FGF21 attenuates neurodegeneration through modulating neuroinflammation and oxidant-stress

Kang, Kai; Xu, Pengfei; Wang, Mengxia; Chunyu, Jian; Sun, Xu; Ren, Guangxin; Xiao, Wei; Li, Deshan

doi:10.1016/j.biopha.2020.110439

Cited by 60 publications

(49 citation statements)

References 61 publications

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“…The cytoprotective effects of FGF21, whether direct or indirect, are also evident in the nervous system, where FGF21 treatment attenuates neuroinflammation, neuronal oxidative stress, and neurodegeneration and preserves cognitive function in diabetic mice and high fat fed rats (270,271). As in other tissues, FGF21 exerts anti-inflammatory effects by suppressing microglial NF-kB signaling, thereby attenuating LPS-induced inflammatory cytokine expression (272).…”

Section: Nervous Systemmentioning

confidence: 99%

FGF21: An Emerging Therapeutic Target for Non-Alcoholic Steatohepatitis and Related Metabolic Diseases

2020

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The rising global prevalence of obesity, metabolic syndrome, and type 2 diabetes has driven a sharp increase in non-alcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation in the liver. Approximately one-sixth of the NAFLD population progresses to non-alcoholic steatohepatitis (NASH) with liver inflammation, hepatocyte injury and cell death, liver fibrosis and cirrhosis. NASH is one of the leading causes of liver transplant, and an increasingly common cause of hepatocellular carcinoma (HCC), underscoring the need for intervention. The complex pathophysiology of NASH, and a predicted prevalence of 3–5% of the adult population worldwide, has prompted drug development programs aimed at multiple targets across all stages of the disease. Currently, there are no approved therapeutics. Liver-related morbidity and mortality are highest in more advanced fibrotic NASH, which has led to an early focus on anti-fibrotic approaches to prevent progression to cirrhosis and HCC. Due to limited clinical efficacy, anti-fibrotic approaches have been superseded by mechanisms that target the underlying driver of NASH pathogenesis, namely steatosis, which drives hepatocyte injury and downstream inflammation and fibrosis. Among this wave of therapeutic mechanisms targeting the underlying pathogenesis of NASH, the hormone fibroblast growth factor 21 (FGF21) holds considerable promise; it decreases liver fat and hepatocyte injury while suppressing inflammation and fibrosis across multiple preclinical studies. In this review, we summarize preclinical and clinical data from studies with FGF21 and FGF21 analogs, in the context of the pathophysiology of NASH and underlying metabolic diseases.

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Section: Nervous Systemmentioning

confidence: 99%

FGF21: An Emerging Therapeutic Target for Non-Alcoholic Steatohepatitis and Related Metabolic Diseases

2020

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“…For example, a knockout of their co-receptor, Klotho, resulted in delayed skin wound healing in mice and was accompanied by an increased expression of proinflammatory cytokines in wound lesions [ 51 ]. Moreover, the systemic administration of FGF21 attenuated neurodegeneration and neuroinflammation in aged and diabetic mice [ 52 ] and improved the recovery of spinal cord injury in rats [ 53 ]. Finally, Fgf15 −/− mice demonstrated a strongly suppressed ability to regenerate the liver after partial resection [ 54 ].…”

Section: Fgf As Stimulators Of Regeneration and Repairmentioning

confidence: 99%

Cellular Mechanisms of FGF-Stimulated Tissue Repair

Prudovsky

2021

Cells

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Growth factors belonging to the FGF family play important roles in tissue and organ repair after trauma. In this review, I discuss the regulation by FGFs of the aspects of cellular behavior important for reparative processes. In particular, I focus on the FGF-dependent regulation of cell proliferation, cell stemness, de-differentiation, inflammation, angiogenesis, cell senescence, cell death, and the production of proteases. In addition, I review the available literature on the enhancement of FGF expression and secretion in damaged tissues resulting in the increased FGF supply required for tissue repair.

