scholarly journals Fibroblast Growth Factor 21 Modulates Microglial Polarization That Attenuates Neurodegeneration in Mice and Cellular Models of Parkinson's Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Changwei Yang ◽  
Wuqiong Wang ◽  
Pengxi Deng ◽  
Chen Li ◽  
Liangcai Zhao ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Growth Factor ◽  
Culture System ◽  
Inflammatory Factors ◽  
Fibroblast Growth Factor 21 ◽  
Protective Effects ◽  
Fibroblast Growth ◽  
Microglial Polarization

Microglial polarization and the subsequent neuroinflammatory response were identified as key contributors to the progress of Parkinson's disease (PD). Researchers have shown that fibroblast growth factor 21 (FGF21) plays multiple biological functions, including anti-inflammation and neuroprotection. However, the knowledge of FGF21 on microglial polarization in PD in vivo is far from completion. In this study, both in vivo and in vitro models were used to investigate whether FGF21 enhances the brain function by modulating microglial polarization in PD. The protective effects of FGF21 in vivo were conducted using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mice model alongside intraperitoneally received FGF21. A behavioral test battery and tyrosine hydroxylase (TH) immunohistochemistry were conducted to evaluate the neuronal function and nigrostriatal tract integrity. Immunofluorescence assay and Western blot were used to examine M1/M2 microglial polarization. Then, a microglia-neuron co-culture system was adopted in vitro to identify the underlying molecular mechanisms of FGF21. The results showed that FGF21 significantly alleviated motor and cognitive impairment in mice with PD. FGF21 also protected TH-positive neuron cells in the striatum and midbrain. Mechanistically, FGF21 suppressed M1 microglial polarization and the subsequent mRNA expression of pro-inflammatory factors while promoting M2 microglial polarization with increasing anti-inflammatory factors in mice with PD. Furthermore, sirtuin 1 (SIRT1) and the nuclear factor-kappa B (NF-κB) pathway were involved in the FGF21-induced M2 microglial polarization. Conversely, SIRT1 inhibitor EX527 significantly prevented both the FGF21-induced SIRT1 expression and M2 microglial polarization. Moreover, FGF21 pretreatment of microglia significantly prevented neuronal cell apoptosis in a microglia-neuron co-culture system. In conclusion, our data demonstrate that FGF21 exerted its protective effects in the pathology of PD through SIRT1/NF-κB pathway-mediated microglial polarization. Given the safety record of human clinical trials, FGF21 could be a promising therapy for clinical trials to ameliorate motor and nonmotor deficits in patients with PD.

Effects of fibroblast growth factor 21 on cell damage in vitro and atherosclerosis in vivo

2014 ◽  
Vol 92 (11) ◽  
pp. 927-935 ◽  
Author(s):  
Wenhe Zhu ◽  
Changwen Wang ◽  
Lei Liu ◽  
Yan Li ◽  
Xiaokun Li ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Cell Damage ◽  
Density Lipoprotein ◽  
Serum Levels ◽  
Lipoprotein Cholesterol ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth

Fibroblast growth factor 21 (FGF-21), which is a modulator of glucose and lipid homeostasis, acts as a novel therapeutic reagent for many metabolic perturbations. However, its potential as a treatment for cardiovascular disease, especially atherosclerosis (AS) has not been fully explored. Here, we report that recombinant FGF-21 improves resistance to cell damage from oxidative stress in vitro, and from atherosclerosis in vivo. Human umbilical vein endothelial cells (HUVECs) were induced with H2O2, followed by treatment with high purity recombinant FGF-21. The results indicated that FGF-21 significantly enhanced cell viability and decreased the degree of DNA fragmentation in HUVECs, as caused by H2O2 stress induction. Further studies revealed that FGF-21 inhibited H2O2-induced cell apoptosis by preventing the activation of mitogen-activated protein kinase (MAPK) signaling pathways. In an established rat model, FGF-21 dramatically improved the condition of atherosclerotic rats by decreasing serum levels of total triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and total cholesterol (TC), and by increasing the serum levels of high density lipoprotein cholesterol (HDL-C). FGF-21 also has antioxidant effects in the atherosclerotic rat, such that increased levels of superoxide dismutase, reduced glutathione, and reduced malondialdehyde were observed. These data provide novel insight into the potential use of FGF-21 in the prevention and treatment of human cardiovascular diseases.

scholarly journals Orphan Nuclear Receptor Nur77 Mediates Fasting-Induced Hepatic Fibroblast Growth Factor 21 Expression

