COLLOIDS AND SURFACES B-BIOINTERFACES
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2023
·
IF 5.8
Li Shen,Shiyan Fu,Yonglai Chen,Wenrun Li,Suiyi Liu,Zhi Li,Jie Li,Yong Li,Yonghong Ran,Jing Zhang,Lu Qiao,Yuhui Hao
Radiation-induced pulmonary fibrosis (RIPF), one type of pulmonary interstitial diseases, is frequently observed following radiation therapy for chest cancer or accidental radiation exposure. Current treatments against RIPF frequently fail to target lung effectively and the inhalation therapy is hard to penetrate airway mucus. Therefore, this study synthesized mannosylated polydopamine nanoparticles (MPDA NPs) through one-pot method to treat RIPF. Mannose was devised to target M2 macrophages in the lung through CD 206 receptor. MPDA NPs showed higher efficiency of penetrating mucus, cellular uptake and ROS-scavenging than original polydopamine nanoparticles (PDA NPs) in vitro. In RIPF mice, aerosol administration of MPDA NPs significantly alleviated the inflammatory , collagen deposition and fibrosis. The western blot analysis demonstrated that MPDA NPs inhibited TGF-β1/Smad3 signaling pathway against pulmonary fibrosis. Taken together this study provide a novel M2 macrophages-targeting nanodrugs through aerosol delivery for the prevention and targeted treatment for RIPF.
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Nature Communications
·
2023
·Vol. 14
·期 1
·1-19
·
IF 16.6
Da Xingwen,Li Ziyan,Huang Xiaofan,He Zuhan,Yu Yubing,Tian Tongtong,Xu Chengqi,Yao Yufeng,Wang Qing K.
Thoracic aortic aneurysm (TAA) is a localized or diffuse dilatation of the thoracic aortas, and causes many sudden deaths each year worldwide. However, there is no effective pharmacologic therapy. Here, we show that AGGF1 effectively blocks TAA-associated arterial inflammation and remodeling in three different mouse models (mice with transverse aortic constriction, Fbn1 C1041G/+ mice, and β-aminopropionitrile-treated mice). AGGF1 expression is reduced in the ascending aortas from the three models and human TAA patients. Aggf1 +/- mice and vascular smooth muscle cell (VSMC)-specific Aggf1 smcKO knockout mice show aggravated TAA phenotypes. Mechanistically, AGGF1 enhances the interaction between its receptor integrin α7 and latency-associated peptide (LAP)-TGF-β1, blocks the cleavage of LAP-TGF-β1 to form mature TGF-β1, and inhibits Smad2/3 and ERK1/2 phosphorylation in VSMCs. Pirfenidone, a treatment agent for idiopathic pulmonary fibrosis, inhibits TAA-associated vascular inflammation and remodeling in wild type mice, but not in Aggf1 +/- mice. In conclusion, we identify an innovative AGGF1 protein therapeutic strategy to block TAA-associated vascular inflammation and remodeling, and show that efficacy of TGF-β inhibition therapies require AGGF1.
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Acta Biomaterialia
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2024
·
IF 9.4
Xinqi Zeng,Yanhao Li,Gang Zhao,Xiaoer Wei,Rongpu Wu,Sa Pang,Yuange Li,Zaijing Tao,Shuo Wang,Jixian Yue,Xu Chen,Yajun Xu,Yongjun Rui,Jingyi Mi,Yang Liu,Jinglei Wu,Jian Tian
Post-traumatic tendon adhesions significantly affect patient prognosis and quality of life, primarily stemming from the absence of effective preventive and curative measures in clinical practice. Current treatment modalities, including surgical excision and non-steroidal anti-inflammatory drugs, frequently exhibit limited efficacy or result in severe side effects. Consequently, the use of anti-adhesive barriers for drug delivery and implantation at the injury site to address peritendinous adhesion (PA) has attracted considerable attention. Electrospun nanofiber membranes (ENMs) have been extensively employed as drug-delivery platforms. In this study, we fabricated a polylactic acid (PLA)–dipyridamole (DP)-graft copolymer ENM called PLC-DP. This membrane exhibits enzyme-sensitive features, allowing more controlled and sustained drug release compared with conventional drug-loaded ENMs. In experiments, PLC-DP implantation reduced tissue adhesion by 47 % relative to the control group while not adversely affecting tendon healing. Mechanistically, PLC-DP effectively activates the FXYD domain containing ion-transport regulator 2 (FXYD2) protein, thereby downregulating the fibroblast-transforming growth factor beta (TGF-β)/Smad3 signaling pathway. PLC-DP leverages the anti-adhesive properties of DP and the enzyme-sensitive characteristics of graft copolymers, providing a promising approach for the future clinical treatment and prevention of PA. Statement of significance Peritendinous adhesions (PA) are a common and disabling condition that seriously affects the prognosis and quality of life of post-trauma patients. Current treatments often have limited efficacy or severe side effects, leaving a serious gap in clinical practice. We developed a significant biomaterial, poly(lactic acid)-dipyridamole graft copolymer electrospun nanofibrous membrane (PLC-DP), specifically for PA inhibition. In addition, this study uniquely combines dipyridamole, an anti-adhesive agent, and enzyme-sensitive copolymers in electrospun nanofibrous membrane. Unlike conventional drug-loaded electrospun nanofibrous membranes, PLC-DPs have enzyme-sensitive drug properties that allow for sustained drug release on demand. Our experiments showed that implantation of PLC-DP was effective in reducing tissue adhesions by 47 % without affecting tendon healing. We elucidated the mechanism behind this phenomenon, suggesting that PCD activates FXYD2 to inhibit TGF-β-induced expression of Col III, which is a key factor in PA development.
