ACTA BIOCHIMICA ET BIOPHYSICA SINICA
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2024
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IF 3.3
Yanyan Heng,Wei Wei,Linzhong Cheng,Feifei Wu,Haoyu Dong,Jingxia Li,Jianing Fu,Bingjie Yang,Xinyue Liang,Chunyan Liu,Haiju Li,Haihua Liu,Pengfei Zhang
Diabetes accelerates vascular senescence, which is the basis for atherosclerosis and stiffness. The activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and oxidative stress are closely associated with progressive senescence in vascular smooth muscle cells (VSMCs). The vascular protective effect of FGF21 has gradually gained increasing attention, but its role in diabetes-induced vascular senescence needs further investigation. In this study, diabetic mice and primary VSMCs are transfected with an FGF21 activation plasmid and treated with a peroxisome proliferator-activated receptor γ (PPARγ) agonist (rosiglitazone), an NLRP3 inhibitor (MCC950), and a spleen tyrosine kinase (SYK)-specific inhibitor, R406, to detect senescence-associated markers. We find that FGF21 overexpression significantly restores the level of catalase (CAT), vascular relaxation, inhibits the intensity of ROSgreen fluorescence and p21 immunofluorescence, and reduces the area of SA-β-gal staining and collagen deposition in the aortas of diabetic mice. FGF21 overexpression restores CAT, inhibits the expression of p21, and limits the area of SA-β-gal staining in VSMCs under high glucose conditions. Mechanistically, FGF21 inhibits SYK phosphorylation, the production of the NLRP3 dimer, the expression of NLRP3, and the colocalization of NLRP3 with PYCARD (ASC), as well as NLRP3 with caspase-1, to reverse the cleavage of PPARγ, preserve CAT levels, suppress ROSgreen density, and reduce the expression of p21 in VSMCs under high glucose conditions. Our results suggest that FGF21 alleviates vascular senescence by regulating the SYK-NLRP3 inflammasome-PPARγ-catalase pathway in diabetic mice.
研究领域:
内分泌学
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心血管生物学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
INFLAMMATION
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2024
·
IF 4.5
Cai Lu-Qiong,Li Xiu-Chun,Wang Yang-Yue,Chen Yu-Xin,Zhu Xia-Yan,Zuo Zi-Yi,Si-Ma Yi-Qun,Lin Yi-Nuo,Li Xiao-Kun,Huang Xiao-Ying
Aging is a physiological condition accomplished with persistent low-grade inflammation and metabolic disorders. FGF21 has been reported to act as a potent longevity determinant, involving inflammatory response and energy metabolism. In this study, we engineered aging FGF21 knockout mice of 36–40 weeks and observed that FGF21 deficiency manifests a spontaneous inflammatory response of lung and abnormal accumulation of lipids in liver. On one hand, inflamed state in lungs and increased circulating inflammatory cytokines were found in FGF21 knockout mice of 36–40 weeks. To evaluate the ability of FGF21 to suppress inflammation, a subsequent study found that FGF21 knockout aggravated LPS-induced pulmonary exudation and inflammatory infiltration in mice, while exogenous administration of FGF21 reversed these malignant phenotypes by enhancing microvascular endothelial junction. On the other hand, FGF21 knockout induces fatty liver in aging mice, characterized by excessive accumulation of triglycerides within hepatocytes. Further quantitative metabolomics and lipidomics analysis revealed perturbed metabolic profile in liver lacking FGF21, including disrupted glucose and lipids metabolism, glycerophospholipid metabolism, and amino acid metabolism. Taken together, this investigation reveals the protective role of FGF21 during aging by weakening the inflammatory response and balancing energy metabolism.
