INTERNATIONAL UROLOGY AND NEPHROLOGY
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2026
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IF 2.2
Chen Huihui,Zhang Guolei,Jin Jingjing,Cheng Mei Juan,Zhang Dongxue,Niu Zhezhe,Zhu Rongfang,Qian Yuetong,Liang Xiangnan,He Lei,Zhou Wei,Zhang Shenglei,Bai Yaling,Xu Jin Sheng
Purpose Vascular calcification (VC) is highly prevalent and a significant cardiovascular risk factor in patients with chronic kidney disease (CKD). Secreted frizzled-related protein 1 (SFRP1) is a secreted glycoprotein closely associated with the Wnt/β-catenin pathway which plays a crucial role in bone formation, but its function and mechanism in VC remain unknown. Methods Serum and radial artery tissues were collected from CKD patients with or without VC. The cellular model of VSMCs’ calcification was established under high-phosphate conditions in vitro. Western blot, qRT-PCR, and immunofluorescence were used to detect SFRP1 expression. The function of SFRP1 was identified by transfection with sh-SFRP1 and pCMV3-SFRP1 plasmid. Results Initially, bioinformatics analysis showed that SFRP1 expression was significantly elevated in high-phosphate-stimulated rat VSMCs. Subsequently, we discovered that the expression of SFRP1 was dramatically increased in the calcified arteries of CKD patients. Functionally, when SFRP1 was knocked down, the calcification process and the expression of Runx2 were attenuated. In contrast, SFRP1 overexpression exacerbated the β-GP-induced VSMCs’ calcification. Mechanistically, we confirmed the activation of Wnt/β-catenin signaling in the in vitro calcification model and this activation was inhibited by SFRP1 knockdown. Furthermore, when the Wnt/β-catenin signaling was enhanced with LiCl, the suppressing effect of SFRP1 knockdown on β-GP-induced osteogenic transdifferentiation of VSMCs was reversed, and calcification was promoted. Conclusion We identified that SFRP1 promoted vascular calcification in CKD partly by regulating the Wnt/β-catenin/Runx2 axis, suggesting that SFRP1 may be a potential biomarker and therapeutic target for VC in CKD.
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Nature Biomedical Engineering
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2026
·
IF 26.3
Yu Fanyuan,Li Feifei,Yu Peng,Zhou Bin,Wang Cun-Yu,Ye Ling
WNT proteins have been recognized as key regulators of skeletal health. However, developing WNT-associated bone anabolic agents is clinically challenging and expensive. Here we identify the reconstructed thumb and index domains of WNT7B (WNT7B RTID ) as a WNT-derived bone anabolic peptide via Alphafold-empowered sequence prediction and in silico docking screening. In aged mice and pigs models of osteoporosis, WNT7B RTID peptides demonstrate therapeutic potential by improving the osteogenic potential of mesenchymal stromal/stem cells (MSCs) and enhancing bone regeneration. Using single-cell sequencing, transgenic lineage tracking and biochemical approaches, we show that WNT7B RTID harnesses the function and osteogenic lineage generation of intrinsic tissue-residual MSCs without needing MSC transplantation to repair a critical-sized defect effectively. Mechanistically, WNT7B RTID activates non-canonical Ca 2+ -NFAT signalling through RECK/GPR124 to drive its bone anabolic effects, independent of canonical Wnt/β-catenin signalling known for its oncogenic effects. Our results suggest that WNT7B RTID could work as bone anabolic agent for alleviating bone loss in aging and for fracture repair by promoting MSC function via Ca 2+ -NFAT signalling.
