HUMAN & EXPERIMENTAL TOXICOLOGY
·
2020
·Vol. 39
·期 5
·683-695
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IF 2.067
Y Chen,Q Zhang,Y Zhou,Z Yang,M Tan
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease with high morbidity and mortality. miR-182-5p is overexpressed in several fibrosis-related diseases but its effect in pulmonary fibrosis has not been reported yet. To investigate the function of miR-182-5p in pulmonary fibrosis, we established bleomycin (BLM)-induced fibrotic mice model and transforming growth factor-β1 (TGF-β1)-treated human embryonic lung fibroblasts model. In this study, miR-182-5p was highly expressed in pulmonary tissues of BLM-induced fibrotic mice. The content of hydroxyproline and TGF-β1 was decreased by downregulating the expression of miR-182-5p, indicating that fibrosis was alleviated in mice treated with Lentivirus-anti-miR-182-5p.Quantification of fibrosis-related proteins demonstrated that downregulation of miR-182-5p inhibited the expression of profibrotic proteins (fibronectin, α-smooth muscle actin, p-Smad2/p-Smad3) as well as enhanced the level of Smad7. In vitro assays validated that miR-182-5p was induced by TGF-β1 with the function of promoting fibrosis. In dual-luciferase reporter assay, Smad7 was demonstrated to be negatively regulated by miR-182-5p. Moreover, the effect of knocking down miR-182-5p on inhibiting fibrosis was achieved by upregulating the expression of Smad7. Therefore, miR-182-5p can be regarded as a biomarker of IPF and its inhibition may be a promising therapeutic approach in treating IPF.
研究领域:
肺病学
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分子生物学
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病理学
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高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2022
·
IF 5.195
Xiao-guo Suo,Fang Wang,Chuan-hui Xu,Xiao-yan He,Jia-nan Wang,Yao Zhang,Wei-jian Ni,Hao Lu,Ming-lu Ji,Yuan He,Shuai-shuai Xie,Ya-ru Yang,Jia-gen Wen,Juan Jin,Qian Gong,Jun Li,Ming-ming Liu,Xiao-ming Meng
Renal fibrosis , a common feature of chronic kidney disease , causes the progressive loss of renal function, in which TGF-β 1 plays a critical role. In this study, we found that expression levels of TGF-β 1 and its receptor 1 (TGF-βR1) were both significantly increased in obstructive fibrosis kidneys. AZ12601011 is a small molecular inhibitor of TGF-βR1; however, its therapeutic potential for renal fibrosis remains unclear. During the experiments, AZ12601011 was applied to various models of renal fibrosis followed by unilateral ureteral obstruction (UUO) and ischemia/reperfusion (I/R) in vivo , in addition to renal tubular epithelial cells (TECs) challenged by hypoxia/reoxygenation (H/R) and TGF-β 1 in vitro. Our results revealed that AZ12601011 ameliorated renal injuries and fibrosis shown by PAS, HE , and Masson staining , which was consistent with the decrease in Col-1 and α-SMA expression in the kidneys from UUO and I/R mice. Similarly, in vitro data showed that AZ12601011 inhibited the induction of Col-1 and α-SMA in both TECs treated with TGF-β 1 and H/R. In addition, the results of cellular thermal shift assay (CETSA), molecular docking , and western bolt indicated that AZ12601011 could directly bind to TGF-βR1 and block activation of the downstream Smad3. Taken together, our findings suggest that AZ12601011 can attenuate renal fibrosis by blocking the TGF-β/Smad3 signaling pathway and it might serve as a promising clinical candidate in the fight against fibrotic kidney diseases.