Endocrinology ◽  
2014 ◽  
Vol 155 (8) ◽  
pp. 2924-2931 ◽  
Author(s):  
Ae-Kyung Min ◽  
Kwi-Hyun Bae ◽  
Yun-A Jung ◽  
Yeon-Kyung Choi ◽  
Mi-Jin Kim ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Nuclear Receptor ◽  
Fibroblast Growth Factor 21 ◽  
Orphan Nuclear Receptor ◽  
Fibroblast Growth ◽  
Cultured Hepatocytes ◽  
Fgf21 Expression

The fasting-induced hepatic hormone, fibroblast growth factor 21 (FGF21), is a potential candidate for the treatment of metabolic syndromes. Although peroxisome proliferator-activated receptor (PPAR)α is known to play a major role in the induction of hepatic FGF21 expression, other fasting-induced transcription factors that induce FGF21 expression have not yet been fully studied. In the present study, we investigated whether the fasting-induced activation of the orphan nuclear receptor Nur77 increases hepatic FGF21 expression. We found that fasting induced hepatic Nur77 and FGF21 expression. Glucagon and forskolin increased Nur77 and FGF21 expression in vivo and in vitro, respectively, and adenovirus-mediated overexpression of Nur77 (Ad-Nur77) increased FGF21 expression in vitro and in vivo. Moreover, knockdown of endogenous Nur77 expression by siRNA-Nur77 abolished the effect of forskolin on FGF21 expression. The results of ChIP assays, EMSA, and mutagenesis analysis showed that Nur77 bound to the putative NBRE of the FGF21 promoter in cultured hepatocytes and fasting induced Nur77 binding to the FGF21 promoter in vivo. Knockdown of PPARα partially inhibited forskolin-induced FGF21 expression, suggesting PPARα involvement in glucagon-stimulated FGF21 expression. In addition, double knockdown of PPARα and Nur77 further diminished FGF21 expression in cultured hepatocytes. In conclusion, this study shows that Nur77 mediates fasting-induced hepatic FGF21 expression, and suggests an alternative mechanism via which hepatic FGF21 transcription is mediated under fasting conditions.

scholarly journals Fibroblast growth factor 21 attenuates salt-sensitive hypertension-induced nephropathy through anti-inflammation and anti-oxidation mechanism

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Hua-Chun Weng ◽  
Xin-Yu Lu ◽  
Yu-Peng Xu ◽  
Yi-Hong Wang ◽  
Dan Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Oxidation Mechanism ◽  
Kidney Injury ◽  
Inflammatory Factors ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Salt Sensitive Hypertension

Abstract Background Patients with salt-sensitive hypertension are often accompanied with severe renal damage and accelerate to end-stage renal disease, which currently lacks effective treatment. Fibroblast growth factor 21 (FGF21) has been shown to suppress nephropathy in both type 1 and type 2 diabetes mice. Here, we aimed to investigate the therapeutic effect of FGF21 in salt-sensitive hypertension-induced nephropathy. Methods Changes of FGF21 expression in deoxycorticosterone acetate (DOCA)-salt-induced hypertensive mice were detected. The influence of FGF21 knockout in mice on DOCA-salt-induced nephropathy were determined. Recombinant human FGF21 (rhFGF21) was intraperitoneally injected into DOCA-salt-induced nephropathy mice, and then the inflammatory factors, oxidative stress levels and kidney injury-related indicators were observed. In vitro, human renal tubular epithelial cells (HK-2) were challenged by palmitate acid (PA) with or without FGF21, and then changes in inflammation and oxidative stress indicators were tested. Results We observed significant elevation in circulating levels and renal expression of FGF21 in DOCA-salt-induced hypertensive mice. We found that deletion of FGF21 in mice aggravated DOCA-salt-induced nephropathy. Supplementation with rhFGF21 reversed DOCA-salt-induced kidney injury. Mechanically, rhFGF21 induced AMPK activation in DOCA-salt-treated mice and PA-stimulated HK-2 cells, which inhibited NF-κB-regulated inflammation and Nrf2-mediated oxidative stress and thus, is important for rhFGF21 protection against DOCA-salt-induced nephropathy. Conclusion These findings indicated that rhFGF21 could be a promising pharmacological strategy for the treatment of salt-sensitive hypertension-induced nephropathy.

scholarly journals Fibroblast Growth Factor 21 Ameliorates Hyperuricemic Nephropathy By Improving Oxidative Stress Through Activating Akt/Nrf2 Signaling Pathway

2021 ◽  
Author(s):  
Xinghao Jiang ◽  
Yimeng Zou ◽  
Yeboah Kwaku opoku ◽  
Shijie Liu ◽  
Dan Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Therapeutic Effect ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Glomerular Mesangial Cells ◽  
Nrf2 Signaling Pathway

