EXPERIMENTAL NEUROLOGY
·
2026
·
IF 4.8
Enzhuang Pan,Juan Chen,Yue Xin,Yaxin Gao,Jingquan Dong,Yingda Xu,Jingyuan Zhou,Xinyu Zhou,Huizhen Chen,Panpan Zhao
Ischemic stroke (IS) is one of the leading causes of global disability and mortality, yet effective treatments targeting oxidative stress (OS) and neuronal apoptosis remain lacking. This study investigates the neuroprotective role of Yes-associated protein (YAP) in IS and its regulatory mechanisms. Using clinical IS patient serum samples, a mouse middle cerebral artery occlusion (MCAO) model, and an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model, we found that YAP protein levels were significantly downregulated post-ischemia, correlating with aggravated OS and neuronal apoptosis. Overexpression of Yap1 via adeno-associated virus (AAV) vectors reduced infarct volume, restored cerebral blood flow, and improved neurological and cognitive functions in MCAO mice. Mechanistically, YAP alleviated oxidative damage by enhancing the activity of antioxidant enzymes ( e.g. , GSH-Px, SOD) and inhibited apoptosis, as validated by TUNEL and Annexin V/PI assays. Intriguingly, under ischemic conditions, YAP phosphorylation was regulated by TAK1 rather than the canonical Hippo signaling pathway. Knockdown of TAK1 synergized with YAP activation to mitigate oxidative damage and neuronal apoptosis. These findings reveal the critical neuroprotective role of YAP in IS and identify the TAK1-YAP interaction as a therapeutic target. This study provides a mechanistic foundation for developing YAP-based interventions for IS.
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高影响因子
Materials Today Advances
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2022
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IF 9.918
Siyong Gao,Yuxin Tang,Wei Sun,Zhixin Liu,Tianyu Zhao,Xiang Li,Tianlu Wang,Guiqing Liao,Tao Xu,Guangsen Zheng,Yujie Liang
Schwann cells (SCs)-based nerve guidance conduits (NGCs) is a promising strategy for repairing long-gap peripheral nerve injury (PNI). But the number of SCs is limited as terminally differentiated cells. Matrix stiffness is able to direct cell fate of stem cells. And nerve-special stiffness (NSS) may contribute to stem cells converting into SCs. However, the potential mechanisms remain uncertain. The present study aimed to elucidate whether the given NSS was able to promote mesenchymal stem cells (MSCs) trans -differentiating into Schwann cell-like cells (SCLCs), facilitating cell-based NGCs repairing PNI. Gelatin methacryloylate (GelMA) hydrogels with different stiffness were manufactured, and their roles in the trans -differentiation of MSCs into SCLCs were investigated in vitro study. The most favorable stiffness (0.9–2.9 kPa) for trans -differentiation and neurotrophic factors expression was confirmed by western blot and immunofluorescence assays. The reason might lie in softer stiffness stretched cell morphology, leading to up-regulation of PIEZO1 and then activating YAP nuclear translocation. As for in vivo study, multi-channel NGCs containing SCLCs were fabricated with extrusion-based bioprinting and then filled a 5 mm gap in sciatic nerve defect of SD rats. It turned out that GelMA-made NGCs with stiffness of 2.9 kPa achieved promising neurogenerative capacity, not only promoting recovering sensory and motor functions, but also improving myelinated nerve fiber regeneration. Our findings demonstrated that 0.9–2.9 kPa might be the desired mechanical strength inducing trans -differentiation into SCLCs via PIEZO1/YAP axis, and the 3D-printed GelMA NGCs combined with SCLCs could be a potential candidate for long-gap peripheral nerve injury.