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JOURNAL OF HAZARDOUS MATERIALS
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2025
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IF 11.3
Shichang Li,Shuxian Zhang,Hanyue Li,Nuoya Yin,Renjun Yang,Yang Zhang,Magdalena J. Koziol,Francesco Faiola
Ultraviolet filters (UVFs) are extensively employed in personal care products, coatings, and food packaging materials, raising increasing concerns regarding developmental vulnerability due to their frequent detection in breast milk and amniotic fluid. This study systematically evaluated the developmental neurotoxicity of representative benzophenone, benzotriazole, and triazine UVFs using human embryonic stem cell (hESC) differentiation models. The dynamic trajectories of both central and peripheral nervous system (CNS and PNS) development were tracked, revealing that UVFs induced an imbalanced CNS/PNS lineage commitment, with UV-328 particularly causing disruptions through direct modulation of the WNT signaling pathway. In the PNS, 10 nM UV-328 significantly inhibited proliferation and migration in neural crest cells by preventing E-cadherin downregulation. Conversely, in the CNS, BP-3, UV-328, and BEMT promoted aberrant midbrain differentiation by upregulating FOXA2, LMX1A, CORIN, OTX2, and EN1 expression, while impairing late-stage dopaminergic neuron specification by downregulating TH. These findings elucidate the molecular mechanisms underlying benzophenone, benzotriazole, and triazine UVF-induced developmental neurotoxicity and underscore the critical need to evaluate the environmental impact and safety of UVFs during sensitive developmental stages. Additionally, this study highlights the potential links between UVF exposure and neurological disorders, emphasizing the importance of continued investigation in this field to inform environmental policies and public health strategies.
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Frontiers in Pharmacology
·
2020
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IF 4.225
Xie Jing,Luo Feng-xian,Shi Chong-ying,Jiang Wei-wei,Qian Ying-yan,Yang Ming-rong,Song Shuang,Dai Tian-yi,Peng Lei,Gao Xiao-yu,Tao Liang,Tian Yang,Sheng Jun
Moringa oleifera Lam. (M. oleifera) is valuable plant distributed in many tropical and subtropical countries. It has a number of medicinal uses and is highly nutritious. M. oleifera has been shown to inhibit tumor cell growth, but this effect has not been demonstrated on prostate cancer cells. In this study, we evaluated the inhibitory effect of M. oleifera alkaloids (MOA) on proliferation and migration of PC3 human prostate cancer cells in vitro and in vivo. Furthermore, we elucidated the mechanism of these effects. The results showed that MOA inhibited proliferation of PC3 cells and induced apoptosis and cell cycle arrest. Furthermore, MOA suppressed PC3 cell migration and inhibited the expression of matrix metalloproteinases (MMP)-9. In addition, MOA significantly downregulated the expression of cyclooxygenase 2 (COX-2), β-catenin, phosphorylated glycogen synthase 3β, and vascular endothelial growth factor, and suppressed production of prostaglandin E2 (PGE2). Furthermore, FH535 (β-catenin inhibitor) and MOA reversed PGE2-induced PC3 cell proliferation and migration, and the effects of MOA and FH535 were not additive. In vivo experiments showed that MOA (150 mg/kg) significantly inhibited growth of xenograft tumors in mice, and significantly reduced the protein expression levels of COX-2 and β-catenin in tumor tissues. These results indicate that MOA inhibits the proliferation and migration, and induces apoptosis and cell cycle arrest of PC3 cells. Additionally, MOA inhibits the proliferation and migration of PC3 cells through suppression of the COX-2 mediated Wnt/β-catenin signaling pathway.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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BIOORGANIC CHEMISTRY
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2022
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IF 5.307
Yongxi Dong,Mingji Liu,Yongqing Mao,Shuxia Wu,Jinlan Wen,Jun Lu,Yaxin Yang,Shiyang Ruan,Lei Li,Xinyun Liu,Jiquan Zhang,Shanggao Liao,Li Dong
Carnosic acid could disrupt the β-catenin/BCL9 protein-protein interaction and inhibit β-catenin dependent transcription, thereby reduce the incidence of colorectal cancer induced by abnormal activation of Wnt/β-catenin signalling pathway. However, its activity was weak (IC 50 for SW480: 28.2 ± 2.05 μM) and total synthesis was difficult. During the structural simplification of natural products, S0 was revealed to be the basic pharmacophore of carnosic acid. Subsequent structural optimization of S0 led to the discovery of S11 as a possible anticancer agent with prominent proliferation inhibition effect (IC 50 for SW480: 9.56 ± 0.91 μM) and best selectivity index (SI = 3.0) against Wnt hyperactive cancer cells. Futher mechanism investigation through TOP/FOP dual luciferase reporter assay, immunofluorescence, co-immunoprecipitation, microscale thermophoresis, downstream oncoprotein expression and cell apoptosis showed that compound S11 could significantly inhibit the proliferation of SW480 cells via obvioudsly decreasing the nucleus translocation of β-catenin and effectively disrupting β-catenin/BCL9 protein-protein interaction. Additionally, cell migration, molecule docking, in vitro stability and solubility assays were also conducted. Overall, S11 was worthy of in-depth study as a potential inhibitor for the Wnt/β-catenin pathway and its discovery also proved that the structural simplification of natural products was still one of the effective methods to find new lead compounds or candidate drugs.
