Molecular Medicine Reports
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2020
·Vol. 22
·期 5
·3687-3694
·
IF 2.1
Yingli Ren,Xiangdong Jian,Zhongchen Zhang,Qiong Ning,Baotian Kan,Li Kong
Paraquat is a highly toxic pesticide, which often causes pulmonary interstitial fibrosis after poisoning, and there is no specific antidote. At present, limited studies have reported that tacrolimus, as an immunosuppressant, can inhibit pulmonary fibrosis, but the specific mechanism remains unknown. The aim of the present study was to demonstrate the effect of tacrolimus on the TGF‑β1 pathway associated with pulmonary fibrosis in paraquat exposed alveolar type II epithelial cells, and to identify the antipulmonary fibrosis mechanism of tacrolimus The rat alveolar epithelial type II RLE‑6TN cell line was exposed to paraquat and treated with or without tacrolimus for 24 h, or with a TGF‑β1 receptor type I/II inhibitor (LY2109761) for 1, 4, 8 or 16 h. MTT assays were used to detect the viability of rat alveolar type II epithelial cells under these different treatment conditions, while the concentrations of TGF‑β1, SMAD3, SMAD7 and connective tissue growth factor (CTGF) in the cell culture supernatant were determined using ELISAs. Additionally, reverse transcription‑quantitative PCR and immunofluorescence were used to analyze the mRNA and protein expression levels of TGF‑β1, SMAD3, CTGF and SMAD7. The results demonstrated that the inhibition of the proliferation of RLE‑6TN cells exposed to 200 nmol/l paraquat was 26.05±2.99%. The inhibition rate of 10 ng/ml tacrolimus on paraquat‑exposed alveolar type II epithelial cells was 18.40±3.49%. The inhibition rate caused by 5 µmol/l LY2109761 was 26.56±4.49%. The expression levels of TGF‑β1, SMAD3 and CTGF, as well as their concentrations in the culture supernatant, were significantly downregulated in the tacrolimus group compared with the paraquat group. However, both the concentration and expression levels of SMAD7 were significantly upregulated in the tacrolimus group compared with the paraquat group. In conclusion, tacrolimus can reduce the levels of TGF‑β1, SMAD3 and CTGF, increase the level of SMAD7 in TGF‑β1 signaling pathway and protect the development of pulmonary fibrosis in paraquat exposed alveolar epithelial cells.
研究领域:
药理学
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肺病学
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细胞生物学
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毒理学
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2025
·
IF 3.1
Liju Yu,Jie Gao,Tingting Deng,Chang Gao,Jiaxing Wang,Nan Wang
Heart failure is a global epidemic characterized by high mortality and morbidity rates. β1-Adrenoceptors (ADRβ1) antagonists are the main drugs used in the treatment of HF. A simple and convenient method for screening ADRβ1 antagonists is necessary. Nebivolol has four chiral centers, and its byproducts, which are not easy to avoid, may interact with ADRβ1. Cell membrane chromatography based on SNAP-tag technology provides a comprehensive solution. In this study, an ADRβ1 target cell membrane chromatography model based on SNAP-tag technology was established, and the selectivity, specificity, repeatability, and column life of the system were validated. Under optimized conditions, this model was used to screen for active components targeting ADRβ1 in nebivolol and its byproducts. The bioactivity of nebivolol and its byproducts was detected by calcium influx. The results showed that the ADRβ1 SNAP-tag/CMC model was successfully established and could be used to screen active drugs targeting ADRβ1. Among nebivolol and its byproducts, D-nebivolol (SRRR-enantiomer) had the best affinity for ADRβ1. Three byproducts of nebivolol also exhibited retention characteristics on ADRβ1. In vitro calcium influx experiments verified the interaction of these components with ADRβ1, showing good inhibitory effects on ADRβ1. In conclusion, the ADRβ1 SNAP-tag/CMC model developed in this study can be used for the comprehensive screening of active components targeting ADRβ1 in complex samples.