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JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-16
·
IF 10.6
Qi Ji,Zhang Long,Ren Zhongyu,Yuan Yi,Yu Jiahao,Zhang Yining,Gu Linbo,Wang Xu,Wang Yan,Xu Haoyue,Yu Rutong,Zhou Xiuping
Background The Hippo pathway is a conserved tumour suppressor signalling pathway, and its dysregulation is often associated with abnormal cell growth and tumorigenesis. We previously revealed that the transcriptional coactivator Yes-associated protein (YAP), the key effector of the Hippo pathway, is a molecular target for glioblastoma (GBM), the most common malignant brain tumour. Inhibiting YAP with small interfering RNA (siYAP) or the specific inhibitor verteporfin (VP) can diminish GBM growth to a certain degree. Results In this study, to enhance the anti-GBM effect of siYAP and VP, we designed stepwise-targeting and hypoxia-responsive liposomes (AMVY@NPs), which encapsulate hypoxia-responsive polymetronidazole-coated VP and DOTAP adsorbed siYAP, with angiopep-2 (A2) modification on the surface. AMVY@NPs exhibited excellent blood‒brain barrier crossing, GBM targeting, and hypoxia-responsive and efficient siYAP and VP release properties. By inhibiting the expression and function of YAP, AMVY@NPs synergistically inhibited both the growth and stemness of GBM in vitro. Moreover, AMVY@NPs strongly inhibited the growth of orthotopic U87 xenografts and improved the survival of tumour-bearing mice without adverse effects. Conclusion Specific targeting of YAP with stepwise-targeting and hypoxia-responsive liposome AMVY@NPs carrying siYAP and VP efficiently inhibited GBM progression. This study provides a valuable drug delivery platform and creative insights for molecular targeted treatment of GBM in the future.
研究领域:
肿瘤学
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药学
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分子生物学
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神经科学
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PubMed
高影响因子
BREAST CANCER RESEARCH AND TREATMENT
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2023
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IF 3.8
Lei Lei,Huang Yuan,Shi Lei,Ye Weiwu,Lv Xianmei,Ying Lisha,Yu Xingfei,Cheng Skye Hung-Chun,Zheng Yabing
Purpose Endocrine therapy is the anti-tumor therapy for human breast cancer but endocrine resistance was a major burden. It has been reported that Palbociclib and fulvestrant can be used in combination for the treatment of patients who are experiencing endocrine resistance. However, the underlying mechanism is unclear. In this study, we aimed to investigate the mechanism by which Palbocicilib affected ER-positive breast cancer, combined with fulvestrant. Methods We first detected the effect of palbociclib on cell survival, growth and cycle distribution separately by MTT, colony formation and flow cytometry. Then SNHG17 was screened as palbociclib-targeted LncRNA by LncRNA-seq, and the SNHG17-targeted mRNAs were selected by mRNA-seq for further determination. Subsequently, the underlying mechanism by which palbociclib promoted the cytotoxicity of fulvestrant was confirmed by qRT-PCR, western blot, and immunoprecipitation. Eventually, the xenograft model and immunohistochemistry experiments were used to validate the sensitization effect of palbociclib on fulvestrant and its mechanism in vivo. Results Palbociclib significantly enhanced the cytotoxicity of fulvestrant in fulvestrant-resistant breast cancer cell lines. Interestingly, this might be related to the lncRNA SNHG17 and the Hippo signaling pathway. And our subsequent western blotting experiments confirmed that overexpressing SNHG17 induced the down-regulation of LATS1 and up-regulated YAP expression. Furthermore, we found that the increased sensitivity of breast cancer cells was closely associated with the LATS1-mediated degradation of ER-α. The following animal experiments also indicated that overexpressing SNHG17 obviously impaired the anti-cancer effect of co-treatment of palbociclib and fulvestrant accompanied by decreased LATS1 and increased ER-α levels. Conclusion Palbociclib might sensitize the cytotoxicity of fulvestrant in ER-positive breast cancer cells by down-regulating SNHG17 expression, and then resulted in the LATS1-inactivated oncogene YAP and LATS1-mediated degradation of ER-α.
