BIOORGANIC CHEMISTRY
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2022
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IF 5.307
Tingting Ma,Huanli Cheng,Tongxi Li,Yifan Chen,Tianying Cai,Junjie Bai,Ziming Wu,Xianming Xia,Tiancheng Liang,Yichao Du,Wenguang Fu
Background Although liver fibrosis is a key pathologic process in many liver diseases, therapeutic approaches for inhibiting liver fibrosis are still very limited. N-Acetyl- l -tryptophan ( l -NAT) has a hepatoprotective effect via inhibiting the destruction of liver cells, enhancing cell viability and reducing the inflammation. However, the effect of l -NAT on liver fibrosis is not determined. Purpose The present study investigated the effect of l -NAT on liver fibrosis and explored it potential molecular mechanism. Methods To address this concern, this study was carried out via fibrotic mice model induced by CCl 4 and many approaches such as various histological staining methods, western blot assay, etc. Result l -NAT decreased the levels of alanine aminotransferase (ALT) and aspartate transaminase (AST) in fibrotic mice model induced by carbon tetrachloride (CCl 4 ). Histological staining showed that l -NAT ameliorated liver injury and fibrosis, and reduced the expression of α-smooth muscle actin (α-SMA) and Collagen I protein. l -NAT also attenuated apoptosis by down-regulating the level of pro-apoptotic protein Bax and up-regulating that of anti-apoptotic protein Bcl-2. Moreover, l -NAT inhibited the expressions of TGF-β1/SMAD and matrix metalloproteinase 9 (MMP9) proteins, and reversed the expression of YAP1 protein in CCl 4 -induced liver fibrosis. Conclusion These results clearly demonstrated that l -NAT attenuated CCl 4 -induced liver fibrosis in mice, and this protective mechanism might relate to TGF-β1/SMAD and Hippo/YAP1 signaling pathway. Thus, this study provided data basis for the prevention and treatment of liver fibrosis.
研究领域:
药理学
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肝病学
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分子生物学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Zuo Wanyun,Liu Na,Zeng Yunhong,Xiao Zhenghui,Wu Keke,Yang Fan,Li Biao,Song Qingqing,Xiao Yunbin,Liu Qiming
Luteolin is a flavonoid compound with a variety of pharmacological effects. In this study, we explored the effects of luteolin on monocrotaline (MCT) induced rat pulmonary arterial hypertension (PAH) and underlying mechanisms. A rat PAH model was generated through MCT injection. In this model, luteolin improved pulmonary vascular remodeling and right ventricular hypertrophy, meanwhile, luteolin could inhibit the proliferation and migration of pulmonary artery smooth muscle cells induced by platelet-derived growth factor-BB (PDGF-BB) in a dose-dependent manner. Moreover, our results showed that luteolin could downregulate the expression of LATS1 and YAP, decrease YAP nuclear localization, reduce the expression of PI3K, and thereby restrain the phosphorylation of AKT induced by PDGF-BB. In conclusion, luteolin ameliorated experimental PAH, which was at least partly mediated through suppressing HIPPO-YAP/PI3K/AKT signaling pathway. Therefore, luteolin might become a promising candidate for treatment of PAH.
研究领域:
药理学
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心血管疾病
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分子生物学
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细胞生物学
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DOI
PubMed
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.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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代谢组学
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表观遗传学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
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IF 13.2
Xuyan Wei,Sicong Ren,Mucong Li,Yihan Wang,Jiameng Zhang,Shaobo Zhai,Lijun Liu,Hanchi Wang,Yanmin Zhou
The treatment of complicated infected skin wounds faces many challenges. The presence of stubborn bacterial biofilms is one of the key reasons why such wounds are difficult to heal, because the bacteria in the biofilms can resist multiple antimicrobial agents and delay the healing process by inhibiting the immune response. In order to effectively manage complicated infected wounds, we are developing a hydrogel dressing (CGOD-FNP) with multiple functions. These FNP-based phenolic network hydrogels can activate the PTT effect through near-infrared light (NIR) irradiation and inhibit iron ion metabolism to achieve dual mechanism antibacterial, thereby effectively removing bacterial biofilms. In addition, in the inflammatory response stage, the hydrogel exerts an immunomodulatory function by activating the Hippo-YAP/TAZ signaling pathway, effectively regulating the immune microenvironment of the wound, and finally showing excellent adhesion, antibacterial, immunomodulatory, and tissue healing promotion in a mouse skin infection model. Therefore, CGOD-FNP will become a promising therapeutic strategy for the clinical treatment of complicated infection injuries.
