Cell and Bioscience
·
2019
·Vol. 9
·期 1
·1-15
·
IF 3.355
Tan Jianxin,Wang Yajun,Wang Siliang,Wu Simeng,Yuan Zhe,Zhu Xike
Background Adipocyte accumulation is a predominant feature of age-related thymic involution, but the mechanisms responsible for thymic adipogenesis remain to be elucidated. The aim of this study was to identify key regulators in thymic adipogenesis. We used rosiglitazone, a potent peroxisome proliferator-activated receptor γ (PPARγ) agonist, to induce adipogenic differentiation of OP9-DL1 cells, and investigated the differentially expressed proteins during adipogenic differentiation by using label-free quantitative proteomics. Furthermore, the effects of transforming growth factor β1 (TGF-β1) on rosiglitazone-induced adipogenic differentiation of OP9-DL1 cells as well as the underlying mechanisms were also investigated. Results Proteomic analysis identified 139 proteins differed significantly in rosiglitazone-treated cells compared with dimethyl sulphoxide (DMSO)-treated cells. Rosiglitazone-induced adipogenic differentiation was inhibited by TGF-β1 treatment in OP9-DL1 cells and primary thymic stromal cells. Real-time PCR analysis showed significant increases in PPARγ and fatty acid binding protein 4 mRNA levels in rosiglitazone-treated cells, which were inhibited by TGF-β1 treatment. TGF-β1 down-regulated PPARγ expression at both mRNA and protein levels in OP9-DL1 cells. Chromatin immunoprecipitation analysis demonstrated that TGF-β1 enhanced the binding of Smad2/3 and histone deacetylase 1, but reduced the binding of H3K14ac to the promoter of PPARγ gene. TGF-β1 partially reversed the inhibitory effects of rosiglitazone on the expression of Axin2 and β-catenin protein levels. TGF-β1 inhibited rosiglitazone-induced adipogenic transformation in OP9-DL1 cells by down-regulation of PPARγ and activation of the canonical Wnt/β-catenin signaling pathway. Conclusion Taken together, activation of TGF-β pathway may serve as a useful strategy to prevent thymic adiposity in age-related thymic involution.
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Oncology Letters
·
2017
·Vol. 15
·期 1
·1362-1372
·
IF 1.39
Chun‑Yu Li,Qi Wang,Shen Shen,Xiao‑Lu Wei,Guo‑Xia Li
Epithelial‑mesenchymal transition (EMT) has been reported to play pivotal roles in tumor invasion and metastasis. Inhibition of EMT may exert beneficial effects in regulating metastasis. Oridonin (ORI), an active diterpenoid compound isolated from Rabdosia rubescens, was found to be a potent anti‑metastatic agent. However, the possible involvement of ORI in the EMT in malignant melanoma is unclear. The present study found that ORI inhibited cell migration, invasion, and adhesion in A375 and B16‑F10 melanoma cells. The transforming growth factor‑β1 (TGF‑β1)‑induced EMT was also inhibited in ORI‑treated cells, as reflected in the upregulation of E‑cadherin, and downregulation of vimentin and Snail. Similar results were observed in A375 and B16‑F10 melanoma cells treated with ORI. Furthermore, pre‑treatment with ORI blocked the TGF‑β1‑induced phosphoinositide 3‑kinase (PI3K)/AKT serine/threonine kinase (Akt)/glycogen synthase kinase (GSK)‑3β signaling pathway activation. These effects mimicked PI3 kinase inhibitor LY294002 treatment. ORI interfered with the PI3K/Akt/GSK‑3β pathway, and reversed TGF‑β1‑induced EMT, which suppressed the invasion and metastasis of melanoma cells. Taken together, the present study demonstrated that ORI inhibits melanoma cells migration, invasion, and adhesion and TGF‑β1‑induced EMT through the PI3K/Akt/GSK‑3β signaling pathway. These findings suggest that ORI is a promising anti‑metastasis agent for melanoma.
