Signal Transduction and Targeted Therapy
·
2023
·Vol. 8
·期 1
·1-21
·
IF 39.3
Wei Wenxia,Qin Baifu,Wen Weijie,Zhang Boyu,Luo Haidan,Wang Yuzhi,Xu Hui,Xie Xiaoshan,Liu Sicheng,Jiang Xin,Wang Mengan,Tang Qin,Zhang Jiayu,Yang Runxiang,Fan Zongmin,Lyu Haiwen,Lin Junzhong,Li Kai,Lee Mong-Hong
Continuous de novo fatty acid synthesis is required for the biosynthetic demands of tumor. FBXW7 is a highly mutated gene in CRC, but its biological functions in cancer are not fully characterized. Here, we report that FBXW7β, a FBXW7 isoform located in the cytoplasm and frequently mutated in CRC, is an E3 ligase of fatty acid synthase (FASN). Cancer-specific FBXW7β mutations that could not degrade FASN can lead to sustained lipogenesis in CRC. COP9 signalosome subunit 6 (CSN6), an oncogenic marker of CRC, increases lipogenesis via interacting with and stabilizing FASN. Mechanistic studies show that CSN6 associates with both FBXW7β and FASN, and antagonizes FBXW7β’s activity by enhancing FBXW7β autoubiquitination and degradation, which in turn prevents FBXW7β-mediated FASN ubiquitination and degradation, thereby regulating lipogenesis positively. Both CSN6 and FASN are positively correlated in CRC, and CSN6-FASN axis, regulated by EGF, is responsible for poor prognosis of CRC. The EGF-CSN6-FASN axis promotes tumor growth and implies a treatment strategy of combination of orlistat and cetuximab. Patient-derived xenograft experiments prove the effectiveness of employing orlistat and cetuximab combination in suppressing tumor growth for CSN6/FASN-high CRC. Thus, CSN6-FASN axis reprograms lipogenesis to promote tumor growth and is a target for cancer intervening strategy in CRC.
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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药理学
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PubMed
高影响因子
Food Bioscience
·
2025
·
IF 5.9
Yingwei Liu,Yunpeng Sun,Ting Zhou,Xiao Huang,Guokai Wang,Lijuan Sun
Swietenia macrophylla King, a medicine food homology, has garnered attention for the hypoglycemic and hypolipidemic activities of its fruit in the improvement of metabolic dysfunction-associated steatotic liver disease (MASLD), yet the glucolipid regulating properties of its leaf remains unexplored. The study sought to examine the pharmacological mechanisms underlying the lipid-lowering effects of Swietenia macrophylla King leaf extract (SLE) and its active constituent senegalension B (one of 31 limonoids in SLE). Glucolipid regulation by SLE and active constituent was evaluated through cellular triglyceride content and peripheral glucose levels in primary mouse hepatocytes (PMHs), SLE dose-dependently reduced lipid accumulation in the range of 23.65±3.41% to 37.39±2.50%, validated by Oil Red O staining. Network pharmacology and RNA sequencing identified SREBP-1c/FASN axis as the key mechanism by which SLE improved lipid accumulation in PMHs, consistent with senegalension B. RT-qPCR and Western blot showed that SLE (40 μg/mL) decreased the lipid synthesis regulator SREBP-1c mRNA and protein levels by 60.69±1.69% and 48.07±11.83%, respectively, whereas senegalension B (40 μM) achieved 55.42 ±2.29% and 34.34±8.49% inhibition. Dual-luciferase reporter assays revealed that senegalension B suppressed SREBP-1c promoter activity in Hep G2 cells. Molecular docking suggested a potential interaction with SREBP1, consistent with molecular dynamics simulation comparing binding affinity and stability with LXRα, indicating that senegalension B may exert lipid-lowering activity by targeting key proteins involved in lipid synthesis, such as SREBP-1c. This study elucidated the mechanisms and potential of SLE and senegalension B in regulating MASLD through in vitro investigation, expanded the utilization of Swietenia macrophylla King resources, and provided a candidate plant-derived compound for dietary therapy.
