BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
·
2024
·
IF 4.2
Dong-Jing Yang,Yang Bai,Min Wu,Yin-Ming Liang,Bin-Hui Zhou,Wenzhi Guo,Shui-Jun Zhang,Ji-Hua Shi
Vascular endothelial inflammation is crucial in hepatic ischemia–reperfusion injury (IRI). Our previous research has shown that connective tissue growth factor (CTGF), secreted by endothelial cells, protects against acute liver injury, but its upstream mechanism is unclear. We aimed to clarify the protective role of CTGF in endothelial cell inflammation during IRI and reveal the regulation between endoplasmic reticulum stress-induced activating transcription factor 6 (ATF6) and CTGF. Hypoxia/reoxygenation in endothelial cells, hepatic IRI in mice and clinical specimens were used to examine the relationships between CTGF and inflammatory factors and determine how ATF6 regulates CTGF and reduces damage. We found that activating ATF6 promoted CTGF expression and reduced liver damage in hepatic IRI. In vitro, activated ATF6 upregulated CTGF and downregulated inflammation, while ATF6 inhibition had the opposite effect. Dual-luciferase assays and chromatin immunoprecipitation confirmed that activated ATF6 binds to the CTGF promoter, enhancing its expression. Activated ATF6 increases CTGF and reduces extracellular regulated protein kinase 1/2 (ERK1/2) phosphorylation, decreasing inflammatory factors. Conversely, inhibiting ATF6 decreases CTGF and increases the phosphorylation of ERK1/2, increasing inflammatory factor levels. ERK1/2 inhibition reverses this effect. Clinical samples have shown that CTGF increases after IRI, inversely correlating with inflammatory cytokines. Therefore, ATF6 activation during liver IRI enhances CTGF expression and reduces endothelial inflammation via ERK1/2 inhibition, providing a novel target for diagnosing and treating liver IRI.
研究领域:
分子生物学
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肝病学
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炎症
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转录因子
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DOI
PubMed
高影响因子
EXPERIMENTAL ANIMALS
·
2021
·
IF 2.319
Abdul Razaq HIRMAN,Lili DU,Shaohang CHENG,Heng ZHENG,Linna DUO,Qianyu ZHAI,Jing XU
Excessive scar formation post burn injury can cause great pain to the patients. MiR-133a-3p has been demonstrated to be anti-fibrotic in some fibrosis-related diseases. However, its possible role in scar formation has not been elucidated yet. In present study, the effect of miR-133a-3p on scar formation was investigated in a scalded model of mice. Moreover, the function of miR-133a-3p on proliferation and migration of scar-derived fibroblasts (SFs) was studied in vitro. It was found that miR-133a-3p was dramatically downregulated in scar tissue of scalded mice. Upregulation of miR-133a-3p by miR-133a-3p agomir obviously inhibited the scar formation in scalded mice. Histological staining showed that upregulation of miR-133a-3p attenuated the excessive deposition of collagen in scar tissue of scalded mice. In vitro study showed that upregulation of miR-133a-3p effectively suppressed the proliferation and migration of SFs. Besides, upregulation of miR-133a-3p attenuated the protein levels of α-smooth muscle actin (α-SMA) and collagen I, indicating that miR-133a-3p could suppress the activation of SFs. The expression of connective tissue growth factor (CTGF), a critical mediator in cell proliferation, migration and extracellular matrix (ECM) synthesis, was also downregulated by the upregulation of miR-133a-3p. Luciferase reporter assay validated that CTGF was directly targeted by miR-133a-3p. In addition, overexpression of CTGF abolished the effect of miR-133a-3p on inhibiting the proliferation, migration and activation of SFs, indicating that miR-133a-3p functioned by targeting CTGF. Therefore, miR-133a-3p might be a promising target for treating pathological scars.
