INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2023
·Vol. 24
·期 7
·6172
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IF 5.6
Tianxiao Sun,Haihua Li,Yan Zhang,Guixin Xiong,Yuerun Liang,Fang Lu,Rong Zheng,Qi Zou,Jiejie Hao
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by lung inflammation and excessive deposition of extracellular matrix components. Transforming growth factor-β1 (TGF-β1) induced epithelial–mesenchymal transformation of type 2 lung epithelial cells leads to excessive extracellular matrix deposition, which plays an important role in fibrosis. Our objective was to evaluate the effects of 3-cyclopropylmethoxy-4-(difluoromethoxy) benzoic acid (DGM) on pulmonary fibrosis and aimed to determine whether EMT plays a key role in the pathogenesis of pulmonary fibrosis and whether EMT can be used as a therapeutic target for DGM therapy to reduce IPF. Firstly, stimulation of in vitro cultured A549 cells to construct EMTs with TGF-β1. DGM treatment inhibited the expression of proteins such as α-SMA, vimentin, and collagen Ⅰ and increased the expression of E-cadherin. Accordingly, Smad2/3 phosphorylation levels were significantly reduced by DGM treatment. Secondly, models of tracheal instillation of bleomycin and DGM were used to treat rats to demonstrate their therapeutic effects, such as improving lung function, reducing lung inflammation and fibrosis, reducing collagen deposition, and reducing the expression of E-cadherin. In conclusion, DGM attenuates TGF-β1-induced EMT in A549 cells and bleomycin-induced pulmonary fibrosis in rats.Keywords:IPF;A549;EMT;TGF-β1/Smad;ECM
研究领域:
药理学
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呼吸医学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
Biomaterials Science
·
2021
·Vol. 10
·期 3
·753-769
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IF 6.843
Zhiwei Yin,Lu Sun,Liyang Shi,Hemin Nie,Jianwu Dai,Can Zhang
Poor tendon repair remains a clinical problem due to the difficulties in replicating the complex multiscale hierarchical structure of native tendons. In this work, a bioinspired fibrous scaffold with bimodal micro-nanofibers and a teno-inductive aligned topography was developed to replicate microscale collagen fibers and nanoscale collagen fibrils that compose native tendons. The results showed indicated that the combination of micro- and nanofibers enhanced the mechanical properties. Furthermore, their biological performance was assessed using tendon stem/progenitor cells (TSPCs). Micro-nanofibers induced a higher cell aspect ratio and enhanced the tenogenic differentiation of TSPCs compared to micro- and nanocontrols. Interestingly, it was observed that scaffold nanotopography and microstructures promoted tenogenesis via activating the TGF-β/Smad2/3-mediated signaling pathway. The in situ implantation study confirmed that micro-nanofibrous scaffolds promoted the structural and mechanical properties of the regenerated Achilles tendon. Overall, our study shows that the bimodal micro-nanofibrous scaffold developed here presents a promising potential to improve the outcomes of tendon tissue engineering.
研究领域:
组织工程
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生物材料
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再生医学
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细胞生物学
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机械工程
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2018
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IF 2.559
Qing Shu,Song Lai,Xiao-Mei Wang,Yun-Long Zhang,Xiao-Lei Yang,Hai-Lian Bi,Hui-Hua Li
Pathological cardiac hypertrophy is the main risk factor for heart diseases. The ubiquitin-proteasome system (UPS) is the major intracellular protein degradation system involved in the development of cardiac hypertrophic remodeling. Ubiquitin-activating enzyme E1, a key component of the UPS, catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation via proteasome . However, the functional role of E1 (UBA1) in regulation of hypertrophic remodeling in angiotensin II (Ang II)-infused mice remains unknown. In this study, male wild-type mice were treated with UBA1 inhibitor PYR-41 at two doses of 5 and 10 mg and infused with Ang II (1000 ng/kg/min) for 14 days. Systolic blood pressure was detected by using tail-cuff system. Cardiac function was assessed by echocardiography. Hypertrophic remodeling was analyzed examined by histological examinations. The expressions of genes and proteins were detected by quantitative real-time PCR and immunoblotting analysis. After 14 days, Ang II infusion significantly increased UBA1 expression at both mRNA and protein levels in the hearts. Furthermore, Ang II-infused mice showed a significant increase in systolic blood pressure compensatory cardiac function, hypertrophy, interstitial fibrosis, inflammation and oxidative stress compared with saline-treated controls, whereas these effects were dose-dependently attenuated in PYR-41-treated mice. These beneficial actions were associated mainly with inhibition of PTEN degradation and multiple downstream mediators (AKT, ERK1/2, STAT3 , TGF-β/Smad2/3 and NF-kB(p65)). In conclusion, these results indicate that inhibition of UBA1 suppresses Ang II-induced hypertrophic remodeling, and suggest that administration of low dose PYR-41 may be a new potential therapeutic approach for treating hypertensive heart diseases.