研究领域:
药理学
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药物筛选
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2025
·
IF 6.3
Li Li,Wenqian Cai,Hao Zhang,Jiuren Tang,Yongjie Yang,Yang Huang,Qing Xi,Rongxin Zhang
Renal fibrosis is the most common pathway for the development of end-stage renal disease (ESRD) in various kidney diseases. Currently, the treatment options for renal fibrosis are limited. Ferroptosis is iron-mediated lipid peroxidation, triggered mainly by iron deposition and ROS generation. Notably, the kidney is the most sensitive of all tissues to iron-dependent ferroptosis, and the inhibition of ferroptosis is an effective therapeutic strategy for the treatment of kidney fibrosis. Nonetheless, the pathways involved in ferroptosis in renal fibrosis are still unclear. Bergapten, a natural coumarin derivative, is mainly found in bergapten essential oil, grapefruit juice, and other commonly used plants, and it has various pharmacological effects. However, the role that ferroptosis plays in renal fibrosis and the potential therapeutic benefits of bergapten remain unclear. In this study, we investigated the therapeutic effects of bergapten on renal fibrosis and its mechanisms. We investigated the anti-fibrotic effects of bergapten in in vivo and in vitro models of renal fibrosis. Initially, network pharmacological analysis was employed to predict the potential therapeutic impact of bergapten on renal fibrosis. We then explored the potential therapeutic role of bergapten in obstructive nephropathy, which is due to unilateral ureteral obstruction (UUO). Furthermore, RNA-Seq was conducted to investigate the possible mechanism of bergapten against renal fibrosis. Additionally, Bergapten demonstrated a significant improvement in TGF-β1-induced fibrosis and RSL3-induced renal tubular epithelial cell ferroptosis; these findings are consistent with those of the in vivo studies. Our findings indicate that bergapten is a potential treatment for renal fibrosis. Treatment with bergapten significantly reduced the expression of fibronectin and α-SMA in the damaged kidneys of UUO mice, thereby improving fibrosis. Meanwhile, bergapten protected against fibrosis caused by TGF-β1 and ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibitor RSL3. Significantly, bergapten therapy alleviated renal fibrosis by modulating ferroptosis. We found that bergapten inhibited PI3K phosphorylation and indirectly restored GPX4 expression. In conclusion, we have revealed the nephroprotective effect of bergapten, whose mechanism of action is related to the inhibition of ferroptosis, and it is expected that it will be developed as a therapeutic agent for the treatment of renal fibrosis. This study aims to explore the effect of bergapten on renal fibrosis ferroptosis. Collectively, these results demonstrate that bergapten is an inhibitor of ferroptosis and provides a new treatment strategy for diseases associated with ferroptosis.
研究领域:
肾病学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR DIVERSITY
·
2024
·
IF 3.9
Ding Shu-Yan,Yang Yu-Xuan,Liu Chuang,Quan Xu-Yin,Zhao Zi-Han,Jin Cheng-Hua
Four series of sulfonamide derivatives ( 13a – b , 14a – d , 15a – b , and 16a – d ) were synthesized and evaluated for their activin receptor-like kinase 5 (ALK5) inhibitory activities. Of these, compounds 13b (IC 50 = 0.130 μM) and 15a (IC 50 = 0.130 μM) showed the highest inhibitory activities against ALK5 kinase, with activities similar to the positive control LY - 2157299 . Notably, we discovered that introduction of sulfonamide group at the 2-position of the central imidazole ring significantly increased ALK5 inhibitory activity. Compounds 13b and 15a did not show toxicity in A549 cells up to the maximum concentration of 50 μM, and effectively inhibited TGF-β1-induced Smad-signaling and cell motility in A549 cells. The results indicate that compounds 13b and 15a are worth of further development as anticancer agents.
