ACTA PHARMACOLOGICA SINICA
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2020
·Vol. 42
·期 7
·1190-1194
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IF 5.064
Shen Zhu-qing,Wang Juan,Tan Wen-fu,Huang Tao-min
Hedgehog plays an important role in a wide range of physiological and pathological conditions. Paracrine activation of Hedgehog pathway in stromal cells increases the expression of VEGF, which promotes neovascularization in colorectal cancer and ultimately the growth of colorectal cancer. Berberine (BBR) has anticancer activity. In this study we investigated whether BBR inhibited the growth of colon cancer through suppressing the paracrine sonic hedgehog (SHH) signaling in vitro and in vivo. We showed that BBR (1–10 μM) dose-dependently inhibited the secretion and expression of SHH protein in HT-29 and SW480 cells. BBR did not influence the transcription of SHH, but promoted the degradation of SHH mRNA, thus decreased the SHH mRNA expression in the colorectal cancer cells. In nude mice bearing HT-29 xenograft, oral administration of BBR (100 mg · kg − 1 · d −1 ) or a positive control drug GDC-0449 (100 mg · kg −1 · d −1 ) for 4 weeks markedly suppressed the growth of HT-29 tumor with BBR exhibiting a better antitumor efficacy. The tumor growth inhibition caused by BBR or GDC-0449 was comparable to their respective inhibitory effect on the mouse-specific Gli mRNA expression in the tumor. However, BBR (20 μM) did not affect the expression of human transcription factor Gli1 mRNA in HT-29 and SW480 cells. In conclusion, BBR promotes the degradation of SHH mRNA in colorectal cancer cells, interrupting the paracrine Hedgehog signaling pathway activity thus suppresses the colorectal cancer growth. This study reveals a novel molecular mechanism underlying the anticancer action of BBR.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Oncologie
·
2023
·Vol. 25
·期 3
·233-243
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IF 0.9
Simin Deng,Yuan Xu,Binbin Gao,Tingting Yu,Lun Kuang,Bo’ang Han,Shaolun Feng,Haodong Chi,Qing Cao,Shen Yue,Chen Liu
Objectives
The Sonic hedgehog (SHH) signaling is essential in animal development and tissue homeostasis. Aberrant activation of SHH pathway has been implicated in tumorigenesis and progression of several cancers, including ovarian cancer. Therefore, targeting SHH pathway may pave the way for successful ovarian cancer treatment.
Methods
To identify the potential SHH inhibitors from traditional Chinese medicines, we herein employed two in vitro cell models. In addition, western blotting and quantitative real-time PCR were performed to evaluate the inhibitory activity of Anemarrhenasaponin I (An-I) on SHH signaling in ovarian cancer cells. Cell proliferation assay and transwell assay were used to assess the effect of An-I on tumorigenicity. We also applied RNA-seq to examine the potential mechanism of An-I against ovarian cancer.
Results
Drug screening results showed that An-I drastically inhibited SHH signaling. More importantly, An-I effectively suppressed ovarian cancer cell proliferation and aggressiveness. RNA-seq-based transcriptome data showed that An-I affected ovarian cancer cells by suppressing SHH-WNT-Matrix metalloproteinases (MMPs) pathway.
Conclusions
An-I suppressed ovarian cancer progression by inhibiting SHH-WNT-MMP signaling transduction, providing a new treatment strategy for ovarian cancer.