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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DOI
PubMed
高影响因子
ONCOGENE
·
2026
·
IF 9.1
Tian Shuai,Gu Shuchen,Sun Shuangwu,Wang Zhaoyang,Zhao Yingming,Yuan Bo,Liu Xia,Zhao Bin,Xu Pinglong,Cao Jin,Xiao Mu,Yu Yi,Feng Xin-Hua
Transforming growth factor-β (TGF-β) is a multifunctional cytokine that regulates cell proliferation, differentiation, migration, and apoptosis. It is generally accepted that TGF-β induces cellular responses through Smad-dependent gene transcription. However, the underlying mechanisms that modulate the transcriptional activities of Smads are not yet fully understood. Here, we identify BRD2, a member of the bromodomain and extraterminal (BET) family, as a key transcriptional coactivator for Smad3. BRD2 physically interacts with Smad3 through a newly identified Smad3-binding region (SBR). This BRD2-Smad interaction enhances Smad’s association with chromatin and amplifies its transcriptional activity, playing a vital role in TGF-β transcriptional and tumor-suppressive responses. Our findings establish BRD2 as an important modulator of TGF-β signaling and suggest that it may serve as a potential target for TGF-β-related diseases.
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高影响因子
Cells
·
2026
·Vol. 15
·期 19
·1765
·
IF 6
Lin Guo 1,2,†,Yuanli He 1,†,Feiming Hu 1,†,Yuanjie Sun 1,†,Yajie Zhang 1,3,Junyi Ren 4,Ren Zheng 1,Junqi Zhang 1,Yubo Sun 1,Sirui Cai 1,Yueyue Wang 1,Kun Yang 1,Chenchen Hu 1,* andShuya Yang
Cervical cancer remains one of the major gynecological malignancies worldwide, with tumor immune evasion playing a critical role in disease progression. Although accumulating evidence has implicated BAP31 in tumor progression and immune regulation, its role in immune evasion in cervical cancer remains poorly understood. In this study, we found that BAP31 was significantly upregulated in cervical cancer tissues and that elevated BAP31 expression was associated with poor patient prognosis. Functional assays demonstrated that BAP31 silencing restored the immune activity of dendritic cells. Mechanistically, BAP31 was found to regulate TGF-β at the post-transcriptional level and to facilitate its transport from the endoplasmic reticulum to the Golgi apparatus through an interaction involving the Asn-381 residue, thereby affecting its intracellular maturation and extracellular secretion. Additional functional analyses showed that exogenous TGF-β impaired dendritic cell maturation and migration while enhancing phagocytic activity. Collectively, these findings indicate that BAP31 regulation of TGF-β contributes to dendritic cell dysfunction and the establishment of an immunosuppressive microenvironment in cervical cancer.
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高影响因子
Frontiers in Medicine
·
2026
·
IF 3.6
Wenbing Lai,Lurun Wang,Wei Tang,Yuze Liu
Background Skin photoaging, primarily caused by chronic ultraviolet B (UVB) exposure, is characterized by cellular senescence and extracellular matrix (ECM) degradation. Suppression of transforming growth factor-β (TGF-β)/Smad signaling plays a critical role in UVB-induced collagen loss and impaired skin repair. Azelaic acid (AzA), a clinically established dermatological agent with antioxidant and anti-inflammatory properties, has been reported to maintain skin homeostasis; however, its mechanistic role in protecting against UVB-induced photoaging remains unclear. Objective This study aimed to investigate whether AzA alleviates UVB-induced photoaging in keratinocytes and to determine whether its protective effects are mediated through the restoration of Smad-dependent TGF-β signaling. Methods An in vitro UVB-induced photoaging model was established using HaCaT keratinocytes. Following UVB irradiation, cells were treated with AzA. Cell viability and cytotoxicity were evaluated using CCK-8 and LDH assays, respectively. Cellular senescence was assessed by senescence-associated β-galactosidase staining. ECM-related markers were measured by ELISA. TGF-β/Smad signaling activity was analyzed by Western blotting, quantitative real-time PCR, and immunofluorescence. The selective TGF-β/Smad inhibitor SB431542 was used to verify pathway dependence. A keratinocyte–fibroblast conditioned medium model was also employed to assess the paracrine regulation of fibroblast ECM metabolism. Results AzA significantly attenuated UVB-induced cellular senescence and partially restored cell viability in HaCaT cells. It significantly increased pro-collagen I levels and reduced MMP-1 levels, indicating the restoration of ECM-related protein balance. Mechanistically, AzA reversed UVB-induced suppression of TGF-β/Smad signaling by enhancing Smad2/3 phosphorylation, decreasing Smad7 expression, promoting the nuclear translocation of phosphorylated Smad2/3, and restoring Smad-dependent transcription. Pharmacological inhibition of TGF-β/Smad signaling largely abrogated these protective effects. Conditioned medium from AzA-treated keratinocytes also improved ECM-related responses in fibroblasts in a Smad-dependent manner. Conclusion AzA alleviates UVB-induced photoaging by restoring Smad-dependent TGF-β signaling, preserving ECM homeostasis, and modulating epidermal–dermal crosstalk in vitro. These findings provide mechanistic support for the potential application of AzA in anti-photoaging strategies.
