PHYTOMEDICINE
·
2025
·
IF 8.3
Jun-Han Wang,Min Li,Peng-Fei Xie,Jia-Yao Si,Zhen-Jie Feng,Chuan-Feng Tang,Jian-Mei Li
Background Aging-related skin fibrosis (SF) is a complex condition with limited treatment options. Procyanidin C1 (PCC1), a natural polyphenolic compound with demonstrated senolytic activity, has emerged as a potential therapeutic agent for fibrotic disorders through its selective elimination of senescent cells. However, its therapeutic efficacy and mechanisms in aging-related SF remain unclear. Purpose This study aimed to investigate the mechanisms of PCC1 in aging-related SF. Results In D-galactose-induced L929 cells, PCC1 treatment significantly attenuated the expression of both senescence-associated markers (IL-1β, P16, P21 and LMNB1) and fibrosis-related markers (α-SMA, LOXL2 and COL1). Network pharmacology and experimental validation (molecular docking, DARTS, CETSA, MST) identified EGFR as a primary target, with PCC1 directly binding to and inhibiting EGFR phosphorylation. Furthermore, PCC1 treatment effectively down-regulated TGFβ1 expression and suppressed SMAD2/3 phosphorylation in D-galactose-induced L929 cells. Notably, PCC1 blocked NSC228155-induced EGFR phosphorylation and inhibited ERK/MAPK, AKT/mTOR and TGFβ/SMAD pathway activation. In bleomycin-induced SF mice, PCC1 significantly attenuated epidermal hyperplasia, improved collagen structure, restored the collagen I/III ratio, and reduced EGFR phosphorylation along with TGFβ1 expression and SMAD2/3 phosphorylation. Conclusion This study elucidates that PCC1 exerts its anti-fibrotic effects through dual mechanisms: resistance to cellular senescence and modulation of fibroblast heterogeneity. By directly binding to EGFR and inhibiting its phosphorylation, PCC1 subsequently suppresses multiple downstream signaling cascades, ultimately ameliorating TGFβ/SMAD-mediated SF. These findings establish PCC1 as a promising therapeutic candidate for aging-related skin fibrosis, offering a novel approach through targeted EGFR inhibition and comprehensive pathway modulation .
研究领域:
医学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2018
·
IF 3.831
Zhang Zhi-Hao,Li Ming-Hua,Liu Dan,Chen Hua,Chen Dan-Qian,Tan Ning-Hua,Ma Shuang-Cheng,Zhao Ying-Yong
Tubulointerstitial fibrosis is the final common pathway for all kidney diseases leading to chronic kidney disease (CKD). TGF-β/Smad signaling pathway plays a key role in renal fibrosis. Previous studies have revealed that rhubarb extracts attenuated the increase of transforming growth factor-β 1 (TGF-β1) in CKD rats. To gain an in-depth insight into the mechanism of the anti-fibrotic activities of the rhubarb extracts, we investigated the influence of rhubarb extracts on TGF-β/Smad signaling pathway and the influence on metabolome in a rat model of CKD with adenine-induced chronic tubulointerstitial nephropathy. Male Sprague-Dawley rats were divided into four groups, including control, CKD, CKD + petroleum ether extract, CKD + ethyl acetate extract, and CKD + n-butanol extract groups. Kidneys harvested on the week three were evaluated for renal fibrosis, the expression of proteins in TGF-β/Smad signaling pathway and metabolomic study. We found rhubarb extracts suppressed TGF-β/Smad3-mediated renal fibrosis by reducing the TGF-β1, transforming growth factor-β receptor I (TGF-β RI), transforming growth factor-β receptor II (TGF-β RII), Smad2, p-Smad2, Smad3, p-Smad3, and Smad4, meanwhile increased Smad7. In addition, rhubarb extracts mitigated renal injury and dysfunction, and either fully or partially reversed the abnormalities of tissue metabolites. Thus, rebalancing the disorder of TGF-β/Smad signaling and metabolic dysfunction by treatment with rhubarb extracts may represent as an effective therapy for CKD associated with fibrosis.
