SCIENCE OF THE TOTAL ENVIRONMENT
·
2023
·
IF 9.8
Yang Yang,Yue Tao,Xiaodong Yi,Guanyu Zhong,Yanyan Gu,Yunhe Cui,Ying Zhang
Typical plasticizer di (2-ethylhexyl) phthalate (DEHP) has been demonstrated to induce cardiotoxicity in zebrafish, but the potential molecular mechanisms involved have not been fully elucidated. Aryl hydrocarbon receptor (AhR), an essential protein for inducing developmental abnormalities, has been demonstrated to be activated by DEHP in other species, but whether the AhR signaling pathway also contributes to DEHP-mediated cardiac developmental toxicity in zebrafish remains unclear. Firstly, molecular docking simulations initially confirmed the possibility that DEHP has AhR agonistic activity. To further confirm this conjecture, this work analyzed the changes of cardiac-related indexes in zebrafish stressed by DEHP at individual, protein, and gene levels. The results showed that DEHP mediated cardiac phenotypic developmental defects, increased CYP1A1 activity, and oxidative stress as well as significant changes in the expression levels of key proteins and genes of AhR, Wnt/β-catenin, and Nrf2-Keap1 signaling pathways. Notably, the addition of AhR inhibitors effectively alleviated the above negative effects, indicating that the AhR signaling pathway and its crosstalk with the Wnt/β-catenin signaling pathway is an essential pathway for DEHP-mediated cardiac developmental toxicity. Overall, this work enriches the molecular mechanism of DEHP-mediated cardiac developmental defects in zebrafish and provides a reliable biomarker for future environmental risk assessment of DEHP.
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CELLULAR SIGNALLING
·
2024
·
IF 4.4
Zheng-Ming Cao,Su Fu,Chao Dong,Teng-Yue Yang,Xiao-Kang Liu,Chun-Lin Zhang,Dong-Zhe Li
The progression of osteoarthritis (OA) includes the initial inflammation, subsequent degradation of the extracellular matrix (ECM), and chondrocyte apoptosis. Down syndrome candidate region 1 (DSCR1) is a stress-responsive gene and expresses in varied types of cells, including chondrocytes. Bioinformatics analysis of GSE103416 and GSE104739 datasets showed higher DSCR1 expression in the inflamed cartilage tissues and chondrocytes of OA. DSCR1 had two major isoforms, isoform 1 (DSCR1–1) and isoform 4 (DSCR1–4). We found that DSCR1–1 had a faster ( in vitro ) and higher expression ( in vivo ) response to OA compared to DSCR1–4. IL-1β-induced apoptosis, inflammation, and ECM degradation in chondrocytes were attenuated by DSCR1–1 overexpression. DSCR1–1 triggered the phosphorylation of cAMP response element-binding 1 (CREB1) at 133 serine sites by decreasing calcineurin activity. Moreover, activated CREB1 moved into the cell nucleus and combined in the promoter regions of aldehyde dehydrogenase 2 (ALDH2), thus enhancing its gene transcription. ALDH2 could recover Wnt/β-catenin signaling transduction by enhancing phosphorylation of β-catenin at 33/37 serine sites and inhibiting the migration of β-catenin protein from the cellular matrix to the nucleus. In vivo , adenoviruses (1 × 10 8 PFU) overexpressing DSCR1–1 were injected into the articular cavity of C57BL/6 mice with medial meniscus surgery-induced OA, and it showed that DSCR1–1 overexpression ameliorated cartilage injury. Collectively, our study demonstrates that DSCR1–1 may be a potential therapeutic target of OA.