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PubMed
高影响因子
IBRO Neuroscience Reports
·
2025
·
IF 2.9
Penghui Cao,Shichuan Shen,Ziyan Fang,Junjie Tan,Jinwei Wang,Nannan Pan
Objective This study aims to investigate the role of the TGF-β/Smad Signaling in depression comorbidity in epileptic individuals and to evaluate the effect of losartan on depressive symptoms. Methods Li-Popilocarpine was used to induce status epilepticus (SE) in rats. The rats in which SE was successfully induced were randomly divided into the SE saline group and the SE losartan group. Then, the rats in the different groups were given the corresponding interventions for 20 days. After the intervention, the depression levels of the rats in each group were evaluated. Upon completion of the intervention, brain tissue was collected for comprehensive assessment of TGF-β mRNA levels, TGF-β/Smad Signaling-related protein expression, and GFAP⁺ astrocyte density in the rat hippocampus. Results The depression-like behavior of SE rats was more obvious than that of control rats. TGF-β mRNA, p-Smad2, p-Smad3 and GFAP⁺ astrocyte expression levels were significantly greater in SE rats than in control rats. Compared with the SE-saline group, the depression-like behavior of the SE-losartan group improved. The expression levels of TGF-β mRNA p-Smad2, p-Smad3 and GFAP⁺ astrocyte expression in the SE-losartan group rats were lower than those in the SE-saline group. Conclusion The TGF-β/Smad Signaling is an important Signaling leading to depression-like behavior in epileptic rats. Losartan is a drug that can significantly improve the depression-like behavior of epileptic rats by regulating the TGF-β/Smad Signaling. Findings in this study support losartan as a repurposable central nervous system drug for comorbid depression in epilepsy, warranting further clinical investigation.
研究领域:
神经病学
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精神病学
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分子神经生物学
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信号转导
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转化医学
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药物重定位
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高影响因子
Oncotarget
·
2017
·
IF 5.168
Ling Zhou,Xiaoying Dong,Linlin Wang,Lanlan Shan,Ting Li,Wanfu Xu,Yan Ding,Mingqiang Lai,Xiaojun Lin,Meng Dai,Xiaochun Bai,Chunhong Jia,Hang Zheng
Although many advances have been made in understanding the pathogenesis of liver fibrosis, few options are available for treatment. Casticin, one of the major flavonoids in Fructus Viticis extracts, has shown hepatoprotective potential, but its effects on liver fibrosis are not clear. In this study, we investigated the antifibrotic activity of casticin and its underlying mechanism in vivo and in vitro . Male mice were injected intraperitoneally with carbon tetrachloride (CCl 4 ) or underwent bile duct ligation (BDL) to induce liver fibrosis, followed by treatment with casticin or vehicle. In addition, transforming growth factor-β1(TGF-β1)-activated LX-2 cells were used. In vivo experiments showed that treatment with casticin alone had no toxic effect while significantly attenuating CCl 4 -or BDL-induced liver fibrosis, as indicated by reductions in the density of fibrosis, hydroxyproline content, expression of α-SMA and collagen α1(I) mRNA. Moreover, casticin inhibited LX2 proliferation, induced apoptosis in a time- and dose-dependent manner in vitro . The underlying molecular mechanisms for the effect of casticin involved inhibition of hepatic stellate cell (HSC) activation and reduced the expression of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 resulting from blocking TGF-β1/Smad signaling, as well as increased the apoptosis of HSCs. The results suggest that casticin has potential benefits in the attenuation and treatment of liver fibrosis.