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DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY
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2024
·
IF 2.4
Xingbo Wang,Hong Huang,Wenxiu Xu,Yanling Gong,Songbo Shi,Xu Wan,Li Pengbiao
Introduction Triple negative breast cancer (TNBC) is characterized with higher malignancy and mortality and is prone to distant metastasis, among which bone is the most common site. It’s urgent to explore new strategies for treatment of TNBC and its bone metastases.Methods A tumor environment responsive vector, poly-(dimethylaminoethyl methacrylate)-SS-poly(ethylene glycol)-SS-poly-(dimethylaminoethyl methacrylate) (PDMAEMA-SS-PEG-SS-PDMAEMA), was constructed to co-delivery transforming growth factor-β1 (TGF-β1) siRNA and forkhead box M1 (FOXM1) siRNA in MDA-MB-231 cells. The preparation, characterization, in vitro release, stability, and transfection efficiency of nanoparticles were measured. Cell viability, migration and invasion of MDA-MB-231 cells were determined. Cell chemotactic migration and cell heterogeneity adhesion of MDA-MB-231 cells to the human osteoblast-like cell line MG-63 were determined.Results PDMAEMA-SS-PEG-SS-PDMAEMA self assembled with siRNA at N/P of 15:1 into nanoparticles with particle size of 122 nm. In vitro release exhibited redox and pH sensitivity, and the nanoparticles protected siRNA from degradation by RNase and serum protein, remaining stable at 4 °C with similar transfection efficiency with lipo2000. Nanoparticles co-loaded with TGF-β1 siRNA and FOXM1 siRNA inhibited the cell viability, migration and invasion of MDA-MB-231 cells, as well as chemotactic migration and heterogeneous adhesion of MDA-MB-231 cells to MG-63 cells, showing a synergetic effect. After gene silencing on TGF-β1 and FOXM1, the epithelial to mesenchymal transition (EMT) related molecules vimentin mRNA expression decreased while E-cadherin increased.Conclusion PDMAEMA-SS-PEG-SS-PDMAEMA was suitable for TGF-β1 siRNA and FOXM1 siRNA delivery, exhibiting synergetic inhibition effect on TNBC and its bone metastases, which might be related to its synergetic inhibition on EMT.
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INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2018
·Vol. 42
·期 4
·2155-2162
·
IF 2.784
Tao Song,Jingdong Zhao,Tongbai Jiang,Xing Jin,Yubin Li,Xinrong Liu
The present study investigated the effects of formononetin (FMN) against balloon injury‑induced neointima formation in vivo and platelet‑derived growth factor (PDGF)‑BB‑induced proliferation and migration of vascular smooth muscle cells (VSMCs) in vitro, and explored the underlying mechanisms. A rat model of carotid artery injury was established, in order to examine the effects of FMN on balloon injury‑induced neointima formation. Histological observation of the carotid artery tissues was conducted by hematoxylin and eosin staining. VSMC proliferation during neointima formation was observed by proliferating cell nuclear antigen staining. Subsequently, rat aortic VSMCs were isolated, and the effects of FMN on PDGF‑BB‑induced VSMC proliferation and migration were determined using Cell Counting Kit‑8 and Transwell/wound healing assays, respectively. Immunohistochemical and immunocytochemical staining was applied to measure the expression of transforming growth factor (TGF)‑β in carotid artery tissues and VSMCs, respectively. SMAD family member 3 (Smad3)/phosphorylated (p)‑Smad3 expression was examined by western blotting. FMN treatment significantly inhibited the abnormal proliferation of smooth muscle cells in neointima, and alterations to the vascular structure were attenuated. In addition, pretreatment with FMN effectively inhibited the proliferation of PDGF‑BB‑stimulated VSMCs (P<0.05). FMN also reduced the number of cells that migrated to the lower surface of the Transwell chamber and decreased wound‑healing percentage (P<0.05). The expression levels of TGF‑β were decreased by FMN treatment in vivo and in vitro, and Smad3/p‑Smad3 expression was also markedly inhibited. In conclusion, FMN significantly protected against balloon injury‑induced neointima formation in the carotid artery of a rat model; this effect may be associated with the regulation of VSMC proliferation and migration through altered TGF‑β1/Smad3 signaling.
