EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2023
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IF 6.7
Jianv Wang,Jing Jia,Qingqing He,Yang Xu,Hongye Liao,Xia Xiong,Li Liu,Changzhen Sun
Recent advancements in tumour-targeted therapies and immunotherapy offer hope to patients with various malignancies. However, the uncontrolled growth and metastatic infiltration of malignant tumours remain a huge therapeutic challenge. Therefore, this study aimed to develop an integrated multifunctional diagnostic and treatment reagent IR-251 that can not only be used for tumour imaging but also to inhibit tumour growth and metastasis. Besides, our results showed that IR-251 targeted and damaged the mitochondria in cancer cells via organic anion-transporting polypeptides . Mechanistically, IR-251 induced ROS overproduction by inhibiting PPARγ and then inhibiting the β-catenin signalling pathway and downstream protein molecules related to the cell cycle and metastasis. Moreover, the excellent anti-tumour proliferation and metastasis ability of IR-251 were verified in vitro/in vivo . And histochemistry staining revealed that IR-251 inhibited tumour proliferation and metastasis, which showed no significant side effect. In conclusion, this novel, multifunctional, mitochondria-targeting near-infrared fluorophore probe IR-251 has great potential in achieving accurate tumour imaging and inhibiting tumour proliferation and metastasis, and the underlying mechanism of action of IR-251 is mainly via the PPARγ/ROS/β-catenin pathway.
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高影响因子
NEUROSCIENCE
·
2026
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IF 3.3
Xiaoyu Lin,Wanliang Du,Ruile Fang,Ying Ma,Yongjun Wang,Jialei Yang
Systemic inflammation worsens ischemic stroke by increasing brain injury, neurological deficits, and neuroinflammation. • Systemic inflammation enhances microglial NF-κB activity and promotes p65/β-catenin interaction. • Systemic inflammation downregulates microglial Wnt/β-catenin/CD36 axis and impairs microglial efferocytosis. • Lithium chloride restores Wnt/β-catenin signaling and microglial efferocytosis, improving stroke outcome under systemic inflammation. Systemic inflammation is associated with worse outcomes after ischemic stroke, but the underlying mechanisms remain poorly understood. Microglial efferocytosis limits post-stroke inflammation and promotes recovery, whereas Wnt/β-catenin signaling has been implicated in neuroprotection and in regulation of CD36, a key efferocytotic receptor. Here, we investigated whether systemic inflammation is associated with alterations in microglial Wnt/β-catenin/CD36 axis and efferocytosis during ischemic injury. Mice were pretreated with lipopolysaccharide (LPS) before transient middle cerebral artery occlusion/reperfusion (tMCAO/R), and BV2 microglia were exposed to LPS before oxygen-glucose deprivation/reoxygenation (OGD/R). LPS pretreatment markedly increased infarct volume, worsened neurological deficits, and amplified post-ischemic neuroinflammatory responses. These effects were accompanied by enhanced microglial NF-κB signaling, increased p65/β-catenin interaction, and reduced nuclear β-catenin, consistent with suppression of Wnt/β-catenin signaling. Reduced CD36 expression and impaired microglial efferocytosis were observed in parallel. Notably, pharmacological activation of Wnt/β-catenin signaling with lithium chloride (LiCl) restored CD36 expression and microglial efferocytosis under LPS-pretreated conditions, and was accompanied by smaller infarcts, improved neurological function, and attenuated neuroinflammation. Collectively, these findings show that LPS pretreatment exacerbates ischemic stroke and is associated with enhanced microglial NF-κB signaling, dysregulation of the Wnt/β-catenin/CD36 axis, and impaired microglial efferocytosis. These results support defective microglial efferocytosis as a potential biological link between systemic inflammation and aggravated ischemic injury and identify Wnt/β-catenin signaling as a candidate pathway for further therapeutic investigation Download: Download high-res image (128KB) Download: Download full-size image
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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2023
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IF 5.3
Xiaojing Xing,Meichen Liu,Xuguang Wang,Qianxue Guo,Hongyue Wang,Wenxue Wang
