TOXICOLOGY
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2025
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IF 4.6
Hua Zhang,Fei Lin,Bo-Han Lin,Xiong-Lin Sun,Qing-Shui Zheng,Rui Gao,Yong Wei,Shao-Hao Chen,Xue-Yi Xue
Bisphenol S (BPS) is widely used in the production of food containers and children's toys and is known to have endocrine-disrupting effects linked to various cancers; however, its role in renal cell carcinoma (RCC) development remains unclear. This study investigates the mechanisms by which BPS may promote RCC progression. The effects of BPS on proliferation and migration were evaluated in HK-2 and 786-O cells using CCK-8, scratch, and Transwell assays. A LASSO regression model and functional analysis were employed to identify candidate genes involved in BPS-related renal cancer progression and to construct a prognostic model, which was validated using Kaplan-Meier and ROC curves. Additionally, the impact of BPS on epithelial-mesenchymal transition (EMT)-related markers was examined. Results showed that BPS did not significantly affect the proliferation of HK-2 and 786-O cells at concentrations of 0-10 μM but significantly enhanced cell migration and invasion, inducing EMT. The LASSO model identified nine key genes associated with BPS-related renal cancer progression, with WNT5A expression positively correlated with BPS concentration. Knockdown of WNT5A significantly inhibited BPS-induced migration of HK-2 and 786-O cells and disrupted the EMT process. These findings demonstrate that BPS promotes HK-2 and 786-O cell migration through the WNT5A-dependent EMT pathway, and inhibition of WNT5A expression can suppress this process. This study provides novel insights into the role of BPS in renal cancer progression and highlights potential therapeutic targets for RCC.
研究领域:
肿瘤学
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分子生物学
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毒理学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2025
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IF 4.8
Eryang Chen,Lei Wang,Qu Wang,Yan Cai,Yaning Dou,Hongyan Qu,Junyi Zhu,Haiyang Zhao,Suqing Zheng,Chengguang Zhao,Bin Chen
Background: Psoriasis, an immune-mediated chronic inflammatory skin disease, is characterized by keratinocyte proliferation and inflammatory cell infiltration. T ripterygium wilfordii is a potential treatment option for psoriasis, and triptolide (TP) is one of its active components. TP may possess the potential to treat psoriasis; however, its mechanism of action remains unknown.Objective: The research aims to explore the therapeutic effect of TP on psoriasis and elucidate its potential targets.Methods: The imiquimod-induced psoriasis-like lesion mouse model was used to identify the mechanism underlying the therapeutic effect of TP.RNA-seq strategy was utilized to forecast the targets and mechanisms of TP in the context of psoriasis.Finally, we verify the effect of TP in the IL-17A-induced keratinocyte hyperproliferation and inflammation model.Results: TP reduced epidermal hyperplasia as well as psoriasis area and severity index scoring. Moreover, treatment with TP inhibited IMQ-induced splenomegaly and T-helper 17 cell differentiation in the psoriatic mice. Additionally, the treatment reduced the serum levels of pro-inflammatory cytokines such as interleukin (IL)-17A, IL-22, IL-23, IL-6, and tumor necrosis factor-α in the mice. The sequencing of RNA obtained from skin lesions of the psoriatic mice indicated that treatment with TP significantly downregulated Wnt5a RNA levels. Moreover, the Wnt5a/β-catenin pathway upregulated by IMQ was downregulated by treatment with TP. Additionally, IL-17A induced and upregulated Wnt5A and β-catenin mRNA expression, and TP inhibited this upregulated expression in HaCaT cells. Furthermore, TP inhibited proliferation, promoted apoptosis, and arrested the cell cycle in the IL-17A-induced keratinocyte hyperproliferation and inflammation model, thereby exhibiting its anti-inflammatory properties.Conclusion: TP alleviated psoriasis in mice by exerting anti-inflammatory effects and inhibited keratinocyte proliferation, which was partly achieved by regulating the Wnt5a/β-catenin signaling pathway.
