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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Frontiers in Microbiology
·
2022
·
IF 6.064
Gao Haijun,Huo Lele,Mo Xiaojin,Jiang Bin,Luo Yanping,Xu Bin,Li Jingzhong,Ma Xingming,Jing Tao,Feng Zheng,Zhang Ting,Hu Wei
Echinococcus multilocularis, the causative agent of alveolar echinococcosis (AE), severely threats human health and livestock farming. The first line of chemotherapeutic drug for AE is albendazole, which limits rapid extension of E. multilocularis metacestodes, but is rarely curative for AE, with severe side effects in long-term use, thus development of new anti-echinococcal drugs is mandated. Pseudolaric acid B (PAB) has long been used to treat fungal-infected dermatosis, and exerted anti-tumor, -fertility, -angiogenesis, -tubulin and antiparasitic activity. However, the effect of PAB against Echinococcus spp. remains unclear. The present study is to understand the effect of PAB against E. multilocularis in vitro and in vivo, and identify potential anti-echinococcal mechanism, as well as its toxicity. After exposure to PAB at 20 μg/ml, significant reduction of the survival rate and substantial ultrastructural destructions in E. multilocularis protoscoleces were observed in vitro. Furthermore, the wet weight of E. multilocularis cysts in the infected mice was significantly decreased after treatment with PAB (40, 20 or 10 mg/kg) for 12 weeks. Meanwhile, significant increase of both protein and mRNA expression of transforming growth factor beta 1 (TGF-β1) was detected in the serum and liver of the infected mice, whereas PAB administration lowered its expression significantly. The toxicity tests demonstrated that PAB displayed lower cytotoxicity to human liver and kidney cells (HL-7702 and HK-2 cell) with IC50 = 25.29 and 42.94 μg/ml than albendazole with IC50 = 3.71 and 21.22 μg/ml in vitro, and caused lower hepatoxicity and nephrotoxicity in mice than ABZ. Our findings indicated that PAB possesses potent anti-echinococcal effect, with lower toxicity than albendazole, implying a potential chemotherapeutic agent for AE. Additionally, the present study demonstrated that the suppressive effect of PAB on the parasite may involve down-regulation of TGF-β1 signaling.
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FASEB JOURNAL
·
2024
·Vol. 38
·期 15
·e23495
·
IF 4.4
Yuwei Liu,Xiaomei Wang,Zhongfeng Wang,Xiuzhu Gao,Hongqin Xu,Yanhang Gao,Junqi Niu
Hepatic stellate cell (HSC) activation is the essential pathological process of liver fibrosis (LF). The molecular mechanisms regulating HSC activation and LF are incompletely understood. Here, we explored the effect of transcription factor SRY-related high mobility group box 7 (SOX7) on HSC activation and LF, and the underlying molecular mechanism. We found the expression levels of SOX7 were decreased in human and mouse fibrotic livers, particularly at the fibrotic foci. SOX7 was also downregulated in primary activated HSCs and TGF-β1 stimulated LX-2 cells. SOX7 knockdown promoted activation and proliferation of LX-2 cells while inhibiting their apoptosis. On the other hand, overexpression of SOX7 suppressed the activation and proliferation of HSCs. Mechanistically, SOX7 attenuates HSC activation and LF by decreasing the expression of β-catenin and phosphorylation of Smad2 and Smad3 induced by TGF-β1. Furthermore, overexpression of SOX7 using AAV8-SOX7 mouse models ameliorated the extent of LF in response to CCl 4 treatment in vivo. Collectively, SOX7 suppressed HSC activation and LF. Targeting SOX7, therefore, could be a potential novel strategy to protect against LF.
