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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DOI
PubMed
高影响因子
IBRO Neuroscience Reports
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2025
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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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DOI
PubMed
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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DOI
PubMed
高影响因子
Oncotarget
·
2017
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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
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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DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2016
·Vol. 13
·期 4
·3567-3573
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IF 1.559
Ke Jiang,Guo Chun,Ziming Wang,Quanyin Du,Aimin Wang,Yan Xiong
Tendon adhesion is a common problem in the healing of injured tendons. The molecular mechanisms of the TGF-β/Smad signaling pathway have been determined, and the role of TGF-β has been well characterized in wound healing. However, the intracellular mechanism or downstream signals by which TGF-β3 modulates its effects on tendon healing have not been well elucidated. The aim of this study was to determine the effect of TGF‑β3 on the TGF-β/Smad signaling pathway in tenocytes. Quantitative polymerase chain reaction and western blot analysis were used to analyze the effect of TGF‑β3 on the regulation of the expression of Smad proteins in tenocytes. The results demonstrated that TGF‑β3 has no significant effect on the proliferation of tendon cells. The addition of TGF‑β3 to tenocytes can significantly downregulate the expression of Smad3 and upregulate the expression of Smad7 at the gene and protein levels. The results demonstrate that TGF‑β3 may regulate Smad3 and Smad7 proteins through the TGF-β/Smad signaling pathway to minimize extrinsic scarring. Thus, it may provide a novel approach to decrease tendon adhesion and promote tendon healing.
研究领域:
分子生物学
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细胞生物学
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骨科
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DOI
PubMed
高影响因子
Frontiers in Oncology
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2020
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IF 4.848
Chen Shuo,Shen Jiaqi,Zhao Jing,Wang Jiazhong,Shan Tao,Li Junhui,Xu Meng,Chen Xi,Liu Yang,Cao Gang
Magnolol, a hydroxylated biphenyl extracted from Magnolia officinalis, has recently drawn attention due to its anticancer potential. The present study was aimed to explore the effects of Magnolol on restraining the proliferation, migration and invasion of pancreatic cancer in vivo and in vitro. Magnolol showed significant anti-growth effect in an orthotopic xenograft nude mouse model, and immunohistochemical staining of the xenografts revealed that Magnolol suppressed vimentin expression and facilitated E-cadherin expression. The cytoactive detection using CCK-8 assay showed Magnolol inhibited PANC-1 and AsPC-1 concentration-dependently. Scratch healing assay and the Transwell invasion assay proved the inhibiting effects of Magnolol on cellular migration and invasion at a non-cytotoxic concentration. Western blot and rt-PCR showed that Magnolol suppressed epithelial-mesenchymal-transition by increasing the expression level of E-cadherin and decreasing those of N-cadherin and vimentin. Magnolol suppressed the TGF-β/Smad pathway by negatively regulating phosphorylation of Smad2/3. Moreover, TGF-β1 impaired the antitumor effects of Magnolol in vivo. These results demonstrated that Magnolol can inhibit proliferation, migration and invasion in vivo and in vitro by suppressing the TGF-β signal pathway and EMT. Magnolol could be a hopeful therapeutic drug for pancreatic malignancy.
研究领域:
肿瘤学
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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
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
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IF 4.7
Xue-Li Jiang,Chuang Liu,Zi-Ying Zhan,Xiao-Qi Lan,Yan-Ling Wu,Ji-Xing Nan,Cheng-Hua Jin,Li-Hua Lian
Liver fibrosis is a critical precursor to the progression of cirrhosis and liver cancer. However, the development of precision therapies for this condition has been impeded by incompletely elucidated molecular mechanisms. Activin receptor like kinase 5 (ALK5), termed TGF-β type I receptor (TGF-βRI), has been identified as a promising therapeutic target for antifibrotic drug development. In this study, we designed and synthesized two novel thiazole derivatives (J-1155 and J-1156) featuring enantiomeric amino acid moieties to selectively target ALK5 for hepatic fibrosis treatment. Our data demonstrated that both compounds effectively attenuate hepatic fibrosis and associated inflammation through dual inhibition of the TGF-β/Smad signaling pathway and blockade of the P2X7R-NLRP3 inflammasome axis. In comparison, J-1156 demonstrated superior overall therapeutic efficacy to J-1155 in terms of anti-fibrotic efficacy, while J-1155 exhibited superior modulation of Smurf2. Collectively, our observations demonstrate the potential of J-1155 and J-1156 as dual novel therapeutic agents targeting hepatic fibrosis.
