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C36H32Co2N8O4, monoclinic, P21/c (no. 14), a = 12.2971(12) Å, b = 13.1008(13) Å, c = 11.0864(11) Å, β = 99.174(2)°, V = 1763.2(3) Å3, Z = 2, Rgt(F) = 0.0277, wRref(F2) = 0.0818, T = 296 K.

Background: Microglia/macrophages, as pivotal immune cells in the central nervous system (CNS), play a critical role in neuroinflammation associated with ischemic brain injury. Targeting their activation through pharmacological interventions represents a promising strategy to alleviate neurological deficits, thereby harboring significant implications for the prevention and treatment of ischemic stroke. Ligusticum cycloprolactam (LIGc), a novel monomeric derivative of traditional Chinese medicine, has shown potential as a therapeutic agent; however, its specific role in cerebral ischemic injury remains unclear. Methods: In vitro experiments utilized lipopolysaccharide (LPS)‐induced inflammation models of RAW264.7 cells and primary mouse microglia. In vivo studies employed LPS‐induced neuroinflammation models in mice and a transient middle cerebral artery occlusion (tMCAO) mouse model to evaluate the impact of LIGc on neuroinflammation and microglia/macrophage phenotypic alterations. Further elucidation of the molecular mechanisms underlying these effects was achieved through RNA‐Seq analyses. Results: LIGc exhibited the capacity to attenuate LPS‐induced production of pro‐inflammatory markers in macrophages and microglia, facilitating their transition to an anti‐inflammatory phenotype. In models of LPS‐induced neuroinflammation and tMCAO, LIGc ameliorated pathological behaviors and neurological deficits while mitigating brain inflammation. RNA‐seq analyses revealed formyl peptide receptor 1 (FPR1) as a critical mediator of LIGc's effects. Specifically, FPR1 enhances the pro‐inflammatory phenotype of microglia/macrophages and inhibits their anti‐inflammatory response by upregulating NLR family pyrin domain protein 3 (NLRP3) inflammasomes, thus aggravating inflammatory processes. Conversely, LIGc exerts anti‐inflammatory effects by downregulating the FPR1/NLRP3 signaling axis. Furthermore, FPR1 overexpression or NLRP3 agonists reversed the effects of LIGc observed in this study. Conclusion: Our findings suggest that LIGc holds promise in improving ischemic brain injury and neuroinflammation through modulation of microglia/macrophage polarization. Mechanistically, LIGc attenuates the pro‐inflammatory phenotype and promotes the anti‐inflammatory phenotype by targeting the FPR1/NLRP3 signaling pathway, ultimately reducing inflammatory responses and mitigating neurological damage. [ABSTRACT FROM AUTHOR]

Microglia are resident immune cells in the central nervous system(CNS), it play an important role in both physiological and pathological conditions of the CNS, and can be activated by a variety of physicochemical factors to produce pro-inflammatory phenotype (M1 type) and anti-inflammatory phenotype (M2 type). Milk fat globule epidermal growth factor 8(MFG-E8) is closely related to the biological function of microglia, which can regulate microglia neuroprotective effects such as promoting phagocytosis, anti-inflammatory, and inhibiting oxidative stress in CNS related diseases. It also regulates microglia pro-tumor effect, which in turn affects the outcome of the disease. This article reviews the role of targeting MFG-E8 in regulating the function of microglia, and provides a basis for finding therapeutic targets for CNS related diseases in the future. [ABSTRACT FROM AUTHOR]

