Nature Communications
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2025
·Vol. 16
·期 1
·1-16
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IF 15.7
Xie Qian,Du Xiangfu,Liang Jianhui,Shen Yanni,Ling Yufan,Huang Zhengji,Ke Zekai,Li Tai,Song Bing,Wu Tailin,Wang Yan,Tao Huiren
Postmenopausal osteoporosis (PMOP) is a condition in women caused by estrogen deficiency, characterized by reduced bone mass and increased fracture risk. Fatty acid-binding protein 4 (FABP4), a lipid-binding protein involved in metabolism and inflammation, has emerged as a key regulator in metabolic disorders and bone resorption; however, its direct role in PMOP remains unclear. Here, we show that serum FABP4 levels in PMOP patients negatively correlate with bone mineral density, a trend also observed in ovariectomized mice. FABP4 promotes osteoclast formation and bone resorption without affecting osteoblast differentiation. The FABP4 inhibitor BMS309403 suppresses osteoclast differentiation by modulating calcium signaling and inhibiting the Ca 2+ -Calcineurin-NFATc1 pathway. Oral BMS309403 increases bone mineral density in ovariectomized mice, though less effectively than alendronate. Notably, bone-targeted delivery of BMS309403 achieves comparable efficacy to alendronate. In this work, we demonstrate that FABP4 is a critical mediator in PMOP and that its inhibition offers a promising therapeutic strategy.
研究领域:
骨骼生物学
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代谢疾病
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药理学
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DOI
PubMed
高影响因子
Antioxidants
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2022
·Vol. 12
·期 1
·74
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IF 7.675
Wanying Liu,Ke Li,Menglin Zheng,Ling He,Tong Chen
The present study was conducted to evaluate the effect of genipin (GEN) on the microglia of diabetic cognitive impairment and explore its potential mechanism. Diabetic mice were induced by STZ/HFD, while GEN was intragastrically and intraventricularly treated. The human microglia cell HMC3 was induced by LPS/HG/PA. As a result, GEN attenuated diabetic symptoms and diabetic cognitive impairment-related behavior in novel object recognition, Morris water maze and passive avoidance tests. GEN inhibited M1 microglia polarization, lipid accumulation, oxidative stress and promoted mitochondrial fusion via FABP4/Mfn1. FABP4 overexpression, Mfn1 overexpression, selective FABP4 inhibitor BMS, and Mfn1 SiRNA were employed for investigating the mechanism. The inhibitory effect of GEN on ROS may be associated with NOX2 signaling and the translocation of p47phox/p67phox to the cell membrane. With the ROS scavenger NAC, it was proved that ROS participated in GEN-mediated inflammation and lipid accumulation. GEN inhibited the phosphorylation and nucleus translocation of NF-κB. GEN inhibited the ubiquitination of Mfn1, which was mediated by the E3 ligase Hrd1. GEN also enhanced microglia phagocytosis. Molecular docking predicted that GEN may interact with FABP4 by hydrogen bond at the S53 and R78 residues. In conclusion, GEN attenuated diabetic cognitive impairment by inhibiting inflammation, lipid accumulation and promoting mitochondrial fusion via FABP4/Mfn1 signaling.Keywords:diabetic cognitive impairment;genipin;microglia;FABP4;Mfn1
研究领域:
神经科学
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药理学
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糖尿病
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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 IMMUNOPHARMACOLOGY
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2026
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IF 5.6
Hao Kan,Yuan Liu,Ka Zhang,Aiqin Mao,Li Geng,Fan Yu,Lei Feng
Background Endothelial dysfunction induced by lipotoxicity is a critical initiating factor in atherosclerosis. Sweroside, a bioactive iridoid glycoside, possesses significant anti-inflammatory activities; however, its therapeutic potential in regulating vascular endothelial inflammation and dysfunction remains unexplored. This study aimed to investigate the protective effects of Sweroside against endothelial injury and to elucidate the underlying molecular mechanisms, specifically focusing on the transcriptional regulation of inflammatory cascades. Methods Human umbilical vein endothelial cells (HUVECs) and mouse aortic endothelial cells (MAECs) stimulated with palmitic acid (PA), along with C57BL/6J mice fed a high-fat diet (HFD), served as the in vitro and in vivo models, respectively. Transcriptome sequencing (RNA-seq) was employed to screen for potential therapeutic targets. Molecular mechanisms were validated using small interfering RNA (siRNA) knockdown, Western blotting, and dual-luciferase reporter assays. Vascular function was evaluated via wire myograph to assess endothelium-dependent relaxation and pulse wave velocity (PWV) to measure arterial stiffness. Results Sweroside treatment significantly attenuated PA-induced cytotoxicity, oxidative stress, inflammation, and cytoskeletal disruption in ECs. RNA-seq identified Krüppel-like Factor 2 ( KLF2 ) as a core target up-regulated by Sweroside. Mechanistically, Sweroside restored KLF2 expression, which subsequently functioned as a transcriptional repressor by directly binding to the promoter of Fatty Acid Binding Protein 4 ( FABP4 ). This repression reduced FABP4 levels, thereby alleviating the suppression of PPAR-γ and blocking the NF-κB-dependent induction of the downstream chemokine CCL20. In vivo, Sweroside administration effectively improved endothelium-dependent relaxation, and reduced aortic stiffness and vascular inflammation in HFD-fed mice. Conclusions Sweroside ameliorates endothelial dysfunction and vascular remodeling by activating the KLF2-mediated signaling axis to repress FABP4 and the downstream CCL20 inflammatory cascade. These findings highlight Sweroside as a promising therapeutic candidate for the treatment of atherosclerosis and cardiovascular diseases associated with metabolic inflammation.
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DOI
PubMed
高影响因子
Cell Communication and Signaling
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2025
·Vol. 23
·期 1
·1-18
·
IF 8.9
Zhang Jiaqi,Li Jinjin,Cheng Mengting,Zhou Haiyang,Zhang Xiaochen,Yan Hao,Xu Zhifei,Yang Bo,He Qiaojun,Gao Zizheng,Chen Xueqin,Luo Peihua
Sotorasib, the first FDA-approved KRAS G12C inhibitor, has demonstrated remarkable clinical efficacy in non-small cell lung cancer (NSCLC). However, its clinical utility is hampered by life-threatening interstitial lung disease (ILD), whose molecular basis remains unknown. Through the integration of transcriptomic and metabolomic analyses, we revealed that sotorasib activates PPAR-γ signaling, upregulating fatty acid oxidation (FAO) via its downstream effector CPT1B. This metabolic shift triggered mitochondrial ROS overproduction, which drives alveolar epithelial apoptosis and fibrosis in vivo and in vitro . Mechanistically, sotorasib directly binds to PPAR-γ via Thr325, facilitated by FABP4-mediated nuclear translocation, amplifying its transcriptional activity via a feedforward loop. Pharmacological inhibition of FABP4 attenuated PPAR-γ activation, mitigated ROS-driven apoptosis, and rescued pulmonary fibrosis in mice. Taken together, these findings identify the FABP4-PPARγ-CPT1b axis as a novel off-target mechanism of sotorasib-induced lung toxicity and propose FABP4 inhibition as a promising therapeutic target to enhance its clinical safety.
Section
Graphical
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PubMed
高影响因子
Chinese Journal of Natural Medicines
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2025
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IF 4.9
Yongsheng Fang,Zhiyun Zhu,Chun Xie,Dazhen Xia,Huimin Zhao,Zihui Wang,Qian Lu,Caimei Zhang,Wenyong Xiong,Xiaodong Yang
Saponins associated with Panax notoginseng ( P. notoginseng ) demonstrate significant therapeutic efficacy across multiple diseases. However, certain high-yield saponins face limited clinical applications due to their reduced pharmacological efficacy. This study synthesized and evaluated 36 saponin-1,2,3-triazole derivatives of ginsenosides Rg1/Rb1 and notoginsenoside R1 for anti-adipogenesis activity in vitro . The research revealed that the ginsenosides Rg1-1,2,3-triazole derivative a17 demonstrates superior adipogenesis inhibitory effects. Structure-activity relationships (SARs) analysis indicates that incorporating an amidyl-substituted 1,2,3-triazole into the saponin side chain via Click reaction enhances anti-adipogenesis activity. Additionally, several other derivatives exhibit general adipogenesis inhibition. Compound a17 demonstrated enhanced potency compared to the parent ginsenoside Rg1. Mechanistic investigations revealed that a17 exhibits dose-dependent inhibition of adipogenesis in vitro , accompanied by decreased expression of preadipocytes. Peroxisome proliferator-activated receptor γ (PPARγ), fatty acid synthase (FAS), and fatty acid binding protein 4 (FABP4) adipogenesis regulators. These findings establish the ginsenoside Rg1-1,2,3-triazole derivative a17 as a promising adipocyte differentiation inhibitor and potential therapeutic agent for obesity and associated metabolic disorders. This research provides a foundation for developing effective therapeutic approaches for various metabolic syndromes.
