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Preeclampsia is a pregnancy-specific disorder characterized by de novo development of hypertension and proteinuria over 20 weeks gestation that has been associated with the dysfunction of trophoblasts. Current evidence suggests that syncytin-1 plays an important role in the non-fusogenic biological activity of trophoblasts, except for specific fusogenic function. However, the underlying mechanism remains unclear. The expression and location of syncytin-1 in normal and the late-onset preeclampsia placentas were detected by quantitative real-time PCR, western blotting and immunofluorescence. Morphological and apoptosis analysis were processed in placentas. The ex vivo extravillous explant culture model was used to explore the effect of syncytin-1 on EVT outgrowths. Real-time quantitative PCR and immunoblotting were used to calculate syncytin-1 levels in the trophoblast cells before and after syncytin-1 knockdown or overexpression. CCK-8 assay was used to detect the cell viability. TUNEL staining and immunoblotting were processed in trophoblast cells. Transwell assays and wound healing assays were utilize to assess the invasion and migration of trophoblastic cells. Conditional knockout of syncytin-a mouse model was conducted to present the change of placentas in vivo. The ex vivo extravillous explant culture model was used to explore the effect of syncytin-1 on EVT outgrowths. Western blotting was used to identify the key proteins of PI3K/Akt pathways and invasion-related proteins in trophoblast cells. Here, reduced syncytin-1 was identified in the late-onset preeclampsia placentas. Reduced syncytin-1 may attenuates the EMT process by promoting apoptosis, inhibiting proliferation and invasion by suppressed PI3K/Akt pathway in trophoblast cells. Our findings provide novel insights into the non-fusogenic biological function of reduced syncytin-1 that may be involves in the pathogenesis of preeclampsia. • Reduced syncytin-1 inhibited trophoblast cells function • Which may be involved in the pathogenesis of preeclampsia. [ABSTRACT FROM AUTHOR]

Poor placental angiogenesis is associated with several pregnancy complications including fetal growth restriction (FGR), which causes low birth weight (LBW) babies to have a high risk of growth disorders and metabolic disorders in adulthood. Recent research using syncytin knock-out mice showed significant disruption in the growth of placental vascularization. Syncytin-1 which encoded by ERVW-1 gene, is proposed to have a role in placental angiogenesis, but its relationship with other proangiogenic factors such as vascular endothelial growth factor (VEGF) in the placenta of LBW babies has not yet been determined. By knowing the mechanisms of FGR, more proactive preventive and therapeutic measures can be taken in the future. This study aimed to determine the expression of ERVW-1 , proangiogenic gene VEGF and its receptor (FLT-1), and hypoxia inducible factor-1 (HIF-1) in LBW placentas, and investigate the relationship between these genes' expression in the placenta of LBW babies. Total RNA was extracted from placental tissue. Total RNA is used as a cDNA synthesis template, followed by qRT-PCR. Correlations of ERVW-1, VEGF, FLT-1 and HIF-1 genes' expression were analyzed by linear regression. The age and body mass index of mothers with LBW and normal birth weight (NBW) babies were not significantly different. ERVW-1 expression in LBW placentas was lower than in NBW placentas, but VEGF, FLT-1 and HIF-1 expressions were higher. ERVW-1 was negatively correlated with HIF-1 and VEGF. Low expression of ERVW-1 in the placenta of LBW babies may result in impaired placental angiogenesis and possibly lead to hypoxia. • Lower expression of ERVW-1 was found in the placenta of Low Birth Weight babies. • Low ERVW-1 expression leads to hypoxia, as indicated by high HIF-1 expression. • Hypoxic conditions are compensated by upregulation of VEGF and its receptor, FLT-1. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. Syncytin‐1 (Syn), an envelope glycoprotein encoded by the env gene of the human endogenous retrovirus‐W family, has been resorted to be highly expressed in biopsies from the muscles from ALS patients; however, the specific regulatory role of Syn during ALS progression remains uncovered. In this study, C57BL/6 mice were injected with adeno‐associated virus‐overexpressing Syn, with or without Fasudil administration. The Syn expression was assessed by quantitative real‐time polymerase chain reaction and immunohistochemistry analysis. The histological change of anterior tibial muscles was determined by hematoxylin‐eosin staining. Qualitative ultrastructural analysis of electron micrographs obtained from lumbar spinal cords was carried out. Serum inflammatory cytokines were assessed by enzyme linked immunosorbent assay (ELISA) assay and motor function was recorded using Basso, Beattie, and Bresnahan (BBB) scoring, climbing test and treadmill running test. Immunofluorescence and western blot assays were conducted to examine microglial‐ and motor neurons‐related proteins. Syn overexpression significantly caused systemic inflammatory response, muscle tissue lesions, and motor dysfunction in mice. Meanwhile, Syn overexpression promoted the impairment of motor neuron, evidenced by the damaged structure of the neurons and reduced expression of microtubule‐associated protein 2, HB9, neuronal nuclei and neuron‐specific enolase in Syn‐induced mice. In addition, Syn overexpression greatly promoted the expression of CD16/CD32 and inducible nitric oxide synthase (M1 phenotype markers), and reduced the expression of CD206 and arginase 1 (M2 phenotype markers). Importantly, the above changes caused by Syn overexpression were partly abolished by Fasudil administration. This study provides evidence that Syn‐activated microglia plays a pivotal role during the progression of ALS. [ABSTRACT FROM AUTHOR]