研究领域:
心脏病学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
AMERICAN JOURNAL OF CHINESE MEDICINE
·
2024
·
IF 4.8
Xiaowei Zhang,Jiajun Wang,Shixie Xiang,Liang Zhao,Mingzhen Lv,Yafei Duan,Gai Gao,Pan Wang,Jenny Jie Chen,Jiangyan Xu,Zhishen Xie,Zhenqiang Zhang
Diabetic kidney disease (DKD) has become the primary cause of end-stage renal disease (ESRD), causing an urgent need for preventive strategies for DKD. Astragaloside I (ASI), a bioactive saponin extracted from Astragalus membranaceus (Fisch.) Bunge has been demonstrated to possess a variety of biological activities. This study investigates the therapeutic potential of ASI in DKD and the underlying molecular mechanism using db/db mice in vivo and high glucose (HG)-induced SV40-MES-13 cells in vitro . The results indicated that ASI significantly ameliorated renal dysfunction and mitigated the pathological alterations in the renal tissues of db/db mice. Moreover, ASI was found to reduce the levels of renal fibrosis makers and suppress the activation of TGF- β 1/Smad2/3 pathway in both db/db mice and HG-induced SV40-MES-13 cells. Furthermore, ASI downregulated HDAC3 expression, upregulated Klotho expression, and enhanced Klotho release. ASI is directly bound to HDAC3, and the beneficial effects of ASI on Klotho/TGF- β 1/Smad2/3-mediciated renal fibrosis in DKD were reversed by the HDAC3 agonist ITSA-1. In conclusion, ASI attenuates renal fibrosis in DKD, and may act through concurrently inhibiting HDAC3 and TGF- β 1, thereby regulating HDAC3-mediciated Klotho/TGF- β 1/Smad2/3 pathway.
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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糖尿病
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DOI
PubMed
高影响因子
Journal of Cachexia Sarcopenia and Muscle
·
2022
·Vol. 13
·期 6
·2740-2751
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IF 12.063
Fengju Li,Ting Luo,Honghui Rong,Lu Lu,Ling Zhang,Chuanfeng Zheng,Dali Yi,Yi Peng,Enyu Lei,Xiaotao Xiong,Fengchao Wang,Jose M. Garcia,Ji-an Chen
Background Di-(2-ethylhexyl) phthalate (DEHP) and its metabolites can cross the placenta and may cause birth defects and developmental disorders. However, whether maternal DEHP exposure affects skeletal muscle development in the offspring and the pathways involved are unknown. This study investigated the effects of maternal DEHP exposure and the contribution of myostatin (MSTN) to skeletal muscle development in the offspring. Methods Pregnant wild-type and muscle-specific myostatin knockout (MSTN KO) C57BL/6 mice were randomized to receive vehicle (corn oil) or 250 mg/kg DEHP by gavage every other day until their pups were weaned (postnatal day 21 [PND21]). Body weights of the offspring mice were measured longitudinally, and their hindleg muscles were harvested at PD21. Also, C2C12 cells were treated with mono-2-ethylhexyl phthalate (MEHP), the primary metabolite of DEHP, and proteolysis, protein synthesis, and myogenesis markers were measured. The contribution of myostatin to maternal DEHP exposure-induced muscle wasting in the offspring was determined. Results Maternal DEHP exposure reduced body weight growth, myofibre size, and muscle mass in the offspring compared