PHYTOTHERAPY RESEARCH
·
2019
·Vol. 33
·期 5
·1579-1591
·
IF 3.766
Li Wan,Qun Zhang,Sheng Wang,Yong Gao,Xiaofei Chen,Yang Zhao,Xiaoping Qian
Angiogenesis is central to a wide range of physiological and pathological processes including wound healing, macular degeneration, and cancer. Excessive or inappropriate vascular supply of tumors is one of the main targets for cancer therapy. Recently, critical and selective transcriptional factors such as yes-associated protein (YAP) that control the expression of angiogenesis factors have gained increasing attention in antiangiogenic therapy. In this study, we have identified and characterized a novel inhibitor of YAP, gambogic acid (GA), which exerted striking antiangiogenic effects both in vitro and in vivo. We demonstrated that GA remarkably inhibited a variety of vascular endothelial growth factor-induced angiogenesis processes including proliferation, migration, sprouting, and tube formation of endothelial cells in vitro. In addition, GA resulted in decreased neo-vessel formation in Matrigel plugs of mice and chick chorioallantoic membrane. More importantly, we showed that GA limited tumor growth via preventing tumor angiogenesis and vascular maturation. Further mechanistic studies illustrated that GA directly targeted YAP/STAT3 signaling axis, which is critical for the transcriptional regulation of a series of angiogenic factors. Taken together, these preclinical findings suggest that GA significantly repressed tumor angiogenesis and may serve as a promising drug candidate against cancer.
研究领域:
肿瘤学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2024
·
IF 4.7
Huilin Li,Yanying Zhou,Chenghui Cai,Hangfei Liang,Xuan Li,Min Huang,Shicheng Fan,Huichang Bi
Fenofibrate is a clinically prescribed drug for treating hypertriglyceridemia, which is also a classic peroxisome proliferator activated receptor α (PPARα) agonist. We previously reported that fenofibrate induced liver enlargement in adult mice partially through yes-associated protein (YAP) signaling pathway. However, the effects of fenofibrate on liver enlargement and the YAP signaling pathway in aging mice remain unclear. In this study, D-galactose-induced aging mice, naturally aging mice and senescence accelerated mice P8 (SAMP8) were used to investigate the effects of aging on fenofibrate-induced liver enlargement and YAP signaling activation. The results showed that fenofibrate-induced liver enlargement in aging mice was consistent with that of adult mice. The effect of fenofibrate on hepatocyte enlargement around the central vein (CV) area and hepatocyte proliferation around the portal vein (PV) area was comparable between adult and aging mice. There was no significant difference in the upregulation of PPARα downstream proteins between the two groups following fenofibrate treatment. Fenofibrate treatment also increased the expression of proliferation-related proteins and activated the YAP signaling pathway to a similar degree in both groups. In summary, these results demonstrated that the fenofibrate-induced liver enlargement and activation of the YAP pathway are consistent between adult and aging mice, indicating that the effect of fenofibrate on promoting liver enlargement and its activation of the PPARα and YAP pathway were independent of aging. These findings provide a new perspective for the clinical use of fenofibrate in elderly patients and provide a new insight for role of PPARα in liver enlargement.
研究领域:
药理学
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老年学
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分子生物学
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肝病学
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
·
2024
·
IF 3.3
Ruige Yang,Xiangjing Fu,Jiangping Fan,Tingting Wang,Jian Song,Ting Xu,Yong Guo,Sai-Yang Zhang
Honokiol, derived from Magnolia officinalis (a traditional Chinese medicine), has been reported to have anticancer activity. Here, a series of novel honokiol thioethers bearing a 1,3,4-oxadiazole moiety were prepared and evaluated for their anticancer activities against three types of digestive system tumor cells. Biological evaluation showed that honokiol derivative 3k exhibited the best antiproliferative activity against HCT116 cells with an IC 50 value of 6.1 μmol/L, superior to the reference drug 5-fluorouracil (IC 50 : 9.63 ± 0.27 µmol/L). The structure–activity relationships (SARs) indicated that the introduction of –(4-NO 2 )Ph, 3-pyridyl, –(2-F)Ph, –(4-F)Ph, –(3-F)Ph, –(4-Cl)Ph, and –(3-Cl)Ph groups was favorable for enhancing the anticancer activity of the title honokiol thioethers. Further study revealed that honokiol thioether 3k can well inhibit the proliferation of colon cancer cells HCT116, arresting the cells in G1 phase and inducing cell death. Moreover, a preliminary mechanism study indicated that 3k directly inhibits the transcription and expression of YAP protein without activating the Hippo signaling pathway. Thus, honokiol thioether 3k could be deeply developed for the development of honokiol-based anticancer candidates.