Cell fusion is a biological process that is crucial for the development and homeostasis of different tissues, but it is also pathophysiologically associated with tumor progression and malignancy. The investigation of cell fusion processes is difficult because there is no standardized marker. Many studies therefore use different systems to observe and quantify cell fusion in vitro and in vivo. The comparability of the results must be critically questioned, because both the experimental procedure and the assays differ between studies. The comparability of the fluorescence-based fluorescence double reporter (FDR) and dual split protein (DSP) assay was investigated as part of this study, in which general conditions were kept largely constant. In order to be able to induce both a high and a low cell fusion rate, M13SV1 breast epithelial cells were modified with regard to the expression level of the fusogenic protein Syncytin-1 and its receptor ASCT2 and were co-cultivated for 72 h with different breast cancer cell lines. A high number of fused cells was found in co-cultures with Syncytin-1-overexpressing M13SV1 cells, but differences between the assays were also observed. This shows that the quantification of cell fusion events in particular is highly dependent on the assay selected, but the influence of fusogenic proteins can be visualized very well. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the expression and clinical significance of syncytin-1 in the serum exosomes of hepatocellular carcinoma (HCC) patients. Serum samples were collected from 61 patients with newly diagnosed HCC and 61 healthy individuals. Exosomes were extracted from serum samples and identified using transmission electron microscopy and Western blot. The relative expression levels of syncytin-1 in exosomes were determined by real-time quantitative PCR. The protein expression levels of alpha-fetoprotein and syncytin-1 in HCC patients were detected using enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed to evaluate the sensitivity and specificity of serum exosomal syncytin-1 in diagnosing HCC. The relationships between syncytin-1 expression and clinical pathological features were analyzed using receiver operating characteristic curve analysis. The results showed that the expression level of syncytin-1 in the serum of patients with newly diagnosed HCC was significantly higher than that in the normal control group (P < 0.0001). Using pathological diagnosis as the gold standard, the sensitivity and specificity of syncytin-1 for the auxiliary diagnosis of HCC were 91.3% and 75.5%, respectively, which were significantly higher than those of alpha-fetoprotein (P < 0.0001). The relative expression level of serum exosomal syncytin-1 was significantly associated with lymph node metastasis, degree of differentiation, and CNLC staging of HCC patients (P < 0.05). In conclusion, syncytin-1 in serum exosomes has high sensitivity and specificity for diagnosing HCC and can serve as a novel tumor marker for early screening, detection, and staging of HCC.

The role of retroviral envelope proteins belonging to the Human Endogenous Retroviral family 'W' (HERV‐W), specifically syncytin‐1 and pathogenic HERV‐W (pHERV‐W), as potential risk factors in multiple sclerosis (MS) has been established. This study aimed to investigate the humoral response to syncytin‐1 and pHERV‐W‐derived peptides in a group of relapsing remitting MS patients categorized as having acute or stable disease. Furthermore, an inhibition assay was conducted to assess the extent of cross‐reactivity between the two epitopes. The findings revealed that MS patients in the acute phase exhibited a higher specific antibody response to the pHERV‐W env epitope compared to syncytin‐1. This suggests a potential pathogenic role for pHERV‐W env during the inflammatory stages of central nervous system involvement, and these antibody responses could serve as useful biomarkers for monitoring the progression of the disease. [ABSTRACT FROM AUTHOR]