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高影响因子
MOLECULAR NUTRITION & FOOD RESEARCH
·
2024
·Vol. 68
·期 19
·2400098
·
IF 4.5
Xinqi Huang,Lu Xiu,Yumei An,Yuan Gong,Sunao Li,Xueshi Chen,Chao Liu,Jianghuiwen Lu,Haiyan Shan,Jie Chang,Mingyang Zhang
The objective of this study is to elucidate how Royal jelly (RJ) and 10-hydroxy-2-decanoic acid (10-HDA) prevents diabetic skin dysfunction by modulating the pyroptosis pathway. Type 2 diabetes models are induced by fat diet consumption and low dose of streptozotocin (STZ) in C57BL/6J mice and treated with RJ (100 mg kg –1 day –1 ) and 10-HDA, the major lipid component of royal jelly (100 mg kg −1 day −1 ) for 28 weeks. The results show that serum concentrations of glucose and triglyceride are significantly lower in the RJ group or 10-HDA than diabetes mellitus (DM) group. Compared to the control group, pyroptosis proteins, GSDMD, ASC, Caspase-1, and IL-1β are increased in the skin of the diabetic model, accompanied by the activation of the Wnt/β-catenin signal pathway. Further evaluations by RJ exhibit superior improvement of skin damage, repress activation of the Wnt/β-catenin pathway, and attenuate keratinocyte pyroptosis, but 10-HDA cannot completely suppress the activation of Wnt/β-catenin pathway and pyroptosis, which shows a relatively weak protective effect on skin damage which shows that RJ is a better effect on skin injury after DM.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 19
·11434
·
IF 6.208
Yanyi Xu,Junru Liu,Yonghui Tian,Zuo Wang,Zan Song,Kemin Li,Shengxiang Zhang,Haiyu Zhao
Cadmium (Cd) is a toxic heavy metal and worldwide environmental pollutant which seriously threatens human health and ecosystems. It is easy to be adsorbed and deposited in organisms, exerting adverse effects on various organs including the brain. In a very recent study, making full use of a zebrafish model in both high-throughput behavioral tracking and live neuroimaging, we explored the potential developmental neurotoxicity of Cd2+at environmentally relevant levels and identified multiple connections between Cd2+exposure and neurodevelopmental disorders as well as microglia-mediated neuroinflammation, whereas the underlying neurotoxic mechanisms remained unclear. The canonical Wnt/β-catenin signaling pathway plays crucial roles in many biological processes including neurodevelopment, cell survival, and cell cycle regulation, as well as microglial activation, thereby potentially presenting one of the key targets of Cd2+neurotoxicity. Therefore, in this follow-up study, we investigated the implication of the Wnt/β-catenin signaling pathway in Cd2+-induced developmental disorders and neuroinflammation and revealed that environmental Cd2+exposure significantly affected the expression of key factors in the zebrafish Wnt/β-catenin signaling pathway. In addition, pharmacological intervention of this pathway via TWS119, which can increase the protein level of β-catenin and act as a classical activator of the Wnt signaling pathway, could significantly repress the Cd2+-induced cell cycle arrest and apoptosis, thereby attenuating the inhibitory effects of Cd2+on the early development, behavior, and activity, as well as neurodevelopment of zebrafish larvae to a certain degree. Furthermore, activation and proliferation of microglia, as well as the altered expression profiles of genes associated with neuroimmune homeostasis triggered by Cd2+exposure could also be significantly alleviated by the activation of the Wnt/β-catenin signaling pathway. Thus, this study provided novel insights into the cellular and molecular mechanisms of Cd2+toxicity on the vertebrate central nervous system (CNS), which might be helpful in developing pharmacotherapies to mitigate the neurological disorders resulting from exposure to Cd2+and many other environmental heavy metals.Keywords:cadmium (Cd);zebrafish;neurotoxicity;neurobehavioral tests;in vivo two-photon neuroimaging;microglia;Wnt/β-catenin signaling pathway
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Food & Function
·
2022
·Vol. 13
·期 8
·4612-4623
·
IF 6.317
Xiang Ye,Wen Chen,Pengcheng Tu,Ruoyi Jia,Yangyang Liu,Qiong Tang,Chuan Chen,Caihong Yang,Xiaodong Zheng,Qiang Chu
Cyanidin-3-O-glucoside (C3G), an essential representative of anthocyanins, has been proved to possess a myriad of biological activities. However, the effects of C3G on glucose metabolism and its underlying molecular mechanisms remain elusive. The aim of the present study was to investigate the metabolic impact of C3G on db/db mice and to determine whether its consequent anti-diabetic effects were related to glucose transporter-1 (GLUT-1) by in vivo and in vitro studies. As a result, through diabetic db/db mice, C3G treatment was found to significantly reduce the fasting blood glucose level and increase glycogen synthesis, which were associated with upregulation of GLUT-1 expression in the liver of the mice. In addition, in liver cells of the HepG2 and L02 lines, we further discovered that C3G could effectively promote glucose consumption by regulating the Wnt/β-catenin-WISP1 signaling pathway. Nevertheless, such effects would be restricted when the expression of GLUT-1 was blocked by the inhibitor IWR-1. Meanwhile, molecular docking technology was applied to simulate the possible action sites of C3G at the molecular level, and the results indicated that C3G might bind to β-catenin. In conclusion, our study provided evidence of the antihyperglycemic effect of C3G in vivo and in vitro via regulating GLUT-1 expression and the related signaling pathways.
