TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2022
·
IF 4.46
Lin Leilei,Qiu Wenke,Luo Yuyuan,Lin Sihang,Sun Xue,Chen Weiqiang,Ye Lianbao,Wang Ying,Li Yan,Li Ming
Liver fibrosis has the potential to progress into liver cirrhosis , liver failure, and even death. Hepatic stellate cells (HSCs) activation play a central role in liver fibrosis, and persistently damaged hepatocytes secrete soluble factors that activate transdifferentiation of HSCs into myofibroblasts. Our previous studies indicated that fine particulate matter (PM2.5) can activate HSCs by stimulating hepatocytes to secrete TGF-β1. However, whether PM2.5 activates HSCs by regulating oxidative stress in hepatocytes remains uncertain. Oleanolic acid (OA) has been widely used in the clinic for hepatoprotection in Chinese medicine. In the present study, OA-loaded nanoparticles (OA-NP) with high solubility were used to attenuate the activation of HSCs induced by PM2.5-treated hepatocytes, and further studies were performed to explore the mechanism in which OA-NP plays a vital part. Our results showed that consistently PM2.5 treatment induced oxidative stress in hepatocytes. Moreover, the activation of HSCs induced by PM2.5-treated hepatocytes was reversed by antioxidant N -acetylcysteine treatment. Hence, PM2.5 may participate in the activation of HSCs by regulating oxidative stress in hepatocytes. Using a co-cultivation system, our results proved pretreatment with OA-NP significantly attenuates the activation of HSCs induced by PM2.5-exposed hepatocytes. In addition, the TGF-β1 expression and oxidative stress in hepatocytes with PM2.5 treated were reduced by the incubation with OA-NP. These observations demonstrated that OA-NP protects against the activation of HSCs by decreasing the TGF-β1 level and oxidative stress in PM2.5-exposed hepatocytes.
研究领域:
药理学
·
毒理学
·
细胞生物学
·
环境健康
✓ 已验证
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2023
·
IF 5.8
Shuanghui Lu,Xiu Chen,Yujia Chen,Yingqiong Zhang,Jun Luo,Huidi Jiang,Luo Fang,Hui Zhou
Transforming growth factor-beta 1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) of renal tubular cells promotes renal fibrosis and the progression of chronic kidney disease (CKD). PDZ domain-containing 1 (PDZK1) is highly expressed in renal tubular epithelial cells; however, its role in TGF-β1-induced EMT remains poorly understood. The present study showed that PDZK1 expression was extremely downregulated in fibrotic mouse kidneys and its negative correlation with TGF-β1 expression and the degree of renal fibrosis. In addition, TGF-β1 downregulated the mRNA expression of PDZK1 in a time- and concentration-dependent manner in vitro . The downregulation of PDZK1 exacerbated TGF-β1-induced EMT upon oxidative stress, while the overexpression of PDZK1 had the converse effect. Subsequent investigations demonstrated that TGF-β1 downregulated PDZK1 expression via p38 MAPK or PI3K/AKT signaling in vitro , but independently of ERK/JNK MAPK signaling. Meanwhile, inhibition of the p38/JNK MAPK or PI3K/AKT signaling using chemical inhibitors restored the PDZK1 expression, mitigated renal fibrosis, and elevated renal levels of endogenous antioxidants carnitine and ergothioneine in adenine-induced CKD mice. These findings provide the first evidence suggesting a negative correlation between PDZK1 and renal fibrosis, and identifying PDZK1 as a novel suppressor of renal fibrosis in CKD through ameliorating oxidant stress.