to controls (Quad: 2.70 ± 0.1 vs. 3.38 ± 0.23, Gastroc: 2.29 ± 0.09 vs. 2.81 ± 0.14, Tibialis: 1.01 ± 0.07 vs. 1.25 ± 0.11, mg/tibial length in mm, all P < 0.01, n = 35). Maternal DEHP exposure significantly increased Myostatin expression (2.45 ± 0.41 vs. 0.03 ± 0.00 DEHP vs. controls, P < 0.01, n = 5), Atrogin-1(2.68 ± 0.65 vs. 0.63 ± 0.01, P < 0.05, n = 5), MuRF1 (1.56 ± 0.51 vs. 0.31 ± 0.01, P < 0.05, n = 5), and Smad2/3 phosphorylation (4.12 ± 0.35 vs. 0.49 ± 0.18, P < 0.05), and decreased MyoD (0.27 ± 0.01 vs. 1.52 ± 0.01, P < 0.05, n = 5), Myogenin (0.25 ± 0.03 vs. 1.95 ± 0.56, P < 0.05, n = 5), and AKT phosphorylation (4.12 ± 0.35 vs. 1.00 ± 0.06, P < 0.05, n = 5), in skeletal muscle of the offspring in MSTN flox/flox , but not in MSTN KO mice. Maternal DEHP exposure resulted in up-regulation of CCAAT/enhancer-binding protein δ (C/EBPδ, 4.12 ± 0.35 vs. 1.00 ± 0.19, P < 0.05, n = 5) in skeletal muscle of the offspring in MSTN flox/flox and MSTN KO mice (4.12 ± 0.35 vs. 4.35 ± 0.28, P > 0.05, n = 5). In vitro, C/EBPδ silencing abrogated the MEHP-induced increases in Myostatin, MuRF-1, and Atrogin-1 and decreases in MyoD and Myogenin expression. Conclusions Maternal DEHP exposure impairs skeletal muscle development in the offspring by enhancing the C/EBPδ-myostatin pathway in mice.
研究领域:
发育生物学
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毒理学
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肌肉生理学
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分子生物学
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DOI
PubMed
高影响因子
PULMONARY PHARMACOLOGY & THERAPEUTICS
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2024
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IF 3.3
Huijuan Zhang,Jianli Qiu,Qianyi Zhao,Yong Zhang,Haitao Zheng,Ziying Dou,Yongbin Yan
Pulmonary fibrosis is a complex disease that can occur in a variety of clinical settings. The Zinc Finger and BTB Domain Containing 16 (Zbtb16) is a transcription factor and has not been studied in pulmonary fibrosis. Lung tissues from rats which were treated with bleomycin and Tanshinone IIA (Tan IIA) were collected for mRNA sequencing. Zbtb16, a differentially expressed gene, was screened. Using adeno-associated virus to knock down Zbtb16 in rats, it was found that the lung index and the content of hydroxyproline in lung tissue were decreased. HE and Masson staining revealed that pathological symptoms of lung histopathology were relieved after Zbtb16 knockdown. Protein expressions of α-SMA, Collagen I and Fibronectin were significantly decreased after Zbtb16 knockdown in vivo and in vitro . Meanwhile, the protein content of TGF-β1 and the phosphorylation of Smad2/3 were inhibited by Zbtb16 knockdown. Conversely, under the treatment of Tan IIA and TGF-β1, overexpression of Zbtb16 improved cell viability, increased the expression of fibrosis-related proteins, and promoted the phosphorylation of Smad 2/3. All above demonstrates that Zbtb16 inhibition ameliorates pulmonary fibrosis and suppresses the TGF-β/Smad pathway. Furthermore, Zbtb16 mediates the inhibitory process of Tan IIA on pulmonary fibrosis. This study provides a novel candidate therapeutic target for pulmonary fibrosis.