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ACS Biomaterials Science & Engineering
·
2025
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IF 5.5
Shiyang Wu,Zhen Chai,Yanshen Yang,Rong Ding,Bei Gao,Chen Chen,Siyu He,Zhuofu Zhang,Wanting Wan,Rui Zou
Two-dimensional (2D) models fail to mimic a three-dimensional (3D) environment in studying mechanosensing of stem cells. Here, we present a 3D culture model to investigate how 3D matrix stiffness influences YAP activation and osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) and evaluate the osteogenic potential of hydrogels in vivo. In this study, a 3D culture model with an adjustable matrix stiffness was established. In the in vitro study, first the osteogenic differentiation of hPDLSCs by the expression of OCN, ALP, COL-1, and RUNX-2 was assessed using qRT-PCR, accompanied by ALP staining, and then YAP expression was evaluated by immunofluorescence. In the in vivo study, hPDLSCs, together with gelatin methacrylate (GelMA) hydrogels of different stiffnesses, were implanted into a rat alveolar bone defect model. As matrix stiffness increased, hPDLSCs showed reduced spreading and significantly decreased expression of OCN, ALP, COL-1, RUNX-2, and YAP activation. Specifically, COL-1 expression in the low-stiffness group was 4.3-fold higher than that in the high-stiffness group, and the YAP nuclear/cytoplasmic ratio under low stiffness was 5.5-fold greater than that under high stiffness at day 7. In vivo, the soft-matrix-cell-laden group exhibited more new bone (86.04%) and collagen formation (74.43%) in the defect area than other groups at week 6. Reduced matrix stiffness likely promotes hPDLSC proliferation, spreading, and osteogenic differentiation through YAP activation, and low-stiffness GelMA hydrogels loaded with hPDLSCs significantly enhance alveolar bone regeneration in vivo.
研究领域:
生物医学工程
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干细胞研究
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组织工程
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力学生物学
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再生医学
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Bioactive Materials
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2025
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IF 20.3
Tingting He,Xuemei Liao,Shuangquan Gou,Genhua Liu,Qiaojian Duan,Zizhen Qin,Junli Yang,Yu Sun,Peng Zhao,Zhong Luo,Kaiyong Cai
Inducing immunogenic cell death (ICD) in cancer cells provides a promising approach in immunotherapy, however, oxidative stress relief and metabolic plasticity enhancement limit the immune-stimulating effect of traditional ICD inducer in sentinel lymph nodes (SLN), owing to the metabolism of fatty acids. In this article, a biocompatible green liposome CL-Lip was designed to not only selectively induce ICD in primary and metastatic 4T1 cells, but also relieved the immunosuppression in invasive SLN. CL-Lip is composed of engineered liposomes modified with linoleic acid and catalase, which synergistically trigger ICD, stimulate lipid peroxidation, PD-L1 carbonylation and effectively promote the maturation of dendritic cells and T cell differentiation. Moreover, catalase also downregulated the hypoxia level in SLN. Through cellular experiments and transcriptome analysis, it is proved that the ICD induction via CL-Lip is mediated by ROS generation, resulting from the YAP-dependent fatty acid oxidation (FAO) interference. Transcriptome analysis revealed that engineered CL-Lip diminishes YAP-dependent FAO pathway and effectively antagonizes the metabolic flexibility, thereby selectively triggering the metabolic dead-associated ICD process in both primary and metastatic 4T1 cells. In animal experiments, this little reported metabolic-driven ICD route not only significantly reduces metastatic foci, but also induces a “cold-to-hot” remodeling of SLN, resulting in the formation of a in situ tumor vaccine. These findings hold great significance for the development of next-generation ICD inducers and immunotherapy approaches.