研究领域:
肾病学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioactive Materials
·
2022
·
IF 16.874
Qiang Wei,Dachuan Liu,Genglei Chu,Qifan Yu,Zhao Liu,Jiaying Li,Qingchen Meng,Weishan Wang,Fengxuan Han,Bin Li
Annulus fibrosus (AF) repair remains a challenge because of its limited self-healing ability. Endogenous repair strategies combining scaffolds and growth factors show great promise in AF repair. Although the unique and beneficial characteristics of decellularized extracellular matrix (ECM) in tissue repair have been demonstrated, the poor mechanical property of ECM hydrogels largely hinders their applications in tissue regeneration. In the present study, we combined polyethylene glycol diacrylate (PEGDA) and decellularized annulus fibrosus matrix (DAFM) to develop an injectable, photocurable hydrogel for AF repair. We found that the addition of PEGDA markedly improved the mechanical strength of DAFM hydrogels while maintaining their porous structure. Transforming growth factor-β1 (TGF-β1) was further incorporated into PEGDA/DAFM hydrogels, and it could be continuously released from the hydrogel. The in vitro experiments showed that TGF-β1 facilitated the migration of AF cells. Furthermore, PEGDA/DAFM/TGF-β1 hydrogels supported the adhesion, proliferation, and increased ECM production of AF cells. In vivo repair performance of the hydrogels was assessed using a rat AF defect model. The results showed that the implantation of PEGDA/DAFM/TGF-β1 hydrogels effectively sealed the AF defect, prevented nucleus pulposus atrophy, retained disc height, and partially restored the biomechanical properties of disc. In addition, the implanted hydrogel was infiltrated by cells resembling AF cells and well integrated with adjacent AF tissue. In summary, findings from this study indicate that TGF-β1-supplemented DAFM hydrogels hold promise for AF repair.
研究领域:
生物医学工程
·
组织工程
·
骨科
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Nutrition
·
2022
·
IF 6.59
Xiaoxiao Xu,Chuang Ma,Hang Wu,Yuanqiao Ma,Zejin Liu,Peijie Zhong,Chaolei Jin,Wenjuan Ning,Xiao Wu,Yijie Zhang,Jichang Han,Junpeng Wang
Fructose is a commonly used food additive and has many adverse effects on human health, but it is unclear whether fructose impacts pulmonary fibrosis. TGF-β1, a potent fibrotic inducer, is produced as latent complexes by various cells, including alveolar epithelial cells, macrophages, and fibroblasts, and must be activated by many factors such as reactive oxygen species (ROS). This study explored the impact of fructose on pulmonary fibrotic phenotype and epithelial-mesenchymal transition (EMT) using lung epithelial cells (A549 or BEAS-2B) and the underlying mechanisms. Fructose promoted the cell viability of lung epithelial cells, while N-Acetyl-l-cysteine (NAC) inhibited such. Co-treatment of fructose and latent TGF-β1 could induce the fibrosis phenotype and the epithelial-mesenchymal transition (EMT)-related protein expression, increasing lung epithelial cell migration and invasion. Mechanism analysis shows that fructose dose-dependently promoted the production of total and mitochondrial ROS in A549 cells, while NAC eliminated this promotion. Notably, post-administration with NAC or SB431542 (a potent TGF-β type I receptor inhibitor) inhibited fibrosis phenotype and EMT process of lung epithelial cells co-treated with fructose and latent TGF-β1. Finally, the fibrosis phenotype and EMT-related protein expression of lung epithelial cells were mediated by the ROS-activated latent TGF-β1/Smad3 signal. This study revealed that high fructose promoted the fibrotic phenotype of human lung epithelial cells by up-regulating oxidative stress, which enabled the latent form of TGF-β1 into activated TGF-β1, which provides help and reference for the diet adjustment of healthy people and patients with fibrosis.
研究领域:
肺科学
·
细胞生物学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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.
研究领域:
寄生虫学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
LABORATORY INVESTIGATION
·
2023
·
IF 5
Rui Yu,Yan Wu,Ping He,Yu Bai,Yongzhe Zhang,Xiaohui Bian,Guangping Sun,Beiru Zhang
Renal fibrosis is the major pathologic manifestation of chronic kidney disease (CKD). LIM and cysteine-rich domains 1 (LMCD1) is upregulated in the kidney tissue from patients with CKD and the transforming growth factor β1 (TGF-β1)–treated human renal tubular epithelial cell line human kidney 2 (HK-2) (Gene Expression Omnibus: GSE66494 and GSE23338). Previously, we have demonstrated that the knockdown of LMCD1 ameliorated renal fibrosis in mice by blocking the activation of the extracellular signal-regulated kinase pathway. In this study, we sought to further investigate whether LMCD1 affects TGF-β1–induced epithelial–mesenchymal transition (EMT) of kidney tubular epithelial cells and its potential role in the TGF-β1/Smad signaling pathway. First, we confirmed that LMCD1 expression was increased in the fibrotic kidneys of patients with CKD compared with that in normal kidneys and that LMCD1 was predominantly localized in the renal tubules. LMCD1 and mesenchymal markers were upregulated in obstructed kidney tissues of mice at 21 days after unilateral ureteral obstruction surgery compared with the tissues in sham mice. Next, we demonstrated that TGF-β1 significantly increased LMCD1 expression through Smad-mediated transcription in HK-2 cells in vitro. In turn, LMCD1 acted as a transcriptional coactivator of E2F transcription factor 1 to promote the transcription of TGF-β1 . Moreover, TGF-β1 increased the interaction between LMCD1 and Smad ubiquitination regulatory factor 2 (Smurf2) and accelerated Smurf2-mediated LMCD1 degradation via the ubiquitination system. The knockdown of LMCD1 inhibited TGF-β1–induced EMT in both HK-2 cells and unilateral ureteral obstruction mice. Our results indicate a positive feedback loop between TGF-β1 and LMCD1 for EMT induction in HK-2 cells and that Smurf2 acts as a negative regulator in this process by accelerating LMCD1 degradation.