研究领域:
生物学
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医学
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病理学
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分子生物学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2012
·
IF 3.268
Yi Cai,Shan-Shan Yu,Ting-Ting Chen,Si Gao,Biao Geng,Yang Yu,Jian-Tao Ye,Pei-Qing Liu
Connective tissue growth factor (CTGF) has been reported to play an important role in tissue fibrosis and presents a promising therapeutic target for fibrotic diseases . In heart, inappropriate increase in level of CTGF promotes fibroblast proliferation and extracellular matrix (ECM) accumulation, thereby exacerbating cardiac hypertrophy and subsequent failure. Epigallocatechin-3-gallate (EGCG), the major polyphenol found in green tea, possesses multiple protective effects on the cardiovascular system including cardiac fibrosis . However, the molecular mechanism by which EGCG exerts its anti-fibrotic effects has not been well investigated. In this study, we found that EGCG could significantly reduce collagen synthesis , fibronectin (FN) expression and cell proliferation in rat cardiac fibroblasts stimulated with angiotensinII (AngII). It also ameliorated cardiac fibrosis in rats submitted to abdominal aortic constriction (AAC). Moreover, EGCG attenuated the excessive expression of CTGF induced by AAC or AngII, and reduced the nuclear translocation of NF-κB p65 subunit and degradation of IκB-α. Subsequently, we demonstrated that in cardiac fibroblasts NF-κB inhibition could suppress AngII-induced CTGF expression. Taken together, these findings provide the first evidence that the effect of EGCG against cardiac fibrosis may be attributed to its inhibition on NF-κB activation and subsequent CTGF overexpression, suggesting the therapeutic potential of EGCG on the prevention of cardiac remodeling in patients with pressure overload hypertrophy.
研究领域:
心脏病学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
Journal for ImmunoTherapy of Cancer
·
2025
·Vol. 13
·期 6
·e012144
·
IF 10.6
Shiru Chen,Yuchong Zhao,Mengdie Cao,Wang Peng,Hai Huang,Yilei Yang,Jingwen Liang,Wei Chen,Shuya Bai,Qiaodan Zhou,Jiamei Jiang,Yilin Gu,Ronghua Wang,Bin Cheng
Background Pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic and immunosuppressive tumor microenvironment (TME), limiting the efficacy of immune checkpoint inhibitors such as anti-programmed cell death 1 (PD-1). Methods This study aimed to evaluate the therapeutic potential of Y126S, a recombinant IgG1/IgG2 hybrid bispecific antibody (BsAb), in reshaping the immunotherapy-resistant TME in PDAC. Orthotopic PDAC and KPC (Kras LSL-G12D/+ ; Trp53 LSL-R172H/+ ; Pdx1-Cre) mouse models were established and treated with Y126S, α-connective tissue growth factor (CTGF), α-PD-1, or a combination of α-CTGF and α-PD-1. TME remodeling, antibody distribution, and therapeutic efficacy were assessed using flow cytometry, immunohistochemical/Masson staining, atomic force microscopy, positron emission tomography (PET) imaging, distribution analysis, and other experimental techniques. Results Here, Y126S was characterized in vitro and its antitumor efficacy was evaluated and validated in orthotopic PDAC mice and KPC mouse models. Notably, Y126S significantly remodeled the TME and demonstrated superior tumor-specific accumulation compared with single α-PD-1 treatment, leading to markedly enhanced antitumor efficacy relative to its parental antibodies or their combination. Mechanistically, Y126S suppressed cancer-associated fibroblasts (CAFs) activation, reduced collagen deposition, and downregulated programmed cell death ligand 1 (PD-L1) expression on CAFs by targeting CTGF and enhanced the anti-PD-1-mediated reinvigoration of cytotoxic CD8 + T cells, thereby establishing a less desmoplastic and potent tumor-killing microenvironment. Conclusions Our findings highlight the potential of Y126S as a promising BsAb-based immunotherapy strategy for PDAC by remodeling the desmoplastic and immunosuppressive TME.