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BIOCHEMICAL PHARMACOLOGY
·
2017
·
IF 4.581
Yuan Liu,Shuai Hao,Beibei Yang,Yi Fan,Xiaodong Qin,Yun Chen,Jun Hu
Parkinson’s disease (PD) is a neurodegenerative disorder with an incidence second only to Alzheimer’s disease. The main pathological feature of PD is the death of dopaminergic neurons in the substantia nigra pars compacta. Nicotinic receptor agonists are neuroprotective in several PD models and there is considerable evidence that α7 nicotinic acetylcholine receptors (α7-nAChRs) are important therapeutic targets for neurodegenerative diseases . However, the involvement of α7-nAChRs and underlying signaling mechanisms in PD pathogenesis are unclear. The objective of the present study was to explore the potential functions of α7-nAChRs in PD pathology, and to determine whether these effects are exerted via Wnt/β-catenin signaling in a mouse PD model. In the in vivo study, α7-nAChR knockout (α7-KO) reversed the beneficial effects of nicotine on motor deficits, dopaminergic neuron loss, astrocyte and microglia activation, and reduced striatal dopamine release induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Injury to SH-SY5Y cells by 1-methyl-4-phenylpyridinium treatment was also ameliorated by nicotine, and this effect was abolished by methyllycaconitine (MLA), a selective α7-nAChR antagonist, or by siRNA-mediated α7-nAChR knockdown. Furthermore, nicotine increased expression levels of Wnt/β-catenin signaling proteins in the PD mouse model or in the SH-SY5Y cells treated by 1-methyl-4-phenylpyridinium, and these effects were also reversed by MLA or α7-siRNA treatment in vivo or in vitro . These results suggest that endogenous α7-nAChR mechanisms play a crucial role in a mouse PD model via regulation of Wnt/β-catenin signaling.
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高影响因子
Foods
·
2026
·Vol. 15
·期 8
·1349
·
IF 6
Xingyuan Peng,Xuan Zheng,Xiyu Li,Xiaona Pang,Junhua Jin,Hui Liu,Hongxing Zhang,Yuanhong Xie
Osteoporosis is a major global health challenge, particularly among aging populations, underscoring the need for safe and effective nutritional interventions. Probiotics and their metabolites have emerged as promising candidates for modulating bone health via the gut-bone axis. In this study, we investigated the effects of a cell-free culture supernatant (CFS) from the food-grade bacteriumLimosilactobacillus fermentumGBE18 on the proliferation, differentiation, and mineralization of MC3T3-E1 pre-osteoblasts. GBE18 CFS exhibited no cytotoxicity at concentrations ranging from 1% to 4% (v/v). Notably, 2% (v/v) CFS significantly enhanced alkaline phosphatase (ALP) activity and extracellular matrix mineralization (p< 0.05). Transcriptomic profiling revealed that differentially expressed genes were enriched in osteoblast-related processes and two key signaling pathways: Wnt/β-catenin and PI3K/Akt. Subsequent qRT-PCR and Western blot analyses confirmed the upregulation of critical regulators (Rspo2,Pdpk1,Malat1) and demonstrated coordinated activation of Akt phosphorylation, β-catenin stabilization, and Runx2 protein expression. Our findings indicate that GBE18 CFS promotes osteogenic differentiation through coordinated modulation of the PI3K/Akt and Wnt/β-catenin pathways. Consequently, this study provides mechanistic evidence supporting the potential application ofL. fermentumGBE18-derived metabolites as functional food ingredients or dietary interventions for bone health and osteoporosis management.