研究领域:
生物材料
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伤口愈合
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抗菌治疗
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免疫调节
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组织工程
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纳米医学
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产品关联
DOI
高影响因子
Oncology Letters
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2017
·Vol. 15
·期 3
·3192-3196
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IF 1.39
Meng Zhou,Youli Zhang,Hong Wei,Junbo He,Dawei Wang,Baoding Chen,Jian Zeng,Aihua Gong,Min Xu
Hexa-D-arginine (D6R), an inhibitor of furin, has potential therapeutic applications in different types of human tumor. However, the function of D6R in targeting pancreatic cancer cells remains to be elucidated. In the present study, the proliferation, invasion and migration abilities of SW1990 and PaTu8988 cells were examined using a Cell Counting Kit‑8, and Transwell and wound healing assays. Subsequently, the expression of proteins associated with epithelial‑mesenchymal transition (EMT) and the Hippo‑yes‑associated protein (YAP) pathway were detected using western blot analysis. It was revealed that D6R significantly inhibited the proliferation, migration and invasion abilities of SW1990 and PaTu8988 cells. Additionally, D6R led to the upregulation of E‑cadherin (an epithelial marker), and the downregulation of N‑cadherin and vimentin (mesenchymal markers) in SW1990 and PaTu8988 cells. Furthermore, the results of the present study revealed that D6R significantly affected the YAP phosphorylation level and the total YAP protein level, indicating that D6R was functionally involved in the Hippo‑YAP signaling pathway. It has been suggested that D6R‑suppressed EMT in SW1990 and PaTu8988 cells may occur via the Hippo‑YAP pathway and that it may be a feasible drug to ameliorate the malignant phenotype of SW1990 and PaTu8988 cells.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Clinical and Translational Medicine
·
2022
·Vol. 12
·期 4
·e836
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IF 8.554
Yuechao Liu,Yang Song,Mengru Cao,Weina Fan,Yaowen Cui,Yimeng Cui,Yuning Zhan,Ruixue Gu,Fanglin Tian,Shuai Zhang,Li Cai,Ying Xing
Background There is growing evidence that endocytosis plays a pivotal role in cancer metastasis. In this study, we first identified endocytic and metastasis-associated genes (EMGs) and then investigated the biological functions and mechanisms of EMGs. Methods Cancer stem cells (CSCs)-like characteristics were evaluated by tumour limiting dilution assays, three-dimensional (3D) spheroid cancer models. Microarray analysis was used to identify the pathways significantly regulated by mammalian Eps15 homology domain protein 1 (EHD1) knockdown. Mass spectrometry (MS) was performed to identify EHD1-interacting proteins. The function of EHD1 as a regulator of cluster of differentiation 44 (CD44) endocytic recycling and lysosomal degradation was determined by CD44 biotinylation and recycling assays. Results EHD1 was identified as a significant EMG. Knockdown of EHD1 suppressed CSCs-like characteristics, epithelial–mesenchymal transition (EMT), migration and invasion of lung adenocarcinoma (LUAD) cells by increasing Hippo kinase cascade activation. Conversely, EHD1 overexpression inhibited the Hippo pathway to promote cancer stemness and metastasis. Notably, utilising MS analysis, the CD44 protein was identified as a potential binding partner of EHD1. Furthermore, EHD1 enhanced CD44 recycling and stability. Indeed, silencing of CD44 or disruption of the EHD1/CD44 interaction enhanced Hippo pathway activity and reduced CSCs-like traits, EMT and metastasis. Interestingly, specificity protein 1 (SP1), a known downstream target gene of the Hippo-TEA-domain family members 1 (TEAD1) pathway, was found to directly bind to the EHD1 promoter region and induce its expression. Among clinical specimens, the EHD1 expression level in LUAD tissues of metastatic patients was higher than that of non-metastatic patients. Conclusions Our findings emphasise that EHD1 might be a potent anti-metastatic target and present a novel regulatory mechanism by which the EHD1/CD44/Hippo/SP1 positive feedback circuit plays pivotal roles in coupling modules of CSCs-like properties and EMT in LUAD. Targeting this loop may serve as a remedy for patients with advanced metastatic LUAD.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症研究