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2025
·
IF 4.7
Lijun Fang,Linmao Lyu,Hongyu Zhong,Jiamao Lin,Pengtao Ren,Yu Wang,Yunhong Yin,Mengyu Zhang,Yiqing Qu
Idiopathic pulmonary fibrosis (IPF) is a kind of chronic and progressive interstitial lung disease of unclear aetiology. A key aspect of IPF is transforming growth factor-β1 (TGF-β1)-induced mitophagy dysfunction and senescence in lung fibroblasts. Mesenchyme homeobox 1 (MEOX1) is a critical transcription factor in the regulation of cell differentiation. However, the role of MEOX1 in the pathogenesis of lung fibrosis and mitophagy has not been clarified. In this study, RNA-sequencing analysis was employed to identify the differentially expressed genes in TGF-β1-treated lung fibroblasts and IPF lung tissue. In vivo , the mouse model of lung fibrosis was established by intratracheal injection of bleomycin (BLM), and fibroblast-specific knockdown of MEOX in mice was achieved by intratracheal injection of adeno-associated viruse-shMEOX1. And in vitro experiments were also carried out on human lung fibroblasts. Our results indicated that fibroblast-specific knockdown of MEOX1 protected mice from BLM-induced pulmonary fibrosis, connective tissue growth factor (CTGF) expression, and lung fibroblast activation, as well as mitophagy deficiency and senescence. In vitro , MEOX1 knockdown abolished TGF-β1-induced mitophagy deficiency by downregulating CTGF expression, thereby inhibiting senescence, over-activation and collagen production in lung fibroblasts. Furthermore, we also found that TGF-β1 upregulated the expression of MEOX1 through the NOX4-ROS-Smad pathway. In conclusion, MEOX1 knockdown may ameliorate pulmonary fibrosis by regulating mitophagy and senescence and may be a potential therapeutic target for IPF and other types of interstitial lung diseases.
研究领域:
分子生物学
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细胞生物学
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呼吸病学
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遗传学
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生物信息学
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病理学
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FISH & SHELLFISH IMMUNOLOGY
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2024
·
IF 4.1
Qiulu Li,Kaixin Ping,Yannan Xiang,Ying Sun,Zunhan Hu,Shujuan Liu,Xinying Guan,Mian Fu
Avamectin (AVM), a macrolide antibiotic, is widely used in fisheries, agriculture, and animal husbandry, however, its irrational use poses a great danger to aquatic organisms. Ferulic acid (FA) is a natural chemical found in the cell walls of plants. It absorbs free radicals from the surrounding environment and acts as an antioxidant. However, the protective effect of FA against kidney injury caused by AVM has not been demonstrated. In this study, 60 carp were divided into the control group, AVM group (2.404 μg/L), FA+AVM group and FA group (400 mg/kg). Pathological examination, quantitative real-time PCR (qPCR), reactive oxygen species (ROS) and western blot were used to evaluate the preventive effect of FA on renal tissue injury after AVM exposure. Histological findings indicated that FA significantly reduced the swelling and infiltration of inflammatory cells in the kidney tissues of carp triggered by AVM. Dihydroethidium (DHE) fluorescent probe assay showed that FA inhibited the accumulation of kidney ROS. Biochemical results showed that FA significantly increased glutathione (GSH) content, total antioxidant capacity (T-AOC) and catalase (CAT) activity, and decreased intracellular malondialdehyde (MDA) content. In addition, western blot results revealed that the protein expression levels of Nrf2 and p-NF-κBp65 in the carp kidney were inhibited by AVM, but reversed by the FA. The qPCR results exhibited that FA significantly increased the mRNA levels of tgf-β1 and il-10 , while significantly down-regulated the gene expression levels of tnf-α , il-6 and il-1β . These data suggest that FA can reduce oxidative stress and renal tissue inflammation induced by AVM. At the same time, FA inhibited the apoptosis of renal cells induced by AVM by decreasing the transcription level and protein expression level of Bax, and increasing the transcription level and protein expression level of Bcl2, PI3K and AKT. This study provides preliminary evidence for the theory that FA reduces the level of oxidative stress, inflammation response and kidney tissue damage caused by apoptosis in carp, providing a theoretical basis for the prevention and treatment of the AVM.