研究领域:
肿瘤学
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免疫学
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代谢生物学
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分子生物学
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纳米医学
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转化医学
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JOURNAL OF ETHNOPHARMACOLOGY
·
2026
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IF 5.4
Shusen Yang,Min Wang,Siyue Liu,Yilin Zhang,Yushan Liu,Mingjie Yang,Wenba Wang,Pengli Wang,Junbo Zou,Jingtao Li,Shuguang Yan,Mingming Si,Hailiang Wei
Ethnopharmacological relevance Colorectal cancer(CRC) is one of the most common malignant tumors of the digestive system, and Traditional Chinese Medicine has shown good efficacy in its treatment and prognosis. Wumei Wan(WMW) is widely used in the treatment of digestive system and tumor diseases, with effects such as anti-diarrheal, anti-dysentery, and pain relief. Modern pharmacological studies suggest that its active ingredients have anti-inflammatory, antioxidant, and anti-tumor properties. However, there is still a lack of systematic research on the role of WMW in the prevention and treatment of CRC and its molecular mechanisms. Aim of this study The aim of this study is to clarify the key active components and primary mechanisms by which WMW inhibits the initiation and progression of CRC, utilizing a multi-faceted approach including chemical composition analysis, network pharmacology, multi-omics studies, molecular biology validation, and molecular simulations. Methods UHPLC-HRMS/MS was used to identify the chemical components in WMW decoction and post-administration serum, and network pharmacology analysis was combined to predict potential targets and signaling pathways. Key differential pathways were selected through combined transcriptomics and proteomics analysis, and the expression patterns of the FAK/Src/YAP axis in CRC were verified using the GEO database. An azoxymethane/dextran sulfate sodium (AOM/DSS)-induced CRC mouse model was constructed to assess the effects of WMW on survival rate, tumor burden, histological changes in the colon, and the expression of related proteins. The expression of downstream genes CTGF and Axin2 was detected via qRT-PCR, and the regulatory effects of WMW-containing serum on FAK/Src/YAP signaling were examined in the HCT116 cells model. Finally, molecular docking and molecular dynamics simulations were performed. Results UHPLC-HRMS/MS analysis identified 15 circulating components of WMW following administration. Network pharmacology analysis revealed 241 overlapping targets between WMW-related targets and CRC-associated genes, which were enriched in pathways related to inflammation regulation, cell proliferation, and focal adhesions, with FAK/Src/YAP-related signaling features emerging as a central network module. In the AOM/DSS-induced CRC model, WMW treatment was associated with changes in body weight, tumor burden, and colonic mucosal structure, along with reduced tissue expression levels of VEGF and p53. Multi-omics analyses showed coordinated alterations in pathways related to inflammation, proliferation, and extracellular matrix (ECM) remodeling following WMW intervention. Analysis of GEO datasets confirmed elevated expression of PTK2, Src, and YAP1 in CRC tissues, supporting aberrant focal adhesion-YAP-associated signaling features in clinical CRC. In vivo and in vitro experiments showed that WMW intervention was associated with reduced phosphorylation levels of FAK, Src, and YAP, decreased stress fiber formation, attenuated YAP nuclear localization, and lower expression of CTGF and PCNA. Molecular docking and molecular dynamics simulations indicated that several circulating components could stably interact with the FAK kinase domain, with auraptene exhibiting relatively favorable binding characteristics. Conclusion These findings suggest that WMW intervention is associated with coordinated alterations in inflammation-related signaling, cell proliferation, and extracellular matrix remodeling in CRC, with focal adhesion-YAP-related mechanotransduction representing a potential associated feature. This study provides integrated experimental evidence supporting further investigation of WMW and traditional Chinese medicine-based strategies targeting focal adhesion-associated signaling in CRC research.
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ACS Biomaterials Science & Engineering
·
2024
·
IF 5.4
Xinyue Xu,Youwei Wang,Changhao Han,Jingsong Lin,Qingan Shen,Youyi Lan,Linjing Long,Xudong Tan,Jiankai Liu,Siyi Liu,Lanxinhui Luo,Mingqi Lv,Yuchan Zhang,Guixue Wang,Guangchao Zang
Without intervention, the natural wound healing process can often result in scarring, which can have detrimental effects on both the physical and mental well-being of patients. Therefore, it is crucial to develop biomaterials that can promote healing without scarring. Regulating the Yes-associated protein-1/PDZ-binding motif (YAP/TAZ) signaling pathway is possible to reduce excessive fibrosis of fibroblasts and proliferation of vascular endothelial cells, ultimately impacting scar formation. Arsenic trioxide (ATO), an ancient drug with medicinal and toxic properties, has shown promise in regulating this pathway. An ATO-loaded hydrogel dressing (ATO@CS/SA) was created to facilitate scarless wound healing, utilizing chitosan (CS) and sodium alginate (SA) to prevent direct contact of ATO with the wound tissue and minimize potential side effects. In vitro studies demonstrated that low concentrations of ATO did not impact cell viability and even promoted proliferation and migration. Co-culturing the hydrogel with fibroblasts and vascular endothelial cells led to decreased expression levels of YAP and TAZ. Animal studies over a 90-day period revealed significant inhibition of scar formation with this system. Histological experiments further confirmed that the decreased expression of YAP and TAZ was responsible for this outcome. In conclusion, when administered at the appropriate dose, ATO can be repurposed from a traditional poison to a therapeutic agent, effectively suppressing excessive cell fibrosis and blood vessel proliferation and offering a novel approach to scar-free treatment.
