ACTA BIOCHIMICA POLONICA
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2021
·Vol. 68
·期 4
·765-774
·
IF 2.149
Shaoyi Li,Yong Li,Bibo Tan,Zhaojie An
Krüppel-like factor 1 (KLF1) is a transcription factor that exhibits promoting effect in cervical cancer, but its correlation with gastric cancer (GC) has not been reported yet. In this study, we explored the role and potential mechanism of KLF1 in GC progression by using a series of experimental methods including RT-qPCR, Western blot, CCK-8 assay, EdU staining, and cell cycle analysis. KLF1 was found to be elevated in GC tissues (n=415) compared with the normal tissues by applying UALCAN to analyze datasets from The Cancer Genome Atlas (TCGA). The upregulation of KLF1 was also validated in GC cell lines. Functional studies proved that RNA interference-mediated silencing of KLF1 inhibited GC cell growth, as evidenced by the decreased cell viability, DNA synthesis, and arrested cell cycle in G1 phase. Moreover, KLF1 knockdown exerted the inhibitory effects on cell migration and invasion as well as the epithelial-mesenchymal transition (EMT) in GC cells. Conversely, overexpression of KLF1 had the opposite effects on GC progression. Furthermore, we proved that the activation of Wnt/β-catenin pathway was markedly inhibited by KLF1 knockdown and promoted by KLF1 overexpression. The blockade of Wnt/β-catenin pathway rescued the effects of KLF1 overexpression. These results suggested that KLF1 promoted the growth, migration, invasion, and EMT process in GC cells, and this promotion was achieved by activating the Wnt/β-catenin pathway. This work will be helpful for searching the potential therapeutic targets for treatment of GC.
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PHYTOMEDICINE
·
2021
·
IF 5.34
Yongmei Li,Zean Zhao,Jian Luo,Yanqing Jiang,Lu Li,Yanyu Chen,Leqi Zhang,Qinghua Huang,Ying Cao,Pingzheng Zhou,Ting Wu,Jianxin Pang
Background Hyperuricemia (HUA) is characterized by abnormal serum uric acid (UA) levels and demonstrated to be involved in renal injury leading to hyperuricemic nephropathy (HN). Apigenin (API), a flavonoid naturally present in tea, berries, fruits, and vegetables, exhibits various biological functions, such as antioxidant and anti-inflammatory activity. Purpose To investigate the effect of API treatment in HN and to reveal its underlying mechanisms. Methods The mice with HN were induced by potassium oxonate intraperitoneally and orally administered for two weeks. The effects of API on renal function, inflammation, fibrosis, and uric acid (UA) metabolism in mice with HN were evaluated. The effects of API on urate transporters were further examined in vitro . Results The mice with HN exhibited abnormal renal urate excretion and renal dysfunction accompanied by increased renal inflammation and fibrosis. In contrast, API reduced the levels of serum UA, serum creatinine (CRE), blood urea nitrogen (BUN) and renal inflammatory factors in mice with HN. Besides, API ameliorated the renal fibrosis via Wnt/β-catenin pathway suppression. Furthermore, API potently promoted urinary UA excretion and inhibited renal urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in mice with HN. In vitro , API competitively inhibited URAT1 and GLUT9 in a dose-dependent manner, with IC 50 values of 0.64 ± 0.14 μM and 2.63 ± 0.69 μM, respectively. Conclusions API could effectively attenuate HN through co-inhibiting UA reabsorption and Wnt/β-catenin pathway, and thus it might be a potential therapy to HN.
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CHEMOSPHERE
·
2020
·
IF 5.778
Qi Qin,Bingwei Yang,Zixuan Liu,Lei Xu,Erqun Song,Yang Song
Polychlorinated biphenyls (PCBs) are persistent industrial pollutants that have been linked to breast cancer progression. However, their molecular mechanism(s) are currently unclear. Our previous assessment suggested that the highly reactive PCB metabolite 2,3,5-trichloro-6-phenyl-[1,4]-benzoquinone (PCB29-pQ) induces the metastasis of breast cancer. Here, our data illustrate that PCB29-pQ increases cancer stem cell (CSC) marker expression, resulting in an increase in the epithelial-mesenchymal transition (EMT) in MDA-MB-231 breast cancer cells; further, the Wnt/β-catenin pathway also becomes activated by PCB29-pQ. When the Wnt/β-catenin pathway is inhibited, the promotion of CSC properties and EMT by PCB29-pQ were accordingly reversed. In addition, the overproduction of reactive oxygen species (ROS) mediated by PCB29-pQ plays a key role in Wnt/β-catenin activation. Collectively, our current data designated the regulatory role of Wnt/β-catenin in PCB29-pQ-triggered acquisition of CSC properties and EMT.
