Nutrients
·
2022
·Vol. 14
·期 12
·2411
·
IF 6.706
Zhuohui Zhao,Zhen-Tao Deng,Suling Huang,Mengmeng Ning,Ying Feng,Yu Shen,Qin-Shi Zhao,Ying Leng
Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease worldwide, with no effective therapies available. Discovering lead compounds from herb medicine might be a valuable strategy for the treatment of NASH. Here, we discovered Alisol B, a natural compound isolated fromAlisma orientalis(Sam.), that attenuated hepatic steatosis, inflammation, and fibrosis in high-fat diet plus carbon tetrachloride (DIO+CCl4)-induced and choline-deficient and amino acid-defined (CDA)-diet-induced NASH mice. RNA-seq showed Alisol B significantly suppressed CD36 expression and regulated retinol metabolism in NASH mice. In mouse primary hepatocytes, Alisol B decreased palmitate-induced lipid accumulation and lipotoxicity, which were dependent on CD36 suppression. Further study revealed that Alisol B enhanced the gene expression of RARα with no direct RARα agonistic activity. The upregulation of RARα by Alisol B reduced HNF4α and PPARγ expression and further decreased CD36 expression. This effect was fully abrogated after RARα knockdown, suggesting Alisol B suppressed CD36 via regulating RARα-HNF4α-PPARγ cascade. Moreover, the hepatic gene expression of RARα was obviously decreased in murine NASH models, whereas Alisol B significantly increased RARα expression and decreased CD36 expression, along with the downregulation of HNF4α and PPARγ. Therefore, this study showed the unrecognized therapeutic effects of Alisol B against NASH with a novel mechanism by regulating RARα-PPARγ-CD36 cascade and highlighted Alisol B as a promising lead compound for the treatment of NASH.Keywords:Alisol B;non-alcoholic steatohepatitis;RARα;CD36
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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PubMed
高影响因子
Frontiers in Genetics
·
2021
·
IF 4.599
Li Jia,Shen Jie,Qin Lan,Lu Dongyan,Ding Enci
Background: Thyroid cancer is a frequent endocrine tumor in women. It is of great significance to investigate the molecular mechanism of progression of thyroid cancer.Methods: Gene expression data set and clinical data were downloaded from The Cancer Genome Atlas database for differential expression analysis. The triplet of downstream transcription factors (TFs) and modulatory genes of target lncRNA in thyroid cancer was predicted by the lncMAP database. mRNA and protein expression of lncRNA LBX2-AS1, RARα, and FSTL3 were detected by qRT-PCR and western blot. The localization of lncRNA LBX2-AS1 in cells was tested by Fluorescence in situ hybridization assay. The RNA immunoprecipitation assay was applied to verify the binding relationship between lncRNA LBX2-AS1 and FSTL3. ChIP and dual-luciferase assays were used to prove the binding relationship between RARα and FSTL3. Cell function experiments were used to test cell proliferation, migration and invasion in each treatment group. The role of lncRNA LBX2-AS1 in thyroid cancer progression was also confirmed in nude mice.Results: Bioinformatics analysis indicated that lncRNA LBX2-AS1, RARα, FSTL3 were remarkably fostered in thyroid cancer tissue, and LBX2-AS1 was evidently correlated with clinical features. The LncMAP triplet prediction showed that LBX2-AS1 recruited TF RARα to modulate FSTL3. RIP assay confirmed that LBX2-AS1 was prominently enriched on RARα. ChIP and dual-luciferase report assays unveiled that RARα bound to the promoter region of FSTL3 and functioned as a TF. Cell function experiments uncovered that LBX2-AS1 boosted the progression of thyroid cancer. The rescue experiments showed that LBX2-AS1 recruited the TF RARα to hasten the transcription activity of FSTL3 and thus promoted the development of thyroid cancer.Conclusion: The integrative results demonstrated that LBX2-AS1 activated FSTL3 by binding to TF RARα to hasten proliferation, migration and invasion of thyroid cancer.
