A fragment of cell adhesion molecule L1 reduces amyloid-β plaques in a mouse model of Alzheimer’s disease

Deposition of amyloid-β (Aβ) in the brain is one of the important histopathological features of Alzheimer’s disease (AD). Previously, we reported a correlation between cell adhesion molecule L1 (L1) expression and the occurrence of AD, but its relationship was unclear. Here, we report that the expression of L1 and a 70 kDa cleavage product of L1 (L1-70) was reduced in the hippocampus of AD (APPswe) mice. Interestingly, upregulation of L1-70 expression in the hippocampus of 18-month-old APPswe mice, by parabiosis involving the joining of the circulatory system of an 18-month-old APPswe mouse with a 2-month-old wild-type C57BL/6 mouse, reduced amyloid plaque deposition. Furthermore, the reduction was accompanied by the appearance of a high number of activated microglia. Mechanistically, we observed that L1-70 could combine with topoisomerase 1 (Top1) to form a complex, L1-70/Top1, that was able to regulate expression of macrophage migration inhibitory factor (MIF), resulting in the activation of microglia and reduction of Aβ plaques. Also, transforming growth factor β1 (TGFβ-1) transferred from the blood of young wild-type C57BL/6 mice to the aged AD mice, was identified as a circulating factor that induces full-length L1 and L1-70 expression. All together, these findings suggest that L1-70 contributes to the clearance of Aβ in AD, thereby adding a novel perspective in understanding AD pathogenesis.

Downregulated miR-1271-5p inhibits proliferation and invasion of trophoblast cells by activates Grhl2/CHL1 axis in preeclampsia

Objective: Abnormal cell growth and invasion are known to be involved in the pathogenesis of preeclampsia (PE). Previous studies have shown that miR-1271-5p promotes cell proliferation and migration. However, the expression and function of miR-1271-5p in PE still remains unclear.Materials and Methods: The expression of miR-1271-5p was detected from blood serum from pregnant and placental tissues. Silence or overexpression of miR-1271-5p in HTR8/SVneo cells. Real-time quantitative PCR was used to detect miR-1271-5p expression. Cell proliferation and invasion were determined using separately MTT assay Wound-scratch healing assay.Results: In this study, we identified a downregulation in miR-1271-5p in blood samples and placentas of PE patients compared to healthy pregnant controls. In addition, overexpression of miR-1271-5p promoted trophoblast cell proliferation and invasion, while depletion of miR-1271-5p reduced these effects. Importantly, we revealed that grainyhead-like protein 2 homolog (Grhl2), which could inhibit proliferation and migration of trophoblast cells, was a direct target gene of miR-1271-5p in primary trophoblast cells and HTR-8/SVneo cells. Furthermore, Our results showed that Grhl2 bound to the cell adhesion molecule L1-like protein (CHL1) promoter and regulated it transcription in trophoblast cells.Conclusion: Grhl2-mediated effects of miR-1271-5p on cell invasion and proliferation of trophoblast cells by promoting CHL1 transcription. The miR-1271-5p/Grhl2/CHL1 axis potentially provides a new therapeutic target for PE.

Small compounds mimicking the adhesion molecule L1 improve recovery in a zebrafish demyelination model

Demyelination leads to a loss of neurons, which results in, among other consequences, a severe reduction in locomotor function, and underlies several diseases in humans including multiple sclerosis and polyneuropathies. Considerable clinical progress has been made in counteracting demyelination. However, there remains a need for novel methods that reduce demyelination while concomitantly achieving remyelination, thus complementing the currently available tools to ameliorate demyelinating diseases. In this study, we used an established zebrafish demyelination model to test selected compounds, following a screening in cell culture experiments and in a mouse model of spinal cord injury that was aimed at identifying beneficial functions of the neural cell adhesion molecule L1. In comparison to mammalian nervous system disease models, the zebrafish allows testing of potentially promotive compounds more easily than what is possible in mammals. We found that our selected compounds tacrine and duloxetine significantly improved remyelination in the peripheral and central nervous system of transgenic zebrafish following pharmacologically induced demyelination. Given that both molecules are known to positively affect functions other than those related to L1 and in other disease contexts, we propose that their combined beneficial function raises hope for the use of these compounds in clinical settings.