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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药物化学
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Pharmaceuticals
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2026
·Vol. 19
·期 3
·469
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IF 5.7
Lili Li,Xiaoya Zhang,Guangyuan Tang,Jianxin Wu,Qing Huang
Background: Glabridin, a natural compound derived fromGlycyrrhiza glabraL., possesses skin-lightening effects. This study aims to further elucidate the depigmentation mechanism of glabridin by investigating its effects on melanogenesis and melanin transfer.Methods: We initially confirmed the anti-melanogenic effects of glabridin in MNT-1 human melanoma cells. Then, we investigated the mechanism of its anti-melanogenic effect by evaluating the protein expression of β-catenin and MITF via Western blot. To investigate melanin transfer, we compared glabridin’s efficacy with that of niacinamide, a recognized inhibitor of melanosome transfer and employed two complementary experimental models: (1) α-melanocyte-stimulating hormone (α-MSH)-stimulated MNT-1 cells to analyze dendrite formation, and (2) a UVB-irradiated co-culture system of MNT-1 cells and HaCaT keratinocytes to evaluate melanin transfer.Results: By measuring glabridin’s effects on melanin content, tyrosinase activity, and melanogenesis-related protein expression confirmed its inhibition of melanin synthesis. Further investigation demonstrated that glabridin suppresses melanogenesis by downregulating β-catenin and MITF, indicating inhibition of the Wnt/β-catenin pathway. Furthermore, in α-MSH-treated MNT-1 cells, both glabridin and niacinamide were found to suppress dendrite formation and elongation. In a UVB-exposed co-culture system, both glabridin and niacinamide inhibited melanin transfer to keratinocytes. Mechanistically, these effects were linked to the regulation of Rho GTPases (Rac1, RhoA, Cdc42) and suppression of F-actin reorganization.Conclusions: This study provides, for the first time, evidence that the skin-lightening effect of glabridin involves two complementary mechanisms: inhibition of melanogenesis through suppression of the Wnt/β-catenin pathway, and attenuation of both dendricity and melanin transfer via the influence of Rho family GTPases expression.
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MOLECULAR BIOTECHNOLOGY
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2023
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IF 2.6
Lv Chen-Guang,Cheng Yao,Zhang Lei,Wu Guo-Gang,Liang Chun-Yan,Tao Zuo,Chen Bo
BC (breast cancer) is the leading cause of cancer death in women. Exosome component 2 (EXOSC2), an RNA exosome component, is elevated in BC tissues and may relate to BC carcinogenesis. In this work, the high EXOSC2 expression was correlated with TNM (Tumor Node Metastasis) stage. Moreover, overexpression of EXOSC2 enhanced tumorigenic capacity of BC cells via facilitating cell proliferation and cell cycle progression, increasing migration and angiogenesis, as well as exacerbating xenograft formation in vivo. Whereas, EXOSC2 knockdown showed anti-cancer effects, including inhibition of cell proliferation and angiogenesis. Mechanistically, EXOSC2 activated the wnt/β-catenin pathway, which was also abolished by EXOSC2 knockdown. In addition, there were m6A methylation modification sites in the mRNA of EXOSC2. WTAP (Wilms tumor 1-associated protein) bound to EXOSC2 mRNA and increased its m6A methylation, resulting in extending the half-life of EXOSC2 mRNA. Luciferase data also confirmed that WTAP enhanced EXOSC2 mRNA stability through binding with the 3′-UTR containing m6A sites. Furthermore, WTAP silencing exhibited cancer-inhibiting effects on cell viability, cell cycle progression and tube formation, which was effectively reversed by EXOSC2 overexpression. In conclusion, our results demonstrate that EXOSC2 promotes the malignant behaviors of BC cells via activating the wnt/β-catenin pathway. In addition, EXOSC2 mediates the function of WTAP which contributes to the m6A modification of EXOSC2. Totally, this study suggested that EXOSC2 mediated the pro-tumor role of WTAP via activating the wnt/β-catenin signal.