研究领域:
药物化学
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分子生物学
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肿瘤学
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DOI
PubMed
高影响因子
Cancers
·
2022
·Vol. 14
·期 5
·1333
·
IF 6.575
Jichen Sha,Rongrong Zhang,Jiteng Fan,Yong Gu,Yiqing Pan,Jing Han,Xiaoyan Xu,Shifang Ren,Jianxin Gu
Simple SummaryAs serum IgG glycosylation is associated with various cancers, our goal is to explore whether serum IgG galactosylation and its associated glycans could be used as tumor markers associated with hepatocellular carcinoma (HCC). At the same time, we explore the effect of the B-cell-specific ablation of B4GALT1 on HCC and finally analyze whether the low incidence of female cancer was related to the findings from the above perspective. The results demonstrate that the tumor marker of serum IgG glycosylation is galactosylation and its associated glycans and that the B-cell-specific ablation of B4GALT1 reduces HCC formation by reducing serum IgG galactosylation levels and by modulating the associated glycans, meaning that the lower incidence of cancer in women may be related to minor changes in the B-cell B4GALT1 and unchanged serum IgG galactosylation levels. This study aims to provide a theoretical basis for the early diagnosis and prevention of HCC and to determine why it has such a high incidence in males.AbstractSerum immunoglobulin G (IgG) glycosylation, especially galactosylation, has been found to be related to a variety of tumors, including hepatocellular carcinoma (HCC). However, whether IgG glycan changes occur in the early stages of HCC formation remains unclear. We found that the galactosylation level increased and that the related individual glycans showed regular changes over the course of HCC induction. Then, the effect of the B-cell-specific ablation of β1,4galactosyltransferase 1 (CKO B4GALT1) and B4GALT1 defects on the IgG glycans that were modified during the model induction process and HCC formation is investigated in this study. CKO B4GALT1 reduces serum IgG galactosylation levels and reduces cancer formation. Furthermore, insignificant changes in the B-cell B4GALT1 and unchanged serum IgG galactosylation levels were found during cancer induction in female mice, which might contribute to the lower cancer incidence in female mice than in male mice. The gender differences observed during glycan and B4GALT1 modification also add more evidence that the B4GALT1 in B cells and in serum IgG galactosylation may play an important role in HCC. Therefore, the findings of the present research can be used to determine the methods for the early detection of HCC as well as for prevention.Keywords:hepatocellular carcinoma;immunoglobulin G;glycan;β1,4-galactosyltransferase 1;mouse
研究领域:
医学
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分子生物学
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DOI
PubMed
高影响因子
EXPERIMENTAL EYE RESEARCH
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2023
·
IF 3.4
Duo Li,Ting-Ting Wei,Jiping Cai,Tian-Hua Xie,Yong Yao,Lingpeng Zhu
Smad ubiquitylation regulatory factor-1 (Smurf1) is one of C2-WW-HECT domain E3 ubiquitin ligases , it can regulate BMP pathway by mediating ubiquitylation degradation of Smad1/Smad5. Many functions about Smurf1 also are still unknown, especially in retina . This research is about to explore the role of Smurf1 in retina degeneration . Tail vein injection of sodium iodate (NaIO 3 ) in C57BL/6J mice was the animal model of retina degeneration. In NaIO 3 model, Smurf1 had more expression than normal mice. Specific Smurf1 inhibitor, A01, was injected into vitreous cavity. Results showed that inhibiting Smurf1 could alleviate acute retina injury, such as keeping a better retina structure in living imaging and histologic sections, less cell death and inflammation activation. Tert-butyl hydroperoxide (TBH) was used to establish oxidative stress injury in human retinal pigments epithelial cell line (ARPE-19). Oxidative stress injury gradually caused co-upregulation of Smurf1, TGF-β1 and phosphorylated NF-κB (pNF-κB). TGF-β1 could directly induce Smurf1 expression. Inhibiting Smurf1 had an anti-epithelial mesenchymal transition (anti-EMT) function. Similarly, A01 also could inhibit the expression of pNF-κB, NLRP3 and IL-1β. At last, after searching bioinformatics database, Smurf1 had a possible interaction with beta-transducin repeat containing E3 ubiquitin protein ligase (β-TrCP), another E3 ubiquitin ligases. β-TrCP can mediate ubiquitination degradation of p-IκBα. Lentivirus- SMURF1 was used to overexpress Smurf1, and GS143 was used to inhibit β-TrCP. The results showed Smurf1 could directly induce NF-κB, pNF-κB, and NLRP3 expression, and keep a stable β-TrCP expression. However, inhibiting β-TrCP could cause more NF-κB activation and NLRP3 expression. Therefore, β-TrCP may play a negative role in NF-κB pathway activation. In summary, Smurf1 plays a role in exacerbating oxidative stress injury and inflammation in retina and may become a potential therapeutic target in ROS injury of retina.
