Aging-US
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2024
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IF 3.9
Xiao-Xiao Jiang,Ri Zhang,Hui-Shan Wang
Background: Atrial fibrillation (AF) is often associated with atrial fibrosis and oxidative stress. Neferine, a bisbenzylisoquinoline alkaloid, has been reported to exert an antiarrhythmic effect. However, its impact on Angiotensin II (Ang II) infusion-induced AF and the underlying mechanism remains unclear. This study aimed to investigate whether neferine alleviates Ang II-induced AF and explore the underlying mechanisms. Methods: Mice subjected to Ang II infusion to induce AF were concurrently treated with neferine or saline. AF incidence, myocardial cell size, fibrosis, and oxidative stress were then examined. Results: Neferine treatment inhibited Ang II-induced AF, atrial size augmentation, and atrial fibrosis. Additionally, we observed that Ang II increased reactive oxygen species (ROS) generation, induced mitochondrial membrane potential depolarization, and reduced glutathione (GSH) and superoxide dismutase (SOD) levels, which were reversed to some extent by neferine. Mechanistically, neferine activated the Nrf2/HO-1 signaling pathway and inhibited TGF-β/p-Smad2/3 in Ang II-infused atria. Zinc Protoporphyrin (ZnPP), an HO-1 inhibitor, reduced the anti-oxidative effect of neferine to some extent and subsequently abolished the beneficial effect of neferine on Ang II-induced AF. Conclusions: These findings provide hitherto undocumented evidence that the protective role of neferine in Ang II-induced AF is dependent on HO-1.
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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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
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IF 5.7
Manman Yuan,Jing Ye,Xiangqiao Sun,Zhiwu Tong,Tingting Wang,Renxiang Tan,Xingxin Wu
Acaudiolide ameliorates liver fibrosis in mice • Acaudiolide inhibits TGF-β1/SMAD signaling in HSCs • Acaudiolide inhibits the nuclear translocation of p-SMAD2/3 • Acaudiolide weakens the interaction between SMAD4 and p-SMAD2/3 • SMAD4 is a candidate covalent target of acaudiolide Hepatic stellate cell (HSC) activation is a central driver of fibrosis progression in metabolic dysfunction-associated steatohepatitis (MASH), yet effective antifibrotic pharmacotherapies remain limited. Here, we identify acaudiolide, a sulfur-bridged symmetric dimeric macrodiolide isolated from the fungus Acaulium sp. H-JQSF, as a natural-product lead that suppresses HSC activation and experimental liver fibrosis. In a Western diet (WD)/CCl 4 murine model of MASH, acaudiolide reduced collagen deposition, alpha-smooth muscle actin (α-SMA) expression and fibrogenic gene expression. Transcriptomic profiling of HSCs showed that acaudiolide antagonized transforming growth factor-β1 (TGF-β1)-driven profibrotic programs. Mechanistically, acaudiolide did not measurably alter SMAD2/3 phosphorylation but markedly reduced the nuclear accumulation of phosphorylated SMAD2/3 (p-SMAD2/3). Integration of Connectivity Map (CMap) analysis with isotopic tandem orthogonal proteolysis-activity-based protein profiling (isoTOP-ABPP) chemical proteomics nominated SMAD4 as a candidate covalent target of acaudiolide. Covalent docking suggested Cys363 as a potential engagement site, and co-immunoprecipitation showed that acaudiolide weakened the association of SMAD4 with p-SMAD2/3. These findings support a model in which acaudiolide interferes with SMAD complex assembly, thereby attenuating TGF-β-dependent profibrotic transcription and HSC activation. Collectively, our data nominate acaudiolide as a preclinical antifibrotic lead and SMAD4 as a potentially tractable downstream node for pharmacological modulation of TGF-β signaling in MASH-related fibrosis. Download: Download high-res image (386KB) Download: Download full-size image
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DOI
高影响因子
EXPERIMENTAL ANIMALS
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2022
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IF 1.798
Kai KANG,Lukuan CUI,Qian ZHANG,Shijun GAO
Although many surgical or non-operative therapies have been developed to treat Achilles tendon injuries, the prognosis of which is often unsatisfactory. Recently, biologic approaches using multipotent stem cells like tendon-derived stem cells (TDSCs) pose a possible treatment option. To evaluate whether the Leucine rich repeat containing 32 (Lrrc32) affects the tenogenic differentiation of TDSCs and thus promotes Achilles tendon healing. TDSCs were infected with the recombinant Lrrc32-overexpressing lentivirus (LV-Lrrc32) and then locally injected into the injured site of rat. Four weeks after surgery, the Achilles tendon tissue (~0.5 cm) around the injured area was harvested for analysis. Pathological results showed that Lrrc32-overexpressing TDSCs significantly improved the morphological changes of the injured tendons. Specifically, the increased collagen-I expression and hydroxyproline content in extracellular matrix, and more orderly arrangement of the regenerated collagen fibers were observed in the Lrrc32 overexpression group. Moreover, 4 weeks after injection of Lrrc32-overexpressing TDSCs, the expression of tenocyte-related genes such as tenomodulin (Tnmd), scleraxis (Scx) and decorin (Dcn) were upregulated in the area of the healing tendon. These findings indicated that Lrrc32 promoted the tenogenic differentiation of TDSCs in vivo. Additionally, Lrrc32 overexpression also increased the expression of TGF-β1 and p-SMAD2/3, suggesting that the beneficial effects of Lrrc32 on tendon repair might be associated with the expression of TGF-β1 and p-SMAD2/3. Our findings collectively revealed that Lrrc32-overexpressed TDSCs promoted tendon healing more effectively than TDSCs alone.
研究领域:
干细胞生物学
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组织工程
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再生医学
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骨科
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DOI
PubMed
高影响因子
Frontiers in Nutrition
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2022
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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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DOI
PubMed
高影响因子
TOXICON
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2021
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IF 3.033
Xiong Zhang,Chen Feng,Yimao Li,Chenlin Su,Shuxin Zhao,Shengdi Su,Feng Yu,Ji LI
Aristolactam I (AL-I) is the main active ingredient in the Aristolochia plant species, which have been associated with severe nephrotoxicity. In order to investigate the mechanism of AL-I induced renal epithelial-mesenchymal transition (EMT), we established an AL-I induced EMT model in human proximal tubular epithelial cells (HK-2 cells). Biochemical analysis experiment including Morphological examination, 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide assay, and Western blot analysis were performed. The results showed that AL-I accumulates in the cytosol causing cytotoxicity and inhibition of proliferation in a concentration- and time-dependent manner. Morphological examination showed that with the increasing concentration of AL-I, the tendency of HK-2 cells transform form epithelial cell to fibroblast cells was stronger. In the Western blot analysis, the expression of α-Smooth muscle actin (α-SMA) and Transforming Growth Factor β1 (TGF-β1) were significantly up-regulated, the expression of E-cadherin was significantly down-regulated after administrating. The ratio of the expression of P-Smad2/3 and Smad2/3 was significantly up-regulated, suggested that TGF-β/Smad-dependent signaling pathway was activated in this process. With presence of TGF-β receptor inhibitor (LY364947), we found that the expressions of three EMT related proteins (E-cadherin, α-SMA and TGF-β1) were obviously reversed. In conclusion, we acknowledge that AL-I can induce renal EMT process in HK-2 cell, which is triggered by the activation of TGF-β/Smad-dependent signaling pathway.
研究领域:
药理学
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毒理学
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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
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