Loss of microglial EED impairs synapse density, learning, and memory.

The embryonic ectoderm development (EED) is a core component of the polycomb-repressive complex 2 (PRC2) whose mutations are linked to neurodevelopmental abnormalities, intellectual disability, and neurodegeneration. Although EED has been extensively studied in neural stem cells and oligodendrocytes, its role in microglia is incompletely understood. Here, we show that microglial EED is essential for synaptic pruning during the postnatal stage of brain development. The absence of microglial EED at early postnatal stages resulted in reduced spines and impaired synapse density in the hippocampus at adulthood, accompanied by upregulated expression of phagocytosis-related genes in microglia. As a result, deletion of microglial Eed impaired hippocampus-dependent learning and memory in mice. These results suggest that microglial EED is critical for normal synaptic and cognitive functions during postnatal development.

A nano-innate immune system activator for cancer therapy in a 4T1 tumor-bearing mouse model.

BACKGROUND: Harnessing the immune system to fight cancer has led to prominent clinical successes. Strategies to stimulate innate immune effectors are attracting considerable interest in cancer therapy. Here, through conjugating multivalent Fc fragments onto the surface of mesoporous silica nanoparticles (MSN), we developed a nanoparticle-based innate immune system activator (NISA) for breast cancer immunotherapy. METHODS: NISA was prepared through conjugating mouse IgG3 Fc to MSN surface. Then, long-chain PEG5000, which was used to shield Fc to confer nanoparticle colloidal stability, was linked to the MSN surface via matrix metalloprotease-2 (MMP-2)-cleavable peptide (GPLGIAGQC). The activation of multiple components of innate immune system, including complement and the innate cells (macrophages and dendritic cells) and the associated anticancer effect were investigated. RESULTS: Fc fragments of NISA can be exposed through hydrolysis of long-chain PEG5000 by highly expressed MMP-2 in tumor microenvironment. Then, effective stimulation and activation of multiple components of innate immune system, including complement, macrophages, and dendritic cells were obtained, leading to efficient antitumor effect in 4T1 breast cancer cells and orthotopic breast tumor model in mice. CONCLUSIONS: The antitumor potency conferred by NISA highlights the significance of stimulating multiple innate immune elements in cancer immunotherapy.

TREM2 and Microglia Contribute to the Synaptic Plasticity: from Physiology to Pathology.

Synapses are bridges for information transmission in the central nervous system (CNS), and synaptic plasticity is fundamental for the normal function of synapses, contributing substantially to learning and memory. Numerous studies have proven that microglia can participate in the occurrence and progression of neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), by regulating synaptic plasticity. In this review, we summarize the main characteristics of synapses and synaptic plasticity under physiological and pathological conditions. We elaborate the origin and development of microglia and the two well-known microglial signaling pathways that regulate synaptic plasticity. We also highlight the unique role of triggering receptor expressed on myeloid cells 2 (TREM2) in microglia-mediated regulation of synaptic plasticity and its relationship with AD. Finally, we propose four possible ways in which TREM2 is involved in regulating synaptic plasticity. This review will help researchers understand how NDDs develop from the perspective of synaptic plasticity.

TREM2 in the pathogenesis of AD: a lipid metabolism regulator and potential metabolic therapeutic target.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a single-pass transmembrane immune receptor that is mainly expressed on microglia in the brain and macrophages in the periphery. Recent studies have identified TREM2 as a risk factor for Alzheimer's disease (AD). Increasing evidence has shown that TREM2 can affect lipid metabolism both in the central nervous system (CNS) and in the periphery. In the CNS, TREM2 affects the metabolism of cholesterol, myelin, and phospholipids and promotes the transition of microglia into a disease-associated phenotype. In the periphery, TREM2 influences lipid metabolism by regulating the onset and progression of obesity and its complications, such as hypercholesterolemia, atherosclerosis, and nonalcoholic fatty liver disease. All these altered lipid metabolism processes could influence the pathogenesis of AD through several means, including affecting inflammation, insulin resistance, and AD pathologies. Herein, we will discuss a potential pathway that TREM2 mediates lipid metabolism to influence the pathogenesis of AD in both the CNS and periphery. Moreover, we discuss the possibility that TREM2 may be a key factor that links central and peripheral lipid metabolism under disease conditions, including AD. This link may be due to impacts on the integrity of the blood-brain barrier, and we introduce potential pathways by which TREM2 affects the blood-brain barrier. Moreover, we discuss the role of lipids in TREM2-associated treatments for AD. We propose some potential therapies targeting TREM2 and discuss the prospect and limitations of these therapies.

Systemic Inflammatory Biomarkers, Especially Fibrinogen to Albumin Ratio, Predict Prognosis in Patients with Pancreatic Cancer.

