CLINICAL AND EXPERIMENTAL IMMUNOLOGY
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2025
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IF 3.8
Su Qiyan,Feng Yingyue,Guo Jin,Cui Xi,Zhu Jiarui,Yang Jumei,Zhang Sigong
BackgroundIdiopathic inflammatory myopathy (IIM) is a progressive autoimmune disease characterized by interstitial lung disease (ILD) with limited therapeutics available. Pirfenidone (PFD), a medication utilized for the treatment of idiopathic pulmonary fibrosis, exhibits notable antioxidant, anti-inflammatory and inhibition of collagen synthesis. This study aims to clarify its efficacy and mechanism in treating IIM-ILD.MethodsA murine myositis-associated interstitial lung disease (MAILD) model was used to assess the therapeutic effect of PFD. The serum levels of IL-1β, IL-6 and TNF-α were detected by ELISA. PFD was utilized to disrupt neutrophil extracellular traps (NETs) formation in vitro, and its inhibitory effect on NETs was assessed through immunohistochemistry of CitH3 and MPO in the lung tissue and the serum cfDNA level in mice. Immunohistochemical and western blot was utilized to examine alterations in epithelial-mesenchymal transition (EMT) and NLRP3 inflammasome markers.ResultsPFD treatment inhibited pulmonary inflammation and fibrosis in the MAILD model. PFD intervention reduced NETs formation in vitro. PFD treatment significantly reduce NETs infiltration in the lung tissue and the level of cfDNA in the serum of mice. Additionally, PFD down-regulated EMT and NLRP3-related proteins in vivo. PFD treatment also notably reduced serum levels of IL-1β, IL-6 and TNF-α. After NETs stimulation, A549 cells exhibited EMT and activation of NLRP3 inflammasome. PFD attenuated EMT in A549 cells and suppressed the activation of NLRP3 inflammasome.ConclusionPFD alleviates ILD in a murine MAILD model by inhibiting NETs formation and NLRP3 inflammasome activation, suggesting that PFD might be a potential therapeutic agent for IIM-ILD.
研究领域:
免疫学
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呼吸病学
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药理学
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2023
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IF 5.8
Si Qin,Xuening Du,Kaili Wang,Da Wang,Jiani Zheng,Haiyan Xu,Xiuyan Wei,Yue Yuan
Liver fibrosis (LF) is one of the major diseases that threaten human health. Until now, no effective drugs have been approved for clinical anti-liver fibrosis treatment. In this study, zeolitic imidazolate framework-8 (ZIF-8) lipid nanoparticles loaded with pirfenidone (PFD) and modified with vitamin A (VA) were constructed (VA-PFD@ZIF-8@DMPC NPs). PFD was embedded in ZIF-8 by the “one-pot” method, and the prepared ZIF-8 had a small particle size (84.3 nm) and high drug loading (54.46%). Moreover, the inherent pH sensitivity of ZIF-8 makes it stable in a normal physiological environment and collapsed in an acidic environment, thus controlling drug release and preventing drug leakage. Besides, the phospholipid layer makes the nano-drug delivery system dispersible and improves its biocompatibility . More importantly, VA is modified on the surface of nanoparticles (NPs), which can target the highly expressed retinol-binding protein receptor (RBPR) on the surface of hepatic stellate cells (HSCs), thereby accurately increasing the local drug concentration at the site of LF. In vivo experiments showed that VA-PFD@ZIF-8@DMPC NPs can reduce liver injury, improve the degree of LF, and exert specific therapeutic effects on LF. In conclusion, this nano-delivery system may become a novel and effective anti-liver fibrosis treatment.
研究领域:
药学
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生物医学工程
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肝脏病学
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PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2020
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IF 6.205
Shenzhi Zhou,Wei Li,Min Tian,Na Zhang,Xiaojing Yang,Weiwei Li,Ying Peng,Jiang Zheng
Pirfenidone is approved for the treatment of idiopathic pulmonary fibrosis. Idiosyncratic drug reactions, due to clinical application of pirfenidone, have been documented, even along with death cases resulting from acute liver failure. The present study aimed at the investigation of metabolic activation of pirfenidone possibly participating in the reported adverse reactions. Pirfenidone-derived glutathione/N-acetylcysteine (GSH/NAC) conjugates were detected in microsomal/primary hepatocyte incubations after exposure to pirfenidone. The GSH/NAC conjugates were also observed in bile and urine of rats given pirfenidone, respectively. The observation of the conjugates suggests the formation of a quinone methide intermediate derived from pirfenidone. The intermediate was possibly generated through two pathways. First, pirfenidone was directly metabolized to the quinone methide intermediate via dehydrogenation; second, pirfenidone was oxidized to 5-hydroxymethyl pirfenidone, followed by sulfation to a benzyl alcohol-sulfate derivative. The findings facilitate the understanding of the mechanisms of pirfenidone-induced idiosyncratic toxicity and assist medicinal chemists to minimize toxicities in the development of new pharmaceutical agents.