研究领域:
肿瘤学
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分子生物学
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癌症遗传学
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生物信息学
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Yuan Chen,Yi Zhou,Jinhan Cai,Jiayi Xu,Chenwei Hu,Huiyue Chen,Yirui Hong,Nanyi Pan,Yujie Jiang,Chenhui Zhou,Hua Wei,Zhipeng Xu,Lin Liu,Xiang Wu,Wei Cui
Post-operative cognitive dysfunction (POCD) is a multi-etiological symptom mainly occurred in elderly people after surgery. The activation of retinoic acid receptor α (RARα), a transcriptional factor, was previously predicated to be negatively associated with the occurrence of POCD. However, the mechanisms underlying anti-POCD effects of RARα were still unclear. In this study, AM580, a selective agonist of RARα, and all-trans-retinoic acid (ATRA), a pan agonist of RAR, significantly alleviated cognitive dysfunction and increased the expression of RARα in elderly mice after surgery, which was decreased by RO41-5253, an antagonist of RARα. A bioinformatic study further predicted that the activation of RARα might produce anti-POCD effects via the restoration of synaptic proteins. Both agonists inhibited the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (Myd88) and the phosphorylation of nuclear factor kappa-B (NF-κB), leading to the prevention of microglial over-activation and pro-inflammatory cytokines secretion in the hippocampal regions of elderly mice after surgery. Moreover, AM580 and ATRA increased the expression of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95), and the phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP-response element binding protein (CREB). All these results suggested that the activation of RARα prevented surgery-induced cognitive impairments via the inhibition of neuroinflammation by the reduction of the TLR4/Myd88/NF-κB pathway and the restoration of synaptic proteins by the activation of the BDNF/ERK/CREB pathway, providing a further support that RARα could be developed as a therapeutic target for POCD.
研究领域:
神经科学
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药理学
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老年医学
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免疫学
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PubMed
高影响因子
Frontiers in Immunology
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2026
·
IF 7
Hongyu Jiang,Wenyan Xiong,Yingna Feng,Xingjie Li,Jinzhuo Tan,Zongde Zhang
IntroductionFast-growing solid tumors exhibit aerobic glycolysis to meet metabolic demands and evade immune surveillance. While the tumor microenvironment (TME) plays a crucial role in supporting this glycolytic phenotype, the contribution of host metabolites remains incompletely understood.MethodsThe role of bile acids (BAs) in tumor progression was evaluated using multiple mouse models, including C57BL/6J mice injected with B16 melanoma cells, BALB/c mice inoculated with 4T1 breast cancer cells, and MMTV-PyMT mice with spontaneous tumor development. To assess the impact of BA depletion, subjects were fed a 2% cholestyramine diet compared to a regular diet. The study employed various analytical techniques, including UPLC-MS to evaluate BA profiles, flow cytometry for immune cell analysis, and Seahorse extracellular flux analyzers to measure oxygen consumption and extracellular acidification rates.ResultsHere, we demonstrate that multiple bile acids (BAs) are significantly enriched in the TMEs of melanoma and breast cancer. Mechanistically, this BA enrichment drives tumor aerobic glycolysis and promotes immune evasion by modulating the interaction between the farnesoid X receptor (FXR) and retinoic acid receptor alpha (RARa). Depletion of BAs in vivo suppressed tumor progression, enhanced T cell infiltration, and alleviated T cell exhaustion, accompanied by transcriptome-wide shifts towardincreased expression of genes involved in oxidative phosphorylation. Furtherinvestigations revealed that BAs activate and stabilize the FXR-RARa complex,thereby upregulating glycolytic pathways and impairing anti-tumor immunity. Conversely, BA depletion reduced FXR/RARa protein levels and disrupted tumorimmune barrier function.DiscussionThese findings unveil a mechanism by which bile acids promote tumor progression by modulating tumor metabolism and the immune microenvironment through FXR-RARa signaling. Targeting the BA-FXR-RARa axiscould offer promising strategies for cancer therapy and diagnosis.