研究领域:
肿瘤学
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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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DOI
高影响因子
LIFE SCIENCES
·
2019
·
IF 3.448
Xue Li,Hao Liu,Yuan Lv,Wenqian Yu,Xiaomei Liu,Caixia Liu
Aims Congenital diaphragmatic hernia (CDH) is a lethal birth defect characterized by congenital lung malformation, and the severity of pulmonary hypoplasia directly affects the prognosis of infants with CDH. Using a nitrofen-induced CDH rat model, we previously reported that Foxa2 expression was downregulated in CDH lungs by proteomics analysis. Here, we investigate the role of miR-130a-5p/Foxa2 axis in lung development of the nitrofen-induced CDH and evaluate its potential role in vivo prenatal therapy. Main methods Nitrofen was orally administrated on embryonic day (E) 8.5 to establish a rat CDH model, and fetal lungs were collected on E13.5, E15.5, E17.5, E19.5 and E21.5. The binding sites of miR-130a-5p on Foxa2 mRNA were identified using bioinformatics prediction software and were validated via luciferase assay. The expression levels of miR-130a-5p and Foxa2 were detected using qRT-PCR, ISH, IHC and western blotting. The role of miR-130a-5p/Foxa2 axis in CDH-associated lung development was investigated in ex vivo lung explants. Key findings We found that Foxa2 was downregulated in CDH lung tissues, and Foxa2 upregulating improved CDH branching morphogenesis in ex vivo lung explants. Meanwhile, we also showed that miR-130a-5p was significantly upregulated in CDH lungs and thus inversely correlated with Foxa2. Increasing miR-130a-5p abundance with mimics decreases Foxa2-driven Shh/Gli1 signaling and inhibits branching morphogenesis in ex vivo lung explants. Significance This study was the first to show that the miR-130a-5p/Foxa2 axis played a crucial role in CDH-associated pulmonary hypoplasia. These findings may provide relevant insights into the prenatal diagnosis and prenatal therapy of CDH.
研究领域:
发育生物学
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分子生物学
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儿科
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PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
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2023
·
IF 3.3
Tianqi Huang,Jinglou Chen,Yumiao Zhang,Yao Chen,Congyue Xu,Jing Guo,Hao Ming
Cadmium (Cd) is a toxic heavy metal pollutant and serves as an important environmental endocrine-disrupting chemical. Cd exposure is believed to can enhance the risks of age-related disorders including benign prostatic hyperplasia (BPH). This study was to investigate the harms of Cd exposure on mice prostate and human nonmalignant prostate epithelial RWPE-1 cells. Mice prostate fibrosis was evaluated by visualizing the prostatic collagen deposition via Masson and Sirius red staining, and detecting the content of hydroxyproline. Additionally, the epithelial-mesenchymal transition (EMT), primary ciliogenesis and SHH signaling pathways in both mice prostate and RWPE-1 cells were evaluated. It was found that Cd exposure stimulated prostatic collagen deposition, EMT and primary ciliogenesis, as well as enhanced the circ_0027470 level and reduced the miRNA-1236-3p level. Circ_0027470 functioned as a sponge of miRNA-1236-3p, which had the inhibiting target of SHH. The whole results showed that circ_0027470 promoted Cd exposure-induced prostatic fibrosis via sponging miRNA-1236-3p and subsequently stimulating SHH signaling pathway. This study shed a light on a novel molecular mechanism involved in circRNA for Cd exposure-induced prostate deficits.
研究领域:
毒理学
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分子生物学
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细胞生物学
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环境健康
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DOI
PubMed
高影响因子
Redox Biology
·
2025
·
IF 11.9
Xue Wang,Xin Liu,Yumei Fan,Ke Tan,Jiaqi Gao,Yuejiao Wang,Ziyi Zhang,Shuyue Liu,Xiaofan Wang,Ke Tan,Baohua Wang,Pengxiu Cao
Pulmonary fibrosis (PF) involves persistent activation of fibroblasts and excessive deposition of extracellular matrix, with limited therapeutic options. Pulmonary iron overload has been identified in PF and is associated with the progression of PF. However, the underlying signaling pathway remains unclear. This study demonstrated that iron accumulates in the mouse lung from day 7 post-bleomycin (BLM) instillation until harvest, coinciding with the activation of pulmonary fibroblasts and the onset of fibrogenesis. Iron supplementation promoted the G 1 /S cell cycle transition and proliferation of fibroblasts, and worsened PF, whereas iron deficiency demonstrated the opposite effects. Mechanistically, both iron and reactive oxygen species (ROS) suppress Forkhead box F1 (FOXF1) expression. FOXF1 overexpression upregulates the expression of antioxidant proteins, including ferredoxin 1 (FDX1) and heme oxygenase-1 (HO-1). Both FOXF1 overexpression and FDX1 overexpression reduced cellular labile iron pool (LIP), ROS levels, and collagen synthesis in human pulmonary fibroblasts. Sonic hedgehog (SHH) signaling elevated intracellular iron, fibroblast proliferation, and its own secretion, establishing a sustained SHH/iron amplifying loop. These findings identify an iron/ROS–FOXF1 positive feedback loop and an SHH–iron self-promoting pathway that drive sustained elevated iron levels and persistent fibroblast activation and fibrogenesis, thereby deepening our understanding of the iron signaling in PF.