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DOI
PubMed
高影响因子
NANOTECHNOLOGY
·
2026
·Vol. 37
·期 7
·075702
·
IF 2.9
Min Gao,Zhongtao Wen,Xinyuan Zhang,Zhouyang Guo,Yu Jiang
Liver fibrosis represents a critical intermediate stage in the progression of chronic liver diseases toward cirrhosis. Conventional therapeutic strategies remain limited by insufficient efficacy, notable side effects, or narrow applicability, making the effective reversal of fibrosis a persistent clinical challenge. Although gene silencing technologies offer a promising therapeutic avenue, their clinical translation is hampered by poor delivery efficiency, instability in vivo, and lack of tissue specificity. To address these issues, we developed a lactobionic acid‐modified aminated glycogen (Lac‐AGly) nanoparticle system for the targeted delivery of connective tissue growth factor (CTGF) targeting small interfering RNA (siRNA). By utilizing natural glycogen as a biodegradable backbone, a degree of amination of 51.2% conferred efficient siRNA binding capacity, while Lac modification enabled selective recognition of hepatocyte-expressed asialoglycoprotein receptors. The resulting Lac-AGly/siCTGF nanocomplexes exhibited a uniform spherical morphology with an average particle size of 247.2 ± 8.8 nm and a zeta potential of 28.5 ± 3.8 mV. In vivo studies demonstrated that Lac-AGly/siCTGF significantly attenuated liver fibrosis, evidenced by a reduction in the collagen-positive area from 14.3% to 3.1%. Collectively, the Lac‐AGly/siCTGF nanoparticle system integrated biocompatibility, serum stability, and active hepatic targeting into a single platform, significantly improving siRNA delivery efficiency and gene‐silencing efficacy while maintaining favorable biosafety. This work provided a novel and translatable strategy for precise molecular intervention in liver fibrosis.
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2021
·Vol. 43
·期 1
·146-156
·
IF 6.15
Yao Xin-peng,Jiao Ting-ying,Jiang Yi-ming,Fan Shi-cheng,Zhao Ying-yuan,Yang Xiao,Gao Yue,Li Fei,Zhou Yan-ying,Chen Pan-pan,Huang Min,Bi Hui-chang
Mifepristone (Mif), an effective synthetic steroidal antiprogesterone drug, is widely used for medical abortion and pregnancy prevention. Due to its anti-glucocorticoid effect, high-dose Mif is also used to treat Cushing’s syndrome. Mif was reported to active pregnane X receptor (PXR) in vitro and PXR can induce hepatomegaly via activation and interaction with yes-associated protein (YAP) pathway. High-dose Mif was reported to induce hepatomegaly in rats and mice, but the underlying mechanism remains unclear. Here, the role of PXR was studied in Mif-induced hepatomegaly in C57BL/6 mice and Pxr -knockout mice. The results demonstrated that high-dose Mif (100 mg · kg −1 · d −1 , i.p .) treatment for 5 days significantly induced hepatomegaly with enlarged hepatocytes and promoted proliferation, but low dose of Mif (5 mg · kg −1 · d −1 , i.p .) cannot induce hepatomegaly. The dual-luciferase reporter gene assays showed that Mif can activate human PXR in a concentration-dependent manner. In addition, Mif could promote nuclear translocation of PXR and YAP, and significantly induced the expression of PXR, YAP, and their target proteins such as CYP3A11, CYP2B10, UGT1A1, ANKRD, and CTGF. However, Mif (100 mg · kg −1 · d −1 , i.p .) failed to induce hepatomegaly in Pxr -knockout mice, as well as hepatocyte enlargement and proliferation, further indicating that Mif-induced hepatomegaly is PXR-dependent. In summary, this study demonstrated that PXR-mediated Mif-induced hepatomegaly in mice probably via activation of YAP pathway. This study provides new insights in Mif-induced hepatomegaly, and provides novel evidence on the crucial function of PXR in liver enlargement and regeneration.