研究领域:
生物材料学
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医学
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药理学
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高影响因子
ACTA PHARMACOLOGICA SINICA
·
2024
·
IF 6.9
Zhao Tong,Zhou Zhi-ruo,Wan Hui-qi,Feng Tian,Hu Xu-hui,Li Xiao-qian,Zhao Shi-mei,Li Hong-lin,Hou Ji-wei,Li Wei,Lu Da-yun,Qian Min-yi,Shen Xu
Pulmonary fibrosis (PF) is a chronic, progressive and irreversible interstitial lung disease characterized by unremitting pulmonary myofibroblasts activation, extracellular matrix (ECM) deposition and inflammatory recruitment. PF has no curable medication yet. In this study we investigated the molecular pathogenesis and potential therapeutic targets of PF and discovered drug lead compounds for PF therapy. A murine PF model was established in mice by intratracheal instillation of bleomycin (BLM, 5 mg/kg). We showed that the protein level of pulmonary protein phosphatase magnesium-dependent 1A (PPM1A, also known as PP2Cα) was significantly downregulated in PF patients and BLM-induced PF mice. We demonstrated that TRIM47 promoted ubiquitination and decreased PPM1A protein in PF progression. By screening the lab in-house compound library, we discovered otilonium bromide (OB, clinically used for treating irritable bowel syndrome) as a PPM1A enzymatic activator with an EC 50 value of 4.23 μM. Treatment with OB (2.5, 5 mg·kg −1 ·d −1 , i.p., for 20 days) significantly ameliorated PF-like pathology in mice. We constructed PF mice with PPM1A-specific knockdown in the lung tissues, and determined that by targeting PPM1A, OB treatment suppressed ECM deposition through TGF-β/SMAD3 pathway in fibroblasts, repressed inflammatory responses through NF-κB/NLRP3 pathway in alveolar epithelial cells, and blunted the crosstalk between inflammation in alveolar epithelial cells and ECM deposition in fibroblasts. Together, our results demonstrate that pulmonary PPM1A activation is a promising therapeutic strategy for PF and highlighted the potential of OB in the treatment of the disease.
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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治疗学
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PubMed
高影响因子
Molecular Medicine Reports
·
2015
·Vol. 12
·期 1
·192-198
·
IF 1.554
Jinpeng Li,Hao Liu,Jieping Yu,Honggang Yu
Doxorubicin (Dox) is a commonly used chemotherapeutic drug in human colon cancer. However, it becomes increasingly ineffective with tumor progression, the underlying mechanism of which remains to be elucidated. Emerging evidence has led to the identification of an association between chemoresistance and the acquisition of epithelial‑mesenchymal transition (EMT) in cancer. However, it remains to be elucidated whether this process is involved in the development of resistance to Dox in colon cancer. In HCT116 human colon cancer cells treated with Dox (50 nmol/l), EMT was induced, and transforming growth factor (TGF)β signaling and multi‑drug resistant plasma membrane glycoprotein levels were significantly increased. By contrast, silencing of Smad4, using stable RNA interference, inhibited TGFβ signaling, reversed the process of EMT and markedly increased the sensitivity of HCT116 cells to Dox. The results of the present study suggested that the combination of Dox with the downregulation of TGFβ signaling may be a potential novel therapeutic strategy with which to overcome chemoresistance during colon cancer chemotherapy.
