INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Xue-na Gong,Yan-xin Zhou,Chen-yu Wang,Tian-tian Wang,Zi-yao Gao,Wen-cai Long,Rong Li,Li Cai
The GSK-3β/β-catenin signaling axis is critically involved in the pathogenesis of depression. Targeted inhibition of GSK-3β to activate β-catenin signaling may provide a promising depression therapy. The novel GSK-3β inhibitor compound 47 (CPD47) has exhibited therapeutic promise in neurodegenerative disorders such as Alzheimer's disease, but its potential antidepressant effects and underlying mechanisms remain to be elucidated. This study assessed CPD47's protective effects against PC12 cell injury induced by corticosterone (CORT) and its antidepressant-like activity in rats exposed to chronic unpredictable mild stress (CUMS), with a special focus on the mechanisms involving the regulation of the GSK-3β/β-catenin signaling pathway. In this research, CPD47 treatment attenuated CORT-induced neurotoxicity in PC12 cells, as indicated by increased viability, decreased apoptosis, reduced oxidative stress, and suppressed inflammatory responses. In vivo, administration of CPD47 substantially alleviated depressive-like behaviors in CUMS rats, as indicated by behavioral improvements in sucrose preference, forced swim, sucrose splash, and open field tests. Additionally, CPD47 ameliorated hippocampal pathological damage and promoted hippocampal neurogenesis in CUMS rats. Notably, CPD47 markedly mitigated neuroinflammation in the hippocampus of CUMS rats. Mechanistically, CPD47 significantly inhibited GSK-3β activity and activated β-catenin signaling both in vitro and in vivo, with upregulated p-GSK-3β (Ser9) and β-catenin expression and decreased p-β-catenin. Importantly, GSK-3β overexpression abolished CPD47's benefits in CORT-stimulated PC12 cells, providing further evidence that GSK-3β is its crucial molecular target. Collectively, our findings indicate that CPD47 produces potent antidepressant-like effects through modulation of the GSK-3β/β-catenin axis, highlighting its promise as a candidate for depression therapy.
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高影响因子
Redox Biology
·
2017
·
IF 6.337
Dan-Qian Chen,Gang Cao,Hua Chen,Dan Liu,Wei Su,Xiao-Yong Yu,Nosratola D. Vaziri,Xiu-Hua Liu,Xu Bai,Li Zhang,Ying-Yong Zhao
Changes in plasma concentration of small organic metabolites could be due to their altered production or urinary excretion and changes in their urine concentration may be due to the changes in their filtered load, tubular reabsorption, and/or altered urine volume. Therefore, these factors should be considered in interpretation of the changes observed in plasma or urine of the target metabolite(s). Fasting plasma and urine samples from 180 CKD patients and 120 age-matched healthy controls were determined by UPLC-HDMS-metabolomics and quantitative real-time RT-PCR techniques. Compared with healthy controls, patients with CKD showed activation of NF-κB and up-regulation of pro-inflammatory and pro-oxidant mRNA and protein expression as well as down-regulation of Nrf2-associated anti-oxidant gene mRNA and protein expression, accompanied by activated canonical Wnt/β-catenin signaling. 124 plasma and 128 urine metabolites were identified and 40 metabolites were significantly altered in both plasma and urine. Plasma concentration and urine excretion of 25 metabolites were distinctly different between CKD and controls. They were related to amino acid, methylamine, purine and lipid metabolisms. Logistic regression identified four plasma and five urine metabolites. Parts of them were good correlated with eGFR or serum creatinine. 5-Methoxytryptophan and homocystine and citrulline were good correlated with both eGFR and creatinine. Clinical factors were incorporated to establish predictive models. The enhanced metabolite model showed 5-methoxytryptophan, homocystine and citrulline have satisfactory accuracy, sensitivity and specificity for predictive CKD. The dysregulation of CKD was related to amino acid, methylamine, purine and lipid metabolisms. 5-methoxytryptophan, homocystine and citrulline could be considered as additional GFR-associated biomarker candidates and for indicating advanced renal injury. CKD caused dysregulation of the plasma and urine metabolome, activation of inflammatory/oxidative pathway and Wnt/β-catenin signaling and suppression of antioxidant pathway.