Diffuse large B-cell lymphoma (DLBCL) is difficult to treat due to the high recurrence rate and therapy intolerance, so finding potential therapeutic targets for DLBCL is critical. FK506-binding protein 3 (FKBP3) contributes to the progression of various cancers and is highly expressed in DLBCL, but the role of FKBP3 in DLBCL and its mechanism are not clear. Our study demonstrated that FKBP3 aggravated the proliferation and stemness of DLBCL cells, and tumour growth in a xenograft mouse model. The interaction between FKBP3 and parkinsonism associated deglycase (PARK7) in DB cells was found using co-immunoprecipitation assay. Knockdown of FKBP3 enhanced the degradation of PARK7 through increasing its ubiquitination modification. Forkhead Box O3 (FOXO3) belongs to the forkhead family of transcription factors and inhibits DLBCL, but the underlying mechanism has not been reported. We found that FOXO3 bound the promoter of FKBP3 and then suppressed its transcription, eventually weakening DLBCL. Mechanically, FKBP3 activated Wnt/β-catenin signalling pathway mediated by PARK7. Together, FKBP3 increased PARK7 and then facilitated the malignant phenotype of DLBCL through activating Wnt/β-catenin pathway. These results indicated that FKBP3 might be a potential therapeutic target for the treatment of DLBCL.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2021
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IF 4.432
Feiran Zhou,Xinyi Hu,Weijing Feng,Minghui Li,Bin Yu,Chenxing Fu,Caiwen Ou
Intimal hyperplasia-induced restenosis is a common response to vascular endothelial damage caused by mechanical force or other stimulation, and is closely linked to vascular remodeling . Curcumin , a traditional Chinese medicine , exhibits potent protective effects in cardiovascular diseases; for example, it attenuates vascular remodeling. Although the suppressive effects of curcumin on diseases caused by vascular narrowing have been investigated, the underlying mechanisms remain unknown. Long non-coding RNAs (lncRNAs) regulate various pathological processes and affect the action of drugs. In the present study, we found that the curcumin remarkably downregulated the expression of lncRNA H19 and thereby inhibited intimal hyperplasia-induced vascular restenosis. Furthermore, the inhibition of the expression of H19 by curcumin resulted in the inactivation of the Wnt/β-catenin signaling. Overall, we show that curcumin suppresses intimal hyperplasia via the H19/Wnt/β-catenin pathway, implying that H19 is a critical molecule in the suppression of intimal hyperplasia after balloon injury by curcumin. These insights should be useful for potential application of curcumin as a therapeutic intervention in vascular stenosis.
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BIOMEDICINE & PHARMACOTHERAPY
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2019
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IF 3.743
Xiao-Jun Chen,Ying-Shan Shen,Min-Cong He,Fan Yang,Peng Yang,Feng-Xiang Pang,Wei He,Yan-ming Cao,Qiu-Shi Wei
Steroid-induced osteonecrosis of the femoral head (SONFH) is a refractory disease induced by glucocorticoids. Marrow mesenchymal stem cells (MSCs) differentiate into multiple bone matrix cells and have been used as cell-based therapies to treat ONFH. However, the osteogenesis of MSCs isolated from patients with SONFH is significantly decreased. Polydatin has been widely used in traditional Chinese remedies due to its multiple pharmacological actions. As shown in our previous study, Polydatin protects from oxidative stress and promotes BMSC migration. However, little is known about its role in BMSC (Bone marrow mesenchymal stem cells) osteogenesis; therefore, we further investigated the effect and mechanism of Polydatin in hBMSC osteogenesis. The ability of Polydatin to promote the proliferation and osteogenic differentiation of hBMSCs was determined using the MTT assay, ALP staining and the ALP activity assay. Next, qPCR and western blotting were performed to measure the levels of genes and proteins related to the osteogenesis of hBMSCs. Then, the effect of Polydatin on the nuclear translocation of β-catenin was determined using immunofluorescence staining. Polydatin (30 μM) markedly enhanced the proliferation of hBMSCs and alkaline phosphatase (ALP) activity. Additionally, it also significantly upregulated the expression of osteogenic genes (Runx2, osteopontin, DLX5, osteocalcin, collagen type I and BMP2) and components of the Wnt signaling pathway (β-catenin, Lef1, TCF7, c-jun, c-myc and cyclin D). These osteogenesis-potentiating effects of Polydatin were blocked by Noggin, an inhibitor of the BMP pathway, and DKK1, an inhibitor of the Wnt/β-catenin pathway. However, DKK1 did not affect Polydatin-induced BMP2 expression. Based on our results, Polydatin promotes the proliferation and osteogenic differentiation of hBMSCs through the BMP2-Wnt/β-catenin signaling pathway.