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Human Cell
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2023
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IF 4.3
Hu Lianying,Cheng Zhen,Wu Lunan,Luo Liangliang,Pan Ping,Li Shujin,Jia Qiyu,Yang Ning,Xu Bin
Osteogenic differentiation plays important roles in the pathogenesis of osteoporosis. In this study, we explored the regulatory mechanism of histone methyltransferase SET domain bifurcated 1 (SETDB1) underlying the osteogenic differentiation in osteoporosis. The common osteoporosis-related genes were retrieved from the GeneCards, CTD, and Phenolyzer databases. The enrichment analysis was conducted on the candidate osteoporosis-related genes using the PANTHER software, and the binding site between transcription factors and target genes predicted by hTFtarget. The bioinformatics analyses suggested 6 osteoporosis-related chromatin/chromatin binding protein or regulatory proteins (HDAC4, SIRT1, SETDB1, MECP2, CHD7, and DKC1). Normal and osteoporosis tissues were collected from osteoporosis patients to examine the expression of SETDB1. It was found that SETDB1 was poorly expressed in osteoporotic femoral tissues, indicating that SETDB1 might be involved in the development of osteoporosis. We induced SETDB1 overexpression/knockdown, orthodenticle homeobox 2 (OTX2) overexpression, activation of Wnt/β-catenin or BMP-Smad pathways alone or in combination in osteoblasts or ovariectomized mice. The data indicated that SETDB1 methylation regulated H3K9me3 in the OTX2 promoter region and inhibited the expression of OTX2. Besides, the BMP-Smad and Wnt/β-catenin pathways were inhibited by OTX2, thereby resulting in inhibited osteogenic differentiation. Animal experiments showed that overexpressed SETDB1 could promote the increase of calcium level and differentiation of femoral tissues. In conclusion, upregulation of SETDB1 promotes osteogenic differentiation by inhibiting OTX2 and activating the BMP-Smad and Wnt/β-catenin pathways in osteoporosis.
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EUROPEAN JOURNAL OF MEDICAL RESEARCH
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2019
·Vol. 24
·期 1
·1-9
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IF 1.736
Han Yanfu,Sun Tianjun,Han Yanqing,Lin Lingling,Liu Chang,Liu Jing,Yan Guangzhi,Tao Ran
ObjectiveDifficulty in wound healing is one common complication of diabetes mellitus. The study explored whether the therapeutic effect of human umbilical cord mesenchymal stem cells (hUCMSCs) on diabetic ulcer wound was enhanced by the activation of the Wnt signaling pathway.Methods Rat diabetic model was established by intraperitoneal injection of Streptozotocin (STZ). hUCMSCs were purified and seeded on the collagen–chitosan laser drilling acellular dermal matrix (CCLDADM) scaffold, which was subsequently implanted into the cutaneous wound of normal and diabetic rats, followed by daily injection of Wnt signaling pathway agonist (Wnt3a) or antagonist (sFRP3) at the edge of the scaffold. Wound healing was checked on days 7, 14, and 21, and the fibrous tissue deposition, capillaries, and epidermal regeneration at the wound were examined by hematoxylin–eosin staining. The hUCMSCs-CCLDADM scaffold was cultured in vitro and treated with Wnt3a or sFRP3, followed by evaluation of cell proliferation, cell proliferation rate, survival status, and altered protein levels in the Wnt signaling pathway using BrdU staining, CCK-8 assay, live/dead staining, and Western blotting, respectively.Results On days 7 and 14 postoperatively, the speed of wound healing was significantly lower in diabetic rats than that in normal control rats. This phenomenon was significantly improved by the activation of the Wnt signaling pathway that also elevated the fibrous protein deposition and the abundance of capillary in the granulation tissue. Conversely, blockade of Wnt signaling slowed the healing of skin wound in diabetic rats. The activation of Wnt signaling pathway promoted the proliferation and differentiation and decreased the apoptosis of hUCMSCs, thereby elevating the number of living hUCMSCs on the CCLDADM scaffold, while the suppression exerted a contrary effect.Conclusion The activation of the Wnt signaling pathway promotes the healing of diabetic skin wound by the regulation of proliferation and differentiation of hUCMSCs on the CCLDADM scaffold.