PURPOSE: Systemic inflammatory response is a critical factor that promotes the initiation and metastasis of malignancies including pancreatic cancer (PC). This study was designed to determine and compare the prognostic value of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and fibrinogen-to-albumin ratio (FAR) in resectable PC and locally advanced or metastatic PC. MATERIALS AND METHODS: Three hundred fifty-three patients with resectable PC and 807 patients with locally advan-ced or metastatic PC were recruited in this study. These patients were classified into a training set (n=758) and a validation set (n=402). Kaplan-Meier survival plots and Cox proportional hazards regression models were used to analyze prognosis. RESULTS: Overall survival (OS) was significantly better for patients with resectable PC with low preoperative PLR (p=0.048) and MLR (p=0.027). Low FAR, MLR, NLR (p < 0.001), and PLR (p=0.003) were significantly associated with decreased risk of death for locally advanced or metastatic PC patients. FAR (hazard ratio [HR], 1.522; 95% confidential interval [CI], 1.261 to 1.837; p < 0.001) and MLR (HR, 1.248; 95% CI, 1.017 to 1.532; p=0.034) were independent prognostic factors for locally advanced or metastatic PC. CONCLUSION: The prognostic roles of FAR, MLR, NLR, and PLR in resectable PC and locally advanced or metastatic PC were different. FAR showed the most prognostic power in locally advanced or metastatic PC. Low FAR was positively correlated with OS in locally advanced or metastatic PC, which could be used to predict the prognosis.

PD-L1 Expression Is Regulated By NF-κB During EMT Signaling In Gastric Carcinoma.

PURPOSE: The aim of this study was to investigate the influence of epithelial-mesenchymal transition (EMT) occurring in gastric carcinoma cells and the involvement of programmed death ligand 1 (PD-L1) expression in tumor cells that undergo EMT. The mechanisms underlying PD-L1 expression during EMT in gastric carcinoma cells were also explored. METHODS: The capacities of migration and invasion were tested by cell scratch-wound assay and transwell chamber assay. PD-L1 expression by SGC7901 cell line and related mechanism were measured by Western blot and QRT-PCR. RESULTS: Treating with TGF-ß1 promotes the motility of SGC7901 and PD-L1 expression in vitro, while activating the NF-κB signal pathway. CONCLUSION: EMT increases the capacities of migration and invasion in gastric cancer cells, which resulted in up-regulation of PD-L1 expression via a mechanism that is dependent on NF-κB activation.

Recent progress in the understanding of complement activation and its role in tumor growth and anti-tumor therapy.

The complement system is indispensable in immune response, responsible for the wide range of immune surveillance, clearance and defense. Its activation, regulated by several crucial factors, is an important prerequisite for its role in tumor growth and anti-tumor therapy. Membrane attack complex (MAC) and anti-tumor anaphylatoxins like C5a have significant effects on promoting tumor, such as upregulation of oncogenic growth factors, activation of mitogenic signaling pathways and breakage of normal cell cycle. Complement cascades, initiated by anti-tumor antibodies, also play a pivotal role in anti-tumor therapy to suppress the tumor growth. Our review focuses on the recent progress in the understanding of complement activation and the role of it in tumor growth and anti-tumor therapy, in the context of rapid development of monoclonal antibodies and nanomaterials for cancer treatment.

New diterpenoid alkaloids from Aconitum coreanum and their anti-arrhythmic effects on cardiac sodium current.

Two new diterpenoid alkaloids, Guan-Fu base J (GFJ, 1) and Guan-Fu base N (GFN, 2) along with nineteen known alkaloids (3-21) were isolated from the roots of Aconitum coreanum (Lèvl.) Rapaics, which is the raw material of a new approval anti-arrhythmia drug "Acehytisine Hydrochloride". The structures of isolated compounds were established by means of 1D, 2D NMR spectroscopic and chemical methods. All isolates obtained in the present study were evaluated for their inhibitory effects on blocking the ventricular specific sodium current using a whole-cell patch voltage-clamp technique. Among these 21 compounds, Guan-Fu base S (GFS, 3) showed the strongest inhibitory effect with an IC50 value of 3.48 µM, and only hetisine-type C20 diterpenoid alkaloids showed promising IC50 values for further development.

[One-stage urethroplasty with circumferential vascular pedicle preputial island flap for perineal hypospadias].

OBJECTIVE: To report the treatment of perineal hypospadias with one-stage urethroplasty with circumferential vascular pedicle preputial island flap. METHODS: A circumferential incision was made proximal to the corona and the urethral plate to correct chordee. A U-shaped skin incision was then made surrounding the meatus, and extended to the dorsal prepuce and parallel to the first incision. The tissue between the prepuce and dartos was dissected on the dorsum of penis to fix the prepuce as a neo urethra. After mobilizing the loop shaped skin flap through the button-hole of the pedicle, the internal and external sides of the loop were sutured to construct a new urethra. The catheter was removed 10-14 days (mean, 12.8 days) after operation. RESULTS: Since 1997, 22 patients with perineal hypospadias were treated. Primary healing was achieved in 18 cases (81.8%). Fistula happened in 4 patients. Among them, one case with meatal stenosis was treated with dilatation. Another 3 patients were reoperated. The neo urethral flap was 3.50-18.00 cm (mean, 9.43 cm) in length. All patients were followed up for more than 6 months. Good cosmetic appearance was achieved in 72.7% (16/22) of the patients. CONCLUSIONS: The circumferential vascular pedicle preputial island flap has advantages of good blood supply and autograft for new meatus, which allows the chordee correction and urethroplasty at one stage. It is a good method for the treatment of perineal hypospadias with severe chordee and penoscrotal transposition.