研究领域:
药理学
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肿瘤学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2023
·
IF 5.8
Xinyu Guo,Mengqing Liu,Bing Han,Yeqing Zheng,Kaina Zhang,Gaowa Bao,Chenying Gao,Hongwen Shi,Qiang Sun,Zhenghang Zhao
The clinic application of doxorubicin (DOX) is severely limited by its severe cardiotoxicity. Tripartite motif-containing protein 16 (TRIM16) has E3 ubiquitin ligase activity and is upregulated in cardiomyocytes under pathological stress, yet its role in DOX-induced cardiotoxicity remains elusive. This study aims to investigate the role and mechanism of TRIM16 in DOX cardiotoxicity. Following TRIM16 overexpression in hearts with AAV9-TRIM16, mice were intravenously administered DOX at a dose of 4 mg/kg/week for 4 weeks to assess the impact of TRIM16 on doxorubicin-induced cardiotoxicity. Transfection of OE-TRIM16 plasmids and siRNA-TRIM16 was performed in neonatal rat cardiomyocytes (NRCMs). Our results revealed that DOX challenge elicited a significant upregulation of TRIM16 proteins in cardiomyocytes. TRIM16 overexpression efficiently ameliorated cardiac function while suppressing inflammation, ROS generation, apoptosis and fibrosis provoked by DOX in the myocardium. TRIM16 knockdown exacerbated these alterations caused by DOX in NRCMs. Mechanistically, OE-TRIM16 augmented the ubiquitination and degradation of p-TAK1, thereby arresting JNK and p38MAPK activation evoked by DOX in cardiomyocytes. Furthermore, DOX enhanced the interaction between p-TAK1 and YAP1 proteins, resulting in a reduction in YAP and Nrf2 proteins in cardiomyocytes. OE-TRIM16 elevated YAP levels and facilitated its nuclear translocation, thereby promoting Nrf2 expression and mitigating oxidative stress and inflammation. This effect was nullified by siTRIM16 or TAK1 inhibitor Takinib. Collectively, the current study elaborates that upregulating TRIM16 mitigates DOX-induced cardiotoxicity through anti-inflammation and anti-oxidative stress by modulating TAK1-mediated p38 and JNK as well as YAP/Nrf2 pathways, and targeting TRIM16 may provide a novel strategy to treat DOX-induced cardiotoxicity.
研究领域:
心脏病学
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分子生物学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-20
·
IF 15.7
Luo Xiaobin,Yang Jia,Zhao Yonggang,Nagayasu Toshitatsu,Chen Junlin,Hu Peilun,He Zhi,Li Zifan,Wu Jun,Zhao Zhe,Duan Guman,Sun Xiaodan,Zhao Lingyun,Pan Yongwei,Wang Xiumei
Chronic allodynia stemming from peripheral stump neuromas can persist for extended periods, significantly compromising patients’ quality of life. Conventional managements for nerve stumps have demonstrated limited effectiveness in ensuring their orderly termination. In this study, we present a spatially confined conduit strategy, designed to enhance the self-organization of regenerating nerves after truncation. This innovative approach elegantly enables the autonomous slowing of axonal outgrowth in response to the gradually constricting space, concurrently suppressing neuroinflammation through YAP-mediated mechanotransduction activation. Meanwhile, the decelerating axons exhibit excellent alignment and remyelination, thereby helping to prevent failure modes in nerve self-organization, such as axonal twisting in congested regions and overgrowth beyond the conduit’s capacity. Additionally, proteins associated with mechanical allodynia, including TRPA1 and CGRP, exhibit a gradual reduction in expression as spatial constraints tighten, a trend inversely validated by the administration of the YAP-targeted inhibitor Verteporfin. This spatially confined conduit strategy significantly alleviates allodynia, thus preventing autotomy behavior and reducing pain-induced gait alterations.