In this review, we summarized the results of experimental and clinical studies about three human endogenous retroviruses and their products—syncytin-1, syncytin-2, and suppressyn in human physiology and pathophysiology. We summed up the described connection with various pathological processes and diseases, mainly with pregnancy-induced hypertensive diseases such as preeclampsia, oncogenesis, gestational trophoblastic disease, and multiple sclerosis. Supposed mechanisms of action and the potential of clinical applications are also described. [ABSTRACT FROM AUTHOR]

Abstract Human endogenous retroviruses (HERVs) have evolved from exogenous retroviruses and account for approximately 8% of the human genome. A growing number of findings suggest that the abnormal expression of HERV genes is associated with schizophrenia, multiple sclerosis, endometriosis, breast cancer, bladder cancer and other diseases. HERV-W env (syncytin-1) is a membrane glycoprotein which plays an important role in placental development. It includes embryo implantation, fusion of syncytiotrophoblasts and of fertilized eggs, and immune response. The abnormal expression of syncytin-1 is related to placental development-related diseases such as preeclampsia, infertility, and intrauterine growth restriction, as well as tumors such as neuroblastoma, endometrial cancer, and endometriosis. This review mainly focused on the molecular interactions of syncytin-1 in placental development-related diseases and tumors, to explore whether syncytin-1 can be an emerging biological marker and potential therapeutic target.

Cell fusion is a biological process that is crucial for the development and homeostasis of different tissues, but it is also pathophysiologically associated with tumor progression and malignancy. The investigation of cell fusion processes is difficult because there is no standardized marker. Many studies therefore use different systems to observe and quantify cell fusion in vitro and in vivo. The comparability of the results must be critically questioned, because both the experimental procedure and the assays differ between studies. The comparability of the fluorescence-based fluorescence double reporter (FDR) and dual split protein (DSP) assay was investigated as part of this study, in which general conditions were kept largely constant. In order to be able to induce both a high and a low cell fusion rate, M13SV1 breast epithelial cells were modified with regard to the expression level of the fusogenic protein Syncytin-1 and its receptor ASCT2 and were co-cultivated for 72 h with different breast cancer cell lines. A high number of fused cells was found in co-cultures with Syncytin-1-overexpressing M13SV1 cells, but differences between the assays were also observed. This shows that the quantification of cell fusion events in particular is highly dependent on the assay selected, but the influence of fusogenic proteins can be visualized very well.

Human endogenous retrovirus type W (HERV-W) is expressed in various cancers. We previously developed an adenovirus-vectored cancer vaccine targeting HERV-W by encoding an assembled HERV-W group-specific antigen sequence and the HERV-W envelope sequence Syncytin-1. Syncytin-1 is constitutively fusogenic and forms large multinucleated cell fusions when overexpressed. Consequently, immunising humans with a vaccine encoding Syncytin-1 can lead to the formation of extensive syncytia, which is undesirable and poses a potential safety issue. Here, we show experiments in cell lines that restoring an evolutionary lost cleavage site of the fusion inhibitory R-peptide of Syncytin-1 inhibit cell fusion. Interestingly, this modification of the HERV-W vaccine's fusogenicity increased the expression of the vaccine antigens in vitro. It also enhanced Syncytin-1-specific antibody responses and CD8+-mediated T-cell responses compared to the wildtype vaccine in vaccinated mice, with a notable enhancement in responses to subdominant T-cell epitopes but equal responses to dominant epitopes and similar rates of survival following a tumour challenge. The impairment of cell–cell fusion and the enhanced immunogenicity profile of this HERV-W vaccine strengthens the prospects of obtaining a meaningful immune response against HERV-W in patients with HERV-W-overexpressing cancers. [ABSTRACT FROM AUTHOR]