研究领域:
药理学
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肝病学
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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
JOURNAL OF INTERFERON AND CYTOKINE RESEARCH
·
2026
·
IF 1.9
Zhiyi Zhang,Haipeng Yu,Liqun Hao
As a key component of the replication protein A (RPA) complex, RPA3 has been identified as oncogenic in multiple solid tumors. However, its specific role in breast cancer remains poorly understood. RPA3 expression and its prognostic relevance in breast cancer were assessed based on the public databases. To further confirm the biological function of RPA3, we knocked down RPA3 in the breast cancer cell line Michigan Cancer Foundation-7 (MCF-7) and then conducted Cell Counting Kit-8, colony formation, Western blot, immunofluorescence, and transmission electron microscopy. In vivo effects of RPA3 were tested in a xenograft model. We found that high expression of RPA3 in breast cancer predicted adverse patient outcomes. RPA3 was mainly involved in multiple oncogenic signaling pathways, including the transforming growth factor-β (TGF-β) pathway. RPA3 knockdown effectively suppressed cancer cell proliferation in vitro and in vivo. Mechanistically, RPA3 knockdown decreased TGF-β1 promoter activity and reduced TGF-β1 expression at mRNA and protein levels, accompanied by decreased p-Smad2/3 levels. RPA3 knockdown also significantly blocked autophagy, as evidenced by decreased microtubule-associated protein 1 light chain 3 (LC3)-II/LC3-I ratio, increased sequestosome 1 (p62) level, and reduced LC3 puncta. Notably, pharmacological activation of the TGF-β pathway partially reversed autophagy alterations induced by RPA3 knockdown. These data support the possibility of RPA3 as a therapeutic target for breast cancer.
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高影响因子
MOLECULAR BIOLOGY REPORTS
·
2026
·Vol. 53
·期 1
·440
·
IF 3.2
Ding Hongran,Slack Maya,McClure Holly,Gu Wen,Gu Helene,Kappes Ferdinand,Schultz Thomas F.,Somarelli Jason A.,Tsigkou Anastasia
Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals extensively used as plastic additives. Their environmental persistence and potential for bioaccumulation have raised significant toxicological concerns. This study evaluates the cytotoxic and molecular effects of Perfluorooctanoic acid (PFOA) and its replacement compound, Perfluoro(2-methyl-3-oxohexanoic) acid (GenX), in human-derived skin (A375), liver (HepG2), kidney (SN12C), and colon (SW620) cell lines. The experimental design assessed cell viability, gene expression, and perturbations in key cellular stress pathways, with a particular focus on TGF-β/SMAD-mediated inflammation and the p53-driven DNA damage response. Our results demonstrate compound- and cell-type-specific toxicity, with GenX displaying reduced cytotoxicity compared to PFOA across all cell types. Molecular analyses revealed that both PFAS induced alterations in the TGF-β/SMAD pathway, consistent with a pro-inflammatory cellular state. Additionally, we observed activation of the DNA damage response, as evidenced by increased expression of ATM, ATR, and p53, alongside ribosomal stress-related changes in RPL5 and RPL11. Notably, while skin and liver cells exhibited similar response profiles, kidney and colon cells showed divergent modulation of SMAD signaling, suggesting tissue-specific susceptibility and mechanistic differences. These findings contribute to a deeper understanding of the differential toxicological profiles of legacy and replacement PFAS, with implications for health risk assessment and regulatory policy. Graphical abstract
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高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2025
·
IF 2.2
Meng Zhang,Congyao Wang,Ruiqi Zhao,Jiabo Yuan
Background Asthma is a chronic disease characterized by airway remodeling, which results in a progressive decline in lung function. Senkyunolide A is one of the effective components of ligusticum chuanxiong Hort, it shows protective effects on many human diseases. However, the role of Senkyunolide A in asthma remains unclear. Results In our study, we established an asthma mouse model by ovalbumin (OVA) sensitization and challenge, and Senkyunolide A (20 mg/kg and 40 mg/kg) was given by intraperitoneal injection. For in vitro study, lung epithelial BEAS-2B cells were treated with TGF-β1 to induce epithelial mesenchymal transformation. Our study showed that Senkyunolide A (40 mg/kg) alleviated airway injury, inflammatory infiltration and airway remodeling induced by OVA in asthma mice. Meanwhile, Senkyunolide A (40 μM) recovered the high level of cell migration and profibrotic factors expression induced by TGF-β1. Mechanistically, Senkyunolide A abolished the effect of OVA or TGF-β1 on Smad2/3 phosphorylation at site Ser 465/467 /Ser 423/425 in mice or BEAS-2B cells and inhibited the activation of NLRP3 inflammasome induced by OVA. Conclusions In total, our study indicated that Senkyunolide A alleviated airway damage and airway remodeling in asthmatic mice and regulated the progress of asthma by inhibiting the TGF-β/Smad2/3 signaling pathway and NLRP3 activation.