研究领域:
药理学
·
肾病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Human Cell
·
2023
·
IF 4.3
Hu Lianying,Cheng Zhen,Wu Lunan,Luo Liangliang,Pan Ping,Li Shujin,Jia Qiyu,Yang Ning,Xu Bin
Osteogenic differentiation plays important roles in the pathogenesis of osteoporosis. In this study, we explored the regulatory mechanism of histone methyltransferase SET domain bifurcated 1 (SETDB1) underlying the osteogenic differentiation in osteoporosis. The common osteoporosis-related genes were retrieved from the GeneCards, CTD, and Phenolyzer databases. The enrichment analysis was conducted on the candidate osteoporosis-related genes using the PANTHER software, and the binding site between transcription factors and target genes predicted by hTFtarget. The bioinformatics analyses suggested 6 osteoporosis-related chromatin/chromatin binding protein or regulatory proteins (HDAC4, SIRT1, SETDB1, MECP2, CHD7, and DKC1). Normal and osteoporosis tissues were collected from osteoporosis patients to examine the expression of SETDB1. It was found that SETDB1 was poorly expressed in osteoporotic femoral tissues, indicating that SETDB1 might be involved in the development of osteoporosis. We induced SETDB1 overexpression/knockdown, orthodenticle homeobox 2 (OTX2) overexpression, activation of Wnt/β-catenin or BMP-Smad pathways alone or in combination in osteoblasts or ovariectomized mice. The data indicated that SETDB1 methylation regulated H3K9me3 in the OTX2 promoter region and inhibited the expression of OTX2. Besides, the BMP-Smad and Wnt/β-catenin pathways were inhibited by OTX2, thereby resulting in inhibited osteogenic differentiation. Animal experiments showed that overexpressed SETDB1 could promote the increase of calcium level and differentiation of femoral tissues. In conclusion, upregulation of SETDB1 promotes osteogenic differentiation by inhibiting OTX2 and activating the BMP-Smad and Wnt/β-catenin pathways in osteoporosis.
研究领域:
分子生物学
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细胞生物学
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医学遗传学
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骨骼生物学
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产品关联
DOI
PubMed
高影响因子
Small
·
2022
·Vol. 18
·期 23
·2201123
·
IF 15.153
Jing Li,Yao Zhang,Zhichao Lou,Mingxi Li,Lin Cui,Zhenrong Yang,Lijuan Zhang,Yu Zhang,Ning Gu,Fang Yang
Neural stem cells (NSCs) are used to treat various nervous system diseases because of their self-renewal ability and multidirectional differentiation potential. However, an insufficient ability to track their migration in vivo and poor control over their survival and differentiation efficiency are two major critical challenges for clinical application. Here, it is shown that when magnetic nanobubbles (MNBs), which are assembled from magnetic nanoparticles, are internalized by NSCs, intramembrane volumetric oscillation of the MNBs induces an increase in intracellular hydrostatic pressure and cytoskeleton force, resulting in the activation of the Piezo1-Ca 2+ mechanosensory channel. This subsequently triggers the BMP2/Smad biochemical signaling pathway, leading to differentiation of NSCs into the neuronal phenotype. Signaling through the Piezo1-Ca 2+ -BMP2/Smad pathway can be further accelerated by application of an external shear stress force using low-intensity pulsed ultrasound. More importantly, magnetic resonance imaging and ultrasound imaging surveillance of NSCs based on MNB labeling can be leveraged to provide NSC therapeutic outcomes. Both the in vitro and in vivo findings demonstrate that a bubble nanostructure-induced physical force can modulate and control the mechanical signaling pathway regulating stem cell development.
研究领域:
神经科学
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生物医学工程
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干细胞生物学
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医学影像学
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力学生物学
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产品关联
DOI
PubMed
高影响因子
American Journal of Translational Research
·
2018
·
IF 3.061
Qian Tang,Minji Tong,Gang Zheng,Liyan Shen,Ping Shang,Haixiao Liu
The Masquelet’s induced membrane (IM) technique is widely used to treat large segmental bone defects due to its physical priority and biological function. However, the underlying molecular mechanism of the IM on bone formation remains unknown. In the present study, rat bone marrow-derived mesenchymal stem cells (BMSCs) were used as an in vitro model and bone morphogenetic protein 2 (BMP-2) was used as a positive control to evaluate the effects of the IM on the osteogenic differentiation of BMSCs. Although the IM group did not exhibit a significant increase in the expression of Runt-related transcription factor 2 (Runx2), Collagen I (Col I), osteocalcin (OCN) and alkaline phosphatase (ALP) relative to the BMP-2 administration, the IM was considerably effective compared with the untreated group. Mechanistically, we found that the IM activated the Smad and mitogen-activated protein kinase (MAPK) pathways, which was further confirmed by application of specific inhibitors of Smad1/5/8 (LDN-193189) and ERK1/2 (U0126). After the combined treatment of the IM and LDN-193189 as well as U0126, the IM-induced increase in Runx2, Col I, and OCN expression was significantly inhibited. These results suggest that IM promotes the osteogenic differentiation of rat BMSCs by activating the Smad1/5/8 and MAPK pathways.