Expression of human endogenous retrovirus type W (HERV-W) has been linked to cancer, making HERV-W antigens potential targets for therapeutic cancer vaccines. In a previous study, we effectively treated established tumours in mice by using adenoviral-vectored vaccines targeting the murine endogenous retrovirus envelope and group-specific antigen (Gag) of melanoma-associated retrovirus (MelARV) in combination with anti-PD-1. To break the immunological tolerance to MelARV, we mutated the immunosuppressive domain (ISD) of the MelARV envelope. However, reports on the immunogenicity of the HERV-W envelope, Syncytin-1, and its ISD are conflicting. To identify the most effective HERV-W cancer vaccine candidate, we evaluated the immunogenicity of vaccines encoding either the wild-type or mutated HERV-W envelope ISD in vitro and in vivo. Here, we show that the wild-type HERV-W vaccine generated higher activation of murine antigen-presenting cells and higher specific T-cell responses than the ISD-mutated counterpart. We also found that the wild-type HERV-W vaccine was sufficient to increase the probability of survival in mice subjected to HERV-W envelope-expressing tumours compared to a control vaccine. These findings provide the foundation for developing a therapeutic cancer vaccine targeting HERV-W-positive cancers in humans. [ABSTRACT FROM AUTHOR]

Shan Qiao,1,2,* Quan-Ye Sun,3,* Shan-Chao Zhang,1 Ran-Ran Zhang,4 Yu-Jiao Wu,4 Zhi-Hao Wang,4 Xue-Wu Liu4,5 1Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, People’s Republic of China; 2Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 3Research Center of Translational Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China; 4Department of Neurology, Qilu Hospital of Shandong University, Jinan, People’s Republic of China; 5Institute of Epilepsy, Shandong University, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xue-Wu Liu, Email snlxw1966@163.comPurpose: Syncytin-1 may play a role in several neuropsychiatric disorders, but its function in anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is unknown. The purpose of this study was to examine the possible mechanism of action of syncytin-1 in patients with anti-NMDAR encephalitis.Patients and Methods: Twenty patients with anti-NMDAR encephalitis and eight controls were recruited. The protein levels of syncytin-1 in serum were determined using an enzyme-linked immunosorbent assay, and the transcript levels of syncytin-1 were determined using real-time quantitative PCR. Flow cytometry was used for peripheral blood lymphocyte subset detection. Further, the relationship between syncytin-1 levels and clinical features of anti-NMDAR encephalitis and peripheral blood lymphocyte subsets was analyzed.Results: Compared with those in controls, higher syncytin-1 levels and percentage of B cells (CD3-CD19+) were observed in patients with anti-NMDAR encephalitis. Among anti-NMDAR encephalitis patients, the level of syncytin-1 positively correlated with the proportion of B cells and modified Rankin scale score at onset and after immunotherapy and negatively correlated with the proportion of CD3+ T cells.Conclusion: An increased expression of Syncytin-1 is associated with the pathogenesis of anti-NMDAR encephalitis, providing evidence for elucidating the pathogenesis of the disease and suggesting novel therapeutic targets. Further, this study clarifies the role of syncytin-1 in neuroimmune disorders.Keywords: autoimmune encephalitis, neuroinflammation, syncytin-1, B cells, pathogenesis

Background: Patients with systemic lupus erythematosus (SLE) often suffer from obstetric complications not necessarily associated with the antiphospholipid syndrome. These events may potentially result from the reduced placental synthesis of the fusogenic proteins syncytin-1 and syncytin-2, observed in women with pregnancy-related disorders. SLE patients have an aberrant noncoding (nc)RNA signature that may in turn dysregulate the expression of syncytin-1 and syncytin-2 during placentation. The aim of this research is to computationally evaluate and characterize the interaction between syncytin-1 and syncytin-2 genes and human ncRNAs and to discuss the potential implications for SLE pregnancy adverse outcomes. Methods: The FASTA sequences of the syncytin-1 and syncytin-2 genes were used as inputs to the Ensembl.org library to find any alignments with human ncRNA genes and their transcripts, which were characterized for their tissue expression, regulatory activity on adjacent genes, biological pathways, and potential association with human disease. Results: BLASTN analysis revealed a total of 100 hits with human long ncRNAs (lncRNAs) for the syncytin-1 and syncytin-2 genes, with median alignment scores of 151 and 66.7, respectively. Only lncRNAs TP53TG1, TTTY14, and ENSG00000273328 were reported to be expressed in placental tissue. Dysregulated expression of lncRNAs TP53TG1, LINC01239, and LINC01320 found in this analysis has previously been described in SLE patients as well as in women with a high-risk pregnancy. In addition, some of the genes adjacent to lncRNAs aligned with syncytin-1 or syncytin-2 in a regulatory region might increase the risk of pregnancy complications or SLE. Conclusions: This is the first computational study showing alignments between syncytin-1 and syncytin-2 genes and human lncRNAs. Whether this mechanism affects syncytiotrophoblast morphogenesis in SLE females is unknown and requires further investigation. [ABSTRACT FROM AUTHOR]