研究领域:
皮肤病学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
INFLAMMATION
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2022
·Vol. 45
·期 3
·1362-1373
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IF 4.657
Ji Xiang-Fen,Fan Yu-Chen,Sun Fei,Wang Jing-Wei,Wang Kai
Acute liver failure (ALF) is a deadly clinical disorder with few effective treatments and unclear pathogenesis. In our previous study, we demonstrated that aberrant Wnt5a expression was involved in acute-on-chronic liver failure. However, the role of Wnt5a in ALF is unknown. We investigated the expression of Wnt5a and its downstream c-Jun N-terminal kinase (JNK) signaling in a mouse model of ALF established by coinjection of D-galactosamine (D-Gal) and lipopolysaccharide (LPS) in C57BL/6 mice. We also investigated the role of Box5, a Wnt5a antagonist, in vivo. Moreover, the effect of Wnt5a/JNK signaling on downstream inflammatory cytokine expression, phagocytosis, and migration in THP-1 macrophages was studied in vitro. Aberrant Wnt5a expression and JNK activation were detected in D-Gal/LPS-induced ALF mice. Box5 pretreatment reversed JNK activation and eventually decreased the mortality rate of D-Gal/LPS-treated mice, with reduced hepatic necrosis and apoptosis, serum ALT and AST levels, and liver inflammatory cytokine expression, although the latter was not significant. We further demonstrated that recombinant Wnt5a (rWnt5a)-induced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) mRNA expression and increased THP-1 macrophage phagocytosis in a JNK-dependent manner, which could be restored by Box5. In addition, rWnt5a-induced migration of THP-1 macrophages was also reversed by Box5. Our findings suggested that Wnt5a/JNK signaling plays an important role in the development of ALF and that Box5 could have particular hepatoprotective effects in ALF.
研究领域:
肝病学
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免疫学
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分子生物学
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细胞生物学
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PubMed
高影响因子
EXPERIMENTAL AND MOLECULAR PATHOLOGY
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2020
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IF 2.28
Zhaohui Shi,Min Xu,Xiaodong Chen,Jian Wang,Tianfeng Zhao,Dingjun Zha
Allergic rhinitis (AR) is tightly associated with type 2 inflammation. SFRP5 combined with WNT5A mainly inhibits chronic inflammatory response, atherosclerosis , and other metabolic disorders . However, the effect of SFRP5/WNT5A axis on recombinant human interleukin-13 (rhIL-13)-induced inflammation has not been studied. In this study, we aimed to investigate whether secreted frizzled-related protein 5 (SFRP5) could modulate the production of cytokines relevant to eosinophil infiltration and mucin secretion through blocking the activation of Wnt family 5A (WNT5A) signaling pathway . A mouse model of AR demonstrated low expression of SFRP5 and high expression of WNT5A, and indicated that the number of eosinophil and goblet cells was increased, concomitant with elevated IL-13, colony stimulating factor 2 (CSF2), chemokine ligand 11 (CCL11), Mucin 4 , and Mucin 5AC levels. Furthermore, lentivirus-SFRP5 overexpression up-regulated the expression of SFRP5 but down-regulated WNT5A level, and inhibited the activation of JNK pathway via decreasing p-JNK1/2 (Thr183/Tyr185) and p-c-Jun (Ser73) protein expressions in rhIL-13-treated human nasal epithelial cells (HNEpCs). Noticeably, SFRP5 overexpression markedly reduced rhIL-13-induced inflammatory protein and mucin generation through lowered CSF2, CCL11, Mucin 4, as well as Mucin 5AC levels. Taken together, these findings confirmed the regulatory role of SFRP5/WNT5A axis in rhIL-13-mediated inflammatory response in HNEpCs.
研究领域:
免疫学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2026
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IF 6.5
Yong Deng,Zhiyi Guo,Lichun Yu,Junhao Zhang,Jintao Qian,Jiahui Wang,Xing Chen,Zhiwei Xu,Dongjin Wang,Chuiyu Kong
Aortic aneurysm and dissection (AAD) are life-threatening vascular diseases for which effective pharmacological therapies remain limited. Smooth muscle cell phenotypic switching plays a central role in AAD development and progression. Orforglipron, a novel orally active non-peptide glucagon-like peptide-1 receptor agonist, has shown potential cardiovascular benefits; however, its role in AAD remains unclear. In this study, male B6 humanized GLP-1R mice were treated with orforglipron by oral gavage for 28 consecutive days and subjected to beta-aminopropionitrile combined with angiotensin II infusion to induce AAD. Orforglipron treatment protected mice from smooth muscle cell phenotypic switching, medial degeneration, and AAD formation. RNA sequencing of human aortic smooth muscle cells identified Wnt5a as a key downstream target regulated by orforglipron. Mechanistically, orforglipron inhibited ERK phosphorylation, reduced EGR1 expression, and thereby suppressed EGR1-mediated Wnt5a transcription. Conditional deletion of Wnt5a in smooth muscle cells significantly attenuated AAD progression, whereas activation of JNK signaling aggravated vascular remodeling and AAD development. These findings demonstrate that orforglipron attenuates smooth muscle cell phenotypic switching and AAD progression by modulating the ERK/EGR1/Wnt5a/JNK signaling axis, supporting orforglipron as a promising therapeutic candidate for aortic diseases.
