, and both early intervention and late treatment effectively inhibited the expression of α-SMA, Col-I, Vimentin, Hydroxyproline, IL-1β, IL-18, and the M2 macrophage marker CD206 and Arg-1, while only early intervention effectively inhibited E-cad, TGF-β1, TNF-α, and the M1 macrophage marker iNOS, CD86. Furthermore, Pirfenidone dramatically reduced the mRNA expression of the JAK2/STAT3. These findings imply that Pirfenidone may reduce pulmonary fibrosis in silicosis rats by inhibiting macrophage polarization via the JAK2/STAT3 signaling pathway.
研究领域:
药理学
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呼吸医学
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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
International Journal of Nanomedicine
·
2023
·
IF 8
Aftab Ullah,Kaikai Wang,Pengkai Wu,David Oupicky,Minjie Sun
Background: Liver fibrosis is a chronic liver disease associated with an excessive accumulation of extracellualr matrix (ECM) proteins which ultimately lead to cirrohosis and hepatocellular carcinoma.Purpose: Liver fibrosis therapies that use combination approaches with the ability to affect multiple disease pathways have proven higher efficacies. This study aimed at optimizing and characterizing the co-encapsulation of pirfenidone (PF) and AMD3100 (AMD) into CXCR4-targeted combination liposomes (CTC liposome) for CXCR4 targeting, and the inhibition of major molecular culprits ie α-SMA, CXCR4, TGFβ, and P-p38 involved in liver fibrosis in-vitro.Methods: The CTC liposomes were prepared using the thin-film hydration method. The concentration of encapsulated AMD and PF was measured by HPLC and UV spectrophotometry, respectively. Tramsmission electron microscopy (TEM) was used to determine the liposomal morphology. The CXCR4 targeting ability was determined by CXCR4 redistribution assay. Confocal microscopy and flowcytometry were used to determine the CXCR4 mediated cell uptake. The apoptosis inducing and protein downreguating ability of CTC liposomes were determined by apoptosis assay and western blot analysis, respectively. In-vivo biodistribution and Hoechst staining were used to confirm the feasibility of CTC liposome for the in-vivo applications and drug targeted accumulation, respectively.Results: The TEM studies revealed that CTC liposomes were spherical in shape. The cumulative release of AMD and PF from CTC liposome was 67% and 84%, respectively, at 48 h. Compared to the free drug counterparts, encapsulated drugs displayed higher cell viability. The CXCR4 redistribution assay confirmed the CXCR4 targeting and antagonistic ability of CTC liposomes. The CTC liposomes were internalized more effectively via caveolae-mediated endocytic pathways. CTC liposomes displayed aggressive apoptosis (87.3%) in TGFβ-induced activated HSC-T6 cells suggesting a propensity to fibrosis regression. Also, CTC liposomes significantly reduced α-SMA (65%), CXCR4 (77%), TGFβ (89%), and P-p38 (66%) expressions, better than free drugs. CTC@IR780 liposomes (CTC liposomes incorporating IR780 dye) were more accumulated in fibrotic livers compared to free IR780, as judged by in-vivo imaging, biodistribution analysis, and Hoechst staining. These findings suggest that this simple and stable CTC liposomal system holds a great promise for the treatment and prevention of liver fibrosis.
研究领域:
药理学
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生物技术
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细胞生物学
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分子生物学
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治疗学
✓ 已验证
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Xinrui Zhang,Xusheng Duan,Xiuzhi Xie,Dan Zhang,Yuan Chen,Ruibing Yu,Yujie Zhou,Yuteng Chu,Jie Shen,Yue Cai,Xuanrong Sun
Idiopathic pulmonary fibrosis (IPF), a lethal respiratory disease with few treatment options, occurs due to an excessive process of epithelial-mesenchymal transition (EMT) and abnormal accumulation of extracellular matrix (ECM), eventually leading to fibrotic scarring and destruction of alveolar structures. Here, a bioinspired inhalable nanocomplex (CCMφ@PTNPs) is reported for inhibiting the EMT progress and clearing the intrapulmonary ECM, thereby reversing established fibrotic foci in IPF. The nanocomplex consists of a PLGA core loaded with Chinese herbal tetrandrine (TET) and pirfenidone (PFD), and a macrophage cell membrane (Mφ) shell modified with collagenase type I (CLN) and collagen-targeting peptide (CBP). Following inhalation, CCMφ@PTNPs achieves precise abilities of targeting and degrading collagen barrier with the aid of CBP and CLN, ultimately achieving efficient penetration and drug delivery of fibrotic lesions in alveoli. The co-delivery of PFD and TET not only inhibited the transforming growth factor-β1(TGF-β1) pathway to achieve collagen modulation but also restored TGF-β1-induced impaired autophagy, which ultimately reduced local collagen production and accelerated clearance, thus synergistically enhancing the lung function of the bleomycin-induced mouse model. In summary, this study proposes a novel inhalation drug delivery strategy for the treatment of IPF.
研究领域:
纳米医学
·
肺纤维化研究
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药物递送系统
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药理学
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生物医学工程
✓ 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）