研究领域:
药理学
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分子生物学
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肝脏疾病研究
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DOI
PubMed
高影响因子
Stem Cell Research & Therapy
·
2026
·Vol. 17
·期 1
·200
·
IF 7.8
Chen Qi,Chen Xiaolong,Yang Qu,Miao Xinxin,Yuan Jinghong,Ding Shuihua,Ding Rui,Cai Shenghao,Li Bin,Cheng Xigao
Background Intervertebral disc degeneration (IVDD) is characterized by progressive nucleus pulposus cell loss and extracellular matrix degradation, in which persistent oxidative stress plays a critical pathogenic role. Transplantation of nucleus pulposus–derived stem cells (NPSCs) is a promising therapeutic strategy, yet the hostile oxidative microenvironment severely compromises cell survival. Although cellular quiescence has been suggested to enhance stress tolerance, its regulatory mechanisms and relevance in NPSCs remain largely unexplored. Methods Oxidative stress was evaluated in human degenerated disc tissues, a rat needle-puncture degeneration model, and tert-butyl hydroperoxide–treated NPSCs in vitro. Proliferating and quiescent NPSCs were compared for reactive oxygen species (ROS) levels, apoptosis, viability, and transcriptomic profiles. Pathway enrichment analyses were performed to identify critical signaling mechanisms. Recombinant transforming growth factor-beta 3 (rhTGF-β3) was used to activate the pathway, while small interfering RNA targeting the transforming growth factor-beta receptor type 2 ( Tgfbr2 ) and the pharmacological inhibitor SB431542 were applied for pathway suppression. Functional assays, organ culture, and in vivo transplantation were conducted to assess cell survival and regenerative effects. Results Elevated oxidative stress was consistently observed across clinical, animal, and cellular models of disc degeneration. Quiescent NPSCs demonstrated enhanced resistance to oxidative injury, with reduced ROS accumulation, decreased apoptosis, and improved survival. Transcriptomic analyses revealed suppression of metabolic and P53-mediated apoptotic pathways, alongside marked activation of TGF-β/SMAD signaling. Activation of this pathway induced quiescence, reduced ROS levels, inhibited mitochondrial apoptotic signaling, and protected NPSCs from oxidative injury, whereas pathway inhibition abolished these protective effects. In both organ culture and in vivo transplantation models, quiescent and TGF-β–activated NPSCs exhibited superior survival and significantly improved disc structural preservation compared with proliferating or pathway-blocked cells. Conclusion Activation of the TGF-β/SMAD pathway induces NPSC quiescence and enhances oxidative stress tolerance by suppressing P53-dependent mitochondrial apoptosis. Pharmacological induction of quiescence represents a potential strategy to improve stem cell–based therapies for intervertebral disc degeneration.
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DOI
高影响因子
Translational Research
·
2025
·
IF 5.9
Junjuan Lu,Caihong Liu,Ting Yuan,Honghui Yang,Li Zhang
Background Chronic obstructive pulmonary disease (COPD) is a chronic respiratory condition primarily caused by inhalation of harmful particles such as tobacco smoke. Cellular senescence serves as a key driver in its pathogenesis. Although endothelial progenitor cells (EPCs) have been shown to alleviate COPD by reducing inflammatory cell infiltration, the role and mechanisms underlying EPC senescence in this disease remain unclear. Methods A cigarette smoke (CS)-exposed COPD mouse model was established. Lung injury was assessed histologically, with concurrent quantification of neutrophil infiltration and cellular senescence levels in lung tissues. Pearson analysis evaluated the correlation between senescence severity and neutrophil numbers. In vivo neutrophil depletion was achieved using anti-Ly6G antibody, while GW4869 was used to inhibit exosome secretion from COPD-derived neutrophils. Neutrophils were then co-cultured with EPCs to assess their impact on EPC senescence and DNA damage. Proteomic analyses were employed to identify mechanisms of neutrophil-derived exosomes in COPD. Results COPD mice exhibited significant lung tissue damage, accelerated cellular senescence, and increased neutrophil infiltration. Senescence severity positively correlated with neutrophil proportion. Mechanistically, thrombospondin-1 (TSP-1) was highly expressed in COPD-derived neutrophils. Knockdown of neutrophil-derived exosomal TSP-1 alleviated EPC senescence. Furthermore, TSP-1 expression was regulated by transcription factor FOS, whereas TGF-β inhibition attenuated the promoting effects of TSP-1 overexpression on cellular senescence and lung injury in COPD mice. Conclusion This study demonstrates that neutrophil-derived exosomal TSP-1 aggravates EPC senescence and lung injury in COPD, revealing the pathogenic role of TSP-1 in disease progression and highlighting its potential as a therapeutic target.