The role of clinical factors and immunocheckpoint molecules in the prognosis of patients with supratentorial extraventricular ependymoma: a single-center retrospective study

Purpose Supratentorial extraventricular ependymoma (SEE) is a rare subset of ependymomas located in the supratentorial parenchyma, and little is known regarding its management and prognosis. Our study aimed to reveal the prognostic factors in patients with SEE and the roles of programmed death ligand-1 (PD-L1), programmed cell death protein 1 (PD-1), Ki-67, and neural cell adhesion molecule L1 (L1CAM) in predicting these patients’ outcomes. Methods We retrospectively studied the clinical features and prognostic factors in 48 patients with SEE admitted to our center from April 2008 to October 2018. Tissue slides were constructed from patient samples, and PD-L1, PD-1, Ki-67, and L1CAM expression levels were evaluated by immunohistochemistry. Results Patients with gross total resection (GTR) had better progression-free survival than patients with subtotal resection (STR). Moreover, the recurrence hazard ratios in patients with STR at 3, 5, and 10 years were 8.746, 6.866 and 3.962 times those of patients with GTR, respectively. PD-L1 positivity predicted worse progression-free survival, while the recurrence hazard ratios for patients with PD-L1 positivity at 3, 5, and 10 years were 10.445, 5.539, and 3.949 times those of patients with PD-L1 negativity, respectively. Multivariate analysis revealed that PD-L1 expression and GTR could independently predict outcomes in patients with SEE. Conclusion PD-L1 expression was an independent and more readily obtained predictor of outcomes, representing a simple and reliable biological prognostic factor for patients with SEE. Further studies are needed to explore PD-L1 inhibitor treatment for patients with ependymoma. Clinical trial registration No clinical trials were performed in the study.

Tacrine alleviates neuropathic pain in mice by mimicking the cell adhesion molecule L1

Neuropathic pain, which is caused by nervous system damage or dysfunctions, remains one of the most intractable challenges in modern medicine due to the lack of effective drugs. Tacrine, which is a small organic compound, is known to mimic the beneficial characteristics of the neural cell adhesion molecule L1 (L1CAM, L1) in vitro. Although previous studies indicated that L1 constitutes a viable strategy for promoting regeneration after nervous system injury, it is not clear whether L1 has a definite role in peripheral nerve injury. In this study, we observed that tacrine eased thermal hyperalgesia and mechanical allodynia after sciatic nerve chronic construction injury and restored functional morphological damage. Furthermore, tacrine suppressed the proliferation and activation of glia and reduced the level of IL-1β, IL-6 and TNF-α. Tacrine also inhibited the JAK2/STAT3 signaling pathway, which is involved in neuroinflammation. These observations indicated that tacrine is a promising candidate for an analgesic agent for neuropathic pain.

L1CAM as an E-selectin Ligand in Colon Cancer

Metastasis is the main cause of death among colorectal cancer (CRC) patients. E-selectin and its carbohydrate ligands, including sialyl Lewis X (sLeX) antigen, are key players in the binding of circulating tumor cells to the endothelium, which is one of the major events leading to organ invasion. Nevertheless, the identity of the glycoprotein scaffolds presenting these glycans in CRC remains unclear. In this study, we firstly have characterized the glycoengineered cell line SW620 transfected with the fucosyltransferase 6 (FUT6) coding for the α1,3-fucosyltransferase 6 (FUT6), which is the main enzyme responsible for the synthesis of sLeX in CRC. The SW620FUT6 cell line expressed high levels of sLeX antigen and E-selectin ligands. Moreover, it displayed increased migration ability. E-selectin ligand glycoproteins were isolated from the SW620FUT6 cell line, identified by mass spectrometry, and validated by flow cytometry and Western blot (WB). The most prominent E-selectin ligand we identified was the neural cell adhesion molecule L1 (L1CAM). Previous studies have shown association of L1CAM with metastasis in cancer, thus the novel role as E-selectin counter-receptor contributes to understand the molecular mechanism involving L1CAM in metastasis formation.

L1CAM, CA9, KLK6, HPN, and ALDH1A1 as Potential Serum Markers in Primary and Metastatic Colorectal Cancer Screening

Background: Colorectal cancer (CRC) screening at the earlier stages could effectively decrease CRC-related mortality and incidence; however, accurate screening strategies are still lacking. Considerable interest has been generated in the detection of less invasive tests requiring a small sample volume with the potential to detect several cancer biomarkers simultaneously. Due to this, the ELISA-based method was undertaken in this study. Methods: Concentrations of neural cell adhesion molecule L1 (L1CAM), carbonic anhydrase IX (CA9), mesothelin (MSLN), midkine (MDK), hepsin (HPN), kallikrein 6 (KLK6), transglutaminase 2 (TGM2) aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), epithelial cell adhesion molecule (EpCAM), and cluster of differentiation 44 (CD44) from blood serum of 36 primary CRC and 24 metastatic CRC (mCRC) were calculated via MAGPIX® System (Luminex Corporation, USA). Results: Significantly increased concentration (p < 0.05) of three serum biomarkers (L1CAM, CA9, and HPN) were shown in mCRC when compared with primary CRC. HPN and KLK6 showed significant differences (p < 0.05) in concentration among different stages of CRC. In contrast, levels of HPN and ALDH1A1 were significantly elevated (p < 0.05) in chemotherapy-treated CRC patients as compared with nontreated ones. Conclusion: Serum biomarkers could act as a potential early CRC diagnostics test, but further additional testings are needed.