研究领域:
神经科学
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生物医学工程
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疼痛研究
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
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2021
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IF 5.34
Ying-yuan Zhao,Xin-peng Yao,Ting-ying Jiao,Jia-ning Tian,Yue Gao,Shi-cheng Fan,Pan-pan Chen,Yi-ming Jiang,Yan-ying Zhou,Yi-xin Chen,Xiao Yang,Min Huang,Hui-chang Bi
Background Schisandrol B (SolB) is one of the bioactive components from a traditional Chinese medicine Schisandra chinensis or Schisandra sphenanthera . It has been demonstrated that SolB exerts hepatoprotective effects against drug-induced liver injury and promotes liver regeneration . It was found that SolB can induce hepatomegaly but the involved mechanisms remain unknown. Purpose This study aimed to explore the mechanisms involved in SolB-induced hepatomegaly. Methods Male C57BL/6 mice were injected intraperitoneally with SolB (100 mg/kg) for 5 days. Serum and liver samples were collected for biochemical and histological analyses. The mechanisms of SolB were investigated by qRT-PCR and western blot analyses, luciferase reporter gene assays and immunofluorescence. Results SolB significantly increased hepatocyte size and proliferation, and then promoted liver enlargement without liver injury and inflammation. SolB transactivated human PXR , activated PXR in mice and upregulated hepatic expression of its downstream proteins, such as CYP3A11 , CYP2B10 and UGT1A1. SolB also significantly enhanced nuclear translocation of PXR and YAP in human cell lines. YAP signal pathway was activated by SolB in mice. Conclusion These findings demonstrated that SolB can significantly induce liver enlargement, which is associated with the activation of PXR and YAP pathways.
研究领域:
药理学
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分子生物学
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肝病学
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产品关联
DOI
PubMed
高影响因子
Cells
·
2024
·Vol. 13
·期 20
·1697
·
IF 5.1
Kai Ni,Bo Che,Rong Gu,Chunhong Wang,Yan Pan,Jingjing Li,Lei Liu,Mingzhi Luo,Linhong Deng
Severe asthma is characterized by increased cell volume (hypertrophy) and enhanced contractile function (hyperresponsiveness) of the airway smooth muscle cells (ASMCs). The causative relationship and underlying regulatory mechanisms between them, however, have remained unclear. Here, we manipulated the single-cell volume of in vitro cultured human ASMCs to increase from 2.7 to 5.2 and 8.2 × 103μm3as a simulated ASMC hypertrophy by culturing the cells on micropatterned rectangular substrates with a width of 25 μm and length from 50 to 100 and 200 μm, respectively. We found that as the cell volume increased, ASMCs exhibited a pro-contractile function with increased mRNA expression of contractile proteins, increased cell stiffness and traction force, and enhanced response to contractile stimulation. We also uncovered a concomitant increase in membrane tension and Piezo1 mRNA expression with increasing cell volume. Perhaps more importantly, we found that the enhanced contractile function due to cell volume increase was largely attenuated when membrane tension and Piezo1 mRNA expression were downregulated, and an auto-regulatory loop between Piezo1 and YAP mRNA expression was also involved in perpetuating the contractile function. These findings, thus, provide convincing evidence of a direct link between hypertrophy and enhanced contractile function of ASMCs that was mediated via Piezo1 mRNA expression, which may be specifically targeted as a novel therapeutic strategy to treat pulmonary diseases associated with ASMC hypertrophy such as severe asthma.
研究领域:
肺生物学
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细胞生物学
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分子生物学
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生物物理学
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呼吸医学
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产品关联
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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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
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
✓ 已验证
产品关联
DOI
高影响因子
CELL BIOCHEMISTRY AND BIOPHYSICS
·
2024
·
IF 1.8
Xu Lei,Zhang Chunfang,Bao Jiawu,Han Guozhu,Wang Changyuan,Cai Yuanqing,Xu Gang,Sun Huijun,Liu Mozhen
This study aims to characterize the bone-protecting effects of Alpha-lipoic acid (ALA), a potent antioxidant, against the detrimental effects of the coexistence of type 2 diabetes mellitus (T2DM) and postmenopausal osteoporosis (POP) and identify the possible mechanisms with particular reference to its modulation of YAP/Glut4 pathway. The T2DM and POP coexisting model was induced in mice by high fat diet (HFD) + Streptozocin (STZ) + ovariectomy (OVX). The mice in the treatment groups were given ALA for 10 weeks. In the in vitro study, MC3T3-E1 cells were induced with 500 μM methylglyoxal for 24 h with or without pretreatment with ALA for 24 h. The oxidative and antioxidative biomarkers, bone microarchitecture, histo-morphology, and related protein expression of apoptosis, osteogenic differentiation and the YAP/Glut4 pathway were detected. The results showed ALA could improve glucose tolerance, inhibit oxidative stress and apoptosis and alleviate bone loss. Further study by siRNA technology revealed that the YAP/Glut4 pathway was implicated in the pathogenesis of bone loss due to the coexistence of T2DM and POP. Taken together, the present study has demonstrated for the first time that ALA exerts potent protective effects against bone loss in T2DM and POP coexisting conditions by modulating the YAP/Glut4 pathway.
