Genes
·
2024
·Vol. 15
·期 12
·1575
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IF 2.8
Dandan Wu,Xinning Sun,Xin Li,Zongchao Zuo,Dong Yan,Wu Yin
Background: Hepatocellular carcinoma (HCC) is a type of malignant tumor with high morbidity and mortality. Untimely treatment and high recurrence are currently the major challenges for HCC. The identification of potential targets of HCC progression is crucial for the development of new therapeutic strategies. Methods: Bioinformatics analyses have been employed to discover genes that are differentially expressed in clinical cases of HCC. A variety of pharmacological methods, such as MTT, colony formation, EdU, Western blotting, Q-PCR, wound healing, Transwell, cytoskeleton F-actin filaments, immunohistochemistry (IHC), hematoxylin–eosin (HE) staining, and dual-luciferase reporter assay analyses, were utilized to study the pharmacological effects and potential mechanisms of ribonucleotide reductase regulatory subunit M2 (RRM2) in HCC. Results: RRM2 expression is significantly elevated in HCC, which is well correlated with poor clinical outcomes. Both in vitro and in vivo experiments demonstrated that RRM2 promoted HCC cell growth and metastasis. Mechanistically, RRM2 modulates the EMT phenotype of HCC, and further studies have shown that RRM2 facilitates the activation of the TGF-β/Smad signaling pathway. SB431542, an inhibitor of TGF-β signaling, significantly inhibited RRM2-induced cell migration. Furthermore, RRM2 expression was correlated with diminished survival in HBV-associated HCC patients. RRM2 knockdown decreased the levels of HBV RNA, pgRNA, cccDNA, and HBV DNA in HepG2.2.15 cells exhibiting sustained HBV infection, while RRM2 knockdown inhibited the activity of the HBV Cp, Xp, and SpI promoters. Conclusion: RRM2 is involved in the progression of HCC by activating the TGF-β/Smad signaling pathway. RRM2 increases HBV transcription in HBV-expressing HCC cells. Targeting RRM2 may be of potential value in the treatment of HCC.
研究领域:
肿瘤学
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分子生物学
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肝脏病学
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DOI
PubMed
高影响因子
Applied Biological Chemistry
·
2024
·Vol. 67
·期 1
·1-11
·
IF 2.3
Yu Ziqing,He Wen,Shi Weiwu
All chronic renal disorders eventually lead to renal interstitial fibrosis (RIF). Chronic inflammation and pro-fibrotic substances are familiar companions of the fibrotic process. The Sulforaphane (Sul) molecule is particularly useful in protecting the liver from oxidative damage. To investigate the Sul effects on fibrosis markers and inflammatory proteins in the kidney of NRK52E cell line and rats and clarify the mechanism of TGF-β/Smad signaling pathway in a rat model of RIF were developed in the present study. Sul (50, 100, and 200 ng/ml) remarkably reduced the gene expressions of tumor necrosis factor (TNF-α), interleukin-6 (IL-6), interleukin (IL)-1β, collagen 3 (COL3A1), collagen 1 (COL1A1), and α-smooth muscle actin (α-SMA) in fibrotic NRK52E cells compared with those in cells inspired by transforming growth factor-α (TGF-α). Histopathological investigations showed that Sul administration retained renal tissue structure and decreased kidney tissue fibrosis in rats subjected to unilateral ureteral blockage (UUO). The expression level of TNF-α, IL-6, IL-1β, COL3A1, COL1A1, and α-SMA in the rats’ kidneys exposed to UUO was also suppressed by the treatment of Sul. In the present study, western blot analysis showed that Sul upregulated the expressions of fibrotic NRK52E cells Smad7 and rat model UUO groups while simultaneously decreasing the stimulation of Smad2/3 and the expressions of cyclooxygenase-2, NF-κB, Smad4, activator protein-1, and high-mobility group protein B1. Ultimately, Sul’s ability to inhibit the TGF-β/Smad pathway and the development of inflammation factors may mitigate RIF.