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Cells
·
2019
·Vol. 8
·期 8
·892
·
IF 5.656
Dattatrya Shetti,Bao Zhang,Conghui Fan,Canlong Mo,Bae Hoon Lee,Kun Wei
Triple-negative breast cancer (TNBC) accounts for 15% of overall breast cancer. A lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2 receptor) makes TNBC more aggressive and metastatic. Wnt signaling is one of the important pathways in the cellular process; in TNBC it is aberrantly regulated, which leads to the progression and metastasis. In this study, we designed a therapeutic strategy using a combination of a low dose of paclitaxel and a Wnt signaling inhibitor (XAV939), and examined the effect of the paclitaxel-combined XAV939 treatment on diverse breast cancer lines including TNBC cell lines (MDA-MB-231, MDA-MB-468, and BT549) and ER+ve cell lines (MCF-7 and T-47D). The combination treatment of paclitaxel (20 nM) and XAV939 (10 µM) exerted a comparable therapeutic effect on MDA-MB-231, MDA-MB-468, BT549, MCF-7, and T-47D cell lines, relative to paclitaxel with a high dose (200 nM). The paclitaxel-combined XAV939 treatment induced apoptosis by suppressing Bcl-2 and by increasing the cleavage of caspases-3 and PARP. In addition, the in vivo results of the paclitaxel-combined XAV939 treatment in a mice model with the MDA-MB-231 xenograft further confirmed its therapeutic effect. Furthermore, the paclitaxel-combined XAV939 treatment reduced the expression of β-catenin, a key molecule in the Wnt pathway, which led to suppression of the expression of epithelial-mesenchymal transition (EMT) markers and angiogenic proteins both at mRNA and protein levels. The expression level of E-cadherin was raised, which potentially indicates the inhibition of EMT. Importantly, the breast tumor induced by pristane was significantly reduced by the paclitaxel-combined XAV939 treatment. Overall, the paclitaxel-combined XAV939 regimen was found to induce apoptosis and to inhibit Wnt signaling, resulting in the suppression of EMT and angiogenesis. For the first time, we report that our combination approach using a low dose of paclitaxel and XAV939 could be conducive to treating TNBC and an external carcinogen-induced breast cancer.Keywords:breast cancer;XAV939;apoptosis;EMT;pristane;angiogenesis;combination treatment;Wnt signaling
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Nature Communications
·
2025
·Vol. 16
·期 1
·1-17
·
IF 15.7
He Hua,Ma Chong,Wei Wei,Wang Haonan,Lai Yutian,Liu Ming,Sun Shenfei,Ma Qing,Lai Jiashuang,Liu Hanxiang,Liu Hanmin,Sun Fei,Lin Xinhua
Postnatal respiration requires bulk formation of alveoli that produces extensive surface area for gas diffusion from epithelium to the circulatory system. Alveolar morphogenesis initiates at late gestation or postnatal stage during mammalian development and is mediated by coordination among multiple cell types. Here we show that fibroblast-derived Heparan Sulfate Glycosaminoglycan (HS-GAG) is essential for maintaining a niche that supports alveolar formation by modulating both biophysical and biochemical cues. Gli1-CreER mediated deletion of HS synthase gene Ext1 in lung fibroblasts results in enlarged and simplified alveolar structures. Ablation of HS results in loss of a subset of PDGFRα hi αSMA + alveolar myofibroblasts residing in the distal alveolar region, which exhibit contractile properties and maintain WNT signaling activity to support normal proliferation and differentiation of alveolar epithelial cells. HS is essential for proliferation while preventing precocious apoptosis of alveolar myofibroblasts. We show that these processes are dependent upon FGF/MAPK signaling and forced activation of MAPK/ERK signaling partially corrected alveolar simplification and restored alveolar myofibroblast number and AT2 cell proliferation in HS deficient mice. These data reveal HS-dependent myofibroblast heterogeneity and function as an essential orchestrator for developing alveolar niche critical for the generation of gas exchange units.