研究领域:
骨科
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干细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2020
·
IF 3.701
Shan Shan Qi,Meng Li Shao,Sun Ze,Hong Xing Zheng
Salidroside from Rhodiola rosea L. has hypoglycemic effects, and has anti-osteoporosis effect in diabetic rats. Whether it has beneficial effects on diabetic nephropathy (DN) has not been fully reported. Here, a DN rat model was established by streptozotocin (STZ). Salidroside (10, and 20 mg kg −1 d −1 ) were orally giving for eight weeks. The purity of salidroside was 99%. The results showed that eight weeks salidroside supplementation dose-dependently decreased blood glucose, serum insulin, serum creatinine, blood urea nitrogen (BUN), as well as urinary albumin of DN rats, repaired the pathological changes of kidney tissue, the renal sclerosis and fibrosis in the kidney of DN rats were improved, and the activities of oxidative defense system associated enzyme such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) were also improved. Serum inflammatory cytokines (including tumor necrosis factor-α, monocyte chemoattractant protein-1, interleukin-1β, and interleukin-6) were decreased significantly in DN rats after eight weeks salidroside supplementation. Immunohistochemical results showed that fibrosis related proteins such as transforming growth factor-β1 (TGF-β1), phospho-Smad2 (p-Smad2), and phospho-Smad3 (p-Smad3) expression levels were decreased significantly in the kidney of salidroside treated group. Our results indicate that daily salidroside consumption could alleviate DN in rats, the main mechanisms are anti-inflammatory, anti-oxidative stress, and inhibition of the TGF-β1/Smad2/3 pathway. This study suggested that salidroside could be used as a nutrient against DN, as well as diabetes.
研究领域:
药理学
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糖尿病学
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肾病学
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产品关联
DOI
高影响因子
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
·
2017
·Vol. 43
·期 4
·1359-1368
·
IF 5.104
Du Lifen,Lei Yongfang,Chen Jinglou,Song Hongping,Wu Xinying
Background/Aims: Cadmium (Cd) is an environmental pollutant with reproductive toxicity. Swertia mileensis is used in Chinese medicine for the treatment of prostatic deficits and named as Qing Ye Dan (QYD). This study was undertaken to investigate the potential protective effects of QYD against Cd-induced prostatic deficits. Method: Rat model of prostatic deficits was induced by 0.2 mg/kg/d CdCl2 subcutaneous injection for 15 days. The prostatic oxidative stress was evaluated by detecting the levels of malondialdehyde, nitric oxide, reduced/ oxidized glutathione, total sulfhydryl groups and enzymatic antioxidant status. The prostatic inflammation was estimated by testing the levels of pro-inflammatory cytokines. The levels of epithelial-mesenchymal transition (EMT) markers E-cadherin, fibronectin, vimentin and α-smooth muscle actin were measured by qPCR analysis. Additionally, the prostatic expressions of transforming growth factor-β1 (TGF-β1), type I TGF-β receptor (TGF-βRI), Smad2, phosphorylation-Smad2 (p-Smad2), Smad3, p-Smad3, Smad7, nuclear related factor-2 (Nrf-2), heme oxygenase-1 (HO-1), B-cell CLL/lymphoma (Bcl)-2 and Bcl-2-associated X protein (Bax) were measured by western blot assay. Results: It was found that QYD ameliorated the Cd-induced prostatic oxidative stress and inflammation, attenuated prostatic EMT, inhibited the TGF-β1/Smad pathway, increased Bcl-2/Bax ratio and enhanced the activity of Nrf-2/HO-1 pathway. Conclusion: These results showed that QYD could ameliorate Cd-induced prostatic deficits via modulating Nrf-2/HO-1 and TGF-β1/Smad pathways
研究领域:
药理学