研究领域:
肾病学
·
细胞生物学
·
分子生物学
·
病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Kuaitian Wang,Mengqi Jian,Yuhang Chen,Mengdi Du,Zhenhua Wang,Bo Xu,Ning Tang,Yongqiang Cheng,Jing Gan
The aim of this study was to determine the osteogenic activity and mechanism of soybean peptide VVELLKAFEEKF (SOP) and the potential relationship between SOP and transforming growth factor-β1 (TGF-β1). The results show that SOP promotes MC3T3-E1 cell proliferation by altering cell progression. SOP induced cell differentiation and mineralization in a dose-dependent manner at 0.7–7 μM. Moreover, SOP stimulates osteoblast differentiation, which may be achieved through the activation of p38-MAPK and Smad2/3 signaling pathways. Furthermore, treatment with a TβRI inhibitor (SB525334) inhibited the phosphorylation levels of p38 and Smad2/3, which indicates the involvement of TβRI in the process of osteoblast differentiation caused by SOP. Besides, in non-FBS-cultured MC3T3-E1 cells, SOP and TGF-β1 promoted the phosphorylation of Smad2/3 and alkaline phosphatase (ALP) activity, but the effect was lost when SOP was incubated separately, indicating that SOP stimulated osteoblast differentiation by promoting TGF-β1 activity. In vivo, SOP significantly restores bone mineral density loss and behavioral deficits in a model of glucocorticoid-induced osteoporosis (GIOP) in zebrafish. These results suggest that SOP may have the function of promoting bone remodeling and may be used as a potential active factor for functional food development to prevent osteoporosis.
研究领域:
生物学
·
药理学
·
医学研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2021
·
IF 4.749
Genbin Wu,Binbin Sun,Chunfeng Zhao,Zhuoying Wang,Songsong Teng,Mengkai Yang,Zhi Cui,Guoliang Zhu,Yinxian Yu
Tendon adhesion formation is associated with the aberrant expression of many genes, and interfering with the expression of these genes can prevent adhesion and promote tendon repair. Recent studies have found that silencing the transforming growth factor β-1 (TGF-β1) gene can reduce the occurrence of tendon adhesions. The development of tissue engineering and three-dimensional (3D) printing technology have provided new solutions for tendon repair. In this study, TGF-β1 gene silencing microRNA (miRNA) based RNAi plasmid was loaded on a 3D tendon scaffold using 3D printing technology. In vitro experiments confirmed the sustained release of plasmid and the good biocompatibility of the printed tendon scaffold. Subsequently, the TGF-β1 gene silencing plasmid loaded tendon scaffold was implanted in a chicken tendon defect model to evaluate the effect of the scaffold in vivo. The results from biomechanical tests and histological examinations showed that the scaffold not only promoted tendon regeneration but also prevented tendon adhesion, which was conducive to the recovery of biofunction. Evaluation of protein expression showed that the loaded plasmids prevented tendon adhesion and promoted tendon functional repair via silencing of the TGF-β1 gene.