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PubMed
高影响因子
BMC BIOLOGY
·
2025
·Vol. 23
·期 1
·1-23
·
IF 4.5
Chen Jiangping,Ren Chengyan,Mao Chuanqing,Lai Yongzhen,Lu Meng,Jiang Yuanjing,Chen Weihui
Background The cranial base develops from multipotent mesenchymal cells through endochondral ossification. Genetic ablation of Sonic hedgehog (Shh) or Smoothened (Smo) leads to early apoptosis of cranial base cells, thus limiting the study of their role in the early development of cranial base. Our previous studies have shown that administration of 150 mg/kg Vismodegib (a Smo-specific small molecule antagonist) in E9.5- or E10.5-mice leads to premature mineralization of the skull base synchondroses. In the current study, we further investigated the molecular mechanisms underlying this model.Results Mice exposed to Vismodegib exhibit premature hypertrophic differentiation and osteogenesis of the cranial base synchondroses after E14.5. However, the expression of Patched1 (Ptch1), Gli1, parathyroid hormone-related protein (PTHrP), and Phh3 was not downregulated in exposure mice. We demonstrate that Shh and Wnt signaling pathways were activated in the cranial base region at E10.5. Administration of Vismodegib at E10.5 transiently inhibited Shh signaling in the cranial base area and caused upregulation of β-catenin expression along with ectopic expression of lymphoid enhancer-binding factor 1 (Lef1) and Runx2 in the ventral mesenchymal cells of the cranial base primordium at E12.5. Diverse degrees of cranial base craniosynostosis induced by various doses of Vismodegib suggest a dose-dependent effect of Shh in early basicranium development.Conclusion sThe present experiment suggests that early activation of Shh standardizes normal embryonic development of cranial base after initial morphogenesis, which may be mediated through the “antagonistic” effect of Shh signaling on Wnt signaling. Our study provides new insights into the role of signal-crosstalk in early morphogenesis of the cranial base.
研究领域:
发育生物学
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分子生物学
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遗传学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A
·
2018
·Vol. 106
·期 5
·1258-1268
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IF 3.231
Xiaopeng Zhou,Yiqing Tao,Erman Chen,Jingkai Wang,Weijing Fang,Tengfei Zhao,Chengzhen Liang,Fangcai Li,Qixin Chen
Adipose-derived stem cells (ADSCs)-based tissue engineering was a promising method to treat intervertebral disc degeneration. Type II collagen is a native component in the nucleus pulposus (NP), and has the ability to promote ADSCs to differentiate into NP-like cells. In this article, we aimed to establish a genipin-cross-linked three-dimensional (3D) type II collagen scaffold, and determine the biological effects of the scaffold on ADSCs differentiating into a NP-like phenotype. Different concentrations of genipin were used to cross-link the 3D type II collagen scaffold. Microstructure, surface topography, mechanical strength, porosity, swelling property, and biological stability of the scaffolds were detected to evaluate the scaffold properties. Cell proliferation, gene and protein expression were measured to access the biological effects of the scaffolds on ADSCs, and the related molecular mechanism was investigated. Cross-linking by genipin increased the stability of the type II collagen scaffolds, but deformed the configuration of scaffolds and changed the intrinsic properties of type II collagen. scaffold cross-linked with 0.1% genipin improved the biostability on the basis of maintaining the configuration of scaffold. In addition, the 0.1% genipin-cross-linked scaffold promoted ADSCs proliferation and differentiation into NP-like cells, along with the increasing gene and protein expressions of Sonic Hedgehog (Shh). All these results suggested that 0.1% genipin was the optimal concentration to establish a bio-stable 3D type II collagen scaffold, which inducing ADSC proliferation and differentiation toward a NP-like phenotype through the activation of Shh signaling pathway. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1258–1268, 2018.
