Stimulator of interferons genes (STING), which is crucial for the secretion of type I interferons and proinflammatory cytokines in response to cytosolic nucleic acids, plays a key role in the innate immune system. Studies have revealed the participation of the STING pathway in unregulated inflammatory processes, traumatic brain injury (TBI), spinal cord injury (SCI), subarachnoid haemorrhage (SAH) and hypoxic–ischaemic encephalopathy (HIE). STING signalling is markedly increased in CNS injury, and STING agonists might facilitate the pathogenesis of CNS injury. However, the effects of STING-regulated signalling activation in CNS injury are not well understood. Aberrant activation of STING increases inflammatory events, type I interferon responses, and cell death. cGAS is the primary pathway that induces STING activation. Herein, we provide a comprehensive review of the latest findings related to STING signalling and the cGAS–STING pathway and highlight the control mechanisms and their functions in CNS injury. Furthermore, we summarize and explore the most recent advances toward obtaining an understanding of the involvement of STING signalling in programmed cell death (autophagy, necroptosis, ferroptosis and pyroptosis) during CNS injury. We also review potential therapeutic agents that are capable of regulating the cGAS–STING signalling pathway, which facilitates our understanding of cGAS–STING signalling functions in CNS injury and the potential value of this signalling pathway as a treatment target.

Spinal cord injury (SCI) results in a wide range of disabilities. Its complex pathophysiological process limits the effectiveness of many clinical treatments. Betulinic acid (BA) has been shown to be an effective treatment for some neurological diseases, but it has not been studied in SCI. In this study, we assessed the role of BA in SCI and investigated its underlying mechanism. We used a mouse model of SCI, and functional outcomes following injury were assessed. Western blotting, ELISA, and immunofluorescence techniques were employed to analyze levels of autophagy, mitophagy, pyroptosis, and AMPK-related signaling pathways were also examined. Our results showed that BA significantly improved functional recovery following SCI. Furthermore, autophagy, mitophagy, ROS level and pyroptosis were implicated in the mechanism of BA in the treatment of SCI. Specifically, our results suggest that BA restored autophagy flux following injury, which induced mitophagy to eliminate the accumulation of ROS and inhibits pyroptosis. Further mechanistic studies revealed that BA likely regulates autophagy and mitophagy via the AMPK-mTOR-TFEB signaling pathway. Those results showed that BA can significantly promote the recovery following SCI and that it may be a promising therapy for SCI.

Background: Glucocorticoids (GCs) overuse is associated with decreased bone mass and osseous vasculature destruction, leading to severe osteoporosis. Platelet lysates (PL) as a pool of growth factors (GFs) were widely used in local bone repair by its potent pro-regeneration and pro-angiogenesis. However, it is still seldom applied for treating systemic osteopathia due to the lack of a suitable delivery strategy. The non-targeted distribution of GFs might cause tumorigenesis in other organs.Results: In this study, PL-derived exosomes (PL-exo) were isolated to enrich the platelet-derived GFs, followed by conjugating with alendronate (ALN) grafted PEGylated phospholipid (DSPE-PEG-ALN) to establish a bone-targeting PL-exo (PL-exo-ALN). The in vitro hydroxyapatite binding affinity and in vivo bone targeting aggregation of PL-exo were significantly enhanced after ALN modification. Besides directly modulating the osteogenic and angiogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and endothelial progenitor cells (EPCs), respectively, PL-exo-ALN also facilitate their coupling under GCs’ stimulation. Additionally, intravenous injection of PL-exo-ALN could successfully rescue GCs induced osteoporosis (GIOP) in vivo.Conclusions: PL-exo-ALN may be utilized as a novel nanoplatform for precise infusion of GFs to bone sites and exerts promising therapeutic potential for GIOP.Graphical

There is an increased interest in enhanced recovery after surgery (ERAS) minimizing adverse events after orthopedic surgery. Little consensus supports the effectiveness of these interventions. The purpose of present systematic review and meta-analysis is to comprehensively analyze and evaluate the significance of ERAS interventions for postoperative outcomes after orthopedic surgery. PubMed, EMBASE, and Cochrane databases were totally searched from the inception dates to May 31, 2018. Two reviewers independently extracted the data from the selected articles using a standardized form and assessed the risk of bias. The analysis was performed using STATA 12.0. A total of 15 published studies fulfilled the requirements of inclusion criteria. We found that the ERAS group showed a significant association with lower incidence of postoperative complications (OR, 0.70; 95% CI, 0.64 to 0.78). Meanwhile, ERAS was also associated with the decline in 30-day mortality rate and Oswestry Disability Index (ODI). However, no significant differences were identified between the two groups regarding the 30-day readmission rate (P = 0.397). Our meta-analysis suggested that the ERAS group had more advantages in reducing incidence of postoperative complications, 30-day mortality rate, and ODI after orthopedic surgery, but not of 30-day readmission rate. However, further research with standardized, unbiased methods and larger sample sizes is required for deeper analysis.

Traumatic brain injury (TBI) and spinal cord injury (SCI) are capable of causing severe sensory, motor and autonomic nervous system dysfunctions. However, effective treatments for TBI and SCI are still unavailable, mainly because the death of nerve cells is uncontrollable. Necroptosis is a type of programmed cell death and a critical mechanism in the process of neuronal cell death. However, the role of necroptosis has not been comprehensively defined in TBI and SCI. This review aimed to summarize the role of necroptosis in central nervous system (CNS) trauma and its therapeutic implications and present important suggestions for researchers conducting in-depth research. Necroptosis is orchestrated by a complex comprising the receptor-interacting protein kinase (RIPK)1, RIPK3 and mixed lineage kinase domain-like protein (MLKL) proteins. Mechanistically, RIPK1 and RIPK3 form a necrosome with MLKL. After MLKL dissociates from the necrosome, it translocates to the plasma membrane to induce pore formation in the membrane and then induces necroptosis. In this review, the necroptosis signalling pathway and the execution of necroptosis are briefly discussed. In addition, we focus on the existing information on the mechanism by which necroptosis participates in CNS trauma, particularly in the temporal pattern of RIPKs and in different cell types. Furthermore, we describe the association of miRNAs and necroptosis and the relationship between different types of CNS trauma cell death. Finally, this study highlights agents likely capable of curtailing such a type of cell death according to results optimization and CNS trauma and presents important suggestions for researchers conducting in-depth research.

Acute central nervous system (CNS) trauma, including spinal cord injury (SCI) and traumatic brain injury (TBI), always leads to severe sensory, motor and autonomic nervous system dysfunction due to a series of processes, including cell death, oxidative stress, inflammation, and excitotoxicity. In recent years, ferroptosis was reported to be a type of programmed cell death characterized by the consumption of polyunsaturated fatty acids and the accumulation of membrane lipid peroxides. The processes that induce ferroptosis include iron overload, imbalanced glutathione metabolism and lipid peroxidation. Several studies have indicated a novel association of ferroptosis and acute CNS trauma. The present paper reviews recent studies of the occurrence of ferroptosis, stressing the definition and process of ferroptosis and metabolic pathways related to ferroptosis. Furthermore, a summary of the existing knowledge of the role of ferroptosis in CNS trauma is presented. The aim here is to effectively understand the mechanisms underlying the occurrence of ferroptosis, as well as the relevant effect on the pathophysiological process of CNS trauma, to present a novel perspective and frame of reference for subsequent investigations.