ABSTRACT
Spinal cord injury (SCI) is one of the most serious health problems, with no effective therapy. Recent studies indicate that Fisetin, a natural polyphenolic flavonoid, exhibits multiple functions, such as life-prolonging, antioxidant, antitumor, and neuroprotection. However, the restorative effects of Fisetin on SCI and the underlying mechanism are still unclear. In the present study, we found that Fisetin reduced LPS-induced apoptosis and oxidative damage in PC12 cells and reversed LPS-induced M1 polarization in BV2 cells. Additionally, Fisetin safely and effectively promoted the motor function recovery of SCI mice by attenuating neurological damage and promoting neurogenesis at the lesion. Moreover, Fisetin administration inhibited glial scar formation, modulated microglia/macrophage polarization, and reduced neuroinflammation. Network pharmacology, RNA-seq, and molecular biology revealed that Fisetin inhibited the activation of the JAK2/STAT3 signaling pathway. Notably, Colivelin TFA, an activator of JAK2/STAT3 signaling, attenuated Fis-mediated neuroinflammation inhibition and therapeutic effects on SCI mice. Collectively, Fisetin promotes functional recovery after SCI by inhibiting microglia/macrophage M1 polarization and the JAK2/STAT3 signaling pathway. Thus, Fisetin may be a promising therapeutic drug for the treatment of SCI.
Subject(s)
Flavonols , Janus Kinase 2 , Macrophages , Microglia , STAT3 Transcription Factor , Signal Transduction , Spinal Cord Injuries , Animals , Humans , Male , Mice , Rats , Cell Polarity/drug effects , Flavonoids/pharmacology , Flavonoids/administration & dosage , Flavonols/pharmacology , Janus Kinase 2/metabolism , Janus Kinase 2/genetics , Macrophages/drug effects , Macrophages/immunology , Macrophages/metabolism , Mice, Inbred C57BL , Microglia/drug effects , Microglia/metabolism , Microglia/immunology , PC12 Cells , Recovery of Function/drug effects , Signal Transduction/drug effects , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/metabolism , Spinal Cord Injuries/genetics , Spinal Cord Injuries/physiopathology , Spinal Cord Injuries/immunology , STAT3 Transcription Factor/metabolism , STAT3 Transcription Factor/geneticsABSTRACT
The adverse microenvironment, including neuroinflammation, hinders the recovery of spinal cord injury (SCI). Regulating microglial polarization to alleviate neuroinflammation at the injury site is an effective strategy for SCI recovery. MG53 protein exerts obvious repair ability on multiple tissues damage, but with short half-life. In this study, we composited an innovative MG53/GMs/HA-Dex neural scaffold using gelatin microspheres (GMs), hyaluronic acid (HA), and dextran (Dex) loaded with MG53 protein. This novel neural scaffold could respond to MMP-2/9 protein and stably release MG53 protein with good physicochemical properties and biocompatibility. In addition, it significantly improved the motor function of SCI mice, suppressed M1 polarization of microglia and neuroinflammation, and promoted neurogenesis and axon regeneration. Further mechanistic experiments demonstrated that MG53/GMs/HA-Dex hydrogel inhibited the JAK2/STAT3 signaling pathway. Thus, this MG53/GMs/HA-Dex neural scaffold promotes the functional recovery of SCI mice by alleviating neuroinflammation, which provides a new intervention strategy for the neural regeneration and functional repair of SCI.
Subject(s)
Gelatin , Hyaluronic Acid , Janus Kinase 2 , Neuroinflammatory Diseases , Recovery of Function , Spinal Cord Injuries , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/metabolism , Animals , Mice , Recovery of Function/drug effects , Hyaluronic Acid/chemistry , Hyaluronic Acid/pharmacology , Neuroinflammatory Diseases/drug therapy , Gelatin/chemistry , Gelatin/pharmacology , Janus Kinase 2/metabolism , Dextrans/chemistry , Tissue Scaffolds/chemistry , Microspheres , STAT3 Transcription Factor/metabolism , Microglia/drug effects , Microglia/metabolism , Nerve Regeneration/drug effects , Matrix Metalloproteinase 9/metabolism , Disease Models, Animal , Neurogenesis/drug effects , Signal Transduction/drug effects , Matrix Metalloproteinase 2/metabolism , Hydrogels/chemistry , Hydrogels/pharmacologyABSTRACT
Alzheimer's disease (AD) is a chronic neurodegenerative disease with high prevalence, long duration and poor prognosis. The blood-brain barrier (BBB) is a physiologic barrier in the central nervous system, which hinders the entry of most drugs into the brain from the blood, thus affecting the efficacy of drugs for AD. Natural products are recognized as one of the promising and unique therapeutic approaches to treat AD. To improve the efficiency and therapeutic effect of the drug across the BBB, a natural polyphenolic compound, procyanidin C-1 (C1) was encapsulated in glucose-functionalized bovine serum albumin (BSA) nanoparticles to construct Glu-BSA/C1 NPs in our study. Glu-BSA/C1 NPs exhibited good stability, slow release, biocompatibility and antioxidant properties. In addition, Glu-BSA/C1 NPs penetrated the BBB, accumulated in the brain by targeting Glut1, and maintained the BBB integrity both in vitro and in vivo. Moreover, Glu-BSA/C1 NPs alleviated memory impairment of 5 × FAD mice by reducing Aß deposition and Tau phosphorylation and promoting neurogenesis. Mechanistically, Glu-BSA/C1 NPs significantly activated the PI3K/AKT pathway and inhibited the NLRP3/Caspase-1/IL-1ß pathway thereby suppressing neuroinflammation. Taken together, Glu-BSA/C1 NPs could penetrate the BBB and mitigate neuroinflammation in AD, which provides a new therapeutic approach targeting AD.