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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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 Cardiovascular Medicine
·
2021
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IF 6.05
Xu Yan,Qu Xiaobo,Zhou Jia,Lv Guangfu,Han Dong,Liu Jinlong,Liu Yuexin,Chen Ying,Qu Peng,Huang Xiaowei
Adriamycin (ADR)-based combination chemotherapy is the standard treatment for some patients with tumors in clinical, however, long-term application can cause dose-dependent cardiotoxicity. Pilose Antler, as a traditional Chinese medicine, first appeared in the Han Dynasty and has been used to treat heart disease for nearly a thousand years. Previous data revealed pilose antler polypeptide (PAP, 3.2KD) was one of its main active components with multiple biological activities for cardiomyopathy. PAP-3.2KD exerts protective effects againt myocardial fibrosis. The present study demonstrated the protective mechanism of PAP-3.2KD against Adriamycin (ADR)-induced myocardial injury through using animal model with ADR-induced myocardial injury. PAP-3.2KD markedly improved the weight increase and decreased the HW/BW index, heart rate, and ST height in ADR-induced groups. Additionally, PAP-3.2KD reversed histopathological changes (such as disordered muscle bundles, myocardial fibrosis and diffuse myocardial cellular edema) and scores of the heart tissue, ameliorated the myocardial fibrosis and collagen volume fraction through pathological examination, significantly increased the protein level of Bcl-2, and decreased the expression levels of Bax and caspase-3 in myocardial tissue by ELISA, compared to those in ADR-induced group. Furthermore, ADR stimulation induced the increased protein levels of TGF-β1 and SMAD2/3/4, the increased phosphorylation levels of SMAD2/3 and the reduced protein levels of SMAD7. The expression levels of protein above in ADR-induced group were remarkably reversed in PAP-3.2KD-treated groups. PAP-3.2KD ameliorated ADR-induced myocardial injury by regulating the TGF-β/SMAD signaling pathway. Thus, these results provide a strong rationale for the protective effects of PAP against ADR-induced myocardial injury, when ADR is used to treat cancer.
研究领域:
药理学
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心脏病学
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传统中药
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
·
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
Current Molecular Pharmacology
·
2024
·Vol. 17
·期 1
·e18761429315125
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IF 2.4
YiDan Li,BingHua Tu,ZiTong Wang,ZiChen Shao,ChenHao Fu,JianQiang Hua,ZiWen Zhang,Peng Zhang,Hui Sun,ChenYan Mao,Chi-Ming Liu
Background Finasteride and doxazosin are used for the treatment of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). Epithelial–mesenchymal transition (EMT) and TGF-β/Smad signaling pathway play an important role in BPH, little is known about the growth inhibition and anti-fibrosis effects of doxazosin on the regulation of EMT and morphology in the prostate. Objectives The present study examined the effects of doxazosin on testosterone propionate (TP)-induced prostate growth in vivo and in vitro and its impact on the EMT and TGF-β/Smad signaling pathway. Methods Mice were treated with TP. Doxazosin (5 or 10 mg/kg) and finasteride (10 mg/kg) were administered orally for 28 days in TP-induced mice. The prostate index (prostate/body weight ratio), morphological characteristics and the protein expression of the prostate were examined. We further examined the effects of doxazosin and finasteride on the EMT and TGF-β/Smad signaling pathway in mice and in human prostate stroma cell (WPMY-1). The protein expressions of TGF-β1, TGFBR2, p-Smad2/3, N-cadherin, vimentin, fibronectin and α-SMA, E-cadherin and prostate specific antigen (PSA) were determined after treatment by western blot. Results The prostate wet weight, prostate index decreased after treatment. Doxazosin (5 or 10 mg/kg), finasteride (10 mg/kg) or a combination treatment (doxazosin 10 mg/kg + finasteride 10 mg/kg) were shown to reverse the pathological and morphological characteristics of the prostate. Doxazosin and finasteride inhibited TP-induced prostate growth, EMT, and the TGF-β/Smad signaling pathway by downregulating the expression of TGF-β1, TGFBR2, p-Smad2/3, N-cadherin, vimentin, fibronectin and α-SMA, whereas expression of E-cadherin was increased after treatment with either doxazosin or finasteride. Doxazosin (1-50 μM) inhibited normal human prostate stroma cell growth (WPMY-1) after 48 h with or without testosterone treatment. Doxazosin also regulated the EMT and proteins related to the TGF-β/Smad signaling pathway in WPMY-1 cells after 24 h. Additionally, doxazosin decreased protein expression of the PSA both in vivo and in vitro. Conclusion This study demonstrated that doxazosin inhibits prostate growth by regulating the EMT and TGF-β/Smad signaling pathways in the prostate. This finding suggests that doxazosin has potential as a new signaling pathway for the treatment of BPH.