研究领域:
眼科学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Nutrients
·
2019
·Vol. 11
·期 2
·483
·
IF 4.171
Zhonghua Dong,Yueyue Sun,Guangwei Wei,Siying Li,Zhongxi Zhao
(1) Background: Diabetic nephropathy, a microvascular complication of diabetes, is one of the principal causes of end-stage renal disease worldwide. The aim of this study was to explore the therapeutic effects of ergosterol on diabetic nephropathy. (2) Methods: Streptozotocin (STZ)-induced C57BL/6 diabetic mice were treated with ergosterol (10, 20, 40 mg/kg/day) for 8 weeks by oral gavage. The in vitro study employed rat mesangial cells exposed to 30 mM glucose for 48 h in the presence of 10 or 20 μM ergosterol. (3) Results: Ergosterol treatment improved body weights, ameliorated the majority of biochemical and renal functional parameters and histopathological changes, and reduced extracellular matrix (ECM) deposition in diabetic mice. In vitro, ergosterol suppressed proliferation, reduced the levels of ECM proteins, and increased the expression of matrix metalloproteinase-2 and -9 in high glucose-induced mesangial cells; Furthermore, ergosterol markedly improved transforming growth factor-β1 (TGF-β1) expression, enhanced phosphorylation levels of drosophila mothers against decapentaplegic 2 (Smad2), and regulated the downstream factors in vivo and in vitro. (4) Conclusions: Ergosterol alleviated mesangial cell proliferation and the subsequent ECM deposition by regulating the TGF-β1/Smad2 signaling pathway.Keywords:ergosterol;diabetic nephropathy;mesangial cells;ECM;TGF-β1
研究领域:
药理学
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肾病学
·
糖尿病
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DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2019
·Vol. 458
·期 1
·71-78
·
IF 2.884
Ba Fang,Zhou Yuxin,Zhou Jie,Chen Xueyun
Repetitive transcranial magnetic stimulation (rTMS) is a technique protecting neurons against diverse neurodegenerative disorders by delivering magnetic stimuli into the brain through the intact scalp. In the current study, the protection effect of rTMS on Parkinson’s disease (PD) and the associated mechanism driving the treatment were explored. The PD symptoms were induced using 6-OHDA in mice, and the effect of rTMS of two frequencies (1 Hz and 10 Hz) on the cognitive behaviors and neuron viability was detected. Afterwards, the level of Aβ 1–42 and activity of MKK7-ERK-Fos-APP axis under the administration of rTMS were recorded as well. The intracranial injection of 6-OHDA impaired the cognitive behaviors of the mice in the test of Morris water maze as well as reducing the viability and number of neurons in PD mice. After the treatment of rTMS of both frequencies, the cognitive function of mice was improved and the neuron viability and number were restored in mice brain tissues. The administration of rTMS also increased the cerebrospinal fluid (CSF) level of Aβ 1–42 in PD mice, which was accompanied by the suppressed levels of p-MKK7, p-ERK1/2, p–c-Fos, and APP. Moreover, the effect of rTMS on mice nerve system was all exerted in a frequency-dependent manner. In conclusion, the findings outlined in the current study affirmed the protection effect of rTMS against PD. The anti-PD function of rTMS was associated with the suppression of MKK7-ERK-Fos-APP axis, which subsequently resulted in the increased CSF Aβ 1–42 level and decreased brain Aβ 1–42 level.
研究领域:
神经科学
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药理学
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神经退行性疾病
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产品关联
DOI
PubMed
高影响因子
OncoTargets and Therapy
·
2019
·
IF 3.046
Ling-Hui Zeng,Qing-Mei Wang,Lin-Yi Feng,Yu-Dun Ke,Qian-Zi Xu,An-Yi Wei,Chong Zhang,Rong-Biao Ying
Purpose Vitamin C (VC) is a kind of essential nutrient in the body regarded as a canonical antioxidant during the past hundred years. However, the anti-cancer effect of VC is controversial. Our study is trying to clarify the relationship between VC dosage and breast cancer metastasis. Methods Human breast cancer cell lines Bcap37 and MDA-MB-453 were treated with VC at three different concentrations (low-dose, 0.01 mM; medium-dose, 0.1 mM; high-dose, 2 mM). Wound healing assays were conducted for migration assay; transwell tests were performed to detect the ability of cell invasion. The protein levels were evaluated by Western blot analysis or immunohistochemistry. Tumor xenografts in nude mice were built to test the effects of VC on breast cancer cell proliferation and metastasis. Results 0.01 and 0.1 mM VC promoted cell migration and invasion when compared with the control group, but 2 mM VC significantly suppressed cell migration and invasion of breast cancer cell lines. High-dose VC increased E-cadherin and reduced Vimentin, indicating that high-dose VC suppressed epithelial-mesenchymal transition (EMT) in breast cancer cells. Besides, high-dose VC inhibited cell invasion promoted by TGF-β1 in breast cancer cells. Meanwhile, high-dose VC reversed the suppression of E-cadherin and enhancement of Vimentin induced by TGF-β1 in breast cancer cells. Furthermore, high-dose VC significantly inhibited breast cancer metastasis in vivo. Conclusion High-dose VC inhibits cell migration and invasion of breast cancer cell lines through suppressing EMT. Thus, it may be considered as an anticancer drug candidate for breast cancer patients.