One of the most troubling developments of 2021 has been the number of fertile-age women who have been led to believe that mRNA vaccines against severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2, coronavirus disease 2019 (COVID-19)] can cause infertility via cross-reactivity of immune response. Specifically, cross-reactivity of developed antibodies to syncytin-1, a protein found in human cell fusion, placentation and recently identified in the envelope gene of a human endogenous defective retrovirus, HERV-W (see “Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis”. Nature. 2000;403:785–9. doi: 10.1038/35001608). The mechanism, evidence, and evaluation of the claim is presented concluding in a rejection due to lack of evidence.

Syncytin-1, a human fusogenic protein of retroviral origin, is crucial for placental syncytiotrophoblast formation. To mediate cell-to-cell fusion, Syncytin-1 requires specific interaction with its cognate receptor. Two trimeric transmembrane proteins, Alanine, Serine, Cysteine Transporters 1 and 2 (ASCT1 and ASCT2), were suggested and widely accepted as Syncytin-1 cellular receptors. To quantitatively assess the individual contributions of human ASCT1 and ASCT2 to the fusogenic activity of Syncytin-1, we developed a model system where the ASCT1 and ASCT2 double knockout was rescued by ectopic expression of either ASCT1 or ASCT2. We demonstrated that ASCT2 was required for Syncytin-1 binding, cellular entry, and cell-to-cell fusion, while ASCT1 was not involved in this receptor interaction. We experimentally validated the ASCT1-ASCT2 heterotrimers as a possible explanation for the previous misidentification of ASCT1 as a receptor for Syncytin-1. This redefinition of receptor specificity is important for proper understanding of Syncytin-1 function in normal and pathological pregnancy., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: To date, no studies have investigated the potential reactivation of human endogenous retroviruses (HERVs) in the pathogenesis of antiphospholipid syndrome (APS). HERV-derived syncytin-1 and syncytin-2 are localized in the plasma membrane of cells and physiologically expressed during pregnancy. The current study aimed to determine whether the epitopes of syncytins can trigger an immune response leading to APS in genetically predisposed individuals., Methods: The TepiTool, ABCpred, and DiscoTope servers were utilized to predict T-cell and B-cell epitopes by inputting the FASTA sequences and 3D structures of syncytin-1, syncytin-2, and β2-glycoprotein I (β2GPI), which served as a reference antigen for APS. T-cell epitopes were selected based on their binding to a panel of human leukocyte antigen (HLA) class II alleles associated with APS according to the literature. Epitope predictions for the different proteins were statistically compared using GraphPad Prism., Results: For syncytin-1, we identified a total of 721 T-cell epitopes, 51 linear B-cell epitopes, and up to 40 conformational epitopes. For syncytin-2, we predicted 705 T-cell epitopes and 28 linear B-cell epitopes, but a lower number of conformational epitopes, which also exhibited lower B-cell receptor (BCR)-binding scores. The predicted T-cell and B-cell conformational epitopes of both syncytin-1 and syncytin-2 demonstrated significantly higher binding affinity to selected HLA alleles and BCR compared with β2GPI. Furthermore, syncytin-1 exhibited significantly higher immunogenicity than syncytin-2., Conclusions: Both syncytin-1 and syncytin-2 are computationally endowed with potential epitopes that may activate either T cells or B cells in individuals genetically predisposed to APS. While these findings may illuminate the possible role of HERVs in the development of APS, they warrant validation in further laboratory studies.

Human endogenous retrovirus type W (HERV-W) is expressed in various cancers. We previously developed an adenovirus-vectored cancer vaccine targeting HERV-W by encoding an assembled HERV-W group-specific antigen sequence and the HERV-W envelope sequence Syncytin-1. Syncytin-1 is constitutively fusogenic and forms large multinucleated cell fusions when overexpressed. Consequently, immunising humans with a vaccine encoding Syncytin-1 can lead to the formation of extensive syncytia, which is undesirable and poses a potential safety issue. Here, we show experiments in cell lines that restoring an evolutionary lost cleavage site of the fusion inhibitory R-peptide of Syncytin-1 inhibit cell fusion. Interestingly, this modification of the HERV-W vaccine’s fusogenicity increased the expression of the vaccine antigens in vitro. It also enhanced Syncytin-1-specific antibody responses and CD8+-mediated T-cell responses compared to the wildtype vaccine in vaccinated mice, with a notable enhancement in responses to subdominant T-cell epitopes but equal responses to dominant epitopes and similar rates of survival following a tumour challenge. The impairment of cell–cell fusion and the enhanced immunogenicity profile of this HERV-W vaccine strengthens the prospects of obtaining a meaningful immune response against HERV-W in patients with HERV-W-overexpressing cancers.