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高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Shan Yang,Cheng Chen,Yang Xiong,Jiaxiu Ling,Lijuan Chen,Chunxia Wang,Xiaoyu Zhang,Jixiu Yi,Wenzhen Deng,Xiaohui Liao
Objective Pirfenidone (PFD) has been used to treat kidney fibrosis. However, the effects of PFD on obesity-related kidney injury and the underlying mechanisms are still poorly understood. Methods Male C57BL/6 J mice were fed a high-fat diet (HFD) for 20 weeks to induce kidney injury, and PFD was added to the feed of the mice in the PFD group beginning at 8 weeks. The controls were fed a normal control diet (NCD), and half of the mice were similarly treated with PFD. Indicators associated with lipid metabolism and kidney injury were assessed in vivo. Furthermore, human proximal tubular epithelial (HK−2) cells and human primary renal proximal tubule epithelial cells (PTECs) were incubated with palmitate (PA) and PFD, to investigate the effect of PFD on tubule cell injury in vitro. Single-cell sequencing analysis, molecular docking, and coimmunoprecipitation were subsequently used to explore the mechanisms of PFD action. Results PFD ameliorated metabolic abnormalities, inflammatory responses and oxidative stress induced by an HFD. PFD alleviated renal fatty acid oxidation and injury indicators in the HFD-fed mice and PA-treated renal tubular cells. PFD reversed the HFD/PA-induced decrease in SIRT3 protein expression. Moreover, transfection with si-SIRT3 abolished the beneficial effects of PFD on kidney injury and lipid metabolism in HK-2 cells. Conclusion In summary, our data revealed that PFD could mitigate obesity-related kidney injury in a SIRT3-dependent manner.
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Jiachen Chen,Zihao Tao,Chenyu Qiu,Rui Wu,Zihao Huang,Xinyu Jiang,Pingyi Zhu,Yifan Wang,Longfa Kou,Xiujun Cai
Liver fibrosis is a major contributor to global mortality due to its progressive disruption of hepatic architecture and function, and it remains a critical unmet medical need. Hepatic stellate cells (HSCs) are considered a key therapeutic target owing to their central role in fibrosis progression, primarily mediated through the TGF-β1/Smad2/3 signaling pathway. Pirfenidone (PFD), a clinically approved broad-spectrum antifibrotic agent, shows potential for repurposing in liver fibrosis therapy. However, its clinical translation is limited by poor aqueous solubility and a lack of cellular targeting specificity. To address these limitations, we developed a vitamin A-conjugated liposomal delivery system (P@GB-Lipo-VA) to enhance the liver-specific accumulation of PFD. In vitro studies demonstrated that P@GB-Lipo-VA significantly increased cellular uptake in TGF-β1-stimulated LX-2 cells and reduced oxidative stress. In a bile duct ligation (BDL)-induced mouse model of liver fibrosis, P@GB-Lipo-VA effectively alleviated collagen deposition, improved liver function, and suppressed activation of the TGF-β1/Smad signaling pathway. These findings support P@GB-Lipo-VA as a promising targeted nanotherapeutic platform for enhancing the efficacy and safety of PFD in the treatment of liver fibrosis.