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DOI
PubMed
高影响因子
CELL PROLIFERATION
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2022
·Vol. 55
·期 5
·e13221
·
IF 8.755
Zhicheng Hu,Peng Chen,Linlin Wang,Yu Zhu,Gen Chen,Yunjie Chen,Zhenyu Hu,Lin Mei,Weijing You,Weitao Cong,Litai Jin,Xu Wang,Yang Wang,Xueqiang Guan
Objectives Myocardial infarction (MI) commonly occurs in patients with coronary artery disease and have high mortality. Current clinical strategies for MI still limited to reducing the death of myocardial cells but failed to replace these cells. This study aimed to investigate the role of fibroblast growth factor 6 (FGF6) in enhancing the proliferative potential of cardiomyocytes (CMs) after ischemic injury via the Hippo pathway. Materials and Methods Expression of FGF6 protein was analysed in mice with MI induced by ligation of the left anterior descending coronary artery. Activation of the Hippo pathway and the proliferation potential were examined in ischemic CMs, treated with FGF6 protein or transfected with an adeno-virus carrying FGF6 sh-RNA. Immunofluorescence staining and western blotting were performed to assess the relationship between FGF6 and the Hippo pathway. Results We found that FGF6 expression was significantly increased in the MI mouse model. Knockdown of FGF6 synthesis resulted in poorer heart function after MI. By contrast, treatment with recombinant human FGF6 protein improved heart function, reduced infarct size, and promoted cardiac repair. Additionally, FGF6 restrains the activation of the Hippo pathway and subsequently promotes nuclear accumulation of YAP. This was largely counteracted by treatment with extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor U0126. Conclusion FGF6 inhibits the Hippo pathway via ERK1/2, and facilitates nuclear translocation of YAP, and thereby promotes cardiac repair after MI.
研究领域:
心脏病学
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分子生物学
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再生医学
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DOI
PubMed
高影响因子
EXPERIMENTAL ANIMALS
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2023
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IF 2.4
Hong-Bo YANG,Ying LI,Xiu-Hai LI,Qing-Ming YAN,Xian-Zhang HAN,Jian CAO,Hong-Peng SANG,Jin-Long LI
Spinal cord injury (SCI) is a devastating disease characterized by neuronal apoptosis. Gli-similar 3 (GLIS3), a transcriptional factor, was involved in cell apoptosis and associated with the transcription of downstream target genes related to neuronal function. However, the function of GLIS3 in SCI remains unknown. Therefore, we used the mouse model of SCI to explore the role of GLIS3 in SCI. The results showed that GLIS3 expression was significantly increased in spinal cord tissues of SCI mice, and GLIS3 overexpression promoted the functional recovery, reserved histological changes, and inhibited neuronal apoptosis after SCI. Through online tools, the potential target genes of GLIS3 were analyzed and we found that Mps One Binder Kinase Activator 1b (MOB1b) had a strong association with SCI among these genes. MOB1b is a core component of Hippo signaling pathway, which was reported to inhibit cell apoptosis. MOB1b expression was significantly increased in mice at 7 days post-SCI and GLIS3 overexpression further increased its expression. Dual-luciferase reporter assay revealed that GLIS3 bound to the promoter of MOB1b and promoted its transcription. In conclusion, our findings reveal that the compensatory increase of GLIS3 promotes functional recovery after SCI through inhibiting neuronal apoptosis by transcriptionally regulating MOB1b. Our study provides a novel target for functional recovery after SCI.