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JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Yonglei Zhang,Fucheng Yin,Zhongwen Luo,Yiwei Zheng,Shunxin Guo,Sijie Wu,Yuhan Jiang,Long Zheng,Liangliang Ma,Meiting Zou,Xiaobing Wang,Lingyi Kong
Poly(ADP-ribose) polymerase (PARP) inhibitors have been approved and marketed for the treatment of BRCA-mutated breast and ovarian cancers. Recent studies have demonstrated that cyclin-dependent kinase 4/6 (CDK4/6) inhibitors can induce defects in homologous recombination (HR) repair, thereby sensitizing breast cancer cells with HR proficiency to PARP inhibitors through a synthetic lethal mechanism. Here, we report the rational design and synthesis of a potent dual PARP/CDK6 inhibitor 11, which was identified through SAR studies. Compound 11 effectively induces excessive DNA damage and apoptosis in MDA-MB-231 cells, while maintaining robust inhibitory activity against both PARP and CDK6. Additionally, 11 demonstrates excellent antitumor efficacy and antimetastatic properties, with no evident toxicity or side effects observed. Further investigations revealed that 11 could inhibit tumor cell proliferation by modulating the Wnt/β-catenin signaling pathway. In summary, these findings highlight the potential therapeutic advantages of 11, coded with KWZY-11, in treating BRCA wild-type tumors.
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Cancer Management and Research
·
2025
·
IF 2.6
Mengzhu Chen,Jian Li,Shaodan Hu,Yuhan Wang,Keju Wang,Tan Wang
Background Lung cancer has high incidence and mortality rates. In consideration of the high toxicity and side effects of traditional chemical drugs and drug resistance, researchers have substituted some natural products for anti-lung cancer drugs. Ziziphi spinosae semen (ZSS) is a famous traditional Chinese herb, and ZSS-based formulas have been used against lung cancer in clinic, such as Xiaoyi Sanjie Formula. Jujuboside B (JUB) is one of the main bioactive components in ZSS; however, JUB’s roles in the treatment of lung cancer, and the mechanism have not been well reported.Objective This study intends to evaluate the effects of JUB on the proliferation and migration of non-small cell lung cancer H1299 cells (NC-1299 cells), as well as the potential related regulatory mechanism.Methods The viability, migration and invasive ability of NC-1299 cells were analyzed by CCK8, wound-healing, transwell invasion, and the expression of proteins was analyzed through Western blotting experiments.Results It showed that 160 and 320 μmol/L JUB significantly inhibited the proliferation of NC-1299 cells, reduced the cell migration in the wound healing test, and decreased the cell number of clonal assay (P < 0.05). JUB also significantly inhibited the expression of Vimentin, MMP2, and MMP9 proteins related to the migration and invasion of tumor cells, as well as inhibited the PI3K/AKT and Wnt/β-catenin pathways.Conclusion The results indicate JUB has a significant inhibitory effect on NC-1299 cells, and such inhibitory effect is associated with inhibiting the expression of migration and invasive proteins such as MMP2, as well as inhibiting the PI3K/AKT and Wnt/β-catenin pathways. The findings provide some references for the application of JUB in the substitution of anti-lung cancer drugs.
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Human Cell
·
2023
·Vol. 36
·期 3
·972-986
·
IF 4.3
Liu Naiquan,Liu Dajun,Cao Shiyu,Lei Jing
Renal fibrosis is the common final pathway in many renal diseases regardless of the underlying etiology. Adipocyte enhancer-binding protein 1 (AEBP1) was reported to play a vital role in the development of organ fibrosis, but its role in renal fibrosis has not been reported. Thus, the aim of this study was to investigate the possible function of AEBP1 in renal fibrosis and the mechanism associated with the β-catenin signaling pathway. A total of 83 genes upregulated after unilateral ureteral obstruction (UUO) were screened from two Gene Expression Omnibus (GEO) datasets and subjected to Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Among them, AEBP1 was enriched in collagen binding and the regulation of collagen fibril organization and was confirmed to be upregulated in UUO kidneys and TGF-β1-induced cells. Knockdown of AEBP1 ameliorated renal fibrosis via reducing collagen accumulation, inhibiting epithelial–mesenchymal transition and fibroblast transformation, as evidenced by decreases in the expression of collagen I and III, Col1a1, Col3a1, fibronectin, Snail, α-SMA, as well as collagen-specific staining of kidney tissues, whereas the E-cadherin was increased. Besides, AEBP1 silencing inhibited the expression of β-catenin in nucleus and β-catenin downstream proteins (Axin2, Myc, and Ccnd1). Continuously active β-catenin–S33Y further restored the inhibitory effect of AEBP1 silencing on renal fibrosis. These findings indicate that knockdown of AEBP1 could potentially slow down renal fibrosis by blocking the β-catenin signaling pathway, highlighting the potential of AEBP1 as a therapeutic target for renal fibrosis.