研究领域:
发育生物学
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细胞生物学
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呼吸系统医学
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Jieyi Zuo,Juan Liao,Lilin Zhu,Shuang Chen,Wenxin Wen,Ying Li,Dawei Sun,Lei Xu
Osteoporosis is one of the most prevalent age-related diseases worldwide. It is characterized by a systemic deterioration in bone strength (bone density and bone mass), leading to an increase in fragility fractures. The complex pathological environment of osteoporosis presents a significant challenge to the induction of bone regeneration under osteoporotic conditions. Therefore, the development of a system for local delivery of active substances with osteoinductive effects is of practical significance in the clinical treatment of osteoporosis. In this study, we successfully loaded the anti-osteoporotic small molecule drug zoledronate (ZOL) into calcium alginate to prepare a biologically functional hydrogel, designated as ALG-ZOL-Ca. The prepared ALG-ZOL-Ca hydrogel gels quickly, making the hydrogel easy to inject and adapt to irregularly shaped bone defects, and simultaneously exhibits good bioactivity and osteoconductivity. The RT-qPCR results suggested that this hydrogel effectively promoted the expression levels of β-catenin and Axin2, which indicating a stimulative effect on the Wnt/β-catenin pathway in vitro. Moreover, ALG-ZOL-Ca hydrogel effectively promoted the expression of the OCN and SP7 genes. Therefore, this study proposes a new functional composite hydrogel that provides a potential treatment strategy for osteoporosis.
研究领域:
药理学
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材料科学
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生物医学工程
·
骨科
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FOOD AND CHEMICAL TOXICOLOGY
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2024
·
IF 3.9
Xiu Wang,Kai Zou,Yu Xiong,Yongwang Zheng,Jiale Zheng,Yong Liu,Ting Zhong,Xincheng Zhao
Intestinal health is closely linked to intestinal stem cells (ISCs), which are highly sensitive to the harmful substances in the lumen. However, there is limited knowledge regarding the effects of food additives on ISCs. This study aims to investigate the impact of dietary titanium dioxide nanoparticles (TiO 2 NPs) compared with titanium dioxide microparticles (TiO 2 MPs) on intestinal health associated with ISCs in response to dextran sodium sulfate (DSS)-induced enteritis in mice, as well as the related mechanism. We found that exposure to 1% (w/w) TiO 2 NPs aggravated DSS-induced enteritis in mice, while this effect could not be observed under exposure to TiO 2 MPs. Additionally, 1% (w/w) TiO 2 NPs exposure under DSS-induced enteritis worsened the ISC-mediated regeneration of intestinal epithelium by decreasing the epithelial cell proliferation and epithelial turnover rate while increasing epithelial cell death. Meanwhile, using a 3D intestinal organoid model, we discovered that 20 μg/mL TiO 2 NPs impaired ISC function and disrupted ISC fate specification both ex vivo and in vitro . Furthermore, TiO 2 NPs hindered the nuclear translocation of β-catenin, reducing the overall output of Wnt signaling. Together, TiO 2 NPs deteriorated the intestinal epithelial regeneration of mice with DSS-induced enteritis by perturbating ISC function and fate specification through a mechanism involving Wnt signaling. These findings highlight the adverse effect of dietary TiO 2 NPs on ISCs and shed light on the particle size optimization of TiO 2 food additive.