研究领域:
药物化学
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药理学
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天然产物
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生物有机化学
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代谢性疾病研究
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2020
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IF 4.545
Yan Li,Chunyi Wang,Yu Jin,Haibo Chen,Meiqun Cao,Weimin Li,Huanmin Luo,Zhengzhi Wu
Numerous researches supported that non-alcoholic fatty liver disease (NAFLD) was an emerging problem associated with increased visceral adiposity (obesity), diabetes and related metabolic disorders. Huang-Qi San (HQS) is composed of three traditional Chinese medicines (Astragali Radix, Pueraria Radix and Cortex Mori Radicis) with a weight ratio of 1:2:1. HQS has been reported to be effective in improving glucose-lipid metabolism, but its underlying mechanism on NAFLD has not been fully understood. The purpose of the present study was to assess the protective effects of HQS on obesity-induced hepatic steatosis in rats fed with high fat diet (HFD). Our data revealed that administration of HQS (1.2 and 2.4 g/kg body weight) resulted in significant reduction in body weight (BW) and organs coefficients of visceral fat. The full-Body CT scan demonstrated that HQS reduced liver fat ratio, visceral and subcutaneous fat mass in a dose-dependent manner. Additionally, HQS decreased plasma TC, TG, FFA and FABP4 levels, normalized glucose and insulin levels, and improved the glucose tolerance. Pathological examination showed that HQS alleviated hepatic steatosis and reduced the cell size of epididymal visceral adipose tissue. Hepatic lipid accumulation was also reduced by HQS treatment compared with HFD fed rats. RNA-Seq analysis combining with qPCR demonstrated that the mRNA expression of some important glucose and lipid metabolism-related genes including Acat2, Apoc4, Bhmt, Cyp3a62, Cyp51, Egln3 (Phd3), Fads1, Fads2, Gnmt, Hmgcs1 and Pemt, were significantly changed by HQS treatment. Taken together, these results suggested that HQS had beneficial effects on glucose-lipid metabolism and hepatic steatosis, and its mechanism might be related to the functions of the genes in regulating glucose and lipid metabolism.
研究领域:
药理学
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营养学
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代谢学
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分子生物学
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基因组学
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DOI
PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
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2019
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IF 5.574
Rinkiko Suguro,Xiao-cong Pang,Zhong-wen Yuan,Si-yao Chen,Yi-Zhun Zhu,Ying Xie
Silybin (SB) is widely used to treat chronic liver diseases , especially this compound is much efficient for the treatments of alcoholic and non-alcoholic steatohepatitis (NASH). However, low bioavailability seriously limits wide-application of SB in biomedical niche. Prior to this study, we found that tangeretin (TG) could remarkably increase the bioavailability of SB by the inhibition of efflux transporters, which encourges us to therapeutical discovery of SB and TG combitional use against NASH. Here, we revealed that TG is capable of improving hepatic-protective activity of SB in mice with NASH by interfering liver oxidative stress, inflammation, and lipid accumulation. In addition, TG was observed to enhance the exposural level of SB in the plasma and liver of mice. Our metabolome assay confirmed that amino acid metabolism and lipid biosynthesis mostly accounted for combitional use of SB and TG to teat NASH in mice, basically biosynthesis of unsaturated fatty acids was mostly affected. Notably, significant inhibitions in fatty acid generating and transporting proteins such as G6PD, FABP4, LPL and CD36/FAT, and cholesterol metabolism enzyme CYP27A1 as well as nuclear transcription factors FXR , PPAR-γ, and LXR were illustrated to decipher therapeutic mechanisms of SB and TG against experimental NASH . Taken together, the strategy based combitional use of SB and TG has a potential-capacity to treat NASH.
研究领域:
肝病学
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药理学
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代谢组学
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DOI
PubMed
高影响因子
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