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Frontiers in Immunology
·
2025
·
IF 5.9
Xinhang Meng,Minfeng Shi,Jinfeng Qian,Yujie Luo,Liyuan Cui,Dajin Li,Songcun Wang
The establishment of placentation and maternal-fetal tolerance are important determinants of a successful pregnancy. Tacrolimus, also known as FK506, is a calcineurin inhibitor that has often been used for pregnant women after solid organ transplantation. Previous therapeutic interventions have shown the benefits of using the immuno-suppressive agent FK506 in improving clinical pregnancy and live birth rates and reducing the risk of spontaneous miscarriage. However, the mechanism(s) by which FK506 is involved in these processes have not been fully elucidated. To further characterize its function in early pregnancy, we explored the effect of FK506 on the human-derived first trimester extravillous trophoblast cells (HTR8/SVneo cells) and found that FK506 promoted invasion, tube formation and proliferation, but inhibited apoptosis of HTR8/SVneo cells. Based on the integrated metabolomics and transcriptomics analyses, the present study provided the cellular and molecular cues evidently showing that FK506 had positive effects on the placentation and maternal-fetal tolerance through modulating FASN-CEACAM1 pathway. The spontaneous-abortion-prone model gave further evidence that FK506 exerted a protective effect on pregnancy by regulating the FASN-CEACAM1 axis. These findings might provide a new fundamental mechanism and promising potential of low-dose FK506 in preventing pregnancy loss.
研究领域:
妇产科学
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免疫学
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生殖生物学
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分子生物学
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PubMed
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2019
·
IF 3.17
Yasi Mo,Yong Wu,Xin Li,Hui Rao,Xianxiang Tian,Danni Wu,Zhenpeng Qiu,Guohua Zheng,Junjie Hu
Hepatocellular carcinoma (HCC) is one of the most common fatal malignancies worldwide. Inhibition of the lipogenic enzymes involved in hepatic de novo lipogenesis can both effectively restrain proliferation of HCC cells in vitro and reduce the risk of hepatocarcinogenesis in vivo . Although a natural coumarin derivative osthole shows efficacy in suppressing cell proliferation and inducing apoptosis in cultured hepatoma cells and HCC xenograft tumors, the molecular mechanism by which osthole delays hepatocellular malignant transformation during lipogenesis-driven hepatocarcinogenesis remains unknown. Here, we evaluate the efficacy of osthole in a rapid HCC mouse model featuring excessive levels of hepatic steatosis established via hydrodynamic transfection of activated forms of AKT and c-Met proto-oncogenes. Moreover, human hepatoma cell lines were employed for in vitro assessment. Hematoxylin and eosin staining , immunoblotting and immunohistochemistry were applied for mechanistic investigations. The results revealed that if osthole was administered in the early stage of AKT/c-Met-driven HCC, it led to disease stabilization. Moreover, osthole alleviated hepatic steatosis in the AKT/c-Met mice. Further evidence at the molecular level suggested that osthole reduced the expression of phosphor-extracellular signal-regulated kinase 1/2 (ERK1/2), proliferating cell nuclear antigen (PCNA) and Ki67 in livers of the AKT/c-Met mice. Mechanically, osthole efficiently repressed the phospho-AKT (Thr308) / ribosomal protein S6 (RPS6) / fatty acid synthase (FASN) signaling both in mice and in vitro . Altogether, this study suggests that osthole exerts its antilipogenic and antiproliferative efficacy by suppressing the AKT/FASN axis and ERK phosphorylation, which contributes to its capacity to delay hepatocarcinogenesis.
研究领域:
癌症研究
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分子生物学
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药理学
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肝病学
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PubMed
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Journal of Functional Foods
·
2024
·
IF 3.8
Shuwei Ke,Siyu Zhang,Dongsheng Liu,Tengjiao Zhao,Xiayan Lou,Sunying Cheng,Tingheng Zhu,Hanbing Li
Ectopic olfactory receptors, such as OR1A1, are involved in the regulation of lipid metabolism homeostasis. In this study, we investigated the effects of three monoterpenes, (+)-limonene, (−)-carvone and thymol, upon hepatic lipid deposition. Oral administration of (+)-limonene, (−)-carvone and thymol for 8 weeks in high-fat-diet (HFD)-fed mice significantly lowered the levels of fasting blood glucose, improved glucose intolerance, serum lipid parameters, adiposity, and hepatic steatosis. In LO2 cells, (+)-limonene, (−)-carvone and thymol increased the cyclic adenosine monophosphate (cAMP), induced protein kinase A (PKA) activity and phosphorylation of AMPK, downregulated the expression of SREBP-1 and FASN, and eventually led to a reduction in hepatic lipid deposition. Meanwhile, these beneficial effects in cultured LO2 cells were negated by OR1A1 knockdown and the adenylyl cyclase inhibitor SQ22536, respectively, indicating that they can ameliorate disorders of lipid metabolism through activating OR1A1 and subsequent AMPK/SREBP-1/FASN pathway, indicating OR1A1 as a potential target for counteracting hepatic steatosis.