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Cancer Medicine
·
2023
·
IF 4
Jun Ma,Di Zhao,Dahai Yu,Wei Song,Xiaofang Yang,Haitao Yin
Background Ginsenoside Rh2 (G-Rh2) exerts anti-tumor activity in non-small cell lung cancer (NSCLC). microRNAs (miRNAs, miRs) play pivotal roles in NSCLC. We aimed to investigate whether G-Rh2 inhibited NSCLC progression by targeting miRNA. Methods Cell viability, apoptosis and cycle were determined by Cell Counting Kit-8, 6-diamidino-2-phenylindole (DAPI) staining and flow cytometry. The potential target miRNAs of G-Rh2 were screened by real-time quantitative polymerase chain reaction (RT-qPCR). The difference in miR-28-5p expression between lung adenocarcinoma (LUAD) tissues and normal tissues or lung squamous cell carcinoma (LUSC) tissues and normal tissues was retrieved from TCGA-LUAD and TCGA-LUSC, respectively. Kaplan–Meier Plotter was conducted to analyze the survival rate for different serine/threonine-protein kinase 4 (STK4) expressions with different prognostic risks. immunohistochemistry of STK4 expression in non-tumor and tumor tissues was analyzed from the HPA database. RT-qPCR and Western blot were adopted for detecting mRNA and protein expression. TargetScan V7.2, miRanda and PITA were adopted for predicting targets of miR-28-5p, overlapped genes were subjected to GO analysis. The interactions of miR-28-5p-Wnt and miR-28-5p-STK4 were detected by TOP/FOP luciferase reporter assay and dual luciferase reporter assay, respectively. Results Current study observed that G-Rh2 reduced miR-28-5p expression in NSCLC cells dose-dependently. miR-28-5p was upregulated in NSCLC tissues and cells. The target genes of miR-28-5p were enriched in negative regulation of Wnt signaling. miR-28-5p inhibitor inactivated Wnt signaling, inhibited cell viability and cell cycle, while enhanced cell apoptosis of NSCLC cells by targeting STK4. G-Rh2 exerted the similar effects with miR-28-5p inhibitor by reducing miR-28-5p. G-Rh2 and miR-28-5p inhibitor exerted a synergistic effect on inhibiting NSCLC tumor growth. Conclusion In conclusion, G-Rh2 attenuates NSCLC development by affecting miR-28-5p/STK4 axis and inactivating Wnt signaling. Taken together, we project out a novel therapeutic target for NSCLC.
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BIOCHEMICAL PHARMACOLOGY
·
2023
·
IF 5.8
Xuepeng Wang,Chunchun Zou,Changju Hou,Zhenyu Bian,Wu Jiang,Maoqiang Li,Liulong Zhu
Mesenchymal stem cells (MSCs) and their derived extracellular vesicles (EVs) have emerged as promising tools for promoting bone regeneration. This study investigates the functions of EVs derived from bone marrow-derived MSCs (BMSCs) in osteoporosis (OP) and the molecular mechanism. EVs were isolated from primary BMSCs in mice. A mouse model with OP was induced by ovariectomy. Treatment with EVs restored bone mass and strength, attenuated trabecular bone loss and cartilage damage, and increased osteogenesis while suppressing osteoclastogenesis in ovariectomized mice. In vitro , the EVs treatment improved the osteogenic differentiation of MC-3T3 while inhibiting osteoclastic differentiation of RAW264.7 cells. Microarray analysis revealed a significant upregulation of ubiquitin specific peptidase 7 (USP7) expression in mouse bone tissues following EV treatment. USP7 was found to interact with Yes1 associated transcriptional regulator (YAP1) and stabilize YAP1 protein through deubiquitination modification. YAP1-related genes were enriched in the Wnt/β-catenin signaling, and overexpression of YAP1 promoted the nuclear translocation of β-catenin. Functional experiments underscored the critical role of maintaining USP7, YAP1, and β-catenin levels in the pro-osteogenic and anti-osteoclastogenic properties of the BMSC-EVs. In conclusion, this study demonstrates that USP7, delivered by BMSC-derived EVs, stabilizes YAP1 protein, thereby ameliorating bone formation in OP through the Wnt/β-catenin activation.
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危险品化学品经营许可证（带存储）