ABSTRACT
BACKGROUND: Subarachnoid hemorrhage (SAH) represents a form of cerebrovascular event characterized by a notable mortality and morbidity rate. Fibroblast growth factor 21 (FGF21), a versatile hormone predominantly synthesized by the hepatic tissue, has emerged as a promising neuroprotective agent. Nevertheless, the precise impacts and underlying mechanisms of FGF21 in the context of SAH remain enigmatic. METHODS: To elucidate the role of FGF21 in inhibiting the microglial cGAS-STING pathway and providing protection against SAH-induced cerebral injury, a series of cellular and molecular techniques, including western blot analysis, real-time polymerase chain reaction, immunohistochemistry, RNA sequencing, and behavioral assays, were employed. RESULTS: Administration of recombinant fibroblast growth factor 21 (rFGF21) effectively mitigated neural apoptosis, improved cerebral edema, and attenuated neurological impairments post-SAH. Transcriptomic analysis revealed that SAH triggered the upregulation of numerous genes linked to innate immunity, particularly those involved in the type I interferon (IFN-I) pathway and microglial function, which were notably suppressed upon adjunctive rFGF21 treatment. Mechanistically, rFGF21 intervention facilitated mitophagy in an AMP-activated protein kinase (AMPK)-dependent manner, thereby preventing mitochondrial DNA (mtDNA) release into the cytoplasm and dampening the activation of the DNA-sensing cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. Conditional knockout of STING in microglia markedly ameliorated the inflammatory response and mitigated secondary brain injuries post-SAH. CONCLUSION: Our results present the initial evidence that FGF21 confers a protective effect against neuroinflammation-associated brain damage subsequent to SAH. Mechanistically, we have elucidated a novel pathway by which FGF21 exerts this neuroprotection through inhibition of the cGAS-STING signaling cascade.
Subject(s)
Fibroblast Growth Factors , Membrane Proteins , Mice, Inbred C57BL , Mitophagy , Neuroinflammatory Diseases , Nucleotidyltransferases , Signal Transduction , Subarachnoid Hemorrhage , Animals , Membrane Proteins/metabolism , Fibroblast Growth Factors/metabolism , Subarachnoid Hemorrhage/complications , Subarachnoid Hemorrhage/metabolism , Subarachnoid Hemorrhage/pathology , Neuroinflammatory Diseases/metabolism , Neuroinflammatory Diseases/etiology , Mitophagy/drug effects , Signal Transduction/drug effects , Nucleotidyltransferases/metabolism , Male , Mice , DNA, Mitochondrial/genetics , DNA, Mitochondrial/metabolism , Microglia/metabolism , Microglia/pathology , Microglia/drug effects , Apoptosis/drug effectsABSTRACT
Objective To investigate the relationship between the serum markers and genotype with viral load in chronic hepati-tis B in order to improve the level of clinical treatment.Methods 819 patients with chronic hepatitis B in our hospital from April 2010 to April 2013were selected as the study subjects and performed the genotyping.The hepatitis B virus(HBV)DNA level was detected by using real-time fluorescence PCR.Results Among the 819 cases of positive HBsAg,357 cases were positive HBV-DNA,accounting for 43.59%;HBeAg(+)accounted for 90.11%;in the positive modes of serum markers and viral load,most of positive cases were HBsAg,HBeAg,HBcAb and HBsAg,HBeAb,HBcAb,accounting for 88.52%;HBV genotyping had B,C,BC mixed types and unclassified type,the logrithm levels of viral DNA were(7.187 ±1.668),(7.184 ±1.558),(7.208 ±1.447)and (7.313±1.505),there was no statistically significant difference among them(P >0.05).Conclusion The virus gene in the patients with chronic hepatitis B is dominated by type C,in which serum markers HBeAg and HBV-DNA viral load have the lose correlated, the infected virus genotype has the low correlation with the viral load.