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COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY
·
2025
·
IF 4.3
Huimin Li,Ziang Wang,Suwei He,Minghui Zhong,Xichen Wang,Weitao Hu,Jingrong Tang,Zhonghao Xiao,Xiaowen Shi,Zigang Cao
2-Hydroxyanthraquinone (2-hATQ), a photooxidation product of anthracene (ANT) within polycyclic aromatic hydrocarbons (PAHs), poses significant risks to ecological safety and human health. ANT is listed as a priority pollutant by the U.S. Environmental Protection Agency (EPA) due to its persistence and resistance to degradation in the environment. Consequently, 2-hATQ, inheriting these characteristics from its parent compound, is ubiquitously present in the environment and exhibits greater toxicity than ANT itself. However, research on its toxicological effects, particularly concerning cerebrovascular toxicity, remains limited. In this study, acute exposure of zebrafish embryos to various concentrations of 2-hATQ resulted in significant cerebrovascular developmental abnormalities, manifested as reduced total vascular area and decreased vessel number in the brain. Moreover, the number of brain microglia, reactive oxygen species (ROS) levels, and apoptotic cell counts were markedly increased. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed that 2-hATQ disrupts zebrafish cerebrovascular and blood-brain barrier development by upregulating pro-inflammatory cytokines ( il1β , tnf-α , nf-κb , il6 ) and inhibiting the Wnt/β-catenin signaling pathway ( lef1 , β-catenin , dkk1 , wif1 ). The co-administration of dexamethasone or BML-284 effectively rescued the cerebrovascular damage. Furthermore, behavioral analysis demonstrated that exposed zebrafish larvae exhibited reduced locomotor activity and anxiety-like states. This study reveals for the first time the adverse effects of 2-hATQ exposure on brain vascular development in aquatic organisms, suggesting that 2-hATQ and its ANT-related derivatives may be potential risk factors for cerebrovascular diseases. Our findings reveal, for the first time, that 2-hATQ impairs cerebrovascular and BBB development through concurrent induction of inflammation and suppression of the Wnt/β-catenin pathway, identifying these as critical mechanistic events in its toxicity.
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高影响因子
Acta Biomaterialia
·
2019
·
IF 6.638
Jieni Fu,Xiangmei Liu,Lei Tan,Zhenduo Cui,Yanqin Liang,Zhaoyang Li,Shengli Zhu,Yufeng Zheng,Kelvin Wai Kwok Yeung,Paul K Chu,Shuilin Wu
Growing evidence suggests that the physical microenvironment can guide cell fate. However, cells sense cues from the adjacent physical microenvironment over a limited distance. In the present study, murine mesenchymal stem cells (MSCs) and murine preosteoblastic cells (MC3T3-E1) behaviors are regulated by the cell–material interface using ordered-micro and disordered-nano patterned structures on Ti implants. The optimal bone formation structure is a stable wave (horizontal direction: ridge, 2.7 µ m; grooves, 5.3 µ m; and vertical direction: distance, 700 µ m) with the appropriate density of nano-branches (6.0 per µ m 2 ). The repeated waves provide cells with directional guidance, and the disordered branches influence cell geometry by providing different spacing and density nanostructure . And micro-nano patterned structure can provide biophysical cues to direct cell phenotype development, including cell size, shape, and orientation, to influence cellular processes including survival, growth, and differentiation. Thus, the overlaid isotropic and anisotropic cues, ordered-micro and disordered-nano patterned structures, could transfer further and alter cell shape and induce nuclear orientation by activating Wnt/ β -catenin signaling to promote integrin α5, integrin β1, cadherin 2, Runx2, Opn , and Ocn . That canonical Wnt signaling inhibitor dickkopf1 further demonstrates osteogenic differentiation induced by ordered-micro and disordered-nano patterned structures, which is related to Wnt/ β -catenin signaling. Our findings show the role of ordered microstructures and disordered nanostructures in modulating stem cell differentiation with potential medical applications. Statement of significance It remains a challenge to modify poor osteogenic and osteoconductive properties of titanium alloy bases on the inherent poverty of titanium. We demonstrate that ordered microtopography and disordered nano topography pattern structure could lead to osteogenic differentiation in vitro and bone regeneration in vivo . Furthermore, the pattern structure is created through selective laser melting and alkali heat. And the structure only takes advantage of titanium itself and does not bring in active film, such as hydroxyapatite . On the other hand, we find that cell shape and orientation show angle-orientation tendency due to the polarity, which involves with mechanical signal created via patterned structure. Meanwhile, the Wnt/Ca 2+ signaling pathway is activated.