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BIOCHEMICAL PHARMACOLOGY
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2025
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IF 5.6
Yanhua Zhen,Dongdong Li,Yulu Meng,Zeyu Xing,Jiahe Zheng
Atherosclerosis is a disorder of lipid metabolism, but its pathogenesis has not yet been fully elucidated. This study aimed to clarify the roles of homeodomain interacting protein kinase 2 (HIPK2) in atherosclerosis. Atherosclerotic model was constructed by feeding apolipoprotein E knockout (ApoE -/- ) mice with a high-fat diet. Human THP-1 macrophages and mouse RAW 264.7 macrophages were stimulated with IFN-γ to establish an in vitro model. We showed an upregulation of HIPK2 in the aorta of atherosclerotic mice. HIPK2 knockdown reduced macrophage infiltration, M1 polarization, and attenuates atherosclerosis development. Downregulation of HIPK2 in macrophages led to a significant suppression in the expression of pro-inflammatory factors, which was accompanied by an enhancement in the phosphorylation and degradation of β-catenin, as well as the activation of the signal transducer and activator of transcription 1 (STAT1) signaling pathway. Silencing of HIPK2 alone in THP-1 macrophages resulted in anti-inflammatory effects and suppression of M1 macrophage polarization. However, simultaneous silencing of HIPK2 and β-catenin (CTNNB1) reversed these effects, counteracting the outcomes observed with HIPK2 silencing alone. We validated that small ubiquitin-like modifier (SUMO)-specific peptidase 1 (SENP1) regulated HIPK2 function by affecting the SUMOylation of HIPK2 at the K32 site. SENP1 knockdown promoted HIPK2 SUMOylation, impairing its protein stability. In the rescue experiments, IFN-γ-induced inflammation and M1 polarization were resumed upon restoration of HIPK2 expression in SENP1-silenced macrophages. Our work demonstrated that HIPK2 accelerated the progression of atherosclerosis by regulating β-catenin/STAT1 signaling cascade to promote macrophage infiltration and M1 polarization. HIPK2 was regulated by SENP1-mediated de-SUMOylation.
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CHEMICAL ENGINEERING JOURNAL
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2025
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IF 13.2
Siyu Zhao,Yue Li,Lin Dai,Bo Cheng
The development of artificial biomaterials that simulate the extracellular matrix of bone tissue is a promising strategy for bone regeneration. Hydrogel has become a feasible alternative, yet its lack of biological activity still needs to be improved. Herein, a piezoelectric composite hydrogel (TBP) based on tripolyglycerol monostearate (TM) and loaded with barium titanate (BTO) nanoparticles through hydrogen bonding provided by polydopamine has been developed to promote osteogenesis. In vitro , TBP exhibits excellent injectability, shape adaptability and biodegradability, ensuring the feasibility of its biological applications. Moreover, by virtue of the piezoelectric conversion capability of BTO, TBP has the response ability to low-intensity pulsed ultrasound (LIPUS) and can generate local electrical signals. Meanwhile, TBP performs outstandingly in promoting the proliferation, migration, adhesion and osteogenic differentiation of MC-3 T3-E1 cells. More importantly, TBP combined with LIPUS stimulation can regulate mitochondrial oxidative phosphorylation (OXPHOS) through the AKT/GSK3β/β-catenin signaling cascade, thereby accelerating osteogenesis. In vivo , the application of TBP hydrogel to the bone defect site of rats, combined with LIPUS stimulation, shows satisfactory effects in promoting bone regeneration. To sum up, this piezoelectric composite hydrogel is expected to become a promising candidate for bone tissue engineering.