研究领域:
衰老
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分子生物学
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免疫学
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代谢
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DOI
PubMed
高影响因子
EBioMedicine
·
2021
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IF 8.143
Qi Pan,Shushan Lin,Yu Li,Liang Liu,Xiaoping Li,Xianglei Gao,Jiangyu Yan,Baohua Gu,Xiaofeng Chen,Wenjia Li,Xinfa Tang,Chao Chen,Lixin Guo
Background Fibroblast growth factor 21 (FGF21) has become a promising therapeutic target for metabolic diseases such as type 2 diabetes (T2D), obesity and non-alcoholic steatohepatitis. However, the clinical application of natural FGF21 molecule is limited because of its instability in vitro and short half-life in vivo . To improve FGF21’s therapeutic property, we screened high receptor binding FGF21 analogs and made FGF21-Fc-GLP-1 dual-targeted constructs to investigate their activity in a number of experiments . Methods Utilizing phage display high-throughput screening we identified mutations that could improve β-Klotho binding property of FGF21. IgG4 Fc was fused to FGF21 variants to extend the in vivo half-life. We further explored the potential synergistic actions of FGF21 with the incretin glucagon-like peptide-1 (GLP-1) by generating GLP-1-Fc-FGF21 dual agonists. Findings Two Fc-FGF21 variants showed enhanced β-Klotho binding affinity in vitro as well as improved glucose lowering effect in vivo . One of the dual agonists, GLP-1-Fc-FGF21 D1, provided potent and sustained glucose lowering effect in diabetic mice models. It also demonstrated superior weight loss effect to GLP-1 or FGF21 alone. Moreover, GLP-1-Fc-FGF21 D1 exhibited strong anti-NASH effect in the high-fat diet-induced ob/ob model as it improved liver function, serum and hepatic lipid profile and reduced NAFLD activity score with an efficacy superior to either FGF21 or GLP-1 analogs alone. Interpretation This novel GLP-1/FGF21 dual agonist is worth clinical development for the treatment of T2D, obesity and NASH. Funding HEC Pharm R&D Co., Ltd, National natural science fund of China.
研究领域:
药理学
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代谢性疾病
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内分泌学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
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2025
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IF 4.3
Yan Qian,Li Xiao-Jun,Wang Qi-Qi,Jia Wei,Wang Shu-Ling
Approaches of promoting a neural milieu permissive for plasticity and resilience against neuronal injury are important strategies for the treatment of a range of neurological disorders. Fibroblast growth factor 21 (FGF21) which is known for its role as a potent regulator of glucose and energy metabolism has also proved to be neuroprotective against various mental diseases. However, the underlying molecular mechanisms remain elusive. Here, we report a study of the neuroprotective effects of FGF21 by promoting 5-HT 1A R-FGFR1 heteroreceptor formation and triggering MEK 1/2 -ERK 1/2 signaling pathway in normal or abnormal neurological conditions. First, the in vitro cellular experiments demonstrated that FGF21 exerted a protective effect against glutamate-induced cytotoxicity and promoted cell differentiation and growth. Then, in wild-type and FGF21 −/− mice, exogenous FGF21 promoted FGFR1-5-HT 1A R heteromers formation in the CA3 and dentate gyrus region of the hippocampus and activated MEK 1/2 -ERK 1/2 signaling. Coordinately, FGF21 exerted similar influences in the hippocampi of IBA-induced neurological injury mice or combined stress-exposed mice. Besides, FGF21 treatment activated the phosphorylation of FGFR1 and elevated the expression of synaptophysin in these mice with neurological injury or combined stress exposure. These results illustrated that FGF21 alleviated neurological impairment through FGFR1-5-HT 1A R heteromer and ERK 1/2 signal activation and suggested that the regulation of FGFR1-5-HT 1A R heteromers and MEK 1/2 /ERK 1/2 pathway may play a key role in mediating the neuroprotective effects of FGF21 against various neurodegeneration conditions.
研究领域:
神经科学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Antioxidants
·
2024
·Vol. 13
·期 9
·1026
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IF 6
Dajin Pi,Zheng Liang,Jinyue Pan,Jianwei Zhen,Chuiyang Zheng,Wen Fan,Qingliang Song,Maoxing Pan,Qinhe Yang,Yupei Zhang
Nonalcoholic steatohepatitis (NASH) is a critical stage in the progression of nonalcoholic fatty liver disease (NAFLD). Tanshinone IIA (TIIA) is a tanshinone extracted from Salvia miltiorrhiza; due to its powerful anti-inflammatory and antioxidant biological activities, it is commonly used for treating cardiovascular and hepatic diseases. A NASH model was established by feeding mice a methionine and choline-deficient (MCD) diet. Liver surface microblood flow scanning, biochemical examination, histopathological examination, cytokine analysis through ELISA, lipidomic analysis, transcriptomic analysis, and Western blot analysis were used to evaluate the therapeutic effect and mechanism of TIIA on NASH. The results showed that TIIA effectively reduced lipid accumulation, fibrosis, and inflammation and alleviated endoplasmic reticulum (ER) stress. Lipidomic analysis revealed that TIIA normalized liver phospholipid metabolism in NASH mice. A KEGG analysis of the transcriptome revealed that TIIA exerted its effect by regulating the PPAR signalling pathway, protein processing in the ER, and the NOD-like receptor signalling pathway. These results suggest that TIIA alleviates NASH by activating the PPARα/FGF21 axis to negatively regulate the ER stress-induced unfolded protein response (UPR).