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“…5-HT1A receptor agonists, such as buspirone and tandospirone, have been shown to promote the formation of neurons in the hippocampus of anxiety and depression rats and improve anxiety and depression. As shown in Figure 6, HE staining of rat hippocampus showed that the morphology of neurons in DG area of DZXYS group was slightly improved compared with that of the model group, most cells had clear outline and were closely arranged, only a small amount of nuclear pyknosis and deep staining of cytoplasm were seen, and the number and number of cell layers in DZXYS group were slightly lower than those in the control group (Kai et al, 2020). To understand the anti-anxiety role of DZXYS, we used double immunofluorescence staining (Donaldson, 2015) to observe neurogenesis in the DG area of the hippocampus of rats in each group at 7 days (Day 35) and 14 days (Day 42) after drug intervention.…”

Section: Discussionmentioning

confidence: 92%

Danzhi Xiaoyao Powder Promotes Neuronal Regeneration by Downregulating Notch Signaling Pathway in the Treatment of Generalized Anxiety Disorder

Liu

Ying

et al. 2021

Front. Pharmacol.

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Background: Generalized anxiety disorder (GAD) is one of the most common types of anxiety disorders with unclear pathogenesis. Our team’s previous research found that extensive neuronal apoptosis and neuronal regeneration disorders occur in the hippocampus of GAD rats. Danzhi Xiaoyao (DZXYS) Powder can improve the anxiety behavior of rats, but its molecular mechanism is not well understood.Objective: This paper discusses whether the pathogenesis of GAD is related to the abnormal expression of Notch signal pathway, and whether the anti-anxiety effect of DZXYS promotes nerve regeneration in the hippocampus by regulating the Notch signaling pathway.Methods: The animal model of GAD was developed by the chronic restraint stress and uncertain empty bottle stimulation method. After the model was successfully established, the rats in the model preparation group were divided into the buspirone, DZXYS, DZXYS + DAPT, and model groups, and were administered the corresponding drug intervention. The changes in body weight and food intake of rats were continuously monitored throughout the process. The changes in anxiety behavior of rats were measured by open field experiment and elevated plus-maze test, and morphological changes and regeneration of neurons in the rat hippocampus were observed by HE staining and double immunofluorescence staining. Changes in the expression of key targets of the Notch signaling pathway in the hippocampus were monitored by real-time fluorescence quantitative PCR and western blotting.Results: In this study, we verified that the GAD model was stable and reliable, and found that the key targets of the Notch signaling pathway (Notch1, Hes1, Hes5, etc.) in the hippocampus of GAD rats were significantly upregulated, leading to the increased proliferation of neural stem cells in the hippocampus and increased differentiation into astrocytes, resulting in neuronal regeneration. DZXYS intervention in GAD rats can improve appetite, promote weight growth, and significantly reverse the anxiety behavior of GAD rats, which can inhibit the upregulation of key targets of the Notch signaling pathway, promote the differentiation of neural stem cells in the hippocampus into neurons, and inhibit their differentiation into astrocytes, thus alleviating anxiety behavior.Conclusion: The occurrence of GAD is closely related to the upregulation of the Notch signaling pathway, which hinders the regeneration of normal neurons in the hippocampus, while DZXYS can downregulate the Notch signaling pathway and promote neuronal regeneration in the hippocampus, thereby relieving anxiety behavior.

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FGF21 attenuates neurodegeneration through modulating neuroinflammation and oxidant-stress

Cited by 60 publications

References 61 publications

FGF21: An Emerging Therapeutic Target for Non-Alcoholic Steatohepatitis and Related Metabolic Diseases

FGF21: An Emerging Therapeutic Target for Non-Alcoholic Steatohepatitis and Related Metabolic Diseases

Cellular Mechanisms of FGF-Stimulated Tissue Repair

Danzhi Xiaoyao Powder Promotes Neuronal Regeneration by Downregulating Notch Signaling Pathway in the Treatment of Generalized Anxiety Disorder

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