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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肝病学
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产品关联
DOI
PubMed
高影响因子
IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL
·
2022
·Vol. 58
·期 2
·96-108
·
IF 2.723
Sun Xiaogang,Hou Zhiyun,Li Ning,Zhang Shuangwei
Hepatocellular carcinoma (HCC) is the most common primary liver cancer with high incidence and mortality. MiR-597-5p is downregulated in tumor tissues of HCC compared with non-tumor tissues. However, its role in HCC is still unknown. This study aims to assess the function of miR-597-5p in HCC development and investigate the underlying mechanism. To perform gain- and loss-of-function studies, SK-HEP-1 cells and Huh-7 cells were transfected with miR-597-5p mimics and inhibitor, respectively. MiR-597-5p markedly reduced the cell viability and the expression of Ki-67 in HCC cells. MiR-597-5p also repressed the cell cycle progression of HCC cells and the protein levels of cyclin D1 and CDK2. Moreover, miR597-5p inhibited the migration and invasion of HCC cells and decreased MMP2 and MMP9 levels. Transcriptional enhancer associate domain transcription factor 1 (TEAD1) was identified as a target of miR-597-5p by luciferase reporter assay. TEAD1 and its downstream target genes, CTGF and CYR61, were downregulated by miR-597-5p in HCC cells. Furthermore, miR-597-5p was demonstrated to function in HCC progression by targeting TEAD1 via TEAD1 expression gain and loss. Our study demonstrates that miR-597-5p represses the proliferation, migration, and invasion of HCC cells through targeting TEAD1, which provides a therapeutic target for HCC treatment.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Ma Yucong,Ye Suping,Sun Kunpeng,Gu Yue
Curcumin (CUR) possesses the capability to inhibit various inflammatory factors, exert anti-inflammatory effects, and alleviate asthma attacks; however, its hydrophobicity and instability significantly impede its clinical application. In this study, we synthesized CUR-loaded nanoparticles (CUR-NPs) and evaluated their impact on the proliferation, migration, and inflammatory infiltration of mouse airway smooth muscle cells (ASMCs), while investigating their underlying mechanisms. To achieve this objective, ASMCs were isolated from BALB/c mice and subjected to TGF-β1-induced cell proliferation and migration. Our findings demonstrate that CUR-NPs effectively regulate the release of CUR within cells with superior intracellular uptake compared to free CUR. The CCK-8 assay results indicate that the blank carrier does not exhibit any cytotoxic effects on cells, thus rendering the impact of the carrier itself negligible. The TGF-β1 group exhibited a significant increase in cell proliferation, whereas treatment with CUR-NPs significantly suppressed TGF-β1-induced cell proliferation. The findings from both the cell scratch assay and transwell assay demonstrated that TGF-β1 substantially enhanced cell migration, while CUR-NPs treatment effectively attenuated TGF-β1-induced cell migration. The Western blot analysis demonstrated a substantial increase in the expression levels of TGF-β1, p-STAT3, and CTGF in ASMCs following treatment with TGF-β1 when compared to the control group. Nevertheless, this effect was effectively counteracted upon administration of CUR-NPs. Furthermore, an asthma mouse model was successfully established and CUR-NPs were administered through tail vein injection. The serum levels of TGF-β1 and the expression levels of TGF-β1, p-STAT3, and CTGF proteins in the lung tissue of mice in the model group exhibited significant increases compared to those in the control group. However, CUR-NPs treatment effectively attenuated this change. Our research findings suggest that CUR-NPs possess inhibitory effects on ASMC proliferation, migration, and inflammatory infiltration by suppressing activation of the TGF-β1/p-STAT3/CTGF signaling pathway, thereby facilitating inhibition of airway remodeling.
研究领域:
药理学
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呼吸病学
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纳米技术
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免疫学
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细胞生物学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Jie Yao,Haoqiang Wan,Jingmei Zhang,Wanying Shen,Xiaofang Wei,Chenyan Shi,Baoru Ou,Dongyu Liu,Lanlan Ge,Jia Fei,Xiaobin Zeng
Background Studies have shown that phenylethanoid glycosides (PhGs) have multiple pharmacological effects such as anti-inflammatory, hepatoprotective or neuroprotective functions, whereas their anti-tumor effects are rarely studied. Tubuloside B (Tub B) is a PhG isolated from Cistanche deserticola , a traditional Chinese medicine. To date, there is a lack of comprehensive research regarding the biological activity of Tub B. Purpose The subject of the current study was to investigate the anti-hepatocellular carcinoma (HCC) cell activity and the underlying mechanism of Tub B. Methods We evaluated the in vitro anti-migratory effect of Tub B by scratch and transwell assays. RNA-seq was employed to identify the differential genes by Tub B. Besides, the functional mechanism of Tub B was investigated by distinct molecular biology techniques including immunofluorescent staining, quantitative PCR, as well as western blot analysis. Subsequently, we utilized Hep3B cells for in vivo metastasis assays through spleen injection and evaluated the anti-migratory effect of Tub B in hepatocellular carcinoma (HCC). Results Tub B exhibited in vitro and in vivo inhibition of HCC cell migration. Tub B decreased the expression of transcriptional target genes downstream of the Hippo pathway, including CTGF, CYR61, and N-cadherin as determined by RNA-seq. Furthermore, mechanistic studies confirmed that Tub B increased phosphorylation of YAP at S127, which contributes to YAP cytoplasmic localization. Additionally, overexpression of YAP abrogated Tub B-induced inhibition of HCC migration and the mRNA levels of CTGF, CYR61, and N-cadherin . Conclusions Taken together, these results illustrated that Tub B demonstrated great potential in inhibiting migration of HCC, and a portion of its impact can be attributed to the modulation of the Hippo-YAP pathway.