研究领域:
药理学
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肝病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
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2022
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IF 6.064
Hong Zhu,Jie Xu,Min Zhao,Hangqi Luo,Minjie Lin,Yuting Luo,Yuan Li,Huacheng He,Jiang Wu
As conventional treatments for diabetic wounds often fail to achieve rapid satisfactory healing, the development of effective strategies to accelerate diabetic wound repair is highly demanded. Herein, fibroblast growth factor 21 (FGF21) and metformin co-loaded multifunctional polyvinyl alcohol (PVA) hydrogel were fabricated for improved diabetic wound healing. The in vitro results proved that the hydrogel was adhesive and injectable, and that it could particularly scavenge reactive oxygen species (ROSs), while the in vivo data demonstrated that the hydrogel could promote angiogenesis by recruiting endothelial progenitor cells (EPCs) through upregulation of Ang-1. Both ROSs’ removal and EPCs’ recruitment finally resulted in enhanced diabetic wound healing. This work opens a strategy approach to diabetic wound management by combining biological macromolecules and small chemical molecules together using one promising environmental modulating drug delivery system.
研究领域:
材料科学
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药剂学
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生物医学工程
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伤口愈合
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产品关联
DOI
PubMed
高影响因子
Genes & Diseases
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2026
·
IF 14.6
Mi Zhang,Hui Gan,Qing Xu,Yaying He,Yuhao Duan,Chenyang Li,Le Qin,Yutong Hu,Lanyu Zhang,Jing Zhao,Xuan Zhai
Ferroptosis plays a critical role in secondary brain injury following intracerebral hemorrhage (ICH). However, the regulatory mechanisms governing ferroptosis after ICH remain unexplored. By transcriptome sequencing of brain tissues from ICH patients and mouse models, we identified myocyte enhancer factor 2C (MEF2C) as a key ferroptosis-related gene. MEF2C was downregulated in human and mouse ICH brains and mainly localized to neurons. Neuron-specific MEF2C overexpression suppressed ferroptosis and improved neurological outcomes after ICH in mice. We further overexpressed and knocked out MEF2C in the mouse neuronal cell line HT22 and conducted in vitro experiments using hemoglobin (Hb) and ferroptosis inducers (RSL3 and erastin). Our findings indicated that MEF2C inhibited reactive oxygen species (ROS) accumulation, lipid peroxidation, and Fe 2+ overload, thereby inhibiting ferroptosis. Subsequent transcriptomic analysis identified fibroblast growth factor 21 (FGF21), a protein previously reported to regulate ferroptosis, as a downstream gene of MEF2C. Dual-luciferase and chromatin immunoprecipitation assays confirmed that MEF2C directly activates Fgf21 transcription. Finally, the in vitro model of ICH demonstrated that FGF21 modulates oxidant stress and Fe 2+ accumulation and that FGF21 knockdown abrogated MEF2C-reduced oxidative stress and Fe 2+ accumulation, indicating that FGF21 is required for MEF2C-mediated anti-ferroptosis. Taken together, MEF2C protects against ICH-induced ferroptosis by transcriptionally regulating FGF21. Our work provides new insights and potential therapeutic targets for the treatment of ICH.