研究领域:
分子生物学
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细胞生物学
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肝病学
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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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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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Evidence-based Complementary and Alternative Medicine
·
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
·
传统医学
·
分子生物学
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Reproductive Biology
·
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
·
表观遗传学
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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
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基因组学
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MOLECULAR AND CELLULAR BIOCHEMISTRY
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2026
·
IF 3.7
Wen Qiang,Yuan Yi,Liu Zhihua,Wang Lei,Pan Chunguo
Lung cancer (LC) is a leading cause of cancer-related mortality worldwide. While the chemokine CCL25 is implicated in the tumor microenvironment, its specific role in LC is not fully understood. Here, we identify CCL25 as a key promoter of tumor progression through a novel macrophage-mediated signaling axis. Bioinformatics and clinical analyses revealed that CCL25 is highly expressed in LC and correlates with M2 macrophage infiltration and poorer patient survival. In vitro, tumor-derived CCL25 drove M2 polarization of macrophages by upregulating its receptor CCR9. Functionally, these CCL25-CCR9-induced M2 macrophages secreted TGF-β1 and significantly enhanced the proliferation, migration, and invasion of LC cells. Mechanistically, this effect was mediated through the activation of the JAK/STAT signaling pathway and the subsequent upregulation of the downstream oncogene PIM2 in tumor cells. Both pharmacological inhibition of JAK/STAT and genetic knockdown of PIM2 reversed the tumor-promoting crosstalk. Single-cell transcriptomics confirmed the presence of a TGF-β1-expressing CCR9 + M2 macrophage subset in human tumors and revealed co-expression of CCR9 and PIM2 in tumor cells. In vivo, CCL25 overexpression accelerated tumor growth and M2 macrophage infiltration. Collectively, our findings define a complete CCL25-CCR9-TGF-β1-JAK/STAT-PIM2 signaling circuit wherein tumor cells educate macrophages to, in turn, fuel their own malignant progression, highlighting this axis as a potential therapeutic target in lung cancer.
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FEBS Open Bio
·
2023
·
IF 2.6
Yu Zhu,Longmei Wang,Rui Liu,Xiurong Ding,Song Yin,Yuankun Chen,Chuanlong Zhu,Zheng Wang,Wenting Li
Sepsis-induced acute kidney injury (SI-AKI) causes renal dysfunction and has a high mortality rate. Protein arginine methyltransferase-1 (PRMT1) is a key regulator of renal insufficiency. In this study, we explored the potential involvement of PRMT1 in SI-AKI. A murine model of SI-AKI was induced by cecal ligation and perforation (CLP). The expression and localization of PRMT1 and molecules involved in the TGF-β1/Smad3 and IL-6/STAT3 signaling pathways were detected in mouse kidney tissues by western blot, immunofluorescence, and immunohistochemistry. The association of PRMT1 with downstream molecules of the TGF-β1/Smad3 and IL-6/STAT3 signaling pathways were further verified in vitro in mouse renal tubular epithelial cells (mRTECs). CLP caused epithelial-mesenchymal transition (EMT), apoptosis, and inflammation in renal tissues, and this was alleviated by inhibition of PRMT1. Inhibition of PRMT1 in SI-AKI mice decreased the expression of TGF-β1 and phosphorylation of Smad3 in the renal cortex, and downregulated the expression of sIL-6R and phosphorylation of STAT3 in the medulla. Knockdown of PRMT1 in mRTECs restricted the expression of Cox-2, E-cad, Pro-caspase3 and p-Smad3 (involved in the TGF-β1-mediated signaling pathway), and blocked IL-6/sIL-6R, inducing the expression of Cox-2 and p-STAT3. In conclusion, our findings suggest inhibition of PRMT1 mitigates SI-AKI by inactivating the TGF-β1/Smad3 pathway in the cortex and IL-6/STAT3 pathway in the medulla. Our findings may aid in the identification of potential therapeutic target molecules for SI-AKI.