研究领域:
生物医学工程
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药学
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组织工程
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再生医学
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细胞生物学
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高影响因子
Cancer Communications
·
2023
·Vol. 43
·期 4
·480-502
·
IF 16.2
Daojia Miao,Qi Wang,Jian Shi,Qingyang Lv,Diaoyi Tan,Chuanyi Zhao,Zhiyong Xiong,Xiaoping Zhang
Background The mechanism of metabolism reprogramming is an unsolved problem in clear cell renal cell carcinoma (ccRCC). Recently, it was discovered that the Hippo pathway altered tumor metabolism and promoted tumor progression. Thus, this study aimed at identifying key regulators of metabolism reprogramming and the Hippo pathway in ccRCC and pinpointing potential therapeutic targets for ccRCC patients. Methods Hippo-related gene sets and metabolic gene sets were used to screen potential regulators of the Hippo pathway in ccRCC. Public databases and samples from patients were applied to investigate the association of dihydrolipoamide branched chain transacylase E2 ( DBT ) with ccRCC and Hippo signaling. The role of DBT was confirmed by gain or loss of function assays in vitro and in vivo. Mechanistic results were yielded by luciferase reporter assay, immunoprecipitation, mass spectroscopy, and mutational studies. Results DBT was confirmed as a Hippo-related marker with significant prognostic predictive value, and its downregulation was caused by methyltransferase-like-3 (METTL3)-mediated N6-methyladenosine (m 6 A) modification in ccRCC. Functional studies specified DBT as a tumor suppressor for inhibiting tumor progression and correcting the lipid metabolism disorder in ccRCC. Mechanistic findings revealed that annexin A2 (ANXA2) interacted with the lipoyl-binding domain of DBT to activate Hippo signaling which led to decreased nuclear localization of yes1-associated transcriptional regulator (YAP) and transcriptional repression of lipogenic genes. Conclusions This study demonstrated a tumor-suppressive role for the DBT/ANXA2/YAP axis-regulated Hippo signaling and suggested DBT as a potential target for pharmaceutical intervention in ccRCC.
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高影响因子
PHARMACEUTICAL BIOLOGY
·
2023
·
IF 3.8
Bing Liang,Xiongbin Chen,Min Li,Lingling Zhang,Xia Yang,Liangqin Shi,Yanju Gong,Yuanyuan Gong,Huan Xu,Xiao Wu,Zhong Jin,Yanru Wang,Luwei Liu,Xiaohong Yi,Lushuang Xie,Hua Zhong,Chongyang Shen,Yong Wang,Lan Yang
Context Liuwei Dihuang pill (LWDH) has been used to treat postmenopausal osteoporosis (PMOP).Objective To explore the effects and mechanisms of action of LWDH in PMOP.Materials and methods Forty-eight female Sprague-Dawley rats were divided into four groups: sham-operated (SHAM), ovariectomized (OVX), LWDH high dose (LWDH-H, 1.6 g/kg/d) and LWDH low dose (LWDH-L, 0.8 g/kg/d); the doses were administered after ovariectomy via gavage for eight weeks. After eight weeks, the bone microarchitecture was evaluated. The effect of LWDH on the differentiation of bone marrow mesenchymal stem cells (BMSCs) was assessed via osteogenesis- and lipogenesis-induced BMSC differentiation. The senescence-related biological indices were also detected using senescence staining, cell cycle analysis, quantitative real-time polymerase chain reaction and western blotting. Finally, the expression levels of autophagy-related proteins and Yes-associated protein (YAP) were evaluated.Results LWDH-L and LWDH-H significantly modified OVX-induced bone loss. LWDH promoted osteogenesis and inhibited adipogenesis in OVX-BMSCs. Additionally, LWDH decreased the positive ratio of senescence OVX-BMSCs and improved cell viability, cell cycle, and the mRNA and protein levels of p53 and p21. LWDH upregulated the expression of autophagy-related proteins, LC3, Beclin1 and YAP, in OVX-BMSCs and downregulated the expression of p62.Discussion and conclusions LWDH improves osteoporosis by delaying the BMSC senescence through the YAP-autophagy axis.