研究领域:
肿瘤学
·
细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Yongrui Huang,Jia Liu,Xiaomin Sun,Yuehai Peng,Yingni Xu,Sa Liu,Wenjing Song,Li Ren
Corneal scarring caused by epithelial-stromal injury impairs corneal transparency and visual acuity. Excess secretion of transforming growth factor-beta 1 (TGF-β1), which promotes wound closure, penetrates the corneal stroma via defects in the epithelial basement membrane and induces the differentiation of corneal fibroblasts to myofibroblasts, leading to scar formation. Modulating TGF-β1 penetration might alleviate corneal scar formation and restore transparency. In this study, sulfated hyaluronan (sHA) coatings were self-assembled above wounded corneal stroma to modulate TGF-β1 penetration, and their ability to alleviate corneal scarring was investigated. The formation of sHA coatings was rapid (within 30 s), and the high-sulfated hyaluronan coating efficiently blocked penetration by TGF-β1 and reduced the concentration of TGF-β1 in the corneal stroma. Further investigation showed that the ability of TGF-β1 to induce differentiation of corneal fibroblasts into myofibroblasts was inhibited by sHA binding. Evaluation of corneal scarring with sHA coating in a rabbit model of lamellar resection indicated that a sHA (high sulfation) coating effectively reduced scar formation. Immunohistochemical staining of α-smooth muscle actin and optical coherence tomography of the anterior segment showed minimal scar tissue formation in the sHA group. This work presents a promising alternative to alleviate scarring in corneal epithelial-stromal injury.
研究领域:
眼科学
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生物材料
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伤口愈合
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组织工程
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产品关联
DOI
PubMed
高影响因子
BIOMACROMOLECULES
·
2025
·
IF 5.4
Ruiying Zhang,Hanfeng Li,Tong Zhang,Bing Zhang,Yihu Wang,Yanchuan Guo
Addressing the underappreciated critical role of angiogenesis and immune dysregulation in keloid formation, we developed a novel nanocarrier (PCS) based on a dual network of physical cross-linking for the efficient release of siTGF-β1 and chlorogenic acid. PCS was self-assembled from polyethylenimine/siTGF-β1 and chlorogenic acid-embedded polylysine/sodium alginate. The results demonstrated that PCS could inhibit the proliferation, induce apoptosis of human umbilical vein endothelial cells and human keloid fibroblasts by regulating their cell cycle, and improve the immune microenvironment at the lesion. By transcriptomics and network pharmacology analysis, PCS inhibited keloid development mainly through the TGF-β1/EGR1 signaling pathway. The final results of animal experiments also proved that the material exerted a favorable effect in keloid treatment. Overall, PCS, as a novel nanocarrier combining siRNA-based gene therapy with chlorogenic acid, was a promising approach for the treatment of keloids.
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产品关联
DOI
PubMed
高影响因子
Nature Chemical Biology
·
2024
·
IF 12.9
Gan Lu,Jiang Qiwei,Huang Dong,Wu Xueji,Zhu Xinying,Wang Lei,Xie Wei,Huang Jialuo,Fan Runzhu,Jing Yihang,Tang Guihua,Li Xiang David,Guo Jianping,Yin Sheng
Liver fibrosis is an urgent clinical problem without effective therapies. Here we conducted a high-content screening on a natural Euphorbiaceae diterpenoid library to identify a potent anti-liver fibrosis lead, 12-deoxyphorbol 13-palmitate (DP). Leveraging a photo-affinity labeling approach, apolipoprotein L2 (APOL2), an endoplasmic reticulum (ER)-rich protein, was identified as the direct target of DP. Mechanistically, APOL2 is induced in activated hepatic stellate cells upon transforming growth factor-β1 (TGF-β1) stimulation, which then binds to sarcoplasmic/ER calcium ATPase 2 (SERCA2) to trigger ER stress and elevate its downstream protein kinase R-like ER kinase (PERK)–hairy and enhancer of split 1 (HES1) axis, ultimately promoting liver fibrosis. As a result, targeting APOL2 by DP or ablation of APOL2 significantly impairs APOL2–SERCA2–PERK–HES1 signaling and mitigates fibrosis progression. Our findings not only define APOL2 as a novel therapeutic target for liver fibrosis but also highlight DP as a promising lead for treatment of this symptom.
研究领域:
药理学
·
分子生物学
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）