研究领域:
组织工程
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干细胞生物学
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骨科
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生物材料
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2021
·Vol. 10
·期 12
·2100028
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IF 9.933
Hang Yang,Yan Luo,Hang Hu,Sibo Yang,Yanan Li,Huijuan Jin,Shengcai Chen,Quanwei He,Candong Hong,Jiehong Wu,Yan Wan,Man Li,Zifu Li,Xiangliang Yang,Ying Su,Yifan Zhou,Bo Hu
Angiogenesis, an essential restorative process following ischemia, is a promising therapeutic approach to improve neurological deficits. However, overcoming the blood–brain barrier (BBB) and effective drug enrichment are challenges for conventional drug delivery methods, which has limited the development of treatment strategies. Herein, a dual-targeted therapeutic strategy is reported to enable pH-sensitive drug release and allow cerebral ischemia targeting to improve stroke therapeutic efficacy. Targeted delivery is achieved by surface conjugation of Pro-His-Ser-Arg-Asn (PHSRN) peptides, which binds to integrin α 5 β 1 enriched in the cerebral vasculature of ischemic tissue. Subsequently, smoothened agonist (SAG), an activator of sonic hedgehog (Shh) signaling, is coupled to PHSRN-HES by pH-dependent electrostatic adsorption. SAG@PHSRN-HES nanoparticles can sensitively release more SAG in the acidic environment of ischemic brain tissue. More importantly, SAG@PHSRN-HES exerts the synergistic mechanisms of PHSRN and SAG to promote angiogenesis and BBB integrity, thus improving neuroplasticity and neurological function recovery. This study proposes a new approach to improve the delivery of medications in the ischemic brain. Dual-targeted therapeutic strategies have excellent potential to treat patients suffering from cerebral infarction.
研究领域:
神经科学
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药学
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分子生物学
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治疗学
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产品关联
DOI
PubMed
高影响因子
Biomed Research International
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2022
·
IF 3.246
Jie Jiang,Zhenghua Liu,Xiuping Zhou,Fenglan Peng,Zhihui Wang,Feng Li,Ming Li
To investigate the effect and mechanism of resveratrol on the biological behavior of cervical cancer cells (HeLa cells), the apoptosis, migration, and invasion of HeLa cells were detected by flow cytometry, wound healing, and transwell assays. The expression levels of Hedgehog signal pathway proteins (smoothened (SMO), zinc finger transcription factors (Gli1), and sonic hedgehog homolog (Shh)) were detected by quantitative real-time PCR (qPCR) and western blotting. Compared with that control group, resveratrol (RES) significantly induced apoptosis, inhibited the migration and invasion of the HeLa cells. The expression of SMO, Gli1, and Shh were downregulated in the HeLa cells treated with RES. The Hedgehog agonist purmorphamine (PUR) reversed the RES-induced increase of apoptosis and reduction of migration and invasion in the HeLa cells. In conclusion, RES induced the apoptosis and suppressed the migration and invasion of HeLa cells by inhibiting Hedgehog signal pathway.
研究领域:
肿瘤学
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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
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2022
·
IF 6.51
Chan Jin,Jinbo Li,Xiaoguang Yang,Shuang Zhou,Chang Li,Jiang Yu,Zhaomeng Wang,Dun Wang,Zhonggui He,Yiguo Jiang,Yongjun Wang
Immune checkpoint inhibitors (ICIs) represent a new class of immunotherapy drugs, and are used to relieve immune suppression or enhance the immune response through the blockade of checkpoint ligands or receptors. ICIs have achieved great success in clinical cancer treatment. Monoamine oxidase A (MAOA) is a potent immune checkpoint of immunotherapy. Recently, it has been reported that MAOA inhibitors could enhance CD8 + T cell activity by upregulating 5-HT autocrine pathway in T cells. In this study, we synthesized doxorubicin (DOX) and isoniazid (INH, a MAOA inhibitor) conjugates through a pH sensitive hydrazone bond. Results of the in vivo studies showed that DOX-INH could effectively enhance the activity of CD8 + T cells and perform a synergistic anti-tumor effect with PD-L1 small molecular inhibitor (BMS202). In addition, in an orthotopic 4T1 breast cancer model, it was demonstrated that DOX-INH could inhibit the epithelial-mesenchymal transition process by blocking Shh, IL-6, and TGF-β signaling pathways, thereby inhibiting the growth and metastasis of breast cancer. Thus, a simple and effective small molecule conjugate produced by the combination of a chemotherapy drug and a MAOA inhibitor shows broad prospect in cancer therapy.