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高影响因子
JOURNAL OF PERIODONTAL RESEARCH
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2023
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IF 3.5
Xiaocen Zhang,Maolin Chang,Beike Wang,Xiaoyu Liu,Zhen Zhang,Guangli Han
Objective To verify the role of YAP/WNT5A/FZD4 axis in stretch-induced osteogenic differentiation of hPDLCs. Background During orthodontic tooth movement, differentiation of human periodontal ligament cells (hPDLCs) at the tension side of the periodontal ligament mediates new bone formation. WNT5A promotes osteogenesis and its regulator Yes-associated protein (YAP) is responsive to mechanical stimulation in hPDLCs. However, the mechanisms of YAP and WNT5A in alveolar bone remodeling remain unclear. Methods Cyclic stretch was applied to hPDLCs to mimic the orthodontic stretching force. Osteogenic differentiation was determined by alkaline phosphatase (ALP) activity, Alizarin Red staining, qRT-PCR and western blotting. To detect activation of YAP and expression of WNT5A and its receptor Frizzled-4 (FZD4), western blotting, immunofluorescence, qRT-PCR and ELISA were performed. Verteporfin, Lats-IN-1, small interfering RNAs and recombinant protein were used to explore the relationship of YAP, WNT5A and FZD4, and the effect of their relationship on stretch-induced osteogenesis of hPDLCs. Results WNT5A, FZD4 and nuclear localization of YAP were upregulated by cyclic stretch. YAP positively regulated WNT5A and FZD4 expression and osteogenic differentiation of hPDLCs under cyclic stretch by YAP inhibition or activation assay. Knockdown of WNT5A and FZD4 attenuated YAP-induced and stretch-induced osteogenic differentiation. Recombinant WNT5A rescued the suppressed osteogenic differentiation by YAP inhibitor in hPDLCs, whereas knockdown of FZD4 weakened the effect of WNT5A and amplified the suppression. Conclusions WNT5A/FZD4 could be positively regulated by YAP and the YAP/WNT5A/FZD4 axis mediated osteogenic differentiation of hPDLCs under cyclic stretch. This study provided further insight into the biological mechanism of orthodontic tooth movement.
研究领域:
牙科学
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细胞生物学
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正畸学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL ENDODONTIC JOURNAL
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2026
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IF 6.4
Yongjie Cai,Xiaoting Peng,Beichen Chen,Yiqing Zhao,Waruna Lakmal Dissanayaka,Yiwen Zhang,Shengyan Yang,Qiong Xu
Aim To delineate the mechanisms underlying the role of lactate-related lactylation, a novel post-translational modification, in the odontogenic differentiation of human dental pulp stem cells (hDPSCs). Methodology Dynamic levels of key glycolytic enzymes and histone lactylation along odontogenic differentiation in hDPSCs were evaluated by Western Blot and quantitative PCR (qPCR). Odontogenic differentiation was assessed via Alkaline Phosphatase and Alizarin Red S staining after treatment with sodium lactate, both with and without p300 knockdown. CUT&Tag sequencing of histone H3K18 lactylation (H3K18la) was performed, and genes identified through this analysis were subjected to pathway enrichment. WNT5A-knockdown hDPSCs were generated to elucidate the impact of both WNT5A and WNT5A/Ca 2+ signalling axis in odontogenesis. Finally, we validated the critical function of lactylation in dentine regeneration using a subcutaneous ectopic transplantation model in nude mice with and without sodium lactate via intraperitoneal injection. Results The similar dynamic trends were observed in glycolytic enzyme expression, intracellular lactate and lactylation levels in hDPSCs. Exogenous lactate dose-dependently increased H3K18 lactylation and significantly promoted hDPSC odontogenic differentiation. Mechanistically, the key lactyltransferase p300 was demonstrated to be a regulator that enhanced lactate-induced H3K18la modification and odontogenic differentiation in hDPSCs. CUT&Tag sequencing identified WNT5A as a target gene whose promoter exhibited increased H3K18la enrichment upon lactate treatment. Lactate upregulated WNT5A expression and activated the WNT5A/Ca 2+ signalling pathway via p300-mediated H3K18la, consequently accelerating the odontogenic differentiation. Further in vivo evidence revealed that lactate administration promoted pulp-like tissue regeneration, accompanied by increased hDPSC odontogenic marker expression and H3K18la levels in nude mice with subcutaneously transplanted dentine slices. Conclusions The lactate-driven mechanism acts through the p300-mediated H3K18la-WNT5A/Ca 2+ signalling axis to promote the odontogenic differentiation of hDPSCs. The crosstalk between metabolism, epigenetic modifications and signalling pathways of hDPSCs might offer novel strategies for dental pulp regeneration.
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高影响因子
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