研究领域:
水生毒理学
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药理学
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生物化学
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分子生物学
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 13
·10839
·
IF 5.6
Mingkang Zhang,Ruirui Cui,Yan Zhou,Yanrong Ma,Yongwen Jin,Lina Wang,Wen Kou,Xin’an Wu
Renal fibrosis is relentlessly progressive and irreversible, and a life-threatening risk. With the continuous intake of a high-purine diet, hyperuricemia has become a health risk factor in addition to hyperglycemia, hypertension, and hyperlipidemia. Hyperuricemia is also an independent risk factor for renal interstitial fibrosis. Numerous studies have reported that increased mast cells (MCs) are closely associated with kidney injury induced by different triggering factors. This study investigated the effect of MCs on renal injury in rats caused by hyperuricemia and the relationship between MCs and renal fibrosis. Our results reveal that hyperuricemia contributes to renal injury, with a significant increase in renal MCs, leading to renal fibrosis, mitochondrial structural disorders, and oxidative stress damage. The administration of the MCs membrane stabilizer, sodium cromoglycate (SCG), decreased the expression of SCF/c-kit, reduced the expression of α-SMA, MMP2, and inhibited the TGF-β1/Smad2/3 pathway, thereby alleviating renal fibrosis. Additionally, SCG reduced renal oxidative stress and mitigated mitochondrial structural damage by inhibiting Ang II production and increasing renal GSH, GSH-Px, and GR levels. Collectively, the recruitment of MCs, activation of the TGF-β1/Smad2/3 pathway, and Ang II production drive renal oxidative stress, ultimately promoting the progression of renal fibrosis in hyperuricemic rats.Keywords:hyperuricemia;renal fibrosis;mast cells;TGF-β1/Smad2/3 pathway;oxidative stress
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Medical Molecular Morphology
·
2021
·Vol. 54
·期 4
·337-345
·
IF 2.309
Xu Sijia,Dong Wenxin,Shi Yu
The purpose of this study is to explore whether LncRNA PICSAR binds to miR-485-5p and thereby activates TGF-β1/Smad signaling pathway, influencing the abnormal proliferation of fibroblasts and excessive deposition of ECM in hypertrophic scar formation. PICSAR and miR-485-5p expressions were detected by qPCR. Cell proliferation was examined by CCK-8. Protein expressions were determined by western blot. Immunofluorescence detected the Ki-67 expression. Dual-luciferase followed by immunoprecipitation was performed to verify the interaction between PICSAR and miR-485-5p. Interference with PICSAR inhibited the abnormal proliferation of hypertrophic scar fibroblasts (HSFs) and the excessive deposition of ECM. It was also confirmed in our study that MiR-485-5p is a direct target of PICSAR in HSFs. Additionally, inhibition of miR-485-5p reversed the effect of PICSAR knockdown in HSFs. LncRNA PICSAR binds to miR-485-5p and thereby activates TGF-β1/Smad signaling pathway, promoting the abnormal proliferation of fibroblasts and excessive deposition of ECM in hypertrophic scar formation.
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ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
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2023
·
IF 3.9
Yingying Chen,Wei Song,He Zhang,Xinping Ji
Epithelial-mesenchymal transition (EMT) of alveolar epithelial cells is a vital process in idiopathic pulmonary fibrosis (IPF), which results in the accumulation of fibroblasts and myofibroblasts and excessive extracellular matrix deposition. Based on RNA sequencing analysis and GEO dataset reanalysis, we screened out MICALL2, a gene upregulated in the lungs of IPF mice and alveolar epithelial type II (ATII) cells from IPF patients, and aimed to explore its role in IPF. We validated the expression of MICALL2 in bleomycin (BLM)-induced IPF mice and TGF-β1-stimulated ATII cells (primary murine ATII cells and A549 cells), and explored the role of MICALL2 in IPF by knockdown of MICALL2 in BLM-induced mice and TGF-β1-stimulated ATII cells. We found that MICALL2 was upregulated in the lungs of BLM-induced mice and TGF-β1-stimulated ATII cells. MICALL2-deficient mice had reduced fibrogenesis and restrained EMT upon BLM challenge. Knockdown of MICALL2 restrained the EMT process, in vitro, through impeding β‐catenin nuclear translocation. Mechanistically, we demonstrated that NPAS2 is directly bound to the promoter of MICALL2. Altogether, our data revealed transactivation of MICALL2 induced by NPAS2, contributing to activation of the Wnt/β-catenin pathway in ATII cells, thus leading to the EMT process and subsequent pulmonary fibrosis. Interfering with MICALL2 may represent an innovative therapeutic target to mitigate the extent of IPF.
研究领域:
肺科学
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细胞生物学
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分子生物学
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病理学
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ACS Pharmacology & Translational Science
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2024
·
IF 4.9
Xiao-Yi Chen,Tian-Tian Wang,Qing Shen,Hao Ma,Zhan-Hua Li,Xi-Na Yu,Xiao-Feng Huang,Lin-Sen Qing,Pei Luo
In traditional Chinese medicine, Radix Astragali has played a vital role in treating progressive fibrotic diseases. One of its main active components, astragaloside IV, is a promising anti-fibrotic treatment despite its extremely low bioavailability. Our study aimed to optimize sodium astragalosidate (SA) by salt formation to improve solubility and oral absorption for anti-fibrotic therapy in vivo. Isoproterenol-induced myocardial fibrosis rat models and obese BKS-db mice presenting diabetic kidney fibrosis were used in this study. Daily oral administration of SA (20 mg/kg) for 14 days ameliorated cardiac fibrosis by reducing collagen accumulation and fibrosis-related inflammatory signals, including TNF-α, IL-1β, and IL-6. In db/db mice, SA (5,10, and 20 mg/kg per day for 8 weeks) dose-dependently alleviated lipid metabolism impairment and renal dysfunction when administered orally. Furthermore, Western blot and immunohistochemistry analyses demonstrated that SA treatment inhibited renal fibrosis by suppressing TGF-β1/Smads signaling. Taken together, our findings provide the oral-route medication availability of SA, which thus might offer a novel lead compound in preclinical trial-enabling studies for developing a long-term therapy to treat and prevent fibrosis.