Abstract Epidemiological investigations have shown an elevated expression of circulating fibroblast growth factor 21 (FGF21) of patients with hyperuricemia. However, the effect of FGF21 on hyperuricemic nephropathy (HN) is still unknown. The purpose of this study, therefore, was to explore the effect and mechanism of action of FGF21 on HN. The level of FGF21 in peripheral blood mononuclear cells (PBMCs) was determined in 10 patients with HN. In vivo models of HN were induced in C57BL/6 mice. Six mice in each group were treated with FGF21 at a dose of 1mg/kg and 5mg/kg for 30 days. For the in vitro studies, glomerular mesangial cells (GMCs) were exposed to lipopolysaccharide and monosodium uric acid to induce inflammation and oxidative stress. This was followed by treatment with 100nM, 1000nM of FGF21 for 72 h to observe the therapeutic effect. The levels of FGF21 in patients with HN were elevated. Also, we found that exogenous injection of FGF21 could significantly improve kidney injury in HN mice. This was characterized by a decrease in inflammatory factors and fibrosis and the improvement of oxidative stress. FGF21 recorded a significant therapeutic effect through the activation of Nrf2 in both in vivo and in vitro studies. However, the effect of enhancement of FGF21 on Nrf2 was reduced by the addition of Akt inhibitor GSK690693. In conclusion, our study found for the first time that FGF21 can significantly improve HN through the promotion of the Akt/Nrf2 signalling pathway leading to improvement in oxidative stress.

scholarly journals Fibroblast Growth Factor 21 Attenuates Salt-sensitive Hypertension-induced Nephropathy Through Anti-inflammation and Anti-oxidation Mechanism

2021 ◽  
Author(s):  
Hua-Chun Weng ◽  
Xin-Yu Lu ◽  
Yu-Peng Xu ◽  
Yi-Hong Wang ◽  
Dan Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Oxidation Mechanism ◽  
Kidney Injury ◽  
Inflammatory Factors ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Salt Sensitive Hypertension

Abstract BackgroundPatients with salt-sensitive hypertension are often accompanied with severe renal damage and accelerate to end-stage renal disease, which currently lacks effective treatment. Fibroblast growth factor 21 (FGF21) has been shown to suppress nephropathy in both type 1 and type 2 diabetes mice. Here, we aimed to investigate the therapeutic effect of FGF21 in salt-sensitive hypertension-induced nephropathy.MethodsChanges of FGF21 expression in deoxycorticosterone acetate (DOCA)-salt-induced hypertensive mice were detected. The influence of FGF21 knockout in mice on DOCA-salt-induced nephropathy were determined. Recombinant human FGF21 (rhFGF21) was intraperitoneally injected into DOCA-salt-induced nephropathy mice, and then the inflammatory factors, oxidative stress levels and kidney injury-related indicators were observed. In vitro, human renal tubular epithelial cells (HK-2) were challenged by palmitate acid (PA) with or without FGF21, and then changes in inflammation and oxidative stress indicators were tested.ResultsWe observed significant elevation in circulating levels and renal expression of FGF21 in DOCA-salt-induced hypertensive mice. We found that deletion of FGF21 in mice aggravated DOCA-salt-induced nephropathy. Supplementation with rhFGF21 reversed DOCA-salt-induced kidney injury. Mechanically, rhFGF21 induced AMPK activation in DOCA-salt-treated mice and PA-stimulated HK-2 cells, which inhibited NF-κB-regulated inflammation and Nrf2-mediated oxidative stress and thus, is important for rhFGF21 protection against DOCA-salt-induced nephropathy. ConclusionThese findings indicated that rhFGF21 could be a promising pharmacological strategy for the treatment of salt-sensitive hypertension-induced nephropathy.

scholarly journals Fibroblast growth factor 21 (FGF21) alleviates senescence, apoptosis, and extracellular matrix degradation in osteoarthritis via the SIRT1-mTOR signaling pathway

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Hongwei Lu ◽  
Chao Jia ◽  
Dengying Wu ◽  
Haidong Jin ◽  
Zeng Lin ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Mtor Signaling Pathway ◽  
Autophagy Flux ◽  
In Vivo Experiments