Expression of human endogenous retrovirus type W (HERV-W) has been linked to cancer, making HERV-W antigens potential targets for therapeutic cancer vaccines. In a previous study, we effectively treated established tumours in mice by using adenoviral-vectored vaccines targeting the murine endogenous retrovirus envelope and group-specific antigen (Gag) of melanoma-associated retrovirus (MelARV) in combination with anti-PD-1. To break the immunological tolerance to MelARV, we mutated the immunosuppressive domain (ISD) of the MelARV envelope. However, reports on the immunogenicity of the HERV-W envelope, Syncytin-1, and its ISD are conflicting. To identify the most effective HERV-W cancer vaccine candidate, we evaluated the immunogenicity of vaccines encoding either the wild-type or mutated HERV-W envelope ISD in vitro and in vivo. Here, we show that the wild-type HERV-W vaccine generated higher activation of murine antigen-presenting cells and higher specific T-cell responses than the ISD-mutated counterpart. We also found that the wild-type HERV-W vaccine was sufficient to increase the probability of survival in mice subjected to HERV-W envelope-expressing tumours compared to a control vaccine. These findings provide the foundation for developing a therapeutic cancer vaccine targeting HERV-W-positive cancers in humans.

Maternal cellular and humoral immune responses to the allogeneic fetoplacental unit are a normal part of pregnancy adaptation. Overactive or dysregulated immune responses that often manifest as inflammation are considered a key element for the development of preeclampsia. Infiltration and activation of macrophages, nature killer cells, and T lymphocytes are frequently observed in the decidua and placenta associated with preeclampsia. In addition to local inflammation, systemic inflammatory changes including increased levels of TNF-α and interleukins (ILs) are detected in the maternal circulation. Syncytin-1 is an endogenous retroviral envelope protein that mediates the fusion of trophoblasts to form syncytiotrophoblasts, a cellular component carrying out most of placental barrier, exchange, and endocrine functions. In addition to these well-defined fusogenic functions that are known for their close association with preeclampsia, multiple studies indicated that syncytin-1 possesses nonfusogenic activities such as those for cell cycle and apoptosis regulation. Moreover, syncytin-1 expressed by trophoblasts and various types of immune cells may participate in regulation of inflammation in preeclamptic placenta and decidua. This review concentrates on the triangular relationship among inflammation, syncytin-1 nonfusogenic functions, and preeclampsia pathogenesis. Data regarding the reciprocal modulations of inflammation and poor vascularization/hypoxia are summarized. The impacts of syncytin-A (the mouse counterpart of human syncytin-1) gene knockout on placental vascularization and their implications for preeclampsia are discussed. Syncytin-1 expression in immune cells and its significance for inflammation are analyzed in the context of preeclampsia development. Finally, the involvements of syncytin-1 nonfusogenic activities in neuroinflammation and multiple sclerosis are compared to findings from preeclampsia. [ABSTRACT FROM AUTHOR]