研究领域:
胃肠病学
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纳米技术
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细胞生物学
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Materials Science & Engineering C-Materials for Biological Applications
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2018
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IF 5.08
Wen Zhang,Deqiu Huang,Fujian Zhao,Wendong Gao,Luyao Sun,Xian Li,Xiaofeng Chen
Strontium-substituted sub-micron bioactive glasses (Sr-SBG) have been reported to have enhanced osteogenic differentiation capacity compared to sub-micron bioactive glasses (SBG) in our previous study. However, the underlying molecular mechanisms of such beneficial effect of Sr-SBG are still not fully understood. In this study, we synthesized Sr-SBG, studied the effects of Sr-SBG on proliferation and osteogenic differentiation of mouse mesenchymal stem cells (mMSCs), and identified the molecular mechanisms of the enhancement effect of Sr-SBG on mMSCs. The results demonstrated that Sr-SBG had more profound promotion effect on proliferation and osteogenic differentiation of mMSCs than SBG and SrCl 2 group which containing identical Sr concentration with Sr-SBG group. RT-qPCR and western blot analysis showed that the mRNA expressions and protein expressions involved in NFATc and Wnt/β-catenin signaling pathways were all upregulated mediated by Sr-SBG, while only Wnt/β-catenin signaling pathway related genes upregulated in SBG group and only NFATc signaling pathway activated in SrCl 2 group, suggesting that NFATc and Wnt/β-catenin signaling pathways played important roles in osteogenesis enhancement induced by Sr-SBG. To conform the above conclusion, cyclosporin A (CSA) was applied to inhibit NFATc signaling pathway. It was found that the enhanced osteogenic differentiation of mMSCs induced by Sr-SBG was partially abrogated and the activated Wnt/β-catenin signaling pathway was also inhibited in part. However, the effects of SBG on proliferation and osteogenesis of mMSCs were unimpaired, yet the effects of SrCl 2 were greatly suppressed. Taken together, these results indicated that strontium activated NFATc signaling pathway and silicate activated Wnt/β-catenin signaling pathway might synergistically mediated the enhanced osteogenesis induced by Sr-SBG.
研究领域:
材料科学
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生物材料
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干细胞生物学
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组织工程
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NEUROBIOLOGY OF DISEASE
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2025
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IF 5.6
Shiyuan Xiao,Yue Li,Jun Wang,Mengran Wang,Bing Bu,Wenmin Jiang
Elevated intraocular pressure (IOP) imposes a substantial glycolytic demand on retinal tissue, driving excessive lactate production to sustain neuronal energy homeostasis. In the present study, we demonstrate that this metabolic stress markedly increases histone H4 lysine 8 lactylation (H4K8la) throughout the glaucomatous retina. Genome-wide profiling using Cleavage Under Targets and Tagmentation (CUT&Tag) revealed pronounced and selective H4K8la enrichment within the promoter region of mitofusin-2 (MFN2), a key mitochondrial fusion GTPase. Functionally, suppression of MFN2 mediated by H4K8la reciprocally enhances β-catenin expression, particularly under oxidative stress, indicating the existence of a lactate-responsive epigenetic circuit that couples mitochondrial dynamics to activation of the Wnt/β-catenin signaling pathway. In vivo experiments demonstrated that activated Müller glia orchestrate synchronous mitochondrial remodeling in retinal ganglion cells (RGCs) and photoreceptors. We propose that MFN2 functions as a molecular conduit, enabling intercellular mitochondrial transfer between Müller glia and neurons to sustain elevated glycolytic flux. This metabolic reprogramming increases lactate release, stimulates Wnt/β-catenin pathway activation, and ultimately leads to RGC apoptosis. Single-cell RNA sequencing (scRNA-seq) further revealed intensified Müller–amacrine/bipolar cell communication under ocular hypertension, accompanied by a marked reduction in neurexin- and VEGF-mediated interactions. Collectively, these findings identify a lactylation-governed epigenetic checkpoint that links mitochondrial dysfunction to glial–neuronal metabolic coupling in glaucoma, nominating MFN2 as a potential neuroprotective therapeutic target.