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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DOI
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2017
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IF 3.791
Yi Cai,Wanqing Ma,Yichuan Xiao,Bo Wu,Xiaobing Li,Fengrong Liu,Jianhua Qiu,Genshui Zhang
Baicalin is a major flavonoid compound purified from Scutellariae radix , which has been described as an herb in the Chinese Pharmacopoeia. Previous studies have suggested baicalin possessed extensive anti-inflammatory, anti-cancer, anti-viral properties. However, up to known, there have been no reports of safety and toxicity in the rats following oral administration of baicalin. In this present study, we showed the first evidence that treatment of baicalin (400, 800 and 1600 mg/kg/day) induced significantly kidney injury and fibrosis . The collagen synthesis and fibrosis-related protein expression were increased in the kidney of Sprague-Dawley (SD) rats after treatment with high doses of baicalin. We further investigated the potential molecular mechanism of baicalin-mediated renal fibrosis and revealed that baicalin activated the transforming growth factor-β (TGF-β)/Smad signaling pathway in a dose-dependent manner. Moreover, we also observed that baicalin induced Smad3 interaction with transcriptional coactivator p300 accompanying with increment of Smad3 acetylation . Our results may contribute to better understanding of the future pharmacological and toxicological studies of Scutellaria baicalensis Georgi and its active compounds on the human disease.
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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DOI
PubMed
高影响因子
CELL BIOCHEMISTRY AND FUNCTION
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2023
·Vol. 42
·期 1
·e3899
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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
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呼吸系统疾病
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DOI
PubMed
高影响因子
NEW JOURNAL OF CHEMISTRY
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2025
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IF 2.5
Yi Yang,Bei Tian,Xinyu Tian,Linyan Yao,Jianxi Xiao
Excessive ultraviolet radiation is one of the most common external factors causing skin photoaging, which leads to collagen degradation, wrinkle formation, pigmentation, and is even associated with skin disorders such as seborrheic keratosis and skin tumors. Although various strategies have been developed to treat photoaging skin; however, they suffer from poor stability, risk of allergic reactions, and prolonged recovery periods. In this study, we develop a novel highly stable and bioactive yak type I collagen-based hydrogels dressing to promote the rejuvenation of photoaged skin. The YIC gel demonstrated excellent stability over a six-month period, and maintained the intact triple-helical structure of collagen. It also displayed shear-thinning behavior and notable ductility. In vitro cell experiments confirmed its favorable biocompatibility and bioactivity.Non-invasive Combo evaluations demonstrated the remarkable ability of YIC gel to restore dermal density, elasticity, hydration, and transepidermal water loss to healthy levels, surpassing the efficacy of the commercial product. Histological analysis revealed YIC gel significantly reduced epidermal thickness, promoted the deposition and regeneration of collagen, demonstrating greater efficacy than the commercial product. Antioxidant indicators further highlighted the antioxidant properties of YIC gel, including reduced MDA content, increased SOD activity and GSH content. Immunofluorescence staining suggested that the YIC gel may enhance collagen synthesis through modulation of the TGF-β/Smad signaling pathway. This YIC gel offers valuable insights into its protective effects against skin photoaging and highlights its promising applications in cosmetic formulations.