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高影响因子
Chemical Biology & Drug Design
·
2025
·Vol. 106
·期 6
·e70226
·
IF 3.3
Yaqiong Wang,Li Ma
Pachymic acid exerts antitumor effects against renal cell carcinoma and breast, lung, and pancreatic cancers; however, its specific inhibitory effect on endometrial cancer progression remains unclear. Therefore, in this study, we investigated the antitumor effects of pachymic acid against endometrial cancer using cell counting kit 8, flow cytometry, wound healing, transwell, cycloheximide chase, and western blot assays. Notably, pachymic acid significantly suppressed the viability, proliferation, and migration of endometrial cancer cells. Nuclear receptor subfamily 3 group C member 1 (NR3C1) was identified as its potential target against endometrial cancer. Pachymic acid promoted NR3C1 degradation. However, NR3C1 overexpression reversed the inhibitory effects of pachymic acid on the proliferation and migration of endometrial cancer cells. Furthermore, an association was observed between NR3C1 expression and the transforming growth factor beta (TGF-β) pathway. NR3C1 knockdown and pachymic acid treatment reduced protein levels of TGF-β1 and p-Smad2/3. TGF-β pathway inhibitor galunisertib reversed the NR3C1 overexpression-induced increase in endometrial cancer cell migration. Collectively, our findings suggest that pachymic acid suppresses endometrial cancer cell migration by inhibiting the NR3C1/TGF-β/Smad signaling pathway, highlighting its potential as a therapeutic agent for endometrial cancer.
研究领域:
肿瘤学
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分子生物学
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药理学
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细胞生物学
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天然产物研究
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高影响因子
PHARMACEUTICAL BIOLOGY
·
2022
·
IF 3.889
Hui Wang,Qingtao Jiang,Lizhu Zhang
Context Baicalin, a flavonoid extracted from radix scutellariae, possesses various pharmacological effects, including protective effects on renal interstitial fibrosis (RIF), but its possible role and mechanisms have not been fully elucidated.Objective This study explores the protective effects and mechanisms of baicalin on RIF.Materials and methods C57BL/6 male mice were divided into six groups: sham, model, low baicalin, middle baicalin, high baicalin and positive drug groups. The unilateral ureteral obstruction (UUO) model of RIF was constructed and treated with baicalin doses (10, 20 and 40 mg/kg) and a positive control drug (valsartan, 8 mg/kg). H&E staining was used to observe the pathological changes in renal tissues, Masson staining was performed to evaluate collagen deposition in renal tissues, and immunohistochemical examination was adopted to determine α-SMA and extracellular matrix (ECM) expression. Primary mouse fibroblasts were isolated, extracted and treated with baicalin and/or TGF-β. qRT-PCR and enzyme-linked immunosorbent assay (ELISA) were applied to detect the inflammatory responses. Moreover, ECM and TGF-β/Smad expression levels were evaluated by western blot assay.Results Baicalin ameliorated RIF in UUO mice by inhibiting fibrosis and inflammatory responses. The TGF-β/Smad pathway was significantly suppressed in the UUO mouse model. Additionally, baicalin significantly inhibited ECM expression and inflammatory factors in fibroblasts treated with TGF-β. TGF-β/Smad pathway activation was significantly decreased in fibroblasts.Discussion and conclusions These findings support the use of baicalin as a potential therapeutic option for the treatment of RIF by possibly inhibiting the TGF-β/Smad signalling 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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PubMed
高影响因子
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