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Biofabrication
·
2020
·Vol. 12
·期 2
·025030
·
IF 8.213
Chong Wang,Haibing Yue,Wei Huang,Xudong Lin,Xiaoqiong Xie,Zhi He,Xiao He,Sanbiao Liu,Lu Bai,Bingheng Lu,Yen Wei,Min Wang
Due to the increasing aging population and the high probability of sport injury among young people nowadays, it is of great demand to repair/regenerate diseased/defected osteochondral tissue. Given that osteochondral tissue mainly consists of a subchondral layer and a cartilage layer which are structurally heterogeneous and mechanically distinct, developing a biomimetic bi-phasic scaffold with excellent bonding strength to regenerate osteochondral tissue is highly desirable. Three-dimensional (3D) printing is advantageous in producing scaffolds with customized shape, designed structure/composition gradients and hence can be used to produce heterogeneous scaffolds for osteochondral tissue regeneration. In this study, bi-layered osteochondral scaffolds were developed through cryogenic 3D printing, in which osteogenic peptide/β-tricalcium phosphate/poly(lactic-co-glycolic acid) water-in-oil composite emulsions were printed into hierarchically porous subchondral layer while poly(D,L-lactic acid-co-trimethylene carbonate) water-in-oil emulsions were printed into thermal-responsive cartilage frame on top of the subchondral layer. The cartilage frame was further filled/dispensed with transforming growth factor-β1 loaded collagen I hydrogel to form the cartilage module. Although the continuously constructed osteochondral scaffolds had distinct microscopic morphologies and varied mechanical properties at the subchondral zone and cartilage zone at 37 °C, respectively, the two layers were closely bonded together, showing excellent shear strength and peeling strength. Rat bone marrow derived mesenchymal stem cells (rBMSCs) exhibited high viability and proliferation at both subchondral- and cartilage layer. Moreover, gradient rBMSC osteogenic/chondrogenic differentiation was obtained in the osteochondral scaffolds. This proof-of-concept study provides a facile way to produce integrated osteochondral scaffolds for concurrently directing rBMSC osteogenic/chondrogenic differentiation at different regions.
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2022
·
IF 5.195
Xiao-guo Suo,Fang Wang,Chuan-hui Xu,Xiao-yan He,Jia-nan Wang,Yao Zhang,Wei-jian Ni,Hao Lu,Ming-lu Ji,Yuan He,Shuai-shuai Xie,Ya-ru Yang,Jia-gen Wen,Juan Jin,Qian Gong,Jun Li,Ming-ming Liu,Xiao-ming Meng
Renal fibrosis , a common feature of chronic kidney disease , causes the progressive loss of renal function, in which TGF-β 1 plays a critical role. In this study, we found that expression levels of TGF-β 1 and its receptor 1 (TGF-βR1) were both significantly increased in obstructive fibrosis kidneys. AZ12601011 is a small molecular inhibitor of TGF-βR1; however, its therapeutic potential for renal fibrosis remains unclear. During the experiments, AZ12601011 was applied to various models of renal fibrosis followed by unilateral ureteral obstruction (UUO) and ischemia/reperfusion (I/R) in vivo , in addition to renal tubular epithelial cells (TECs) challenged by hypoxia/reoxygenation (H/R) and TGF-β 1 in vitro. Our results revealed that AZ12601011 ameliorated renal injuries and fibrosis shown by PAS, HE , and Masson staining , which was consistent with the decrease in Col-1 and α-SMA expression in the kidneys from UUO and I/R mice. Similarly, in vitro data showed that AZ12601011 inhibited the induction of Col-1 and α-SMA in both TECs treated with TGF-β 1 and H/R. In addition, the results of cellular thermal shift assay (CETSA), molecular docking , and western bolt indicated that AZ12601011 could directly bind to TGF-βR1 and block activation of the downstream Smad3. Taken together, our findings suggest that AZ12601011 can attenuate renal fibrosis by blocking the TGF-β/Smad3 signaling pathway and it might serve as a promising clinical candidate in the fight against fibrotic kidney diseases.
研究领域:
药理学
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肾病学
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分子生物学
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