研究领域:
呼吸病学
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细胞生物学
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分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Biomedicines
·
2026
·Vol. 14
·期 7
·1586
·
IF 4.5
Xiaofei Tong,Meina Sun,Xin Gan,Xin Chen,Shiyang Liu,Ieong Sun,Lin Zhang,Weihong Zheng
Background: Capsular contracture is driven by self-amplifying foreign body response (FBR) where inflammatory and fibrotic signals from fibroblasts and macrophages reinforce each other. We hypothesized that cogradient simultaneous blockade of NF-κB as an inflammatory node and TGF-β/Smad as fibrotic node could attenuate the FBR. Emodin has dual inhibitory activity but suffers from poor delivery.Methods: Emodin liposomes (Emo-Lip) were characterized and tested on TGF-β1-stimulated NIH/3T3 fibroblasts and LPS-stimulated RAW264.7 macrophages. In a rat silicone implant model, periprosthetic injections were given for four weeks. Fibrous capsule formation was evaluated by histology, immunofluorescence, and FAPI-PET/CT. Transcriptomic analyses were performed to verify and predict relevant pathways.Results: Emo-Lip had uniform size and high encapsulation efficiency. In vitro, Emo-Lip inhibited fibroblast migration, ROS production, myofibroblast differentiation (α-SMA+) as well asCtgfexpression, while suppressing M1 polarization and reduced IL-12/IL-6 secretion in macrophages. In vivo, Emo-Lip reduced capsule thickness, collagen area, and α-SMA/Col I expression, comparable to dexamethasone. Transcriptomics showed coordinated downregulation of inflammatory/fibrotic genes, and Western blot confirmed suppressed phosphorylation of Smad3.Conclusions: Coordinated two-node blockade of NF-κB and TGF-β/Smad by liposomal emodin reprograms the FBR and effectively prevents capsular contracture in rats, offering a translational strategy for implant-associated fibrosis.
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PubMed
高影响因子
CELL BIOCHEMISTRY AND FUNCTION
·
2023
·Vol. 42
·期 1
·e3899
·
IF 3.6
Tingting Wang,Guihua Song,Mengmeng Sun,Yan Zhang,Bingxue Zhang,Minghao Peng,Mengyin Li
Asthma is a common respiratory disease associated with airway inflammation. Nerolidol is an acyclic sesquiterpenoid with anti-inflammatory properties. BALB/C mice were sensitized with ovalbumin (OVA) to induce asthma symptoms and given different doses of Nerolidol. We found that Nerolidol reduced OVA-induced inflammatory cell infiltration, the number of goblet cells and collagen deposition in lung tissue. Nerolidol reduced the OVA-specific IgE levels in serum and alveolar lavage fluid in an asthma model. Immunohistochemical staining of α-SMA (the marker of airway smooth muscle) showed that Nerolidol caused bronchial basement membrane thinning in asthmatic mice. The hyperplasia of airway smooth muscle cells (ASMCs) is an important feature of airway remodeling in asthma. ASMCs were treated with 10 ng/mL TGF-β to simulate the pathological environment of asthma in vitro and then treated with different doses of Nerolidol. Nerolidol inhibited the activity of TGF-β/Smad signaling pathway both in the lung tissue of OVA-induced mouse and TGF-β-stimulated ASMCs. 16s rRNA sequencing was performed on feces of normal mice, the changes of intestinal flora in OVA-induced asthmatic mice and Nerolidol-treated asthmatic mice were studied. The results showed that Nerolidol reversed the reduced gut microbial alpha diversity in asthmatic mice. Nerolidol changed the relative abundance of gut bacteria at different taxonomic levels. At the phylum level, the dominant bacteria were Bacteroidota, Firmicutes, and Proteobacteria. At the genus level, the dominant bacteria were Lactobacillus, Muribaculaceae, Bacteroides , and Lachnospiraceae . We conclude that Nerolidol attenuates OVA-induced airway inflammation and alters gut microbes in mice with asthma via TGF-β/Smad signaling. Significance statement This research has demonstrated a mitigating effect of Nerolidol on the progress of asthma. TGF-β/Smad signaling pathway is the critical target of Nerolidol. Intestinal flora disorders induced by asthma are also regulated by Nerolidol.
研究领域:
药理学
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免疫学
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微生物学
·
呼吸系统疾病
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DOI
PubMed
高影响因子
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