研究领域:
药理学
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代谢学
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肝病学
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分子生物学
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高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Dan Hu,Xiaoting Wu,Manman Hou,Pin Song,Qu Chen,Yingdong Ni
Ursodeoxycholic acid (UDCA) has been widely used for treatment of biliary diseases with high incidence among pregnant women. However, the effect of maternal UDCA exposure on offspring metabolism particularly on hepatic lipid metabolism has not been reported. Seventeen pregnant Sprague-Dawley rats were administered with low-dosage UDCA (L-UDCA, 250 mg/kg, n = 6), high-dosage UDCA (H-UDCA, 500 mg/kg, n = 6) or phosphate buffered saline (CON, n = 5) during pregnancy. After parturition, pups from each litter were sacrificed for blood and hepatic tissues sampling at 21 days of age. Maternal exposure to H-UDCA increased body weight and liver weight of the offspring before weaning. The levels of triglyceride (TG) in both plasma and liver of offspring were increased in maternal UDCA exposure and led to a greater hepatic lipid deposition in offspring. UDCA treatment predominantly promoted the d e novo lipogenesis (DNL) in offspring liver by upregulating the gene expression of ATP citrate lyase ( Acly ), acetyl-coA carboxylases ( Acc ), and fatty acid synthase ( Fasn ), as well as protein expression of FASN and ACC. The level of fibroblast growth factor 15 (FGF15) in plasma of offspring was increased in UDCA treatment compared to control. Moreover, protein expression of DNA methyltransferase 1 (DNMT1) in the liver of offspring was decreased in a dose-dependent manner and the CpG methylation level in the Fasn promoter region was decreased. This study provides insights into maternal UDCA exposure promoting offspring hepatic lipid deposition, which is associated with hypomethylation modification of cytosine-phosphate-guanine (CpG) islands on the promoter of Fasn gene.
研究领域:
发育毒理学
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表观遗传学
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脂质代谢研究
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围产医学
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药物代谢
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NanoImpact
·
2025
·
IF 5.5
Feng-Jie Shen,Wei-Nan Cao,Xue-Chun Han,Qiu-Yue Pan,Yuan Wang,Rong Zhang,Gang Wei,Jin-Kui Yang
Microplastics (MPs) are environmental pollutants with potential health risks. This study examined the effect of MPs on wound healing in both diabetic and non-diabetic mice. MPs exposure significantly delayed wound healing, particularly in diabetic mice, with reduced epidermal thickness and impaired collagen deposition. Mechanistically, MPs suppressed cell proliferation, angiogenesis, and increased apoptosis. Transcriptomic analysis identified dysregulation of critical wound healing pathways, especially those involved in inflammation, extracellular matrix remodeling, and lipid metabolism. Notably, the PI3K/AKT signaling pathway was inhibited. In vitro experiments using human dermal fibroblasts confirmed that MPs disrupted the PI3K/AKT pathway, reducing cell proliferation and migration. Further investigation revealed that MPs suppressed N -acetyltransferase 10 (NAT10) expression, leading to reduced ac4C-dependent stabilization of Fasn mRNA, which in turn diminished lipid synthesis and further inhibited the PI3K/AKT pathway. Our findings reveal a novel interaction between MPs and diabetes in impairing wound healing and suggest the NAT10-FASN-PI3K/AKT axis as a potential therapeutic target.
研究领域:
环境毒理学
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分子生物学
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皮肤科学
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内分泌学
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药理学
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细胞生物学
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KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY
·
2024
·Vol. 28
·期 3
·219-227
·
IF 1.6
Peiyu Lin,Xiyue Yang,Linghui Wang,Xin Zou,Lingli Mu,Cangcang Xu,Xiaoping Yang
Bladder cancer remains the 10th most common cancer worldwide. In recent years, metformin has been found to have potential anti-bladder cancer activity while high concentration of IC 50 at millimolar level is needed, which could not be reached by regular oral administration route. Thus, higher efficient agent is urgently demanded for clinically treating bladder cancer. Here, by conjugating artesunate to metformin, a novel artesunate-metformin dimer triazine derivative AM2 was designed and synthesized. The inhibitory effect of AM2 on bladder cancer cell line T24 and the mechanism underlying was determined. Anti-tumor activity of AM2 was assessed by MTT, cloning formation and wound healing assays. Decreasing effect of AM2 on lipogenesis was determined by oil red O staining. The protein expressions of Clusterin, SREBP1 and FASN in T24 cells were evaluated by Western blotting. The results show that AM2 significantly inhibited cell proliferation and migration at micromolar level, much higher than parental metformin. AM2 reduced lipogenesis and down-regulated the expressions of Clusterin, SREBP1 and FASN. These results suggest that AM2 inhibits the growth of bladder cancer cells T24 by inhibiting cellular lipogenesis associated with the Clusterin/SREBP1/FASN signaling pathway.