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Frontiers in Oncology
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2020
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IF 4.848
Jiang Tao,Gao Wenyu,Lin Shengjie,Chen Hao,Du Bin,Liu Qing,Lin Xiaoyan,Chen Qiang
Background: Gastric cancer (GC) has a high morbidity and mortality rate, with peritoneal metastasis (PM) identified as the main site of metastasis. Our previous study found that FNDC1 has a higher frequency of mutations in patients with PM by high-throughput sequencing assay, suggesting that it may be associated with GC invasion and PM, however the specific mechanism remains unclear.Methods: First, the correlation between FNDC1 and PM and prognosis of GC was clarified by bioinformatics and clinicopathological analysis. Next, the effect of FNDC1 expression on the invasion and metastasis ability of GC was investigated in vivo and in vitro. Finally, the signaling pathways involved in the regulation of FNDC1 were explored.Results: FNDC1 was highly expressed in GC and was associated with PM and poor prognosis. FNDC1 was also associated with epithelial-mesenchymal transition (EMT) in GC cells. Through in vivo and in vitro experiments, it was clarified that knockdown of FNDC1 could inhibit the proliferation, invasion, and migration of GC cells. In addition, it was elucidated that FNDC1 promotes EMT through the Wnt/β-catenin signaling pathway.Conclusion: FNDC1 may be associated with the invasion of GC and PM after surgery. FNDC1 was highly expressed in GC tissues and cell lines, while significantly associated with poor DFS and OS in GC patients. Both univariate and multivariate analyses suggested that the expression of FNDC1 was an independent factor for GC. Knockdown of FNDC1 also significantly inhibited the proliferation, migration, and activity of GC cells. FNDC1 may promote EMT in GC cells through the regulation of Wnt/β-catenin signaling pathway. FNDC1 has the potential to be used as a predictor of PM and may also be studied in depth as a therapeutic target for GC, which has potential clinical utility and is worthy of further validation.
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高影响因子
BIOORGANIC CHEMISTRY
·
2025
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IF 4.7
Menglong Zhao,Danqing Wu,Weiqian Qiu,Hongchen Zhang,Min Chen,Haixia Zhou,Xiaoxia Ye,Zhong Han,Xiangchao Shi
4-anilinoquinazoline scaffold, a key structure in the development of EGFR-TKI anticancer drugs such as Gefitinib and Erlotinib, continues to drive advancements in non-small cell lung cancer (NSCLC) therapy. In this study, we synthesized a series of novel derivatives ( B3–B11 ). Structure-activity relationship (SAR) analysis revealed that electron-donating groups para-substituted at the 4-anilino position significantly enhanced antiproliferative activity. Notably, B10 incorporating an acrylamide group at the 4-anilino position demonstrated the most potent activity against NSCLC, with an IC 50 of 1.28 μM in A549 cells, nearly six times more effective than Gefitinib (7.81 μM). Acute toxicity studies confirmed that B10 is safe at doses below 50 mg/kg. In vivo studies using an A549 xenograft model showed a 46 % tumor growth inhibition (TGI) with B10 (25 mg/kg), surpassing the 21 % inhibition of Gefitinib at the same dose. Mechanistic studies revealed that B10 inhibited the AKT/GSK-3β/β-catenin signaling pathway, downregulating Wnt target genes (c-Myc, c-Jun), and reduced COX2 expression and IL-8 levels, showcasing its dual anti-inflammatory and antitumor effects. These results position B10 as a promising NSCLC therapeutic candidate, combining potent efficacy with a favorable safety profile, and enhance our understanding of the SAR and mechanism of action of 4-anilinoquinazoline derivatives.
