Journal of neurotrauma
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Journal of neurotrauma · Apr 2023
Therapeutic role of microRNAs of small extracellular vesicles from human mesenchymal stromal/stem cells in the treatment of experimental traumatic brain injury.
Mesenchymal stem/stromal cells (MSC)-derived small extracellular vesicles (sEVs) possess therapeutic potential for treatment of traumatic brain injury (TBI). The essential role of micro ribonucleic acids (miRNAs) underlying the beneficial effects of MSC-derived sEVs for treatment of TBI remains elusive. The present study was designed to investigate the role of microRNAs in sEVs from MSCs with Argonaute 2 knockdown (Ago2-KD) in neurological recovery, neuroinflammation, and neurovascular remodeling in TBI rats. ⋯ The therapeutic effects of Ago2-KD-sEV were comparable to that of vehicle treatment. Our findings demonstrate that attenuation of Ago2 protein in MSCs reduces miRNAs in MSC-derived sEVs and abolishes exosome treatment-induced beneficial effects in TBI recovery, suggesting that miRNAs in MSC-derived sEVs play an essential role in reducing neuronal cell loss, inhibiting neuroinflammation, and augmenting angiogenesis and neurogenesis, as well as improving functional recovery in TBI. The findings underscore the important role of miRNAs in MSC-derived sEVs in the treatment of TBI.
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Journal of neurotrauma · Apr 2023
Innate and peripheral immune alterations after TBI are regulated in a gut microbiota-dependent manner in mice.
Traumatic brain injury (TBI) patients are at high risk for disruption of the gut microbiome. Previously, we have demonstrated that broad-spectrum antibiotic exposure after TBI drastically alters the gut microbiota and modulates neuroinflammation, neurogenesis, and long-term fear memory. However, these data did not determine if the impact of antibiotic exposure on the brain's response to injury was mediated directly by antibiotics or indirectly via modulation of the gut microbiota. ⋯ At 7 days post-injury, GF-VNAM had increased microglial activation, reduced infiltration of T cells, and decreased neurogenesis. Similarly, SPF mice exposed to antibiotics prior to but not after injury demonstrated similar alterations in neuroinflammation and neurogenesis compared with control mice. These data support our hypothesis implicating the gut microbiota as an important modulator of the neuroinflammatory process and neurogenesis after TBI and provide an exciting new approach for neuroprotective therapeutics for TBI.
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Journal of neurotrauma · Apr 2023
LDC7559 Exerts Neuroprotective Effects by Inhibiting GSDMD-dependent Pyroptosis of Microglia in Mice with Traumatic Brain Injury.
Abstract Pyroptosis is considered one of a critical factor in the recovery of neurological function following traumatic brain injury. Brain injury activates a molecular signaling cascade associated with pyroptosis and inflammation, including NLRP3, inflammatory cytokines, caspase-1, gasdermin D (GSDMD), and other pyroptosis-related proteins. In this study, we explored the neuroprotective effects of LDC7559, a GSDMD inhibitor. ⋯ The findings revealed that inflammation and pyroptosis levels were decreased by LDC7559 or si-GSDMD treatment both in vitro and in vivo. Immunofluorescence staining, brain water content, hematoxylin and eosin staining, and behavioral investigations suggested that LDC7559 or si-GSDMD inhibited microglial proliferation, ameliorated cerebral edema, reduced brain tissue loss, and promoted brain function recovery. Taken together, LDC7559 may inhibit pyroptosis and reduce inflammation by inhibiting GSDMD, thereby promoting the recovery of neurological function.