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Cells
·
2019
·Vol. 8
·期 8
·892
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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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Journal of Oncology
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2022
·
IF 4.501
Hongliang You,Dao Wang,Linlin Wei,Jiao Chen,Huanhuan Li,Yufeng Liu
Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer, with a feature of easy to induce multidrug resistance and relapse. Abundant studies have proved that iron overload strengthens the growth and metastasis of tumor cells. Herein, we found that deferoxamine (DFO) effectively decreased the concentration of intracellular iron in ALL cells. DFO inhibited proliferation, induced apoptosis, and obstructed cell cycle of ALL cells, whereas DFO and dextriferron (Dex) used in combination significantly decreased the sensitivity of ALL cells to DFO. Reactive oxygen species (ROS) level was reduced in ALL cells treated with DFO, and the combination of DFO and Dex reversed the effects of DFO. In vivo, DFO inhibited mouse tumor growth. Besides, cyclinD1, β-catenin, c-Myc, hypoxia inducible factor 1 (HIF-1), p-p38MAPK, and p-ERK1/2 protein levels were significantly downregulated, and the levels of prolyl hydroxylase-2 (PHD-2) were upregulated after treated with DFO, whereas Dex treatment reversed those in vivo and in vitro. In conclusion, DFO inhibited the proliferation and ALL xenograft tumor growth, obstructed the cell cycle, and induced apoptosis of ALL cells, probably via inactivating the ROS/HIF-1α, Wnt/β-catenin, and p38MAPK/ERK signaling.
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Foods
·
2021
·Vol. 11
·期 1
·49
·
IF 4.35
Fuhua Li,Huiming Yan,Ling Jiang,Jichun Zhao,Xiaojuan Lei,Jian Ming
Ulcerative colitis (UC) is a chronic and nonspecific inflammatory disease of the colon and rectum, and its etiology remains obscure. Cherry polyphenols showed potential health-promoting effects. However, both the protective effect and mechanism of cherry polyphenols on UC are still unclear. This study aimed to investigate the potential role of the free polyphenol extract of cherry in alleviating UC and its possible mechanism of action. Our study revealed that the free polyphenol extract of cherry management significantly alleviated UC symptoms, such as weight loss, colon shortening, the thickening of colonic mucous layer, etc. The free polyphenol extract of cherry treatment also introduced a significant reduction in levels of malondialdehyde (MDA), myeloperoxidase (MPO) and nitric oxide (NO), while causing a significant elevation in levels of catalase (CAT), glutathione (GSH-Px), superoxide dismutase (SOD), as well as the downregulation of pro-inflammatory cytokines. This indicated that such positive effects were performed through reducing oxidative damage or in a cytokine-specific manner. The immunofluorescence analysis of ZO-1 and occludin proteins declared that the free polyphenol extract of cherry had the potential to prompt intestinal barrier function. The reduced expression levels of β-catenin, c-myc, cyclin D1 and GSK-3β suggested that the cherry extract performed its positive effect on UC by suppressing the Wnt/β-ctenin pathway. This finding may pave the way into further understanding the mechanism of cherry polyphenols ameliorating ulcerative colitis.Keywords:ulcerative colitis;cherry polyphenol;anti-inflammatory;antioxidant;Wnt/β-catenin signaling pathway
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