Gliomas, the most common malignant brain tumor, present a grim prognosis despite available treatments such as surgical resection, temozolomide (TMZ) therapy, and radiation therapy. This is due to their aggressive growth, high level of immunosuppression, and the blood–brain barrier (BBB), which obstruct the effective exchange of therapeutic drugs. Gliomas can significantly affect differentiation and function of immune cells by releasing extracellular vesicles (EVs), resulting in a systemic immunosuppressive state and a highly immunosuppressive microenvironment. In the tumor immune microenvironment (TIME), the primary immune cells are regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs). In particular, glioma-associated TAMs are chiefly composed of monocyte-derived macrophages and brain-resident microglia. These cells partially exhibit characteristics of a pro-tumorigenic, anti-inflammatory M2-type. Glioma-derived EVs can hijack TAMs to differentiate into tumor-supporting phenotypes or directly affect the maturation of peripheral blood monocytes (PBMCs) and promote the activation of MDSCs. In addition, EVs impair the ability of dendritic cells (DCs) to process antigens, subsequently hindering the activation of lymphocytes. EVs also impact the proliferation, differentiation, and activation of lymphocytes. This is primarily evident in the overall reduction of CD4 + helper T cells and CD8 + T cells, coupled with a relative increase in Tregs, which possess immunosuppressive characteristics. This study investigates thoroughly how tumor-derived EVs impair the function of immune cells and enhance immunosuppression in gliomas, shedding light on their potential implications for immunotherapy strategies in glioma treatment. [ABSTRACT FROM AUTHOR]

Ligustilide, a natural phthalide mainly derived from chuanxiong rhizomes and Angelica Sinensis roots, possesses anti‐inflammatory activity, particularly in the context of the nervous system. However, its application is limited because of its unstable chemical properties. To overcome this limitation, ligusticum cycloprolactam (LIGc) was synthesized through structural modification of ligustilide. In this study, we combined network pharmacological methods with experimental verification to investigate the anti‐neuroinflammatory effects and mechanisms of ligustilide and LIGc. Based on our network pharmacology analysis, we identified four key targets of ligustilide involved in exerting an anti‐inflammatory effect, with the nuclear factor (NF)‐κB signal pathway suggested as the main signalling pathway. To verify these results, we examined the expression of inflammatory cytokines and inflammation‐related proteins, analysed the phosphorylation level of NF‐κB, inhibitor of κBα (IκBα) and inhibitor of κB kinase α and β (IKKα+β), and evaluated the effect of BV2 cell‐conditioned medium on HT22 cells in vitro. Our results, demonstrate for the first time that LIGc can downregulate the activation of the NF‐κB signal pathway in BV2 cells induced by lipopolysaccharide, suppress the production of inflammatory cytokines and reduce nerve injury in HT22 cells mediated by BV2 cells. These findings suggest that LIGc inhibits the neuroinflammatory response mediated by BV2 cells, providing strong scientific support for the development of anti‐inflammatory drugs based on natural ligustilide or its derivatives. However, there are some limitations to our current study. In the future, further experiments using in vivo models may provide additional evidence to support our findings. [ABSTRACT FROM AUTHOR]

C36H32Co2N8O4, monoclinic, P21/c (no. 14), a = 12.2971(12) Å, b = 13.1008(13) Å, c = 11.0864(11) Å, β = 99.174(2)°, V = 1763.2(3) Å3, Z = 2, Rgt(F) = 0.0277, wRref(F2) = 0.0818, T = 296 K. [ABSTRACT FROM AUTHOR]

Membrane trafficking process is significant for the complex and precise regulatory of the nervous system. Rab11, as a small GTPase of the Rab superfamily, controls endocytic vesicular trafficking to the cell surface after sorting in recycling endosome (RE), coordinating with its receptors to maintain neurological function. This article reviewed the literature of Rab11 in nervous system. Rab11-positive vesicles targeted transport growth-related molecules, such as integrins, protrudin, tropomyosin receptor kinase (Trk) A/B receptor and AMPA receptor (AMPAR) to membrane surface to promote the regeneration capacity of axon and dendrites and maintain synaptic plasticity. In addition, many studies have shown that the expression of Rab11 is decreased in multiple neurodegenerative diseases, which is highly correlated with the process of production, transport and clearance of disease-related pathological proteins. And overexpression or increased activity of Rab11 can greatly improve the defect of membrane trafficking and slow down the disease process. With increasing research efforts on Rab11-dependent membrane trafficking mechanisms, a potential target for nerve regeneration and neurodegenerative diseases will be provided. [ABSTRACT FROM AUTHOR]