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DOI
高影响因子
Materials Today Bio
·
2026
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IF 11
Xuehai Chen,Yibo Ying,Yuchao Zhang,Jiali Lv,Minghao Jiang,Yujun Mo,Zhiyi Wu,Huixin Lin,Zhiyang Huang,Dawei Jiang,Yanming Zuo,Xiaokun Li,Zhouguang Wang
Mitochondrial dysfunction and defective repair are central drivers of secondary injury following spinal cord injury (SCI), yet effective strategies to restore mitochondrial quality control remain limited. Here, we develop an engineered long-acting fibroblast growth factor 21 fusion protein (SFGF21) by incorporating a linker peptide to enhance molecular targeting and oxidative stability. In a mouse model of SCI, sustained delivery of SFGF21 specifically potentiated dynamic crosstalk between mitochondria and lysosomes, thereby activating the BNIP3/BNIP3L pathway-mediated mitophagic flux and clearing dysfunctional mitochondria in injured neurons. This process restored mitochondrial homeostasis, suppressed lipid peroxidation, and alleviated oxidative stress in injured neurons. Loss-of-function experiments confirmed that both FGFR1 and BNIP3 are required for SFGF21-induced mitophagy and neuroprotection. Together, our findings establish engineered modulation of organelle crosstalk as a therapeutic strategy to activate mitophagy and support neural repair after SCI, highlighting mitochondria-targeted protein engineering as a potential therapeutic path for spinal cord repair. Download: Download high-res image (349KB) Download: Download full-size image
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DOI
高影响因子
Acta Pharmaceutica Sinica B
·
2026
·
IF 14.6
Xinyu Tan,Man Li,Zhibin Lan,Wenxiang Zhang,Junjie Zou,Yibo An,Jingwen Zheng,Xuwen Xiang,Jing Lin,Sheng Lin,Wenjie Ni,Lin Che,Gang Liu,Jing Chen,Zhixiang Lu
To address the intertwined pathologies of oxidative stress, immune dysregulation, and lipid metabolic disorders in acute liver injury (ALI), we engineered an innovative nanosystem: M2@SAM-F21. M2@SAM-F21 features an M2 macrophage membrane coating encapsulating diselenide-bridged mesoporous silica nanoparticles for silymarin and FGF21 plasmid DNA codelivery, enabling synergistic multidimensional treatment. First, reactive oxygen species (ROS)-responsive oxidative stress is mitigated. Diselenide bonds undergo ROS-triggered cleavage, achieving precise silymarin release that efficiently scavenges multiple ROS types, significantly mitigating hepatic oxidative damage. Simultaneously, FGF21 drives immune reprogramming. Efficiently expressed FGF21 protein drives macrophage polarization toward the M2 anti-inflammatory phenotype, effectively reducing proinflammatory cytokine levels, with TNF- α decreased to 61 pg/mL and IL-6 reduced to 20 pg/mL, while increasing IL-10 to 68 pg/mL to reverse the immune microenvironment imbalance. In addition, metabolic homeostasis is restored. Activated fatty acid oxidation pathways substantially decrease serum concentrations of total cholesterol (TC) to 4.984 mmol/L and triglycerides (TG) to 0.586 mmol/L, and almost reduce hepatocellular lipid droplet accumulation by 76%, resolving metabolic dysregulation. In both alcoholic and drug-induced ALI models, M2@SAM-F21 demonstrates exceptional hepatoprotection. For example, it significantly restores serum alanine aminotransferase (ALT) to 46.6 U/L and aminotransferase (AST) to 180 U/L in the alcoholic ALI model, while markedly alleviating histopathological vacuolization and steatosis, with biological distribution imaging confirming inflammation-targeted accumulation and proteomic analysis further elucidating therapeutic mechanisms. Exhibiting superior biosafety and dual therapeutic-prophylactic potential, this system serves as a pioneering paradigm that integrates targeted delivery, intelligent release, and multipathway synergy for ALI treatment.
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产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
·
IF 7.7
Gaolin Wen,Lingling Xue,Mengdi Qiu,Junlan Qiu,Xinhua Zhu,Haozhen Ren
Hepatocellular carcinoma (HCC), ranking as the fourth most prevalent cancer globally, has garnered significant attention due to its high invasiveness and mortality rates. However, drug therapies face challenges of inadequate efficacy and unclear mechanisms. Here, we propose a novel biohybrid hydrogel that targets β-klotho (KLB) for HCC treatment. As a dual-network hydrogel, this gel combines gelatin methacryloyl (GelMA) and polyvinyl alcohol (PVA) to ensure biocompatibility while enhancing controlled drug release. Notably, it exhibits good storage stability, high drug load capacity, and efficient water absorption. By introducing the HDAC3 inhibitor RGFP966, we can selectively inhibit the activation of KLB. This deactivation effectively blocks the FGF21-KLB signaling pathway and inhibits the progression of HCC. Importantly, we have successfully validated this unique phenomenon both in vivo and in vitro, providing substantial evidence for the efficacy of this hydrogel-based anti-tumor drug delivery system as a promising strategy for HCC treatment. This innovative research outcome brings new hope to the field of tumor therapy, providing a reliable theoretical foundation for future clinical applications.