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高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
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IF 5.7
Xiaoling Huang,Jiajie Zhang,Yanping Hou,Fei Yuan,Pengtao Liu,Susu Guo,Kaiping Bai,Jie Sun
Pirfenidone alleviates spinal cord injury-induced bladder fibrosis. • Ferroptosis is involved in bladder fibrosis. • Pirfenidone can modulate ferroptosis pathway. • This work supports Pirfenidone's clinical translation for bladder fibrosis. Pirfenidone (PFD), a broad-spectrum anti-fibrotic agent, shows therapeutic potential in various fibrotic diseases. However, its effect on neurogenic bladder fibrosis following spinal cord injury (SCI) and its association with ferroptosis remain unclear. This study aimed to investigate the therapeutic efficacy of PFD against bladder fibrosis after SCI and to preliminarily analyze its potential link with ferroptosis using a rat SCI model and a Transforming Growth Factor-β1 (TGF-β1)-induced fibrotic model in Simian Virus 40-Transformed Human Urothelial Cells (SV-HUC-1). In SCI rats, PFD treatment significantly improved urodynamic parameters, while markedly reducing collagen deposition, inflammatory infiltration, and the progression of epithelial–mesenchymal transition (EMT) in bladder tissue. In the cellular model, PFD effectively attenuated TGF-β1-induced fibrotic responses. Mechanistically, network pharmacology analysis predicted that PFD could modulate the TGF-β1 signaling and lipid peroxidation pathways. In vivo experiments confirmed that PFD reversed the dysregulation of key ferroptosis-related molecules, and in vitro studies demonstrated that PFD antagonized Erastin-induced ferroptosis, an effect comparable to the ferroptosis inhibitor Ferrostatin-1 (Fer-1). However, in the TGF-β1-induced fibrotic model, inhibition of ferroptosis alone only partially ameliorated the fibrotic phenotype, and its effect was weaker than that of PFD. This study demonstrates that PFD can effectively alleviate bladder fibrosis after SCI, and its therapeutic effect may be associated with the ferroptosis pathway. These findings suggest that PFD likely exerts its anti-fibrotic action through multi-pathway synergy, with ferroptosis inhibition representing an important contributing pathway supported by the current data, providing a new theoretical basis for treating neurogenic bladder fibrosis.
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JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
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2015
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IF 2.729
Wei Sun,Zhe-li Jiang,Lei Zhou,Rui-min Chen,Zhe Wang,Wan-shu Li,Shuo-min Jiang,Guo-xin Hu,Rui-jie Chen
A rapid, sensitive and selective ultra-performance liquid chromatography tandem mass spectrometry (UPLC–MS/MS) was developed and validated for the determination and pharmacokinetic investigation of pirfenidone in rat plasma. Sample preparation was accomplished through a simple one-step deproteinization procedure with 0.2 mL of acetonitrile to a 0.1 mL plasma sample. Plasma samples were separated by UPLC on an Acquity UPLC BEH C18 column using a mobile phase consisting of acetonitrile-0.1% formic acid in water with gradient elution. The total run time was 3.0 min and the elution of pirfenidone was at 1.39 min. The detection was performed on a triple quadrupole tandem mass spectrometer in the multiple reaction-monitoring (MRM) mode using the respective transitions m / z 186.2 → 92.1 for pirfenidone and m / z 237.1 → 194.2 for carbamazepine (IS), respectively. The calibration curve was linear over the range of 5–2000 ng/mL with a lower limit of quantitation (LLOQ) of 5 ng/mL. Mean recovery of pirfenidone in plasma was in the range of 80.4–84.3%. Intra-day and inter-day precision were both <12.1%. This method was successfully applied in pharmacokinetic study after oral administration of 10.0 mg/kg pirfenidone in rats.
研究领域:
分析化学
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药理学
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DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
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2022
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IF 6.064
Qi Fang,Shaoyu Liu,Jiangyu Cui,Ruiyue Zhao,Qian Han,Peng Hou,Youcai Li,Jie Lv,Xiaoyao Zhang,Qun Luo,Xinlu Wang
Recently, fibroblast activation protein (FAP), an overexpressed transmembrane protein of activated fibroblast in pulmonary fibrosis, has been considered as the new target for diagnosing and treating pulmonary fibrosis. In this work, mesoporous polydopamine (MPDA), which is facile prepared and easily modified, is developed as a carrier to load antifibrosis drug pirfenidone (PFD) and linking FAP inhibitor (FAPI) to realize lesion-targeted drug delivery for pulmonary fibrosis therapy. We have found that PFD@MPDA-FAPI is well biocompatible and with good properties of antifibrosis, when ICG labels MPDA-FAPI, the accumulation of the nanodrug at the fibrosis lung in vivo can be observed by NIR imaging, and the antifibrosis properties of PFD@MPDA-FAPI in vivo were also better than those of pure PFD and PFD@MPDA; therefore, the easily produced and biocompatible nanodrug PFD@MPDA-FAPI developed in this study is promising for further clinical translations in pulmonary fibrosis antifibrosis therapy.