研究领域:
眼科学
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表观遗传学
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代谢学
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神经科学
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细胞生物学
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分子生物学
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Anti-Cancer Agents in Medicinal Chemistry
·
2022
·Vol. 22
·期 18
·3172-3181
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IF 2.527
Xie Xiaoliang,Li Yumei,Zhu Haixia,Chen Lin,Chen Deta,Lin Shengming,Fan Tianyou
Background and Purpose: Osteosarcoma is the most commonly seen type of primary malignant bone tumors in children and adolescents. Partial patients with osteosarcoma cannot tolerate the side effects of chemotherapy drugs. Hence, it is urgent to find anti-osteosarcoma drugs with low side
effects. Melittin is an anti-tumor Traditional Chinese Medicine with low side effects. The purpose of this study was to explore the anti-osteosarcoma effect of melittin and its possible molecular mechanisms. Methods: The effects of melittin on cell growth were detected by CCK-8, clonal
formation, and flow cytometry. The related molecules were also investigated by Real-time PCR and Western blot. A xenograft model in nude mice was established to observe the effects of melittin on tumor growth and the related molecular expression was detected by immunohistochemistry. Results:
Melittin can inhibit the proliferation of osteosarcoma 143B cells, reduce colony formation, and induce apoptosis while significantly up-regulating the expression of Bax and Caspase-3 and down-regulating the expression of Bcl-2 proteins. Moreover, treatment with melittin significantly reduced
the mRNA and protein levels of β-catenin and Wnt/β- catenin related genes (LRP5, c-Myc, and Survivin) in osteosarcoma 143B cells in vitro. The xenograft model found that melittin significantly inhibited tumor growth and decreased the protein expression levels of β-catenin and
Wnt/β- catenin related genes in vivo. Conclusion: These findings show that melittin could inhibit the growth of osteosarcoma 143B cells, which may be related to the inhibition of Wnt/β-catenin signaling pathway activity and induce apoptosis by up-regulating the ratio of Bax/Bcl-2
in osteosarcoma 143B cells. Therefore, melittin is a promising anti-tumor drug for the treatment of osteosarcoma.
研究领域:
肿瘤学
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药理学
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分子生物学
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ACTA BIOCHIMICA POLONICA
·
2021
·Vol. 68
·期 4
·725-732
·
IF 2.149
Ziyan Wu,Zhong Zhou,Weiguo Zhang,Yi Yu
MicroRNA (miR)-21 has been found to be overexpressed in osteosarcoma (OS). The aim of the present study was to investigate the effect of miR-21-5p on the Warburg effect and stemness maintenance in OS cells and its potential molecular mechanism. Herein, miR-21-5p was overexpressed or inhibited in MG-63 cells via transfection with mimics or inhibitors. The effect of miR-21-5p on cell viability, apoptosis, Warburg effect and stemness maintenance were explored in OS cells. The results demonstrated that miR-21-5p inhibition suppressed MG-63 cell viability and enhanced their apoptosis. Additionally, miR-21-5p inhibition attenuated the stemness maintenance of MG-63 cells, as demonstrated by the reduced proportion of CD133-positive MG-63 cells, the decrease in tumorsphere formation capacity, and the downregulation of Sox2, Oct4, and Nanog proteins. Moreover, miR-21-5p inhibition suppressed the Warburg effect in MG-63 cells, as indicated by the decrease in glucose uptake, lactic acid production, and ATP level and the downregulation of proteins involved in the Warburg effect (GLUT1, LDHA, HK2, and PKM2). Furthermore, the results suggested that the effect of miR-21-5p suppression on stemness and the Warburg effect may be associated with the decreased activity of the Wnt/β-catenin pathway in OS cells. Our findings suggest a novel potential biomarker for OS therapy.
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Environmental Technology & Innovation
·
2026
·
IF 7.3
Wenjie Wang,Xulong Fan,Yaquan Cao,Ruolin Shi,Ping Wang,Gaofeng Liang
Benzophenone-3 (BP-3), a common ultraviolet (UV) filter widely used in sunscreens, has raised increasing concern because early-life exposure may interfere with normal neurodevelopment. In this study, we fabricated a 3D inverse-opal polyethylene glycol diacrylate (PEGDA) scaffold and established a scaffold-supported brain organoid model for in vitro evaluation of BP-3-induced neurotoxicity. The scaffold was characterized by scanning electron microscopy (SEM), which revealed a highly ordered porous morphology with uniform pore size. It also showed good biocompatibility for organoid culture. BP-3 exposure induced concentration- and time-dependent toxicity in brain organoids, with more pronounced effects observed at 50 and 100 μM after 72 h of exposure. Under these defined exposure conditions, BP-3 was associated with increased oxidative stress, calcium-related functional changes, impaired membrane integrity, increased cytotoxicity, reduced expression of synaptic structural markers, and altered Wnt/β-catenin-related protein expression. These findings suggest that BP-3 exposure may disrupt early neurodevelopment-related processes in this model and is associated with synaptic-related alterations and Wnt/β-catenin dysregulation. Overall, this study supports the applicability of scaffold-supported brain organoids as an in vitro platform for evaluating BP-3-induced neurotoxic responses under controlled experimental conditions.
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