Ly6C-high monocytes alleviate brain injury in experimental subarachnoid hemorrhage in mice.

BACKGROUND: Subarachnoid hemorrhage (SAH) is an uncommon type of potentially fatal stroke. The pathophysiological mechanisms of brain injury remain unclear, which hinders the development of drugs for SAH. We aimed to investigate the pathophysiological mechanisms of SAH and to elucidate the cellular and molecular biological response to SAH-induced injury. METHODS: A cross-species (human and mouse) multiomics approach combining high-throughput data and bioinformatic analysis was used to explore the key pathophysiological processes and cells involved in SAH-induced brain injury. Patient data were collected from the hospital (n = 712). SAH was established in adult male mice via endovascular perforation, and flow cytometry, a bone marrow chimera model, qPCR, and microglial depletion experiments were conducted to explore the origin and chemotaxis mechanism of the immune cells. To investigate cell effects on SAH prognosis, murine neurological function was evaluated based on a modified Garcia score, pole test, and rotarod test. RESULTS: The bioinformatics analysis confirmed that inflammatory and immune responses were the key pathophysiological processes after SAH. Significant increases in the monocyte levels were observed in both the mouse brains and the peripheral blood of patients after SAH. Ly6C-high monocytes originated in the bone marrow, and the skull bone marrow contribute a higher proportion of these monocytes than neutrophils. The mRNA level of Ccl2 was significantly upregulated after SAH and was greater in CD11b-positive than CD11b-negative cells. Microglial depletion, microglial inhibition, and CCL2 blockade reduced the numbers of Ly6C-high monocytes after SAH. With CCR2 antagonization, the neurological function of the mice exhibited a slow recovery. Three days post-SAH, the monocyte-derived dendritic cell (moDC) population had a higher proportion of TNF-α-positive cells and a lower proportion of IL-10-positive cells than the macrophage population. The ratio of moDCs to macrophages was higher on day 3 than on day 5 post-SAH. CONCLUSIONS: Inflammatory and immune responses are significantly involved in SAH-induced brain injury. Ly6C-high monocytes derived from the bone marrow, including the skull bone marrow, infiltrated into mouse brains via CCL2 secreted from microglia. Moreover, Ly6C-high monocytes alleviated neurological dysfunction after SAH.

The Role of Neutrophil Extracellular Traps in Central Nervous System Diseases and Prospects for Clinical Application.

Neutrophil extracellular traps (NETs) are complexes of decondensed DNA fibers and antimicrobial peptides that are released by neutrophils and play important roles in many noninfectious diseases, such as cystic fibrosis, systemic lupus erythematosus, diabetes, and cancer. Recently, the formation of NETs has been detected in many central nervous system diseases and is thought to play different roles in the occurrence and development of these diseases. Researchers have detected NETs in acute ischemic stroke thrombi, and these NETs are thought to promote coagulation and thrombosis. NETs in ischemic brain parenchyma were identified as the cause of secondary nerve damage. High levels of NETs were also detected in grade IV glioma tissues, where NETs were involved in the proliferation and invasion of glioma cells by activating a signaling pathway. Extracellular web-like structures have also recently been observed in mice with traumatic brain injury (TBI), and it was hypothesized that NETs contribute to the development of edema after TBI. This article reviews the effect of NETs on multiple diseases that affect the CNS and explores their clinical application prospects.

Progress in Mesenchymal Stem Cell Therapy for Ischemic Stroke.

Ischemic stroke (IS) is a serious cerebrovascular disease with high morbidity and disability worldwide. Despite the great efforts that have been made, the prognosis of patients with IS remains unsatisfactory. Notably, recent studies indicated that mesenchymal stem cell (MSCs) therapy is becoming a novel research hotspot with large potential in treating multiple human diseases including IS. The current article is aimed at reviewing the progress of MSC treatment on IS. The mechanism of MSCs in the treatment of IS involved with immune regulation, neuroprotection, angiogenesis, and neural circuit reconstruction. In addition, nutritional cytokines, mitochondria, and extracellular vesicles (EVs) may be the main mediators of the therapeutic effect of MSCs. Transplantation of MSCs-derived EVs (MSCs-EVs) affords a better neuroprotective against IS when compared with transplantation of MSCs alone. MSC therapy can prolong the treatment time window of ischemic stroke, and early administration within 7 days after stroke may be the best treatment opportunity. The deliver routine consists of intraventricular, intravascular, intranasal, and intraperitoneal. Furthermore, several methods such as hypoxic preconditioning and gene technology could increase the homing and survival ability of MSCs after transplantation. In addition, MSCs combined with some drugs or physical therapy measures also show better neurological improvement. These data supported the notion that MSC therapy might be a promising therapeutic strategy for IS. And the application of new technology will promote MSC therapy of IS.

Comparison of Operative and Conservative Treatment for Asymptomatic Moyamoya Disease: Preliminary Experience in Small Retrospective Series.

OBJECTIVE: The best management of asymptomatic moyamoya disease (MMD) remains controversial. In this study, the authors aimed to explore an experience for treatment modality for asymptomatic MMD. METHODS: The authors retrospectively reviewed a total of 23 patients (age range 30-58 years) with asymptomatic MMD during the past 5 years at their institutions. The patients were divided into 2 groups: The surgical group included 11 patients, and the conservative group included 12 patients. The demographic, radiologic, and clinical findings of the patients were evaluated. At follow-up over 13-65 months, the future clinical and radiologic progression events were evaluated. RESULTS: During the follow-up period, 3 patients suffered from future clinical progression events in the conservative group: 1 experienced stroke, and 2 experienced transient ischemic attack. Among the patients in the surgical group, only 1 experienced transient ischemic attack. Kaplan-Meier analysis showed that patients undergoing surgeries had longer clinical progression-free survival times compared with patients in the conservative group (P = 0.002). CONCLUSIONS: Surgical treatment may be an alternative choice for patients with asymptomatic MMD. However, the best strategy for asymptomatic MMD in order to reduce future cerebrovascular risks still needs to be further explored.

Structural and functional analysis of two novel somatostatin receptors identified from topmouth culter (Erythroculter ilishaeformis).

In the present study, we cloned and characterized two somatostatin (SS) receptors (SSTRs) from topmouth culter (Erythroculter ilishaeformis) designated as EISSTR6 and EISSTR7. Analysis of EISSTR6 and EISSTR7 signature motifs, 3D structures, and homology with the known members of the SSTR family indicated that the novel receptors had high similarity to the SSTRs of other vertebrates. EISSTR6 and EISSTR7 mRNA expression was detected in 17 topmouth culter tissues, and the highest level was observed in the pituitary. Luciferase reporter assay revealed that SS14 significantly inhibited forskolin-stimulated pCRE-luc promoter activity in HEK293 cells transiently expressing EISSTR6 and EISSTR7, indicating that the receptors can be activated by SS14. We also identified phosphorylation sites important for the functional activity of EISSTR6 and EISSTR7 by mutating Ser23, 43, 107, 196, 311 and Ser7, 29, 61, 222, 225 residues, respectively, to Ala, which significantly reduced the inhibitory effects of SS14 on the CRE promoter mediated by EISSTR6 and EISSTR7. Furthermore, treatment of juvenile topmouth culters with microcystin-LR or 17ß-estradiol significantly affected EISSTR6 and EISSTR7 transcription in the brain, liver and spleen, suggesting that these receptors may be involved in the pathogenic mechanisms induced by endocrine disruptors. Our findings should contribute to the understanding of the structure-function relationship and evolution of the SSTR family.