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高影响因子
Frontiers in Cell and Developmental Biology
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2020
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IF 5.186
Jiang Ying,Song Hanbing,Jiang Ling,Qiao Yu,Yang Dan,Wang Donghua,Li Ji
Background: Silybin was known to exert inhibition in prostate cancer, but the underlying mechanism remained largely unknown. This study was designed to find out the potential target of Silybin on prostate cancer and explore the relative mechanisms.Methods: Firstly, we screened the possible targets of Silybin through the PubChem database and Subpathway – GM. Then DU145 cells were transferred to investigate the correction about related targets, magnetic bead sorting and flow cytometry were used to sort and identify the cells. Proliferation, migration and invasion ability of DU145 cells were detected by MTT assay, Transwell assay, plate clonality and sphere formation assay. BALB/c nude mice were constructed models with implanted sarcoma and measured the tumor volume every 5 days as wells tumor weight. The levels of proteins were detected by Western blot and immunocytochemistry. RT-PCR was selected to test the expression of protein’s mRNA.Results: It was screened out the ALDH1A1 was highly correlated with subpathways of the Silybin risk metabolic pathway. And ALDH1A1 expression was positively correlated RARα with Ets1 by interfering with the ALDH1A1 gene. Importantly, ALDH1A1(+) cells showed proliferation, migration and invasion ability. In addition, it showed that Silybin exerted the inhibition on prostate cells by suppressed the proliferation, migration and invasion ability of cells in vitro experiment. Silybin also reduced the tumor volume and weight. And Silybin displayed obviously reduced the proteins and mRNA of ALDH1A1, RARα, Ets1 and MMP9 expressions.Conclusion: Our results indicated that Silybin showed inhibition of prostate cancer and the mechanism was involving with downregulating ALDH1A1 expression, thereby inhibiting the activation of RARα and preventing the activation of Ets1 to inhibit the growth and invasion of prostate 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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PubMed
高影响因子
Anatomical Record-Advances in Integrative Anatomy and Evolutionary Biology
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2016
·Vol. 299
·期 4
·450-460
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IF 1.507
Fuyin Hou,Min Xiao,Jian Li,Devin W. Cook,Weidong Zeng,Caiqiao Zhang,Yuling Mi
Cadmium (Cd) is an environmental endocrine disruptor that has toxic effects on the female reproductive system. Here the ameliorative effect of grape seed proanthocyanidin extract (GSPE) on Cd-induced meiosis inhibition during oogenesis was explored. As compared with controls, chicken embryos exposed to Cd (3 µg/egg) displayed a changed oocyte morphology, decreased number of meiotic germ cells, and decreased expression of the meiotic marker protein γH2AX. Real time RT-PCR also revealed a significant down-regulation in the mRNA expressions of various meiosis-specific markers ( Stra8 , Spo11 , Scp3 , and Dmc1 ) together with those of Raldh2 , a retinoic acid (RA) synthetase, and of the receptors ( RARα and RARβ ). In addition, exposure to Cd increased the production of H 2 O 2 and malondialdehyde in the ovaries and caused a corresponding reduction in glutathione and superoxide dismutase. Simultaneous supplementation of GSPE (150 µg/egg) markedly alleviated the aforementioned Cd-induced embryotoxic effects by upregulating meiosis-related proteins and gene expressions and restoring the antioxidative level. Collectively, the findings provided novel insights into the underlying mechanism of Cd-induced meiosis inhibition and indicated that GSPE might potentially ameliorate related reproductive disorders. Anat Rec, 299:450–460, 2016. © 2016 Wiley Periodicals, Inc.
研究领域:
毒理学
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生殖生物学
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分子生物学
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PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2020
·Vol. 24
·期 9
·5168-5184
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IF 4.486
Huan Nie,Yuanjun Deng,Chuiyang Zheng,Maoxing Pan,Jiqian Xie,Yupei Zhang,Qinhe Yang
The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is still not fully understood, and currently, no effective pharmacotherapy is available. Nuclear receptors (NRs) are important biological participants in NAFLD that exhibit great therapeutic potential. Chaihu Shugan powder (CSP) is a traditional Chinese medicine (TCM) formula that has a wide therapeutic spectrum including NAFLD, but the effective components and functional mechanisms of CSP are unclear. We adopted a network pharmacology approach using multiple databases for Gene Ontology (GO) enrichment analysis and the molecular complex detection (MCODE) method for a protein-protein interaction (PPI) analysis, and we used molecular docking method to screen the NR targets and determine the corresponding CSP components. The screening results were validated through a NAFLD rat model that was used to explain the possible relationship between CSP and NAFLD. Finally, we screened PPARγ, FXR, PPARα, RARα and PPARδ as target genes and quercetin , kaempferol , naringenin , isorhamnetin and nobiletin as target compounds. The five components were detected through high-performance liquid chromatography-mass spectrometry (HPLC-MS), the results of which aligned with the docking experiments of PPARγ, PPARα and PPARδ. After CSP intervention, the NAFLD rat model showed ameliorated effects in terms of bodyweight, hepatic histopathology, and serum and liver lipids, and the mRNA levels of PPARγ, FXR, PPARα and RARα were significantly changed. The results from this study indicate that CSP exhibits healing effects in an NAFLD model and that the network pharmacology approach to screening NR targets and determining the corresponding CSP components is a practical strategy for explaining the mechanism by which CSP ameliorates NAFLD.
研究领域:
药理学
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中药学
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分子生物学
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病理学
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PubMed
高影响因子
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