研究领域:
内分泌学
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药理学
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分子生物学
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病理生理学
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骨生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Feng Sa,Liu Linyan,Cheng Yuelin,Zhou Mengmeng,Zhu Haoqiang,Zhao Xinyan,Chen Ziyu,Kan Shunli,Fu Xuanhao,Hu Wei,Zhu Rusen
Objective: The limited ability to regenerate axons after spinal cord injury (SCI) is influenced by factors such as astrocyte activation, reactive proliferation, and glial scar formation. The TGF-β/Smad (transforming growth factor-β/mothers against decapentaplegic homolog) pathway, associated with astrocytic scarring, plays a crucial role in recovery post-injury. This study aims to investigate how icariin (ICA) interacts with reactive astrocytes in the treatment of spinal cord injury.Methods: A rat SCI model was constructed, and the recovery of motor function was observed after treatment with ICA.HE staining, LFB staining, immunofluorescence staining, and Western blotting were employed to assess ICA's ability to inhibit astrocyte proliferation in rats following spinal cord injury by modulating YAP, as well as to evaluate the reparative effects of ICA on the injured spinal cord tissue. Primary astrocytes were isolated and cultured. Immunoprecipitation-Western Blot (IP-WB) ubiquitination and cytoplasm-nuclear separation were employed to assess PPM1B ubiquitination and nuclear translocation.Results: The CatWalk XT gait analysis, BBB (Basso, Beattie, and Bresnahan) score, electrophysiological measurements, HE staining, and LFB staining collectively demonstrated that ICA promotes motor function and tissue recovery following spinal cord injury in rats. Immunofluorescence staining and Western Blot analyses revealed that ICA inhibits astrocyte proliferation in rats post-spinal cord injury by suppressing YAP activity. Furthermore, the activation of YAP by XMU-MP-1 was shown to compromise the efficacy of ICA in these rats after spinal cord injury. Additional immunofluorescence staining and Western Blot experiments confirmed that ICA inhibits TGFβ1-induced astrocyte activation through the regulation of YAP. The knockdown of PPM1B (protein phosphatase, Mg2+/Mn2+-dependent 1B) in astrocytes was found to inhibit TGFβ signaling. Additionally, YAP was shown to regulate PPM1B ubiquitination and nuclear translocation through immunoprecipitation-Western blot analysis, along with the segregation of cytoplasm and nucleus.Conclusion: Icariin promotes functional recovery in rats after spinal cord injury by inhibiting YAP and regulating PPM1B ubiquitination to inhibiting the activation of reactive astrocytes.
研究领域:
神经科学
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药理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2022
·Vol. 27
·期 4
·1209
·
IF 4.927
Jiacheng He,Xianhua Lin,Fanhui Meng,Yumiao Zhao,Wei Wang,Yao Zhang,Xiaolei Chai,Ying Zhang,Weiwei Yu,Junjie Yang,Guichao Li,Xuekui Du,Hankun Zhang,Mingyao Liu,Weiqiang Lu
Metastatic pancreatic cancer remains a major clinical challenge, emphasizing the urgent need for the exploitation of novel therapeutic approaches with superior response. In this study, we demonstrate that the aberrant activation of prostaglandin E2(PGE2) receptor 4 (EP4) is a pro-metastatic signal in pancreatic cancer. To explore the therapeutic role of EP4 signaling, we developed a potent and selective EP4 antagonist L001 with single-nanomolar activity using a panel of cell functional assays. EP4 antagonism by L001 effectively repressed PGE2-elicited cell migration and the invasion of pancreatic cancer cells in a dose-dependent manner. Importantly, L001 alone or combined with the chemotherapy drug gemcitabine exhibited remarkably anti-metastasis activity in a pancreatic cancer hepatic metastasis model with excellent tolerability and safety. Mechanistically, EP4 blockade by L001 abrogated Yes-associated protein 1 (YAP)-driven pro-metastatic factor expression in pancreatic cancer cells. The suppression of YAP’s activity was also observed upon L001 treatment in vivo. Together, these findings support the notions that EP4–YAP signaling axis is a vital pro-metastatic pathway in pancreatic cancer and that EP4 inhibition with L001 may deliver a therapeutic benefit for patients with metastatic pancreatic cancer.Keywords:pancreatic cancer;metastasis;EP4;small molecule;YAP
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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