研究领域:
肿瘤学
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分子生物学
·
癌症治疗
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高影响因子
Evidence-based Complementary and Alternative Medicine
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2022
·
IF 2.65
Ziming Jia,Yanhua Zheng,Shaohua Fu,Jingjing Qu,Jie Tian,Wen Qu,Zhinan Mei
Background. Shi-Wei-Gan-Ning-San (SWGNS) is a classic Tibetan prescription, which has obvious clinical effects in the treatment of viral hepatitis, fatty liver, liver fibrosis, liver cirrhosis, liver cancer, and other liver injuries. However, animal studies and mechanism studies are still lacking. This study aimed to investigate its hepatoprotective efficacy and pharmacological mechanism in animal experiments. Methods. Chronic liver injury was induced by oral administration of carbon tetrachloride (CCl4) in Wistar rats for 13 weeks. SWGNS was administered orally to rats at doses of 235, 705, and 1410 mg/kg for 13 weeks. Blood samples were collected for biochemical, ELISA, and radioimmunoassay. Livers were harvested for H&E and immunohistochemical staining. The major constituents of SWGNS were analyzed by HPLC. In vitro experiments were used to explore the protective effect of Crocin on BRL-3A in the environment of H2O2. Results. SWGNS reversed weight loss is induced by CCl4. Serum assays showed that SWGNS reduced CCl4-induced alanine aminotransferase, aspartate aminotransferase, total bilirubin, and γ-glutamyltransferase levels and increased the total protein and albumin levels. Histopathological evaluation showed that SWGNS alleviated hepatic steatosis, fibrosis, and inflammation. Furthermore, SWNGS reduced CCl4-induced elevations of TGF-β1, hyaluronic acid, laminin, and collagen IV in serum and reduced the high expression of α-SMA in tissues. Moreover, Crocin I and II are the main components of SWGNS. Crocin attenuated the damaging effects of H2O2 on BRL-3A. Conclusions. In conclusion, SWGNS alleviated CCl4-induced chronic liver injury by inhibiting the TGF-β1 pathway. This plays an important role in promoting traditional Tibetan medicine in clinical practice.
研究领域:
药理学
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肝病学
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传统医学
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分子生物学
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高影响因子
JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY
·
2022
·Vol. 36
·期 8
·e23084
·
IF 3.568
Qian Shang,Li Zhu,Weina Shang,Jia Zeng,Yong Qi
Dioscin is a natural product that possesses protective effects on multiple chronic injuries, but its effects on asthma are not fully understood. Herein, we evaluated its effects on asthmatic mice established by ovalbumin (OVA) sensitization and challenges and further explored the mechanism. Inflammatory cells in bronchoalveolar lavage fluids (BALFs) were analyzed using Diff-Quik staining. OVA-specific immunoglobulin E (IgE)/IgG1 in serum and inflammatory cytokines (interleukin 4[IL-4], IL-5, IL-13, and tumor necrosis factor-α) in BALFs and lung tissues were measured using Enzyme-Linked Immunosorbent Assay Kits. Hematoxylin and eosin, periodic acid–Schiff, and immunohistochemistry staining showed histopathological changes in lung tissues. Epithelial–mesenchymal transition (EMT) in human bronchial epithelial (16HBE) cells was assessed by immunofluorescence staining. Hydroxyproline content was used to evaluate collagen deposition. Polymerase chain reaction and Western blot were performed to measure messenger RNA and protein expression. We found that dioscin treatment (particularly at the dose of 80 mg/kg) significantly inhibited pulmonary inflammation in asthmatic mice, as evidenced by the decreased serum OVA-specific IgE/IgG1 and the reduced inflammatory cells and cytokines in BALFs and lung tissues. Moreover, dioscin effectively ameliorated the goblet cell hyperplasia, mucus hypersecretion, collagen deposition, and smooth muscle hyperplasia in the airways of asthmatic mice. Mechanistically, dioscin restrained the activated TGF-β1/Smad2/3 and protein kinase B (AKT) signal pathways in lung tissues and potently reversed the TGF-β1-induced EMT and phosphorylation of Smad2/3 and AKT in 16HBE cells. Collectively, dioscin displayed protective effects on OVA-induced asthmatic mice via adjusting TGF-β1/Smad2/3 and AKT signal pathways, supporting the fact that dioscin could be a candidate for chronic asthma prevention in the future.