Abstract Background Human Syncytin-1 is a placentally-expressed cell surface glycoprotein of retroviral origin. After interaction with ASCT2, its cellular receptor, Syncytin-1 triggers cell–cell fusion and formation of a multinuclear syncytiotrophoblast layer of the placenta. The ASCT2 receptor is a multi-spanning membrane protein containing a protruding extracellular part called region C, which has been suggested to be a retrovirus docking site. Precise identification of the interaction site between ASCT2 and Syncytin-1 is challenging due to the complex structure of ASCT2 protein and the background of endogenous ASCT2 gene in the mammalian genome. Chicken cells lack the endogenous background and, therefore, can be used to set up a system with surrogate expression of the ASCT2 receptor. Results We have established a retroviral heterologous chicken system for rapid and reliable assessment of ectopic human ASCT2 protein expression. Our dual-fluorescence system proved successful for large-scale screening of mutant ASCT2 proteins. Using this system, we demonstrated that progressive deletion of region C substantially decreased the amount of ASCT2 protein. In addition, we implemented quantitative assays to determine the interaction of ASCT2 with Syncytin-1 at multiple levels, which included binding of the soluble form of Syncytin-1 to ASCT2 on the cell surface and a luciferase-based assay to evaluate cell–cell fusions that were triggered by Syncytin-1. Finally, we restored the envelope function of Syncytin-1 in a replication-competent retrovirus and assessed the infection of chicken cells expressing human ASCT2 by chimeric Syncytin-1-enveloped virus. The results of the quantitative assays showed that deletion of the protruding region C did not abolish the interaction of ASCT2 with Syncytin-1. Conclusions We present here a heterologous chicken system for effective assessment of the expression of transmembrane ASCT2 protein and its interaction with Syncytin-1. The system profits from the absence of endogenous ASCT2 background and implements the quantitative assays to determine the ASCT2-Syncytin-1 interaction at several levels. Using this system, we demonstrated that the protruding region C was essential for ASCT2 protein expression, but surprisingly, not for the interaction with Syncytin-1 glycoprotein.

Yang Fu,1 Xuewei Zhuang,2,3 Xiyan Xia,4 Xiaohui Li,3 Ke Xiao,3 Xiaojing Liu3 1Department of Reproductive Medicine Center, Jinan Maternity and Child Care Hospital, Jinan, 250001, People’s Republic of China; 2Department of Clinical Laboratory Medicine, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250031, People’s Republic of China; 3Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People’s Republic of China; 4Department of Microbial Immune, Jinan Vocational College of Nursing, Jinan, 250012, People’s Republic of ChinaCorrespondence: Xuewei Zhuang Tel +86-531-81656669Fax +86-531-86927544Email zhuangxuewei@sdu.edu.cnIntroduction: Syncytin-1 is a human endogenous retroviral (HERVW) envelope protein, which has been implicated in trophoblast and cancer cell fusions as well as in immunomodulatory functions. We investigated syncytin-1 expression and promoter methylation in non-small cell lung cancer (NSCLC) and the adjacent, para-carcinoma tissues. In addition, the correlation to patient survival differentiation of between 5-year survival and death group was analyzed.Methods: Survival ratio was calculated by Kaplan-Meier survival curve. Death risk assessment was executed by Cox risk regression model. The 5ʹ-LTR methylation level of HERVW promoter was detected by EpiTYPER method.Results: Syncytin-1 expression in NSCLC tissue was found to be significantly higher than in para-carcinoma tissues. Moreover, the 5-year survival group has a lower syncytin-1 expression than the death group. Clinical stage and the percentage of syncytin-1 positive cells were top risk factors according to Cox ratio risk regression model analysis. While the methylation level of the 5ʹ-LTR in HERVW gene promoter was relatively lower in NSCLC than para-carcinoma tissues, the methylation status of a CpG-2 site overlapping the Oct-1 binding site was found to be an important element potentially involved in the epigenetic regulation of HERVW gene expression.Conclusion: These findings suggest that syncytin-1 could be a biomarker for the diagnosis/prognosis of NSCLC, and further studies are required to elucidate the exact role of syncytin-1 in the development of NSCLC as well as the underlying molecular mechanism for syncytin-1 function and regulation.Keywords: non-small cell lung cancer, syncytin-1, epigenetic regulation, prognosis, DNA methylation

Obesity negatively impacts skeletal muscle protein metabolism, and also impairs skeletal muscle maintenance and regeneration. We analyzed muscle biopsy samples from humans with increased body mass index (BMI) (i.e. > 30 kg/m2) and controls (i.e., BMI < 25 kg/m2) for expression of syncytin-1, a fusogenic protein regulating skeletal muscle regeneration. When compared to controls, humans with increased BMI and concomitant reduction in muscle protein synthesis had higher expression of syncytin-1 in skeletal muscle (p < 0.05). Across human subjects, muscle protein synthesis correlated inversely (r = −0.51; p = 0.03) with syncytin-1 expression in muscle. Using a C2C12 cell line we found that expression of syncytin-A (i.e, corresponding protein in murine tissue) is increased by insulin, and that this response is impaired in the presence of fatty acids, whose metabolism is altered within the metabolic environment induced by increased BMI. In C2C12 cells, the response of the protein 4E-BP1, which signals increase in protein synthesis in muscle, resembled that of syncytin-A. These findings provide novel insights into the expression of syncytin-1 in skeletal muscle of humans with increased BMI, as well as its basic regulation by insulin and fatty acids in muscle. The findings signify the need for further research into the regulation of syncytin-1 in skeletal muscle of humans with increased BMI, as well as its biological implications for altering muscle protein metabolism and regeneration. [ABSTRACT FROM AUTHOR]