研究领域:
癌症免疫治疗
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肿瘤学
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药理学
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免疫学
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2022
·Vol. 11
·期 15
·2200386
·
IF 11.092
Jile Xie,Jiaying Li,Jinjin Ma,Meimei Li,Xingran Wang,Xinya Fu,Yanxia Ma,Huilin Yang,Bin Li,Saijilafu
Because of the limited regenerative ability of the central nervous system (CNS), effective treatments for spinal cord injury (SCI) are still lacking. After SCI, neuron loss and axon regeneration failure often result in irreversible functional impairment. The calcium overload induced by the N-methyl-D-aspartate receptor (NMDAR) overactivation is critical for cell death in SCI. It has been reported that the magnesium ion (Mg 2+ ) can competitively block the NMDAR and reduce the calcium influx, and that sonic hedgehog (Shh) and retinoic acid (RA) are the critical regulators of neuronal differentiation of endogenous neural stem cells (NSCs). Here, magnesium oxide (MgO)/poly ( l -lactide-co- ε -caprolactone) (PLCL) scaffold loaded with purmorphamine (PUR, a Shh signaling agonist) and RA is developed and its feasibility in SCI repair is tested. The results showed that the Mg 2+ released from MgO attenuated cell apoptosis by blocking the calcium influx, and the PUR/RA promoted the recruitment and neuronal differentiation of endogenous NSCs, thereby reducing the glial scar formation at the SCI lesion site. Furthermore, implantation of PUR/RA-loaded MgO/PLCL scaffold facilitates the partial recovery of a locomotor function of SCI mouse in vivo. Together, findings from this study imply that PUR/RA-loaded MgO/PLCL scaffold may be a promising biomaterial for the clinical treatment of SCI.
研究领域:
神经科学
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生物材料
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再生医学
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干细胞生物学
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2023
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IF 7.5
Zhenzhen Zhang,Lingling Yang,Ya Li,Di Sun,Rong Chen,Shengqian Dou,Ting Liu,Sai Zhang,Qingjun Zhou,Lixin Xie
Diabetic keratopathy (DK), the diabetic complication in the cornea, is characterized by the delayed epithelial regeneration and sensory nerve degeneration. The involvement of limbal stem/progenitor cells (LSPCs) dysfunction has been reported, however the pathogenic mechanisms remain unclear. Here, we confirmed the dysfunction of LSPCs in diabetic mouse and human corneas. The sympathetic nerve in the cornea was adjacent to LSPCs, and the sympathetic overactivation was found in diabetic mice. Surgical and pharmacological ablation of sympathetic nerves rescued the LSPCs function and promoted corneal epithelial regeneration in diabetic mice. In contrast, both topical norepinephrine (NE) application and chemogenetic sympathetic overactivation directly impaired the stemness and proliferation characteristics of LSPCs, as well as the normal epithelial regeneration. Moreover, we identified that β2-adrenoceptor ( Adrb2 ) was the predominant adrenergic receptor expressed in LSPCs by corneal limbal single-cell sequencing and real time PCR (RT-PCR) analysis of sorted LSPCs. The Adrb2 knockout mice exhibited the enhancement of epithelial regeneration and LSPCs function, compared with the wild-type mice. Similarly, topical application of the Adrb2 specific antagonist ICI 118, 551 effectively accelerated diabetic corneal epithelial regeneration with the restored LSPCs function. Mechanistically, sonic hedgehog (Shh) activity mediated the downstream effects of NE-Adrb2 signaling pathway in regulating LSPCs and epithelial regeneration. Taken together, our data revealed the involvement of sympathetic overactivation in the impairment of diabetic LSPCs function and corneal epithelial regeneration through the NE-Adrb2-Shh signaling pathway. The interference of sympathetic overactivation may provide novel treatment strategies for diabetic keratopathy.
研究领域:
眼科学
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干细胞生物学
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糖尿病研究
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神经科学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）