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毒理学
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分子生物学
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生殖医学
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DOI
PubMed
高影响因子
BIOMATERIALS
·
2023
·
IF 14
Hong-Lin Qian,Sheng-Yu Chen,Fan Jia,Wei-Pin Huang,Jing Wang,Ke-Feng Ren,Guo-Sheng Fu,Jian Ji
The valid management of inflammation and precise inhibition of smooth muscle cells (SMCs) is regarded as a promising strategy for regulating vascular responses after stent implantation , yet posing huge challenges to current coating constructions. Herein, we proposed a spongy cardiovascular stent for the protective delivery of 4-octyl itaconate (OI) based on a “spongy skin” approach, and revealed the dual-regulation effects of OI for improving vascular remolding. We first constructed a “spongy skin” onto poly-l-lactic acid (PLLA) substrates, and realized the protective loading of OI with the highest dosage of 47.9 μg/cm 2 . Then, we verified the remarkable inflammation mediation of OI, and surprisingly revealed that the OI incorporation specifically inhibited SMC proliferation and phenotype switching, which contributed to the competitive growth of endothelial cells (EC/SMC ratio ∼ 5.1). We further demonstrated that OI at a concentration of 25 μg/mL showed significant suppression of the TGF-β/Smad pathway of SMCs, leading to the promotion of contractile phenotype and reduction of extracellular matrix. In vivo evaluation indicated that the successful delivery of OI fulfilled the inflammation regulation and SMCs inhibition, therefore suppressing the in-stent restenosis. This “spongy skin” based OI eluting system may serve as a new strategy for improving vascular remolding, and provides a potential concept for the treatment of cardiovascular diseases.
研究领域:
心血管工程
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生物材料
·
药物递送系统
·
血管生物学
·
组织工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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
·
细胞生物学
·
呼吸病学
·
遗传学
·
生物信息学
·
病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2021
·
IF 12.479
Anqi Liu,Dan Lin,Hanjiang Zhao,Long Chen,Bolei Cai,Kaili Lin,Steve GF Shen
Mesenchymal stem cell-derived exosomes (MSC-exos), with its inherent capacity to modulate cellular behavior, are emerging as a novel cell-free therapy for bone regeneration . Herein, focusing on practical applying problems, the osteoinductivity of MSC-exos produced by different stem cell sources (rBMSCs/rASCs) and culture conditions (osteoinductive/common) were systematically compared to screen out an optimized osteogenic exosome (BMSC-OI-exo). Via bioinformatic analyses by miRNA microarray and in vitro pathway verification by gene silencing and miRNA transfection, we first revealed that the osteoinductivity of BMSC-OI-exo was attributed to multi-component exosomal miRNAs (let-7a-5p, let-7c-5p, miR-328a-5p and miR-31a-5p). These miRNAs targeted Acvr2b/Acvr1 and regulated the competitive balance of Bmpr2/Acvr2b toward Bmpr-elicited Smad1/5/9 phosphorylation. On these bases, lyophilized delivery of BMSC-OI-exo on hierarchical mesoporous bioactive glass (MBG) scaffold was developed to realize bioactivity maintenance and sustained release by entrapment in the surface microporosity of the scaffold. In a rat cranial defect model, the loading of BMSC-OI-exo efficiently enhanced the bone forming capacity of the scaffold and induced rapid initiation of bone regeneration. This paper could provide empirical bases of MSC-exo-based therapy for bone regeneration and theoretical bases of MSC-exo-induced osteogenesis mechanism. The BMSC-OI-exo-loaded MBG scaffold developed here represented a promising bone repairing strategy for future clinical application.