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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呼吸医学
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Reproductive Biology
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2022
·
IF 2.089
Zhongxue Ye,Yafen Jiang,Junlong Wu
This study intends to investigate the effects of DNA methyltransferase 3B (DNMT3B) and ten-eleven translocation 3 (TET3) on transforming growth factor-β1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) in ovarian cancer (OV) cells. According to the specific experiments, the cells were treated with TGF-β1 for 48 h, and then the expressions of EMT-related proteins (E-cadherin, Vimentin and Snail), TET3 and DNMT3B were quantified by Western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Methprimer, methylation-specific PCR (MSP), bisulfite sequencing PCR (BSP) and chromatin immunoprecipitation (ChIP) were used to determine the regulation of DNMT3B on TET3 promoter. The impacts of DNMT3B and TET3 upon the EMT-related proteins and OV cell migration and invasion abilities were evaluated through the rescue experiments and the loss- and gain-of-function experiments. In line with the results, TGF-β1 down-regulated TET3 and E-cadherin levels, up-regulated Vimentin and Snail levels, promoted migratory and invasive abilities, and increased methylation level of TET3 promoter in OV cells, which however were reversed by shDNMT3B. The binding of DNMT3B to TET3 promoter facilitated the methylation of TET3 promoter. Overexpressed TET3 inhibited the migratory and invasive abilities and EMT of OV cells, whereas shTET3 did the opposite. ShTET3 also offset the regulatory effects of shDNMT3B on EMT, migration and invasion of OV cells. To conclude, DNMT3B mitigates the suppression of TET3 on TGF-β1-induced EMT in OV cells by methylating the promoter region of TET3.
研究领域:
肿瘤学
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分子生物学
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表观遗传学
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高影响因子
Biomedicines
·
2026
·Vol. 14
·期 7
·1586
·
IF 4.5
Xiaofei Tong,Meina Sun,Xin Gan,Xin Chen,Shiyang Liu,Ieong Sun,Lin Zhang,Weihong Zheng
Background: Capsular contracture is driven by self-amplifying foreign body response (FBR) where inflammatory and fibrotic signals from fibroblasts and macrophages reinforce each other. We hypothesized that cogradient simultaneous blockade of NF-κB as an inflammatory node and TGF-β/Smad as fibrotic node could attenuate the FBR. Emodin has dual inhibitory activity but suffers from poor delivery.Methods: Emodin liposomes (Emo-Lip) were characterized and tested on TGF-β1-stimulated NIH/3T3 fibroblasts and LPS-stimulated RAW264.7 macrophages. In a rat silicone implant model, periprosthetic injections were given for four weeks. Fibrous capsule formation was evaluated by histology, immunofluorescence, and FAPI-PET/CT. Transcriptomic analyses were performed to verify and predict relevant pathways.Results: Emo-Lip had uniform size and high encapsulation efficiency. In vitro, Emo-Lip inhibited fibroblast migration, ROS production, myofibroblast differentiation (α-SMA+) as well asCtgfexpression, while suppressing M1 polarization and reduced IL-12/IL-6 secretion in macrophages. In vivo, Emo-Lip reduced capsule thickness, collagen area, and α-SMA/Col I expression, comparable to dexamethasone. Transcriptomics showed coordinated downregulation of inflammatory/fibrotic genes, and Western blot confirmed suppressed phosphorylation of Smad3.Conclusions: Coordinated two-node blockade of NF-κB and TGF-β/Smad by liposomal emodin reprograms the FBR and effectively prevents capsular contracture in rats, offering a translational strategy for implant-associated fibrosis.