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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PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
·
2025
·
IF 3.3
Xinjing Shi,Qingjing Gao,Wenjing Lu,Yuning Xie,Haolin Zhang,Dong Zhang,Yuning Liu,Qiang Weng
SREBP1 (sterol regulatory element binding protein 1) plays an important role in maintaining lipid balance in mammals. Previous research showed that androgen significantly regulated the secretion of lipid-rich musky odor substances from the scented glands of muskrats. Our investigation provides insights into the pathways through which androgen induces SREBP1 expression and affects seasonal changes in triglyceride synthesis in muskrat scented glands. During the breeding season, pronounced Oil Red O staining was confirmed in the scented glandular tissues, and transmission electron microscopy displayed a marked increase in lipid droplets. The scented glands exhibited a higher triglyceride content, which coincided with augmented circulating testosterone, dihydrotestosterone, as well as increased scented glandular testosterone and dihydrotestosterone concentrations. Transcriptomic, proteomic and metabolomic analyses of the scented glands revealed associations with fatty acid biosynthesis, while plasma metabolomic data indicated an increase in metabolites serving as precursors during the breeding season for de novo fatty acid synthesis. Expression levels of genes and proteins related to lipid synthesis and lipid droplets, as well as FASN activity, were significantly elevated in the breeding season. Immunolocalization studies demonstrated the presence of these proteins in glandular and epithelial cells in both seasons. Moreover, in vitro treatment of the scented glandular cells with testosterone resulted in elevated expressions of triglyceride synthesis-related genes. These findings suggested that androgen modulates triglyceride synthesis to enhance lipid droplet formation via the AR-SREBP1-FASN Axis in the scented glands of muskrats, thereby shedding light on the hormonal regulation of lipid metabolism in seasonal breeders.
研究领域:
分子生物学
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内分泌学
·
生物化学
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生殖生物学
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比较生理学
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脂质代谢
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动物生理学
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2022
·
IF 5.195
Yuzhen Lu,Cong Zhang,Yingying Song,Liang Chen,Xin Chen,Guohua Zheng,Yuan Yang,Peng Cao,Zhenpeng Qiu
Accumulating evidence suggests that de novo lipogenesis is a typical characteristic facilitating nonalcoholic fatty liver disease (NAFLD) progression. Gallic acid (GA) is a naturally occurring phenolic acid with metabolic disease-related clinical significance and preclinical benefits. This study aimed to evaluate the anti-steatotic potentials of GA in a fructose-induced NAFLD mouse model featuring a hepatic lipogenic phenotype. The results revealed that GA alleviated hepatic steatosis , oxidative stress , and inflammatory response in fructose-fed mice. Mechanistically, GA treatment restored AMP-activated protein kinase α (AMPKα) phosphorylation, resulting in downregulations of pro-lipogenic factors, including sterol regulatory element binding protein-1 (SREBP-1), fatty acid synthetase (FASN), and acetyl-CoA carboxylase (ACC), in hepatocytes of mice and in vitro . Furthermore, computational docking analysis indicated that GA could directly interact with AMPKα/β subunits to stabilize its activation. These results suggest that GA ameliorates fructose-induced hepatosteatosis by restraining hepatic lipogenesis via AMPK-dependent suppression of the SREBP-1/ACC/FASN cascade. Altogether, this study demonstrates that GA supplement may be a promising therapeutic strategy in NAFLD, especially in the subset with enhanced hepatic lipogenesis.