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BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
·
2024
·
IF 4.6
Jiangxia Wang,Runlin Gui,Yang Li,Zhuozhuo Li,Zi Li,Shanshan Liu,Miao Zhang,Lu Qian,Xiaobin Fan,Yuyan Xiong
Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by chronic ovulation dysfunction and overproduction of androgens. Women with PCOS are commonly accompanied by insulin resistance (IR), which can impair insulin sensitivity and elevate blood glucose levels. IR promotes ovarian cysts, ovulatory dysfunction, and menstrual irregularities in women patients, leading to the pathogenesis of PCOS. Secreted frizzled-related protein 4 (SFRP4), a secreted glycoprotein, exhibits significantly elevated expression levels in obese individuals with IR and PCOS. Whereas, whether it plays a role in regulating IR-induced PCOS still has yet to be understood. In this study, we respectively established in vitro IR-induced hyperandrogenism in human ovarian granular cells and in vivo IR-induced PCOS models in mice to investigate the action mechanisms of SFRP4 in modulating IR-induced PCOS. Here, we revealed that SFRP4 expression levels in both mRNA and protein were remarkably upregulated in the IR-induced hyperandrogenism with elevated testosterone in the human ovarian granulosa cell line KGN. Under normal conditions without hyperandrogenism, overexpressing SFRP4 triggered the remarkable elevation of testosterone along with the increased nuclear translocation of β-catenin, cell apoptosis and proinflammatory cytokine IL-6. Furthermore, we found that phytopharmaceutical disruption of SFRP4 by genistein ameliorated IR-induced increase in testosterone in ovarian granular cells, and IR-induced PCOS in high-fat diet obese mice. Our study reveals that SFRP4 contributes to IR-induced PCOS by triggering ovarian granulosa cell hyperandrogenism and apoptosis through the nuclear β-catenin/IL-6 signaling axis. Elucidating the role of SFRP4 in PCOS may provide a novel therapeutic strategy for IR-related PCOS therapy.
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Chemical Biology & Drug Design
·
2025
·Vol. 105
·期 5
·e70113
·
IF 3.3
Ming Tong,Meng Liu,Liang Chen,Yi-he Lin,Qing Zheng
Liver fibrosis is pathologically associated with ferroptosis. Osthole (OST) has good therapeutic effects on liver fibrosis. Our study sought to investigate the pharmacological effects of OST on ferroptosis in hepatic stellate cells (HSCs) during the development of liver fibrosis and define the mechanisms involved. The in vivo model of liver fibrosis was established by CCl 4 treatment. MTT and EDU assays were used to assess cell viability and proliferation, respectively. The interaction between myocyte enhancer factor 2A (MEF2A) and Y-box binding protein 1 (YBX1) was analyzed by dual luciferase reporter and chromatin immunoprecipitation (ChIP) assays. OST treatment alleviated CCl 4 -induced liver fibrosis in mice by activating ferroptosis. OST induced ferroptosis in HSCs and inhibited the activation of HSCs in vitro, while these effects of OST were reversed by MEF2A overexpression or YBX1 overexpression. Mechanistically, MEF2A activated the Wnt/β-catenin signaling by transcriptionally facilitating YBX1 expression. As expected, the inactivation of Wnt/β-catenin signaling or YBX1 knockdown could reverse the regulatory effect of MEF2A upregulation on the activation of HSCs and ferroptosis in OST-treated HSCs. OST mitigated liver fibrosis by inducing ferroptosis in HSCs and repressing the activation of HSCs through inhibiting the MEF2A/YBX1/Wnt/β-catenin axis.
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Bioengineered
·
2022
·
IF 6.832
Zongting Shi,Jun He,Jian He,Yuan Xu
Hydrostatic pressure is known to regulate bovine nucleus pulposus cell metabolism, but its mechanism in human nucleus pulposus cells (HNPCs) remains obscure, which attracts our attention and becomes the focus in this study. Specifically, HNPCs were treated with SKL2001 (an agonist in the Wnt/β-catenin pathway) or XAV-939 (an inhibitor of the Wnt/β-catenin pathway), and pressurized under the hydrostatic pressure of 1, 3 and 30 atm. The viability, apoptosis and proteoglycan synthesis of treated HNPC were assessed by CCK-8, flow cytometry and radioisotope incorporation assays. The levels of extracellular matrix, Collagen-II, matrix metalloproteinase 3 (MMP3), Wnt-3a and β-catenin were measured by toluidine blue staining, immunocytochemistry and Western blot. Appropriate hydrostatic stimulation (3 atm) enhanced the viability and proteoglycan synthesis yet inhibited the apoptosis of HNPCs, which also up-regulated extracellular matrix and Collagen-II levels, and down-regulated MMP3, Wnt-3a and β-catenin levels in treated HNPCs. Furthermore, high hydrostatic pressure (30 atm) inhibited the viability and proteoglycan synthesis, and promoted the morphological change and apoptosis of HNPCs, which also down-regulated extracellular matrix and Collagen-II levels and up-regulated MMP3, Wnt-3a and β-catenin levels. Besides, SKL2001 reversed the effects of hydrostatic pressure (3 atm) on inhibiting Wnt-3a, β-catenin, and MMP3 levels and promoting Collagen-II level in HNPC; whereas, XAV-939 reversed the effects of high hydrostatic pressure (30 atm) on promoting MMP3, Wnt-3a, and β-catenin levels and inhibiting Collagen-II level and proteoglycan synthesis of HNPCs. Collectively, high hydrostatic pressure promoted the apoptosis and inhibited the viability of HNPCs via activating the Wnt/β-catenin pathway.