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Journal of Materials Chemistry B
·
2024
·
IF 6.1
Yingjun Yang,Kuankuan Han,Siyuan Huang,Kai Wang,Yuchen Wang,Shukai Ding,Le Zhang,Miao Zhang,Bingshe Xu,Shufang Ma,Yongtao Wang,Shengli Wu,Xinlong Wang
Over the past decades, the critical role of cellular contractility associated mechanotransduction in the regulation of cell functions has been revealed. In this case, numerous biomaterials have been chemically or structurally designed to manipulate cell behaviors through the regulation of cellular contractility. In particular, adhesive proteins including fibronectin, poly-l-lysine and collagen type I have been widely applied in various biomaterials to improve cell adhesion. Therefore, clarifying the effects of adhesive proteins on cellular contractility has been valuable for the development of biomaterials design. In this study, a reference-free traction force microscopy with a well-organized microdots array was designed and prepared to investigate the relationship between adhesive proteins, cellular contractility, and mechanotransduction. The results showed that fibronectin and collagen type I were able to promote the assembly of focal adhesions and further enhance cellular contraction and YAP activity. In contrast, although the poly-l-lysine supported cell spreading and elongation, it was inefficient in inducting cell contractility and activating YAP. Additionally, compared with cellular morphogenesis, cellular contraction was essential for YAP activation.
研究领域:
细胞生物学
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生物物理学
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生物材料科学
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机械生物学
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高影响因子
MOLECULAR NUTRITION & FOOD RESEARCH
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2025
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IF 4.2
Qianru Xiang,Xiao Chen,Enhui Tang,Zhi Chen,Zijun Xia,Wenzhen Liao
Current research indicates that insulin secretion deficiency in β-cells contributes to Type 2 diabetes mellitus (T2DM), which is associated with neuropeptide Y 1 receptor (Npy1r) overexpression from neuropeptide Y (NPY) system dysregulation. To date, limited literature has explored nobiletin (NOB) as a circadian modulator for restoring β-cell function through Npy1r regulation. This study investigates NOB's stimulatory effects on insulin secretion via Npy1r and clock-modulatory signaling to elucidate its underlying mechanism. The findings demonstrated that NOB ameliorated hyperglycemia and promoted insulin secretion in two distinct mouse models: T2DM induced by a high-fat diet with low-dose streptozotocin, and acute hyperglycemia triggered by NPY. Moreover, NOB reduced NPY family peptides in the serum and suppressed Npy1r overexpression in β-cells. Comprehensive investigations revealed that NOB mitigated Npy1r-mediated β-cell dysfunction through activating clock-modulatory signaling, evidenced by restored Bmal1::Luc bioluminescence rhythmicity in mouse insulinoma6 (MIN6) cells. Molecular docking confirmed a direct NOB-Npy1r interaction, while mechanistic analyses demonstrated modulation of the retinoic acid-related orphan receptors (RORs)/Bmal1-Yes-associated protein (Yap) pathway via Yap suppression and Bmal1 activation, based on the interventions with palmitic acid, BMS 193885 (Npy1r antagonist), and NPY. Therefore, this study provides evidence that NOB can protect β-cells from insulin secretion dysfunction by downregulating Npy1r expression and activating the RORs/Bmal1-Yap pathway.
研究领域:
内分泌学
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分子生物学
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时间生物学
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糖尿病研究
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药理学
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危险品化学品经营许可证（带存储）