研究领域:
神经科学
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分子生物学
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转录调控
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DOI
PubMed
高影响因子
International Journal of Medical Sciences
·
2020
·
IF 2.523
Hao Hu,Liang Xu,Shao-Ju Luo,Ting Xiang,Yan Chen,Zhi-rui Cao,Yu-jian Zhang,Zhuomao Mo,Yongdan Wang,Dong-fang Meng,Ling Yu,Li-zhu Lin,Shi-Jun Zhang
Retinal dehydrogenase 5 (RDH5) is an important enzyme in the visual cycle. Several studies have reported that the RDH family may play crucial roles in tumor prognosis. However, the role of RDH5 in tumor prognosis is still unclear. We examined the mRNA level of RDH5 by using q-PCR in hepatocellular carcinoma (HCC) and adjacent non-cancerous tissues. The proliferation rate of HCC cells was detected by MTS assay, and the invasive ability was examined by transwell and scratch wound assays. The YAP protein localization and expression were visualized by immunofluorescence in two different cell lines. CpG islands in the promoter region were predicted by using the methprimer database. Clinical characteristics of a patient cohort data came from The Cancer Genome Atlas database. RDH5 was significantly downregulated in hepatocellular carcinoma tissues, and low RDH5 expression was associated with metastasis and poor patient prognosis. Functional assays revealed that the RDH5 promoter is methylated in HCC cell lines. Moreover, overexpressing RDH5 can suppress metastasis by reversing the epithelial-mesenchymal transition (EMT) process, and RDH5 also inhibits cell proliferation in HCC cell lines. Furthermore, suppressing RDH5 can activate the Hippo/YAP signaling pathway and promote the nuclear translocation of YAP. Clinical data demonstrated that RDH5 is an independent prognostic factor in HCC. In our study, we provided the first evidence that RDH5 plays a crucial role in suppressing proliferation and metastasis, and the RDH5 promoter is methylated in hepatocellular carcinoma. And as an important regulator, RDH5 can suppress the Hippo/YAP signaling pathway. Taken together, it revealed that RDH5 might be a potential therapeutic target in HCC patients.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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基因组学
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DOI
PubMed
高影响因子
Advanced Science
·
2026
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IF 14.1
An Xu,Xiang-Nan Xu,Xiao Huang,Zhou Luo,Chun-Lian Li,Yang Du,Cheng Yan,Xiao-Jie Yu,Jian-Wen Wang,Long-Di Yao,De-Yuan Fu
Epithelial-mesenchymal transition (EMT) is a key driver of breast cancer progression, yet the upstream transcriptional and ubiquitin-mediated mechanisms that modulate Hippo signaling remain incompletely defined. In this study, we identify a regulatory axis in which the transcription factor ZBTB11 promotes breast cancer aggressiveness by enhancing the expression of the F-box protein FBXO28. ZBTB11 directly binds to the FBXO28 promoter and increases its transcription, leading to elevated FBXO28 protein levels. We show that FBXO28 functions as an E3 ubiquitin ligase that targets the core Hippo kinase MST1 for K48-linked ubiquitination and proteasomal degradation. Reduction of MST1 diminishes Hippo pathway activity, resulting in decreased phosphorylation and enhanced nuclear accumulation of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), which subsequently activates EMT-related gene expression. Functionally, disruption of the ZBTB11-FBXO28-MST1 axis suppresses EMT, migration, invasion, and tumor growth in vitro and in vivo, whereas reintroduction of FBXO28 or depletion of MST1 reverses these effects. Together, our findings reveal a previously unrecognized transcription-ubiquitination cascade that modulates Hippo signaling and contributes to breast cancer progression, highlighting this axis as a candidate therapeutic vulnerability that warrants further validation for limiting metastasis.