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MEDICAL ENGINEERING & PHYSICS
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2025
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IF 2.3
SHENGJIE WANG,WEI LIU,CHAO YANG,XIANLONG ZHANG,CHUNMING LYU
Prosthetic loosening represents a catastrophic postoperative complication in artificial joint replacement, resulting in severe patient morbidity and substantial healthcare costs. This investigation aimed to develop a novel strategy for preventing prosthetic loosening. Two-dimensional MXene V 2 C nanosheets were synthesized and subsequently immobilized onto three-dimensional porous sulfonated polyetheretherketone (SPEEK) surfaces with polydopamine (PDA) to form V 2 C-PDA@SPEEK (Abbrev. V 2 C-PS). The biocompatibility was systematically evaluated using rat bone marrow mesenchymal stem cells (rBMSCs) and murine models. The osteogenic differentiation potential of V 2 C-PS was assessed through real-time PCR analysis, Alkaline phosphatase (ALP) staining, and Alizarin Red staining. The in vivo osteogenic capacity of V 2 C-PS surrounding the implant material was evaluated in rat femoral models using micro-CT analysis, biomechanical pull-out testing, sequential fluorescent labeling of newly formed bone, and Van Gieson staining. The molecular mechanisms underlying V 2 C-PS -mediated osteogenic differentiation of rBMSCs were investigated both in vitro and in vivo using chemical inhibitors, β-catenin shRNA lentiviral silencing, and β-catenin mRNA lentiviral overexpression. The results demonstrated that V 2 C-PS exhibited excellent biocompatibility. Quantitative analysis revealed substantial upregulation (p<0.05) of critical osteogenic markers, including RUNX2 (4.4-fold), COL-1 (5.7-fold), OCN (3.3-fold), BMP-2 (4.4-fold), OPN (3.1-fold), BSP (3.3-fold), ON (4.3-fold), and OSX (2.83-fold), in the 25V 2 C-PS treatment group compared to PS group. The bone parameters were also remarkably enhanced in the 25V 2 C-PS group (BMD increased by 241 %, bone-implant contact by 159 %, BV/TV by 225 %, Tb.N by 281 %, Tb.Th by 214 %, maximum pull-out force by 250 %, and Tp.Sp decreased by 33 %). Furthermore, V 2 C-PS were found to enhance rBMSC osteogenic differentiation through activation of the Wnt/β-catenin signaling pathway. This study presents a promising approach for preventing orthopedic prosthetic loosening and demonstrates significant potential for clinical translation.
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高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2022
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IF 7.088
Li-An Shen,Xinyan Peng,Ya Bao,Chenglong Liu,Hao Zhang,Jianqi Li,Di Zhu,Qingwei Zhang
The β -catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential target for the suppression of hyperactive Wnt/ β -catenin signaling that is vigorously involved in cancer initiation and development. Herein, we first described quercetin and its derivatives had potential inhibitory effects on β -catenin/BCL9 PPI. The most potent compound, quercetin-3′- O -(4-methylpiperazine-1-yl) propyl ( C1 ), directly binded with β -catenin and disrupted the β -catenin/BCL9 interaction in both the protein level and the cellular context. C1 also effectively inhibited colorectal cancer in vitro and showed better selectivity in inhibiting hyperactive Wnt/ β -catenin signaling cells like CT26 and HCT116. And we further confirmed that C1 could inhibit CT26 tumor growth in vivo and regulate the tumor immune microenvironment. This study provides a good chemical probe to explore β-catenin-related biology and a drug-like quercetin derivative as novel β -catenin/BCL9 PPI inhibitors for further drug development.
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2026
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IF 15
Ma Tianyu,Li Qiang,Chen Xingwu,Dong Jixiang,Jiang Yuqing,Li Shanshan
Bioactive peptides are promising candidates for hair regeneration, but their topical application is often limited by poor skin delivery and the need for frequent dosing. To overcome these challenges, we designed a palmitoylated peptide, Pal-MPAPO, and incorporated it into a hyaluronic acid-based hydrogel microneedle (MN) system for localized transdermal delivery. The fabricated MNs showed adequate mechanical strength for skin insertion and provided a time-dependent, prolonged release of Pal-MPAPO. In human dermal papilla cells (DPCs), Pal-MPAPO activated the Wnt/β-catenin pathway and increased intracellular cyclic adenosine monophosphate (cAMP) levels in a predominantly VPAC1-dependent manner. Additional VPAC2 validation did not reveal a significant contribution to cAMP signaling under the tested conditions. Functional interactions between Pal-MPAPO and VPAC1 were supported by molecular docking, molecular dynamics simulations, receptor knockdown, and fluorescence imaging. In a C57BL/6 mouse model, Pal-MPAPO-loaded MNs significantly promoted hair regrowth, achieving efficacy comparable to minoxidil but at a reduced application frequency. These findings identify Pal-MPAPO as a potential peptide candidate for hair regeneration and suggest that hydrogel MN-assisted delivery provides a localized peptide administration strategy. Graphical The alternative text for this image may have been generated using AI.
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