研究领域:
肿瘤学
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药学
·
生物材料
✓ 已验证
DOI
高影响因子
MATERIALS & DESIGN
·
2026
·
IF 8.2
Zemin Liu,Bin Chen,Wei Han,Liben Cheng,Xiaoli Li,Yutao Zhang,Dong Wang,Yan Li,Yu Wang,Xinxin Wang,Yonghong Zhang
Healthy bone possesses intrinsic strength, and strategies aimed at enhancing osteogenesis to improve bone strength are crucial in the treatment of fractures and osteoporosis. Osteocytes, the most abundant cell type in bone tissue, along with the mineralized matrix, form the structural foundation of bone material properties. However, the role of fibroblast growth factor 21 (FGF21) in bone strength, particularly at the level of osteocytes, remains poorly understood and lacks cell-specific evidence. To address this, we generated Dmp1-CreER; Fgf21 fl/fl mice and examined the impact of osteocyte-specific Fgf21 deletion on bone strength. μCT and histological analyses revealed that osteocyte-specific Fgf21 ablation increased both bone formation and resorption in adult mice, resulting in a net anabolic phenotype. Three-point bending demonstrated a significant enhancement in femoral mechanical strength. Moreover, osteocyte Fgf21 deletion accelerated healing in a closed femoral fracture model and reversed ovariectomy-induced bone loss. Transcriptomic profiling, validated at the RNA and protein levels, uncovered activation of Wnt signaling as the underlying mechanism. Collectively, deleting Fgf21 in osteocytes augments the coupling of bone formation and resorption, leading to greater skeletal strength. Targeting osteocytes boosts bone strength and promises new fracture/osteoporosis therapy.
✓ 已验证
DOI
高影响因子
Acta Biomaterialia
·
2021
·
IF 8.947
Jiameng Gao,Jingjing Liu,Zheying Meng,Yanming Li,Yuping Hong,Lirui Wang,Lan He,Bing Hu,Yuanyi Zheng,Tianliang Li,Daxiang Cui,E. Shen
Diabetic cardiomyopathy (DCM) is a serious cardiac complication of diabetes that currently lacks specific treatment. Fibroblast growth factor 21 (FGF21) has been proved to have cardioprotective effect in DCM. However, the insufficient cardiac delivery effect of FGF21 limits its application in DCM. Therefore, to improve the therapeutic efficacy of FGF21 in DCM, an effective drug delivery system is urgently required. In this study, perfluoropropane (C 3 F 8 ) and polyethylenimine (PEI)-doped poly (lactic-co-glycolic acid) (PLGA) nanobubbles (CPPNBs) were synthesized via double-emulsion evaporation and FGF21 was efficiently absorbed ( [email protected] ) via the electrostatic incorporation effect. [email protected] could effectively deliver FGF21 to the myocardial tissue through the cavitation effect under low-frequency ultrasound (LFUS). The as-prepared [email protected] could efficiently load FGF21 after doping with the cationic polymer PEI, and displayed uniform dispersion and favorable biosafety. After filling with C 3 F 8 , [email protected] could be used for distribution monitoring through ultrasound imaging. Moreover, [email protected] significantly downregulated the expression of ANP, CTGF, and caspase-3 mRNA via the action of LFUS owing to increased FGF21 release, therefore exhibiting enhanced inhibition of myocardial hypertrophy, apoptosis, and interstitial fibrosis in DCM mice. In conclusion, we established an effective protein delivery nanocarrier for the diagnosis and prophylactic treatment of DCM. Statement of significance Diabetic cardiomyopathy (DCM) is a serious cardiac complication of diabetes that currently lacks effective clinical treatments. Fibroblast growth factor 21 (FGF21) can protect cardiomyocytes from diabetic damage, but insufficient cardiac drug delivery limits the application of FGF21 in DCM. In this study, perfluoropropane (C3F8) and polyethylenimine (PEI)-doped poly (lactic-co-glycolic acid) (PLGA) nanobubbles loaded with FGF21 ( [email protected] ) were developed for the prophylactic treatment of DCM. [email protected] could effectively deliver the FGF21 to the myocardial tissue through the cavitation effect of low-frequency ultrasound (LFUS). Our results indicated that [email protected] combined with LFUS could significantly down-regulate the expressions of ANP, CTGF, and caspase-3 mRNA, and as a result, it prevented the myocardial hypertrophy, apoptosis, and interstitial fibrosis of DCM mice. Overall, we established an effective protein delivery nanocarrier for the diagnosis and prophylactic treatment of DCM.
研究领域:
药剂学
·
心脏病学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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