研究领域:
生物医学工程
·
组织工程
·
再生医学
·
分子生物学
·
干细胞研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2023
·
IF 7.9
Jun Jiang,Baixiu Zhao,Jianpeng Xiao,Liang Shi,Wei Shang,Ye Shu,Zhiming Zhao,Junyi Shen,Jingjuan Xu,Hui Cai
Background Clinical studies indicated that postmenopausal osteoporosis (PMOP) often accompanied by iron overload risk factor, which exacerbated bone metabolism disorders and accelerated PMOP. Previous research found that multicomponent in Ligustri Lucidi Fructus (FLL) or wine-steamed FLL (WFLL) acted on the common targets of iron overload and PMOP simultaneously, which indicated that FLL and WFLL probably regulated iron/bone metabolism dually. Additionally, WFLL had more superior effect according to the theory of Chinese medicine for thousands of years. Purpose To reveal the “superior multi-component structure (SMCS)” and its molecular mechanisms in parallelly down-regulating iron overload and rescuing bone metabolism by WFLL. Designs and methods HPLC fingerprinting was established to compare the chemical profiles of FLL and WFLL; Then, the chemical compositions and quality markers of FLL and WFLL were analyzed by UPLC-Orbitrap-MS/MS coupled with OPLS-DA; The dynamic contents of quality markers and the multi-component structure at different wine steaming times (WST) were simultaneously determined by HPLC-DAD; Meanwhile, the dynamic efficacy of FLL at different WST were hunt by systematic zebrafish model. Subsequently, potential mechanism of WFLL in treating PMOP accompanied with iron overload was obtained from network pharmacology (NP) and molecular docking (MD). Finally, zebrafish and ovariectomy rat model were carried out to validate this potential mechanism. Results HPLC fingerprints similarity of 15 batches in FLL and WFLL were among 0.9-1.0. 126 compositions were identified, including 58 iridoids, 25 terpenes, 30 phenylethanoids, 7 flavonoids and 6 others. 20 quality markers associated with WFLL was revealed, and the ratio of Phenylethanols: Iridoids: Triterpenes (P/I/T) was converted from 1: 15: 4.5 to 1: 0.8: 0.9 during steaming (0 - 24 h) calculated by the quantification of 11 quality markers; The bone mineralization and motor performance of zebrafish larvae indicated that the optimum efficacy of WFLL at 12 h ( P < 0.05) in which the SMCS of P/I/T was converted to 1: 4: 1.8. NP discovered that BMP-Smad pathway is one of the potential mechanisms of FLL in anti PMOP and then regulated bone formation and iron overload simultaneously. MD revealed that 17 active ingredients and 10 core targets genes could spontaneously bind with appropriate affinity. Rats model verified that FLL and WFLL significantly reversed PMOP, based on the improvement in bone formation indexes (ALP, OPG, OGN), iron metabolism indicators (hepcidin, ferritin), bone microstructure (BMD, BV/TV, Tb. Th, Tb. N); Moreover, WFLL significant enhanced reversal effect in anti-PMOP compared to FLL ( P < 0.05). FLL and WFLL increased genes and proteins expression (Hep, BMP-6, p-Smad1/5, Smad4) related to BMP-Smad pathway compared with model group, and WFLL was more superior than FLL ( P < 0.05). Conclusion The SMCS of FLL was optimized by wine-steam, WFLL represented a dual effect in downregulating iron overload and promoting bone formation, and the BMP-Smad pathway is one of the potential molecular mechanisms.
研究领域:
药理学
·
中药学
·
骨代谢
·
铁代谢
·
网络药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
·
2018
·Vol. 234
·期 3
·2537-2551
·
IF 3.923
Hai-Ming Xu,Feng-Hua Sui,Mei-Hua Sun,Gong-Liang Guo
Recent studies have shown that circulating microRNAs (miRNA) play a critical role in diagnosing acute coronary syndrome (ACS). This study aims to investigate the effect of miR-224 on atherosclerotic plaques forming and vascular remodeling in ACS and its relationship with TGF-β/Smad pathway. Myocardial infarction (MI) rat model was established and lentivirus vector of miR-224 inhibitor was prepared for investigating the effect of downregulated miR-224 on the contents of nitric oxide (NO) and endothelin-1 (ET-1), blood lipid levels and inflammatory factor levels in serum as well as the TGF-β/Smad pathway. The rats suffering from MI had decreased survival rates and exhibited reduced levels of NO, high-density lipoprotein cholesterol, and lumen diameter, and Smad7 messenger RNA (mRNA) and protein expression; while had significantly increased ratio of heart weight or body weight, levels of ET-1, inflammatory factors, blood lipid indexes, vascular remodeling indexes, collagen volume fraction, vulnerable atherosclerotic plaque area, VCAM-1 and MMP-2 protein expression, TGF-β, Smad2, Smad3, and Smad4 mRNA and protein expression. After inhibiting the TGF-β/Smad pathway, the rats suffering from MI showed notably opposite trend. In conclusion, downregulation of miR-224 expression promotes the formation of vulnerable atherosclerotic plaques and vascular remodeling in ACS through activation of the TGF-β/Smad pathway. Therefore, this study provides a new therapeutic target for ACS.
研究领域:
心脏病学
·
分子生物学
·
病理生理学
✓ 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）