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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病理学
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产品关联
DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR BIOLOGY
·
2024
·Vol. 70
·期 3
·95-101
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IF 1.5
Shanfu Wang,Bing Xu,Heng Yin,Zhen Hua,Yang Shao,Jianwei Wang
Osteoporosis is a common chronic bone disorder in postmenopausal women. Ginsenosides are primary active components in ginseng and the effects of various ginsenoside variants in osteoporosis treatment have been widely revealed. We planned to explore the impact of ginsenoside Rc on bone resorption in an osteoporosis rat model. We used ovariectomized rats to assess the potential impact of ginsenoside Rc on osteoporosis. μ-CT was implemented for analyzing the microstructure of the distal left femur in rats. H&E staining together with Masson staining were applied for bone histomorphometry evaluation. ELISA kits were implemented to detect serum concentrations of TRACP-5b, OCN, CTX, as well as PINP. Ginsenoside Rc treatment lessened the serum levels of TRACP-5b as well as CTX, while increasing serum levels of OCN, and PINP of OVX rats. Moreover, we found that ginsenoside Rc contributed to the synthesis of type I collagen via increasing Col1a1 and Col1a2 levels in femur tissues of ovariectomized rats. Our findings also revealed that ginsenoside Rc activated the TGF-β/Smad pathway by increasing TGF-β as well as phosphorylated Smad2/3 protein levels. Ginsenoside Rc alleviates osteoporosis in rats through promoting the TGF-β/Smad pathway.
研究领域:
药理学
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骨科
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内分泌学
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分子生物学
✓ 已验证
DOI
高影响因子
Frontiers in Nutrition
·
2022
·
IF 6.59
Wenjuan Ning,Xiaoxiao Xu,Shican Zhou,Xiao Wu,Hang Wu,Yijie Zhang,Jichang Han,Junpeng Wang
This study explored the profibrotic impact of high glucose in the lung and potential mechanisms using latent TGF-β1-induced human epithelial cell pulmonary fibrosis and bleomycin (BLM)-induced pulmonary fibrosis models. Results demonstrated that high glucose administration induced epithelial-mesenchymal transition (EMT) in human epithelial cells in a dose-dependent manner via activating latent TGF-β1, followed by increased expression of mesenchymal-related proteins and decreased expression of epithelial marker protein E-cadherin. Further mechanism analysis showed that administration of high glucose dose-dependently promoted total and mitochondrial reactive oxygen species (ROS) accumulation in human epithelial cells, which promoted latent TGF-β1 activation. However, N -acetyl-L-cysteine, a ROS eliminator, inhibited such effects. An in vivo feed study found that mice given a high-glucose diet had more seriously pathological characteristics of pulmonary fibrosis in BLM-treated mice, including increasing infiltrated inflammatory cells, collagen I deposition, and the expression of mesenchymal-related proteins while decreasing the expression of the epithelial marker E-cadherin. In addition, high glucose intake further increased TGF-β1 concentration and upregulated p-Smad2/3 and snail in lung tissues from BLM-treated mice when compared to BLM-treated mice. Finally, supplementation with high glucose further increased the production of lipid peroxidation metabolite malondialdehyde and decreased superoxide dismutase activity in BLM-treated mice. Collectively, these findings illustrate that high glucose supplementation activates a form of latent TGF-β1 by promoting ROS accumulation and ultimately exacerbates the development of pulmonary fibrosis.
研究领域:
肺科学
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细胞生物学
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药理学
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病理学
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产品关联
DOI
PubMed
高影响因子
FITOTERAPIA
·
2023
·
IF 3.4
Xionghua Sun,Mei Zhu,Wei Xia,Xihan Xu,Jian Zhang,Xiaogang Jiang
Eupatorium lindleyanum DC . has been used as a functional food in China for a long time. However, the antifibrotic activity of total sesquiterpenoids from Eupatorium lindleyanum DC . (TS-EL) is still unknown. In this study, we discovered that TS-EL reduced the increase in α-smooth muscle actin (α-SMA), type I collagen and fibronectin content, the formation of cell filaments and collagen gel contraction in transforming growth factor-β1-stimulated human lung fibroblasts. Intriguingly, TS-EL did not change the phosphorylation of Smad2/3 and Erk1/2. TS-EL decreased the levels of serum response factor (SRF), a critical transcription factor of α-SMA, and SRF knockdown alleviated the transition of lung myofibroblasts. Furthermore, TS-EL significantly attenuated bleomycin (BLM)-induced lung pathology and collagen deposition and reduced the levels of two profibrotic markers, total lung hydroxyproline and α-SMA. TS-EL also decreased the levels of SRF protein expression in BLM-induced mice. These results suggested that TS-EL attenuates pulmonary fibrosis by inhibiting myofibroblast transition via the downregulation of SRF.