研究领域:
药理学
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肿瘤学
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分子生物学
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中药学
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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
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细胞生物学
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呼吸病学
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遗传学
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生物信息学
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病理学
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DOI
PubMed
高影响因子
Bioactive Materials
·
2020
·
IF 8.724
Binbin Sun,Meifei Lian,Yu Han,Xiumei Mo,Wenbo Jiang,Zhiguang Qiao,Kerong Dai
Regeneration of Intervertebral disc (IVD) is a scientific challenge because of the complex structure and composition of tissue, as well as the difficulty in achieving bionic function. Here, an anatomically correct IVD scaffold composed of biomaterials, cells, and growth factors were fabricated via three-dimensional (3D) bioprinting technology. Connective tissue growth factor (CTGF) and transforming growth factor-β3 (TGF-β3) were loaded onto polydopamine nanoparticles, which were mixed with bone marrow mesenchymal stem cells (BMSCs) for regenerating and simulating the structure and function of the nucleus pulposus and annular fibrosus. In vitro experiments confirmed that CTGF and TGF-β3 could be released from the IVD scaffold in a spatially controlled manner, and induced the corresponding BMSCs to differentiate into nucleus pulposus like cells and annulus fibrosus like cells. Next, the fabricated IVD scaffold was implanted into the dorsum subcutaneous of nude mice. The reconstructed IVD exhibited a zone-specific matrix that displayed the corresponding histological and immunological phenotypes: primarily type II collagen and glycosaminoglycan in the core zone, and type I collagen in the surrounding zone. The testing results demonstrated that it exhibited good biomechanical function of the reconstructed IVD. The results presented herein reveal the clinical application potential of the dual growth factors-releasing IVD scaffold fabricated via 3D bioprinting. However, the evaluation in large mammal animal models needs to be further studied.
研究领域:
组织工程
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生物医学工程
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再生医学
·
骨科
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产品关联
DOI
PubMed
高影响因子
BIOLOGICAL TRACE ELEMENT RESEARCH
·
2019
·Vol. 193
·期 2
·422-433
·
IF 2.431
Hu Peilin,Du Jie,Zhang Shuai,Wang Ting,Li Jun,Chen Gang,Zhou Guangqian
Osteoarthritis (OA), a common degenerative disease affecting articular cartilage, is caused by multiple factors, and currently, there are few approaches to effectively delay its progression. This study aimed to evaluate whether a strontium compound (in the form of strontium gluconate, Glu-Sr) could reduce OA pathology severity in osteoarthritic rat models by directly targeting chondrocytes, including catabolic/anabolic activities and/or chondrogenic differentiation. Glu-Sr was administered to OA rats by oral gavage beginning during OA induction and continuing for 8 weeks. Glu-Sr treatment was found to significantly reduce cartilage degeneration and delay OA progression. Further examination showed that collagen II, Sox9, and aggrecan (ACAN) genes were up-regulated whereas IL-1β was down-regulated in chondrocytes isolated from Glu-Sr-treated rats. Glu-Sr also antagonized the catabolic effects of IL-1β on chondrocytes. Furthermore, Glu-Sr was shown to promote the chondrogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs), possibly through promoting chondrogenic gene expression, including CTGF and FGF1, as revealed by RNA-sequencing (RNA-seq). These results suggest that systemic administration of Glu-Sr may be useful in prophylactic and therapeutic treatment of chronic cartilage degradation through affecting multiple steps from chondrogenic differentiation of progenitors to matrix formation in mature chondrocytes.
研究领域:
风湿病学
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骨科
·
分子生物学
·
干细胞研究
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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）