研究领域:
组织工程
·
再生医学
·
分子生物学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Interdisciplinary Medicine
·
2025
·Vol. 3
·期 5
·e70055
·
IF 13.6
Zheting Liao,Ru Lian,Shiqi Zhao,Jie Yang,Zhonghao Deng,Desheng Wu,Zhongmin Zhang,Liang Zhao
The management of osteoarthritis (OA) and osteochondral defects faces challenges due to heightened catabolic activity from pro-inflammatory mediators and a lack of reparative cells. Transforming growth factor β1 (TGFβ1) plays a crucial role in cartilage maintenance and cellular recruitment, making it a promising therapeutic target. However, the high cost and unpredictable effects of exogenous TGFβ1 limit its clinical application. Notably, TGFβ1 is primarily found in a latent form within joint tissues, especially during early injury stages. This study proposes that activating endogenous TGFβ1 may serve as an effective treatment strategy. We demonstrate that an ascorbic acid (AA) and ferric chloride (AA/Fe) Fenton reaction system can activate latent TGFβ1 in knee joint tissues. Treatment with AA/Fe-activated synovial fluid protects chondrocytes from interleukin1β-induced damage and enhances chemotactic responses in joint tissues. Intra-articular AA/Fe injections in rats significantly phosphorylated SMAD2/3 and reduced cartilage degradation. Additionally, we developed poly(lactic-co-glycolic acid) microspheres for sustained AA/Fe release within a thermosensitive or photocrosslinkable hydrogel, showing high biocompatibility. These formulations effectively prevented cartilage degeneration and promoted osteochondral repair. Our findings confirm that AA/Fe reliably activates endogenous TGFβ1, providing a novel cell-free and cost-efficient treatment approach for OA and osteochondral defects.
研究领域:
骨科学
·
再生医学
·
分子生物学
·
药剂学
·
转化医学
·
炎症学
·
组织工程
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
·
2018
·Vol. 234
·期 7
·11440-11450
·
IF 3.923
Zheng-Yu Liu,Hong-Wei Pan,Yan Cao,Jiao Zheng,Yu Zhang,Yi Tang,Jin He,Yong-Jun Hu,Chang-Lu Wang,Qiong-Chao Zou,Qing-Hua Fu,Le Zhang,Jian-Qiang Peng,Jing Ling,Ning Peng,Jing-Jing Rong,Zhao-Fen Zheng
microRNAs (miRs) are essential in the development of heart failure. The aim of this study is to investigate the effect of microRNA-330 (miR-330) on left ventricular remodeling via the TGF-β1/Smad3 signaling pathway by targeting the sex-determining region Y (SRY) in mice with myocardial ischemia–reperfusion injury (MIRI). Differentially expressed gene (DEG) in myocardial ischemia–reperfusion (IR) was screened out and the miR that targeted the DEG was also predicted and verified. A model of MIRI was established to detect the expression of miR-330, SRY, transforming growth factor-β (TGF-β1), and Sekelsky mothers against dpp3 (Smad3). To further investigate the role of miR-330 in MIRI with the involvement of SRY and TGF-β1/Smad3 signaling pathway, the modeled mice were treated with different mimic, inhibitor, or small interfering RNA (siRNA) to observe the changes of the related gene expression, as well as the myocardial infarction size and volume of myocardial collagen. SRY was screened out and verified as a target gene of miR-330. The MIRI mice showed enlarged myocardial infarction size, increased volume of myocardial collagen, increased expression of miR-330, TGF-β1 and Smad3, while decreased the expression of SRY. The MIRI mice treated with miR-330 inhibitor showed decreased myocardial infarction size, the volume of myocardial collagen, and expression of TGF-β1 and Smad3 but promoted expression of SRY. Our findings demonstrated that downregulated miR-330 could suppress left ventricular remodeling to inhibit the activation of the TGF-β1/Smad3 signaling pathway via negatively targeting of SRY in mice with MIRI. This can be a potential target in the strategy to attenuate patient suffering.