研究领域:
药理学
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肺科学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomed Research International
·
2022
·
IF 3.246
Xiaomeng Zou,Tiantian Li,Yingxuan Mao,Mingwei Zhu,Xi Chen,Jiamei Niu,Tianxiu Dong,Jian Jiang,Xiuhua Yang
Objectives . Preparation of a multifunctional drug-loaded phase-change nanoparticle (NP), pirfenidone perfluoropentane liposome NPs (PPL NPs), and combined with low-intensity focused ultrasound (LIFU) to influence epithelial mesenchymal transition (EMT) for hepatocellular carcinoma (HCC) by inhibiting the activity of activated Hepatic Stellate Cells (a-HSCs ). Methods . PPL NPs were prepared by the thin film dispersion method. The appearance, particle size, zeta potential, encapsulation efficiency, drug loading rate, drug release in vitro, and stability of PPL NPs were tested. The role of a-HSCs in HCC metastasis was studied by CCK-8, colony formation assay, apoptosis, cellular uptake assay, wound healing assay, and Transwell assay. Western blot was used to detect the related protein expression levels. In vitro and vivo, the acoustic droplet vaporization (ADV) of PPL NPs was tested at different times and LIFU intensities. Biosafety of the PPL NPs was assessed by measuring nude mouse body weight and hematoxylin and eosin (H&E) staining . Results. The results showed that the PPL NPs had good biosafety, with an average particle size of 346.6 ± 62.21 nm and an average zeta potential of -15.23 mV. When the LIFU power is 2.4 W/cm 2 , it can improve the permeability of cells, further promote the uptake of drugs by cells, and improve the toxicity of drugs. In vitro experiments showed that PPL NPs could inhibit the proliferation of a-HSCs cells, thereby affecting the metastasis of HCC, and were related to the TGF β -Smad2/3-Snail signaling pathway. Both in vivo and in vitro PPL NPs enhanced ultrasound imaging by LIFU-triggered ADV . Conclusion. The PPL NPs designed and prepared in this study combined with LIFU irradiation could significantly alter the EMT of HCC by inhibiting LX2. Clinically, PPL NPs will also be considered a promising contrast agent due to their ultrasound imaging capabilities.
研究领域:
纳米技术
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肿瘤学
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药剂学
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超声成像
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细胞生物学
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DOI
PubMed
高影响因子
CHEMICAL & PHARMACEUTICAL BULLETIN
·
2023
·Vol. 71
·期 4
·269-276
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IF 1.7
Xiaoran Ning,Yanhui Ni,Jingjing Cao,Huaxing Zhang
Rheumatoid arthritis (RA) is a common autoimmune disease with increased cardiovascular disease risk. Liquiritigenin (LG) is a triterpene with anti-inflammatory properties. Our study aimed to explore the effect of LG on RA and the cardiac complication. Collagen-induced arthritis (CIA) mice with LG treatment exhibited obvious alleviation in histopathological changes, accompanied by the decreased expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-17A in synovium and serum. LG attenuated cartilage destruction by reducing matrix metalloproteinase (MMP)-3 and MMP-13 expression in the synovium of CIA mice. The echocardiography results proved the alleviation of cardiac dysfunction in CIA mice. The electrocardiogram, biochemical, and histochemical analysis proved the cardioprotection effect of LG against RA. The decreased expression of inflammatory factors (TNF-α, IL-1β, and IL-6) and fibrotic markers (fibronectin, Collagen I, and Collagen III) in cardiac tissues of CIA mice further corroborated the attenuation of myocardial inflammation and fibrosis by LG. Mechanistic studies showed that LG could inhibit transforming growth factor β-1 (TGF-β1) and phos-Smad2/3 expression in cardiac tissues of CIA mice. Our study suggested that LG could relieve RA and its cardiac complication probably by inhibiting the TGF-β1/Smad2/3 pathway. All these suggested that LG might be a potential candidate for RA and its cardiac complication therapy.
研究领域:
免疫学
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风湿病学
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心脏病学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）