AbstractOsteoarthritis (OA) is a complex condition that involves both apoptosis and senescence and currently cannot be cured. Fibroblast growth factor 21 (FGF21), known for its role as a potent regulator of glucose and energy metabolism, protects from various diseases, possibly by mediating autophagy. In the present study, the role of FGF21 in the progression of OA was investigated in both in vitro and in vivo experiments. In vitro, the results revealed that FGF21 administration alleviated apoptosis, senescence, and extracellular matrix (ECM) catabolism of the chondrocytes induced by tert-butyl hydroperoxide (TBHP) by mediating autophagy flux. Furthermore, CQ, an autophagy flux inhibitor, could reverse the protective effect of FGF21. It was observed that the FGF21-induced autophagy flux enhancement was mediated by the nuclear translocation of TFEB, which occurs due to the activation of the SIRT1-mTOR signaling pathway. The in vivo experiments demonstrated that FGF21 treatment could reduce OA in the DMM model. Taken together, these findings suggest that FGF21 protects chondrocytes from apoptosis, senescence, and ECM catabolism via autophagy flux upregulation and also reduces OA development in vivo, demonstrating its potential as a therapeutic agent in OA.

scholarly journals Dynamic changes of podocytes caused by fibroblast growth factor 2 in culture

2021 ◽  
Author(s):  
Eishin Yaoita ◽  
Masaaki Nameta ◽  
Yutaka Yoshida ◽  
Hidehiko Fujinaka
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 2 ◽  
Quiescent State ◽  
Fibroblast Growth ◽  
Gene Expressions ◽  
Dynamic Changes ◽  
Ki 67

AbstractFibroblast growth factor 2 (FGF2) augments podocyte injury, which induces glomerulosclerosis, although the mechanisms remain obscure. In this study, we investigated the effects of FGF2 on cultured podocytes with interdigitating cell processes in rats. After 48 h incubation with FGF2 dynamic changes in the shape of primary processes and cell bodies of podocytes resulted in the loss of interdigitation, which was clearly shown by time-lapse photography. FGF2 reduced the gene expressions of constituents of the slit diaphragm, inflections of intercellular junctions positive for nephrin, and the width of the intercellular space. Immunostaining for the proliferation marker Ki-67 was rarely seen and weakly stained in the control without FGF2, whereas intensely stained cells were frequently found in the presence of FGF2. Binucleation and cell division were also observed, although no significant increase in cell number was shown. An in vitro scratch assay revealed that FGF2 enhanced migration of podocytes. These findings show that FGF2 makes podocytes to transition from the quiescent state into the cell cycle and change their morphology due to enhanced motility, and that the culture system in this study is useful for analyzing the pathological changes of podocytes in vivo.

scholarly journals Propofol attenuates lung ischemia/reperfusion injury though the involvement of the MALAT1/microRNA-144/GSK3β axis

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Jian-Ping Zhang ◽  
Wei-Jing Zhang ◽  
Miao Yang ◽  
Hua Fang
Keyword(s):  
Cell Apoptosis ◽  
Ischemia Reperfusion Injury ◽  
Glycogen Synthase ◽  
Ischemia Reperfusion ◽  
Inflammatory Factors ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Loss Of Function

Abstract Background Propofol, an intravenous anesthetic, was proven to protect against lung ischemia/reperfusion (I/R) injury. However, the detailed mechanism of Propofol in lung I/R injury is still elusive. This study was designed to explore the therapeutic effects of Propofol, both in vivo and in vitro, on lung I/R injury and the underlying mechanisms related to metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)/microRNA-144 (miR-144)/glycogen synthase kinase-3β (GSK3β). Methods C57BL/6 mice were used to establish a lung I/R injury model while pulmonary microvascular endothelial cells (PMVECs) were constructed as hypoxia/reperfusion (H/R) cellular model, both of which were performed with Propofol treatment. Gain- or loss-of-function approaches were subsequently employed, followed by observation of cell apoptosis in lung tissues and evaluation of proliferative and apoptotic capabilities in H/R cells. Meanwhile, the inflammatory factors, autophagosomes, and autophagy-related proteins were measured. Results Our experimental data revealed that Propofol treatment could decrease the elevated expression of MALAT1 following I/R injury or H/R induction, indicating its protection against lung I/R injury. Additionally, overexpressing MALAT1 or GSK3β promoted the activation of autophagosomes, proinflammatory factor release, and cell apoptosis, suggesting that overexpressing MALAT1 or GSK3β may reverse the protective effects of Propofol against lung I/R injury. MALAT1 was identified to negatively regulate miR-144 to upregulate the GSK3β expression. Conclusion Overall, our study demonstrated that Propofol played a protective role in lung I/R injury by suppressing autophagy and decreasing release of inflammatory factors, with the possible involvement of the MALAT1/miR-144/GSK3β axis.

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