研究领域:
药学
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纳米技术
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生物医学工程
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肺科学
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DOI
PubMed
高影响因子
MOLECULES
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2022
·Vol. 27
·期 6
·1830
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IF 4.927
Junwei He,Xinxian Meng,Chen Meng,Jiayu Zhao,Yunsheng Chen,Zheng Zhang,Yixin Zhang
An increase in the levels of reactive oxygen species (ROS) and high expression levels of transforming growth factor-β (TGF-β) in wound tissue are two major problems for wound repair and scar inhibition. Modulation of the wound microenvironment is considered to be able to overcome these issues. Two possible solutions include the use of cerium oxide nanoparticles (CeO2) as an enzyme-like ROS scavenger and pirfenidone (PFD) as an anti-fibrotic drug to inhibit the expression of TGF-β. However, CeO2is easily adsorbed by biological macromolecules and loses its enzyme-like activity. Furthermore, the intracellular delivery of PFD is difficult. Herein, the layer-by-layer method was used to prepare nanocapsules (NCs) with a sophisticated structure featuring PFD at their core and CeO2in their shell; these NCs were referred to as PFD/CeO2NCs. PFD/CeO2NCs were supposed to efficiently achieve intracellular delivery of PFD and successfully scavenged ROS from the microenvironment. Cellular experiments verified that PFD/CeO2NCs had good biocompatibility, satisfactory cellular uptake, and favorable ROS-scavenging capacity. To be applied directly to the wound, PFD/CeO2NCs were then adhered to plasma-etched polylactic acid (PLA) fiber membranes to prepare a new wound dressing. Animal experiments further demonstrated that the dressing accelerated the epithelialization of the wound, reduced the levels of ROS and TGF-β, improved the arrangement and proportion of collagen fibers, and finally, achieved satisfactory wound-repairing and anti-scarring effects. These results provide a new concept for promoting wound repair and preventing scar formation.Keywords:wound repair;scar prevention;cerium oxide nanoparticles;pirfenidone;nanocapsules;dressing
研究领域:
材料科学
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生物医学工程
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药学
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DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2015
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IF 4.152
Lijun Yang,Feng Wang,Haie Han,Liang Yang,Gengshen Zhang,Zhenzeng Fan
Subarachnoid hemorrhage (SAH) is a life-threatening disease that causes high morbidity and mortality. Pirfenidone is a SAH drug that prevents secondary bleeding and cerebral infarction. To improve its therapeutic efficacy, this study aimed to employ a functionalized graphene oxide nanosheet (FGO) as a drug carrier loading pirfenidone to treat SAH. The graphene oxide nanosheet was introduced with transcription activator peptide (Tat), followed by functionalization with methoxy polyethylene glycol (mPEG) and loading with pirfenidone. The pirfenidone-loaded FGO (pirfenidone-FGO) exhibits better treatment efficacy than the single pirfenidone due to more effective loading and controlled release of the drug in tissue. The introduction of Tat and mPEG onto GO nanosheet contributes to the ability to cross the blood–brain barrier and the stability in blood circulation of the drug. At lower pH values, the highly efficient release of the drug from the pirfenidone-FGO exerts effective treatment to acidic inflammatory lesion after severe SAH. Besides its treatment function, FGO is also shown as a strong near infrared absorbing material which can be applied in photoacoustic imaging, allowing rapid real-time monitoring with deep resolution of brain tissues after SAH. The treatment efficacy of pirfenidone-FGO for central nervous system injuries is further demonstrated by hematoxylin and eosin staining of coronal brain slices, as well as measurements of brain water content and blood–brain barrier permeability. Our study supports the potential of FGO in clinical application in treatment of SAH.