研究领域:
代谢生物学
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肝脏疾病
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药物研发
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SEMINARS IN NEUROLOGY
·
2017
·Vol. 37
·期 05
·481-482
·
IF 1.891
David M. Greer
The Guest Editor of this issue of Seminars in Neurology is Dr Joshua P. Klein. Dr Klein is the Associate Professor of Neurology and Radiology at the Harvard Medical School (HMS) and the founding Chief of the Division of Hospital Neurology in the Department of Neurology at the Brigham and Women's Hospital (BWH). Dr Klein is from New York and graduated with honors from the University of Pennsylvania in 1997 and then from the Medical Scientist Training Program at the Yale University School of Medicine in 2005. He is a 2009 graduate of the Harvard (BWH/MGH) Neurology Residency Program where he served as the Chief Resident in his final year. He then completed a fellowship in Diagnostic Neuroimaging at the BWH and is board certified in both Neurology and Neuroimaging. He serves as the Chair of the Membership Committee, member of the Board of Directors, and Secretary of the Executive Committee of the American Society of Neuroimaging . He served as the Chair of the Neurohospitalist Section of the American Academy of Neurology from 2015 to 2017 and is the Section Leader of the RITE Advisory Panel for Neuroimaging. He is a member of the Board of Directors of the Neurohospitalist Society . In addition, he is a member of the Editorial Board of Access Medicine Neurology (McGraw Hill) and Scientific Chair of the Audio Digest Foundation Neurology Board Review Course. At the BWH, he serves as the Clinical Service Director for Inpatient Neurology and Chair of the Neurology Finance Committee. Here, he also served for several years as the Director of Performance Improvement for Neurology. He previously served as the Associate Director of the Neurology Medical Student Clerkship and is the Society Head of the HMS Neuroanatomy Laboratory, where he taught for 10 years. He additionally serves as an Advisor for Best Doctors Inc., Advance Medical Inc., and DocFlight Inc., and is on the Scientific Advisory Board for Aladdin Inc. Dr Klein has participated in neuroimaging research across many areas of clinical neurology, including neuroinflammatory diseases, traumatic brain injury, and neurotoxicity related to cancer therapy. He has published over 70 journal articles, as well as chapters in major textbooks of neurology, hospital medicine, neurosurgery, and psychiatry. He is a frequent lecturer at national and international conferences and has directed or participated in medical education courses in Havana, Pune, Paris, Dubai, and Manila. With Drs Allan H. Ropper and Martin A. Samuels, he coauthored the 10th edition of the textbook “Adams and Victor's Principles of Neurology,” and is also coauthoring the upcoming 11th edition of the same title. Among many clinical and teaching awards, Dr Klein received the HMS Miyawaki Faculty Teaching Award in 2009, the BWH/MGH Neurology Faculty Teacher of the Year Award in 2012, and was selected as a Distinguished Clinician at the BWH in 2017. He is a Fellow of the American Neurological Association , the American Society of Neuroimaging , and the American Academy of Neurology . I greatly appreciate the efforts of Dr Klein, as well as of all the contributing authors, for their superb and insightful work in this issue of Seminars in Neurology , which provides a stellar update of the ever-changing field of neuroimaging. The issue provides not only practical advice to the practicing clinicians, but also deep insights into the cutting-edge research that is taking place rapidly in this field. On a personal note, I express warm thanks to my friend and colleague, Josh, who has been a leader in the field and a mentor to many. We hope you enjoy this marvelous issue!
研究领域:
神经科学
·
医学
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Cell Reports
·
2026
·Vol. 45
·期 8
·
IF 7.7
Jing Wu,Zihan Chen,Shengxiang Yin,Yunqiang Chen,Tianxin Zhang,Yaoyao Gao,Yanfei Wei,Yuhua Liu,Fangji Yang,Ling Sang,Xuesong Liu,Yongxiang Liu,Wenting Zhu,Yuheng Shi,Nan Qi
Dysregulation of innate immunity during respiratory RNA virus infections drives systemic hyperinflammation and lung injury. Here, we show that importin β4 (IPO4) has a role in inhibiting antiviral innate immunity. Transcriptomics analysis illustrated a downregulation of IPO4 in alveolar macrophages, lung ciliated epithelium, and peripheral blood mononuclear cells from severely ill patients with COVID-19 or influenza. We further identified CCAAT/enhancer-binding protein beta (CEBPB) as the transcription factor for IPO4 reduction during RNA viral infections. Loss-of-function validation demonstrated that IPO4 dampens the innate antiviral and inflammatory responses in vitro and in vivo . Mechanistically, IPO4 sequesters fatty acid synthase (FASN) to block palmitic acid production, thereby inhibiting mitochondrial antiviral signaling protein (MAVS) activation and the downstream innate immune signaling. Moreover, Adeno-associated virus (AAV)-mediated pulmonary restoration of IPO4 significantly alleviated viral pneumonia in mice. These results indicate that the CEBPB-IPO4-FASN-MAVS axis preserves innate immune homeostasis to avoid inflammatory pathology, highlighting IPO4 as a potential therapeutic target for severe viral pneumonia.
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