研究领域:
生物材料
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皮肤科学
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生物医学工程
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化妆品科学
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分子生物学
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产品关联
DOI
高影响因子
SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY
·
2023
·
IF 1.9
Wenchao Pan,Yadong Wang,Caiyan Zhao
Objective To explore the protective effect and related mechanism of miR-140-5p on liver fibrosis by interfering with TGF-β/Smad signaling pathway.Methods Liver fibrosis mice models were established by intraperitoneal injection of CCL4. Hematoxylin and eosin (HE) staining was used to detect the structural and morphological changes of the liver. Masson staining was used to detect collagen deposition. Human hepatic stellate cells (HSCs, LX-2) were transfected with miR-140-5p mimic or inhibitor then treated with TGF-β1. The qRT-PCR and Western blotting was used to detect the expression of related molecules. The luciferase reporter assay was used to identify the target of miR-140-5p.Results Our results indicated that miR-140-5p expression was downregulated in fibrotic liver tissues of model mice and LX-2 cells treated with TGF-β1. The overexpression of miR-140-5p decreased the expression of collagen1(COL1) and α-smooth muscle actin(α-SMA), inhibited the phosphorylation of Smad-2/3 (pSmad-2/3) in LX-2 cells. Conversely, the knockdown of miR-140-5p upregulated COL1 and α-SMA expression, increased Smad-2/3 phosphorylation. A dual-luciferase reporter assay showed that TGFβR1 was a target gene of miR-140-5p. The overexpression of miR-140-5p suppressed TGFβR1 expression in LX-2 cells. Additionally, knockdown of TGFβR1 decreased the expression of COL1 and α-SMA. Conversely, the overexpression of TGFβR1 reversed the inhibitory effect of miR-140-5p upregulation on expression of COL1 and α-SMA.Conclusion miR-140-5p bound to TGFβR1 mRNA 3′-untranslated region(3′UTR) and inhibited the expression of TGFβR1, pSmad-2/3, COL1 and α-SMA, thereby exerting a potential therapeutic effect on hepatic fibrosis.
研究领域:
分子生物学
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肝病学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·791
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IF 12.6
Qiao Wenyu,Yang Luling,Liu Yu,Zhang Huaiyuan,Zheng Zhihuan,Gu Tianheng,Zhu Jiaxi,Hu Xinyi,Li Gangze,Zhang Yuxia,Xiao Meng,Zhang Lin
Excessive accumulation of reactive oxygen species (ROS) and dysbiosis of the gut microbiota are pivotal contributors to the pathogenesis of inflammatory bowel disease (IBD) and associated fibrosis. In this study, a microfluidic approach was utilized to fabricate a multifunctional therapeutic microsphere system by encapsulating hollow mesoporous cerium oxide nanoparticles (HCeO 2 ) loaded with KP1 short peptides-specific inhibitors of the TGF-β/Smad signaling pathway. The resulting composite formulation (KP1@HCeO₂@SAM) was designed to achieve synergistic antioxidant, anti-inflammatory, and antifibrotic effects. The developed microspheres exhibited prolonged intestinal retention and effectively modulated gut microbiota composition, increasing the relative abundance of probiotic species by over sevenfold. Moreover, they demonstrated remarkable reactive oxygen species (ROS) scavenging efficiency (> 95%) and significant inhibition of fibrotic signaling cascades. In dextran sulfate sodium (DSS)-induced murine colitis models, treatment with the microspheres led to a substantial reduction in Disease Activity Index (DAI) (> 76%), restoration of intestinal barrier integrity (> 90%), and mitigation of fibrotic progression, as indicated by a 66% decrease in α-SMA expression. These findings establish a novel and integrative therapeutic platform for the effective management of IBD. Graphical abstract
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PubMed
高影响因子
Biomaterials Advances
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2025
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IF 6
Chen Shen,Xingyu Zhou,Junhui Jiang,Junbo Dang,Tong Lin,Ruibo Hu,Tianhao Zhao,Dahui Sun,Mei Zhang
Soft tissue fillers have received much attention for the treatment of skin aging and the restoration of missing or excised soft volumes. However, the development of fillers with both safety and applicability remains a challenge. This study presented a synergistic composite filler comprising aldehyde-modified hyaluronic acid (OHA), hydrazide-modified hyaluronic acid (NHA), amino-modified poly-L-lactic acid microspheres (NPLLA), and antioxidant copper peptide. The hydrogel formed in situ via Schiff base reaction exhibited excellent mechanical properties and immediate filling effect. The amino-modified PLLA microspheres were less likely to agglomerate, avoiding the occurrence of adverse reactions and further enhancing the mechanical properties of the filler. The timed-release platform provided protection for copper peptide stability, scavenged reactive oxygen species during the fibrotic encapsulation phase, and synergistically promoted collagen deposition. In a nude mice skin aging model, hydrogels stimulated collagen production through the TGF-β/Smad signaling pathway with good long-term filler efficacy. Therefore, NPLLA microspheres/hyaluronic acid-based composite hydrogels exhibit great potential as injectable soft tissue fillers.
研究领域:
生物材料
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组织工程
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生物医学工程
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皮肤科学
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药物递送
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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）