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Applied Biological Chemistry
·
2026
·Vol. 69
·期 1
·68
·
IF 4.2
Wang Yujie,Wang Jiajie,Cai Maoxuan,Ren Jie,Jia Fang,Jiang Wenjie,Su Dan,Yang Hao,Chen Guilin
Diabetic nephropathy (DN) ranks as the primary contributor to end-stage renal disease across the globe, characterized by progressive glomerular mesangial proliferation and tubular interstitial fibrosis, which poses a severe threat to public health. Pinocembrin is a major flavonoid compound that has been reported to exhibit a variety of prominent biological effects. However, its dual regulatory effects on glomerular and tubular injuries in DN remain unclear. The present study aims to investigate the potential role of pinocembrin in alleviating the progression of DN, providing a combination therapeutic strategy. In vivo experiments were performed to verify its efficacy in improving renal injury and fibrosis of pinocembrin in Lep db /Lep db ( db/db) mice. Pinocembrin-related targets were retrieved from Traditional Chinese Medicine Systems Pharmacology (TCMSP), Comparative Toxigenomics Database (CTD), Swiss Target Prediction, and Symmap databases. Differentially expressed genes in DN tubules and glomeruli were obtained from Gene Expression Omnibus (GEO) dataset GSE30122. Overlapping targets between pinocembrin and DN tissues were identified, followed by Protein-Protein Interaction (PPI) network construction, Gene Ontology (GO) annotation, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Molecular docking predicted potential binding interactions between pinocembrin and key targets. In vitro experiments demonstrated that in HG-induced HK-2 cells, pinocembrin might target HSP90AB1 to suppress inflammatory response and epithelial-mesenchymal transition, thereby alleviating tubular fibrosis injury. In HG-treated SV40 cells, pinocembrin downregulated expression of VEGFR, thereby inhibiting cell proliferation and extracellular matrix deposition to improve glomerular pathological damage. This study clarifies the dual protective mechanism of pinocembrin on DN via regulatory pathways. These findings provide experimental foundation and theoretical insight for the application of pinocembrin as a functional food ingredient for the prevention and treatment of DN.
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高影响因子
Advanced Science
·
2022
·Vol. 9
·期 10
·2105240
·
IF 17.521
Huiming Peng,Jian Shen,Xin Long,Xiaoqi Zhou,Jiaqi Zhang,Xina Xu,Teng Huang,Hui Xu,Shuguo Sun,Chun Li,Ping Lei,Heshui Wu,Jun Zhao
Pancreatic cancer is a deadly disease with little response to standard therapies. Irreversible electroporation (IRE) has emerged as a novel ablative technique for the clinical treatment of pancreatic cancer. Combinations of IRE and immunotherapies, including anti-programmed death 1 ( α PD1) immune checkpoint blockade, have shown promising efficacy in both preclinical and clinical studies. However, tumor recurrence remains an obstacle that needs to be overcome. It herein is shown that IRE induces a substantial infiltration of neutrophils into pancreatic tumors. These neutrophils are then polarized into a protumor phenotype by immunosuppressive cues, in particular transforming growth factor β (TGF- β ). Using glutathione-responsive degradable mesoporous silica nanoparticles loaded with SB525334, an inhibitor of TGF- β 1 receptor, it is demonstrated that local inhibition of TGF- β within the tumor microenvironment promotes neutrophil polarization into an antitumor phenotype, enhances pancreatic cancer response to combined IRE and α PD1 therapy, and induces long-term antitumor memory. The therapeutic efficacy is also attributed to tumor infiltration by CD8 + cytotoxic T cells, depletion of regulatory T cells, and maturation of antigen-presenting dendritic cells. Thus, modulating neutrophil polarization with nanomedicine is a promising strategy for treating pancreatic cancer.
研究领域:
肿瘤学
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纳米医学
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免疫学
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高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
·
2024
·
IF 4.2
Lin Lv,Keying Yuan,Jiahao Li,Jing Lu,Qi Zhao,Hongyan Wang,Qiuyu Chen,Xinyu Dong,Siqi Sheng,Mingyu Liu,Yuanqi Shi,Hongquan Jiang,Zengxiang Dong
Myocardial fibroblasts transform into myofibroblasts during the progression of cardiac fibrosis, together with excessive cardiac fibroblast proliferation. Hence, the prevention and treatment of cardiac fibrosis are significant factors for inhibiting the development of heart failure. P-element Induced WImpy testis-interacting RNAs (PiRNA) are widely expressed in the heart, but their involvement in cardiac fibrosis has not yet been confirmed. We identified differentially expressed PiRNAs using Arraystar PiRNA expression profiling in Angiotensin II models of cardiac fibrosis in vivo and in vitro. We then explored cardiac-fibrosis-associated PiRNA-related proteins, RNA-protein interactomes, immunoprecipitation, and pulldown. We detected fibrosis markers and pathway-related proteins using immunofluorescence, qRT-PCR, and Western blot. We uncovered cardiac fibrosis associated PiRNA (CFAPIR) that was obviously dysregulated during cardiac fibrosis, whereas its overexpression reversed fibrosis in vivo and in vitro. Mechanistically, CFAPIR competitively bound muscleblind like protein 2 (MBNL2) and the cyclin-dependent kinase inhibitor P21 to regulate the TGF-β1/SMAD3 signaling pathway.
研究领域:
心脏病学
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分子生物学
·
基因组学
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高影响因子
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