研究领域:
心脏病学
·
分子生物学
·
遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2018
·
IF 3.997
Meng Xiao,Jiangwei Xiao,Gang Wu,Yu Ke,Liming Fang,Chunlin Deng,Hua Liao
Protein adsorption on biomaterial surfaces is clinically applied to increase therapeutic effects; however, this adsorption is possibly accompanied by conformational changes and results in loss of protein bioactivity or adverse reactions. In this research, a transforming growth factor β1 (TGF-β1) affinitive peptide HSNGLPL was grafted onto biopolymer surface to stabilize TGF-β1 spatial conformation after adhesion. The peptide with azide end group was combined with the propynyl pendant group on polyurethane via copper-catalyzed azide–alkyne cycloaddition (CuAAC) click reaction. The final polymer was characterized by Fourier transform infrared spectroscopy and proton nuclear magnetic resonance spectroscopy, which indicated that the affinitive peptide was introduced to the polymer. Quartz crystal microbalance with dissipation (QCM-D) was performed to monitor TGF-β1 adsorption and desorption on the surfaces coated with polyurethane with and without peptide combination. Results showed that TGF-β1 adhered on polyurethane surface and formed a compact and rigid layer. This layer showed spatial structural change but presented a loose and diffuse layer on the peptide-grafted polyurethane surface, indicating stable spatial conformation after adherence. Similar regulations were observed on the two surfaces where BSA layer was coated in advance. In vivo animal experiments revealed that immune reactions and tissue regenerations occurred earlier on peptide-modified polyurethane than on polyurethane, which did not undergo peptide grafting. This finding confirmed that affinitive interactions may preserve TGF-β1 bioactivity on polymer surface after adsorption.
研究领域:
生物材料
·
生物医学工程
·
蛋白质工程
·
组织工程
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
IF 5.4
Ye Liu,Jiufeng Zhao,Xingrui Mu,Junyu Deng,Xingqian Wu,Wenjie He,Yiqiu Liu,Rifang Gu,Felicity Han,Xuqiang Nie
Ethnopharmacological relevance Centella asiatica (L.) Urban is an ethnobotanical herb. The main bioactive components of Centella asiatica are pentacyclic triterpenoid glycosides , namely asiaticoside and hydroxyasiaticoside. Asiaticoside possess a diverse array of pharmacological properties, such as wound-healing, anti-inflammatory, antioxidant, anti-allergic, antidepressant, anxiolytic, anti-fibrotic, antibacterial, anti-arthritic, anti-tumor, and immunomodulatory activities. Aim of the study The purpose of this investigation is to explore potential therapeutic interventions for the delayed healing of wounds in diabetic patients (DW) facilitated by Asiaticoside-Nitric Oxide. To clarify the key molecular mechanism of miRNA-21-5p in DW wound repair and to deepen the understanding of DW disease pathogenesis. Materials and methods Firstly, miRNA microarray technology, bioinformatics, and RT-qPCR were used to analyze DW patients' and normal controls' skin tissue samples. Secondly, in order to investigate the role of miRNA-21-5p, a hyperglycemic model was established using HaCaT cells. Overexpressing as well as interfering HaCaT cell lines were constructed by lentiviral infection to further explore the proliferative and migratory effects of Asiaticoside-Nitric Oxide. The next step was to search for potential target genes of miRNA-21-5p and verify them with dual-luciferase reporter assay. Finally, the expression levels of target genes and proteins were detected through the utilization of RT-qPCR and Western blotting under the influence of Asiaticoside-Nitric Oxide. Results A library of miRNAs and target genes expressed explicitly in DW patients and rats was established. The study confirmed the upregulation of miRNA-21-5p in DW patients and identified its involvement in signaling pathways related to chronic ulcer wound repair. Overexpression of LV-miRNA-21-5p significantly promoted cell proliferation , while treatments of Asiaticoside-Low dose (AC-L) and Asiaticoside-Medium dose (AC-M) enhanced proliferation and migration, particularly when combined with nitroprusside (SNP). Further analysis revealed potential target genes of miRNA-21-5p, such as TGF-β1, SMAD7, and TIMP3. Their interaction with miRNA-21-5p was confirmed through dual luciferase assays. The study found that anti-DW drugs increased the expression of TGF-β1 and SMAD7 while inhibiting TIMP3 expression in a high-glucose environment. Conclusions The research concluded that miRNA-21-5p plays a crucial role in the delayed healing of diabetic wounds, and that the combination treatment of AC + SNP shows promise in promoting wound healing in DW rats. Target genes, including TGF-β1, SMAD7, and TIMP3, may contribute to the regulatory mechanisms involved in diabetic wound healing. These findings provide valuable insights for developing novel therapeutic approaches for DW.
研究领域:
药理学
·
分子生物学
·
糖尿病研究
·
伤口愈合
·
民族药理学
✓ 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）