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DOI
PubMed
高影响因子
IUBMB LIFE
·
2025
·Vol. 77
·期 8
·e70033
·
IF 3.2
Yue Wu,Jiahui Gao,Zejie Su,Anran Gao,Jingxiu Zhao,Guanying Qiao,Minling Ye,Dongdong Liu,Jianhua Xu
The development of acquired drug resistance in breast cancer (BC) significantly compromises treatment efficacy and patient survival, yet the underlying molecular mechanisms remain completely understood. In this study, we investigated the role of the Hippo signaling pathway and its regulatory factor, LIM Domain Only 4 (LMO4), in the acquired Adriamycin (ADR)-resistant MCF-7 (AdrR) cells. Using a combination of bioinformatics and experimental approaches, we demonstrated that AdrR cells exhibit defective apoptosis upon ADR treatment, characterized by abnormal expression of apoptotic proteins such as BAX and BCL2. RNA sequencing (RNA-seq) and ATAC sequencing (ATAC-seq) revealed significant dysregulation of the Hippo pathway in AdrR cells compared to parental MCF-7 cells, suggesting its involvement in mediating drug resistance. Further experiments showed that small interfering RNA (siRNA)-mediated knockdown of LMO4 (siLMO4) altered the expression of apoptotic proteins and partially restored ADR sensitivity in AdrR cells. Mechanistically, LMO4 was found to modulate the Hippo pathway, as evidenced by changes in the nuclear translocation of YAP and the phosphorylation levels of key Hippo pathway components (MST1/2 and YAP). Inhibition of the Hippo pathway using a Lats kinase inhibitor further confirmed its role in regulating drug resistance. Our findings highlight the critical involvement of the LMO4-Hippo signaling axis in ADR resistance and propose LMO4 as a potential therapeutic target for reversing chemoresistance in BC. This study provides novel insights into the molecular mechanisms of drug resistance and offers a foundation for future research aimed at improving treatment strategies for ADR-resistant breast cancer.
研究领域:
肿瘤学
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分子生物学
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生物信息学
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信号转导
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药物基因组学
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产品关联
DOI
PubMed
高影响因子
Cell Death Discovery
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2026
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IF 10.4
Hao Wenli,Gao Song,Guo Suhan,Luo Jingjing,Li Siyu,Lu Junze,Jiang Lulu,Lu Jie,Wang Nan,Ran Aijia,Qian Xiaoyun,Gao Xia,Yu Chenjie,Cheng Cheng
Lipid metabolism is an important biological process that maintains the dynamic balance of several key functions, such as intracellular energy metabolism, signal transduction, and membrane remodeling. However, the role of lipid metabolism in auditory function and the underlying mechanisms remain unclear. Our results reveal that the neomycin exposure disrupts lipid metabolism in auditory system. We find that neomycin-induced hair cells (HC) damage leads to abnormal lipid droplets (LD) accumulation. Further research reveals that decreased YAP expression is a key factor that contributes to abnormal LD accumulation. In both in vivo and in vitro studies, Yap overexpression reduces abnormal LD accumulation and mitigated HC damage. To further investigate its downstream mechanisms, we perform a cross-analysis of Yap -related and lipid metabolism–related genes, identifying that Cox2 is a key downstream target of Yap that contributes to LD accumulation and HC damage. Our work provides clear evidence for the role of lipid metabolism in neomycin-induced hearing loss and elucidates underlying mechanism of Yap/Cox2 pathway. These findings provide new perspectives and avenues for the clinical treatment of sensorineural hearing loss.
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DOI
PubMed
高影响因子
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