研究领域:
药理学
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心脏病学
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肾病学
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传统中医
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分子生物学
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MOLECULAR IMMUNOLOGY
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2024
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IF 3.2
Mingkang Zhang,Jinru Yang,Yufan Yuan,Yan Zhou,Yazhi Wang,Ruirui Cui,Yimai Maliu,Fen Xu,Xin’an Wu
Liver diseases caused by viral infections, alcoholism, drugs, or chemical poisons are a significant health problem: Liver diseases are a leading contributor to mortality, with approximately 2 million deaths per year worldwide. Liver fibrosis, as a common liver disease characterized by excessive collagen deposition, is associated with high morbidity and mortality, and there is no effective treatment. Numerous studies have shown that the accumulation of mast cells (MCs) in the liver is closely associated with liver injury caused by a variety of factors. This study investigated the relationship between MCs and carbon tetrachloride (CCl4)-induced liver fibrosis in rats and the effects of the MC stabilizers sodium cromoglycate (SGC) and ketotifen (KET) on CCl4-induced liver fibrosis. The results showed that MCs were recruited or activated during CCl4-induced liver fibrosis. Coadministration of SCG or KET alleviated the liver fibrosis by decreasing SCF/c-kit expression, inhibiting the TGF-β1/Smad2/3 pathway, depressing the HIF-1a/VEGF pathway, activating Nrf2/HO-1 pathway, and increasing the hepatic levels of GSH, GSH-Px, and GR, thereby reducing hepatic oxidative stress. Collectively, recruitment or activation of MCs is linked to liver fibrosis and the stabilization of MCs may provide a new approach to the prevention of liver fibrosis.
研究领域:
肝病学
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药理学
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病理学
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FASEB JOURNAL
·
2024
·Vol. 38
·期 13
·e23756
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IF 4.4
Lishen Shan,Li Chen,Wenxin Shen,Qianlan Zhou,Si Liu,Lina Han,Qinzhen Zhang,Bing Dai,Yuhong Zhao
Asthma is a chronic pulmonary disease with the worldwide prevalence. The structural alterations of airway walls, termed as “airway remodeling”, are documented as the core contributor to the airway dysfunction during chronic asthma. Forkhead box transcription factor FOXK2 is a critical regulator of glycolysis, a metabolic reprogramming pathway linked to pulmonary fibrosis. However, the role of FOXK2 in asthma waits further explored. In this study, the chronic asthmatic mice were induced via ovalbumin (OVA) sensitization and repetitive OVA challenge. FOXK2 was upregulated in the lungs of OVA mice and downregulated after adenovirus-mediated FOXK2 silencing. The lung inflammation, peribronchial collagen deposition, and glycolysis in OVA mice were obviously attenuated after FOXK2 knockdown. Besides, the expressions of FOXK2 and SIRT2 in human bronchial epithelial cells (BEAS-2B) were increasingly upregulated upon TGF-β1 stimulation and downregulated after FOXK2 knockdown. Moreover, the functional loss of FOXK2 remarkably suppressed TGF-β1-induced epithelial-mesenchymal transition (EMT) and glycolysis in BEAS-2B cells, as manifested by the altered expressions of EMT markers and glycolysis enzymes. The glycolysis inhibitor 2-deoxy-d-glucose (2-DG) inhibited the EMT in TGF-β1-induced cells, making glycolysis a driver of EMT. The binding of FOXK2 to SIRT2 was validated, and SIRT2 overexpression blocked the FOXK2 knockdown-mediated inhibition of EMT and glycolysis in TGF-β1-treated cells, which suggests that FOXK2 regulates EMT and glycolysis in TGF-β1-treated cells in a SIRT2-dependnet manner. Collectively, this study highlights the protective effect of FOXK2 knockdown on airway remodeling during chronic asthma.
研究领域:
呼吸病学
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免疫学
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分子生物学
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细胞生物学
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