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Environmental Chemistry and Ecotoxicology
·
2025
·
IF 8.2
Hongmin Lu,Ruoqi Wang,Xin Zhang,Yuze Dong,Hao Liu,Yunfan Zhang,Chengxue Ma,Mingwei Xing
Chronic exposure to fluoride and phenanthrene is recognized as a significant risk factor for neurobehavioral toxicity, and the gut-brain axis has been identified as a key mechanism in the development of anxiety behaviors following prolonged toxic insult. Nevertheless, the connections between gut microbiota disruption, serotonin (5-HT) production, and neurobehavioral toxicity induced by long-term co-exposure to fluoride and phenanthrene remain unclear. In this study, co-exposure model of phenanthrene and fluoride at environmentally relevant concentrations was established in zebrafish. Through comparative database analysis, anxiety behavior tests, 16S rRNA sequencing, metabolomics, qPCR, Western blotting, ELISA, flow cytometry, comet assay, histological analysis, and immunohistochemistry, the neurotoxic effects of fluoride or/and phenanthrene were investigated. In this study, neurobehavioral toxicity was observed in zebrafish following co-exposure to environmentally relevant concentrations of fluoride and phenanthrene, characterized by diminished swimming capacity and heightened anxiety behavior. The toxic mechanism was mediated through disruption of the microbiome–gut–brain axis homeostasis and suppression of the Wnt/β-catenin signalling pathway. Specifically, co-exposure decreased intestinal synthesis of 5-HT and impaired the blood–brain barrier. As the intestine serves as the primary source of 5-HT, its impairment (histopathological alterations, gut microbiota dysbiosis and metabolomics) led to dysregulation of the 5-HT system. Histopathological analysis of brain tissue revealed synaptic loss, nuclear pyknosis, and the presence of apoptotic bodies. Investigations into the molecular mechanisms indicated that fluoride or/and phenanthrene inhibited Wnt signalling, promoted β-catenin degradation, and induced neurological dysfunction, as evidenced by reductions in SYP and MAP2, which subsequently activated pro-apoptotic genes (Bax, Caspase9, and Caspase3) and inflammatory responses (decreased IL-10, elevated NF-κB, IL-6, TNF-α, and cleaved IL-1β). These alterations ultimately contributed to neurobehavioral deficits. Collectively, these findings indicate that fluoride and phenanthrene induce anxiety behavior and neurotoxicity, associated with perturbations in 5-HT metabolism, gut microbiota composition, oxidative stress, apoptosis, and neuroinflammation.
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ACTA BIOCHIMICA ET BIOPHYSICA SINICA
·
2024
·Vol. 57
·期 4
·604
·
IF 3.3
Xuewei Li,Jinghui Feng,Haiqin Cheng,Ning Jin,Shanshan Jin,Zhizhen Liu,Jun Xu,Jun Xie
Liver fibrosis is a critical stage in the progression of various chronic liver diseases to cirrhosis and liver cancer. Early inhibition of liver fibrosis is crucial for the treatment of liver disease. Hepatectomy, a common treatment for liver-related diseases, promotes liver regeneration. However, in the context of liver fibrosis, liver regeneration is hindered. Many studies have shown that mesenchymal stem cells (MSCs) can promote liver regeneration after partial hepatectomy (PH). However, there are few reports on the impact of MSC therapy on liver regeneration post-PH in the context of hepatic fibrosis. The objective of this study is to examine the impact of MSCs on liver regeneration following PH in the fibrotic liver and uncover the related molecular mechanisms. This study reveals that MSC therapy significantly enhances liver function and mitigates liver inflammation after PH in the context of hepatic fibrosis. MSCs also significantly promote liver regeneration and alleviate liver fibrosis. In addition, this study identifies the role of MSCs in promoting liver regeneration and alleviating liver fibrosis via the activation of Wnt/β-catenin signaling. The combination of MSCs with hepatectomy may offer a novel approach for the treatment of liver fibrotic diseases.
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