研究领域:
神经科学
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药学
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纳米技术
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生物医学工程
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Chenggong Yu,Qingwen Xu,Xiaoling Cao,Shengnan Cheng,Zhijun Zhang,Jie Huang
Idiopathic pulmonary fibrosis (IPF) is a challenging interstitial lung disease characterized by heterogeneous manifestations and significant mortality. Due to the relative complexity of IPF pathogenesis, currently approved clinical drugs mainly for anti-inflammatory or anti-fibrotic present limited disease containment and insufficient damage repair, falling far short of previous expectations. To address this limitation, we developed an ionizable liposome nanodrug (named as TPNPs) co-loaded with small interfering RNA targeting TGF-β1 (si TGF-β1 ) and pirfenidone (PFD) for enhanced IPF therapy. The si TGF-β1 (blocking TGF-β signaling pathway) and PFD were carefully selected and integrated in consideration of their crucial roles in endothelial mesenchymal transition, alveolar epithelial cell apoptosis, and fibroblast differentiation and migration, which are closely related to IPF development. As a result, TPNPs exhibited synergistic enhancement effects against the damage of alveolar epithelial cells and fibroblasts in vitro . Notably, repeated administration of TPNPs mitigated the injury to alveolar epithelium, inhibited the excessive accumulation of extracellular matrix (ECM), and alleviated the destruction of lung, thereby synergistically ameliorating the lung function in a bleomycin (BLM)-induced murine model. This work provides a promising therapeutic strategy that combines nucleic acid with small molecule for enhanced treatment of IPF.
研究领域:
药理学
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肺科学
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纳米技术
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分子生物学
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DOI
高影响因子
Frontiers in Pharmacology
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2026
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IF 5.4
Yuexin Yu,Yaping Xu,Jinfu Chen,Yao Yao,Yingtian Liu,Tan Huang,Shaolong Yang,King-Hwa Ling,Jacques P. Guyette,Bakiah Shaharuddin,Zhikun Guo,Jun Jie Tan
BackgroundHeart failure with preserved ejection fraction (HFpEF) accounts for more than half of heart failure cases and is associated with substantial morbidity and mortality. Although sodium–glucose cotransporter-2 inhibitors (SGLT2is) have shown efficacy in reducing HFpEF hospitalizations, the disease’s multi-pathway pathogenesis often limits the effectiveness of single-target interventions. This study examines whether the cardiovascular benefits of empagliflozin (EMPA) can be synergistically enhanced by co-administration with the targeted anti-fibrotic agent pirfenidone (PFD).AimsWe hypothesized that simultaneous modulation of metabolic stress and pro-fibrotic signaling would lead to synergistic structural and functional recovery in a severe HFpEF phenotype.MethodsHFpEF was induced in Sprague–Dawley rats (n = 16/group) using a two-hit model [NG-nitro-L-arginine methyl ester (L-NAME) and a high-fat diet (HFD)] over 5 weeks. The rats subsequently received daily oral EMPA (0.35 g/kg/d), PFD (0.3 g/kg/d), or combination therapy (EMPA + PFD) for 4 weeks. Treatment efficacy was evaluated via echocardiography, histopathology, and exercise tolerance testing. Further insights into the underlying transcriptional mechanisms were gained through RNA sequencing and semi-quantitative Western blotting. Bliss independence analysis was used to analyze pharmacological synergy.ResultsCo-treatment with EMPA + PFD significantly enhanced diastolic indices, left ventricular ejection fraction (LVEF), fractional shortening (FS), and cardiac output (CO) compared with controls and monotherapy groups (p < 0.05). Histological analysis revealed reduced cardiomyocyte hypertrophy and lower collagen deposition, particularly in the endocardium. Although additive improvement in systemic hemodynamics was observed, EMPA + PFD co-treatment exerted compartmentalized synergy within the myocardium. The combination reversed cellular hypertrophy and deep fibrosis, restoring diastolic and systolic function (p < 0.05). Transcriptomic profiling revealed that local myocardial rescue was mediated by gene networks linked to protein kinase C-activating G-protein-coupled receptor signaling, which blocked the downstream PKC/NF-κB inflammatory pathway and transforming growth factor-beta (TGF-β)-driven fibrosis, thereby explaining the molecular basis of functional improvement.ConclusionDual therapy with EMPA and PFD achieves compartmentalized synergy, effectively eliminating cellular hypertrophy and deep fibrosis, thereby restoring cardiac mechanics. These findings provide mechanistic proof of concept that multi-axis metabolic and antifibrotic combinations can disrupt the complex pathological cycle of HFpEF.
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高影响因子
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