Syncytin-1 (gene ERVW-1) has been proposed as a marker of pre-eclampsia and malfunctions in placental development. Placenta is heterogeneous tissue, hence the method of biopsy can significantly affect the outcome of analyses. A total of 44 placentae were analyzed by taking 3–30 samples from each. Relative levels of ERVW-1 expression in the placental biopsies were characterized by RT-qPCR. Evaluation of ten biopsies from one placenta individually (not pooling them) is recommended due to the high variability of expression. No significant correlation was found between biopsy localization and level of ERVW-1 expression; therefore, random sampling is recommended. A long cut from the umbilical cord to the edge of the placenta is a convenient approach to placental sampling.

Obesity negatively impacts skeletal muscle protein metabolism, and also impairs skeletal muscle maintenance and regeneration. We analyzed muscle biopsy samples from humans with increased body mass index (BMI) (i.e. > 30 kg/m2) and controls (i.e., BMI < 25 kg/m2) for expression of syncytin-1, a fusogenic protein regulating skeletal muscle regeneration. When compared to controls, humans with increased BMI and concomitant reduction in muscle protein synthesis had higher expression of syncytin-1 in skeletal muscle (p < 0.05). Across human subjects, muscle protein synthesis correlated inversely (r = −0.51; p = 0.03) with syncytin-1 expression in muscle. Using a C2C12 cell line we found that expression of syncytin-A (i.e, corresponding protein in murine tissue) is increased by insulin, and that this response is impaired in the presence of fatty acids, whose metabolism is altered within the metabolic environment induced by increased BMI. In C2C12 cells, the response of the protein 4E-BP1, which signals increase in protein synthesis in muscle, resembled that of syncytin-A. These findings provide novel insights into the expression of syncytin-1 in skeletal muscle of humans with increased BMI, as well as its basic regulation by insulin and fatty acids in muscle. The findings signify the need for further research into the regulation of syncytin-1 in skeletal muscle of humans with increased BMI, as well as its biological implications for altering muscle protein metabolism and regeneration.

Human endogenous retrovirus W family envelope proteins (pHERV-W ENV/syncytin-1) have been repeatedly associated with multiple sclerosis (MS). Here, we have focused on the study of pHERV-W ENV/syncytin-1 expression levels in MS patients (relapsing and progressive forms) and in healthy donors (HD) and on exploring their possible relationship with Epstein-Barr virus (EBV) and human herpesvirus-6A/B (HHV-6A/B). We included blood samples from 101 MS patients and 37 HD to analyze antiviral antibody titers by ELISA and pHERV-W ENV/syncytin-1 expression levels by flow cytometry as well as by qPCR. Patients with relapsing MS forms showed significantly higher pHERV-W ENV/syncytin-1 protein and gene expression levels than HD. Progressive MS patients also showed significantly higher protein and gene expression levels than both HD and relapsing MS patients. Regarding antiviral antibodies titers, anti-HHV-6A/B IgM levels were positively correlated with pHERV-W ENV/syncytin-1 protein expression levels in patients with relapsing MS, while in the progressive forms patients this correlation was found with anti-HHVA/B IgG levels. Therefore, pHERV-W ENV could be involved in MS pathogenesis, playing a role in relapsing and progressive forms. Besides, anti-HHV-6A/B antibodies positively correlated with pHERV-W ENV expression. Further studies are needed to better understand this possible relationship. [ABSTRACT FROM AUTHOR]

Human endogenous retrovirus W family envelope proteins (pHERV-W ENV/syncytin-1) have been repeatedly associated with multiple sclerosis (MS). Here, we have focused on the study of pHERV-W ENV/syncytin-1 expression levels in MS patients (relapsing and progressive forms) and in healthy donors (HD) and on exploring their possible relationship with Epstein-Barr virus (EBV) and human herpesvirus-6A/B (HHV-6A/B). We included blood samples from 101 MS patients and 37 HD to analyze antiviral antibody titers by ELISA and pHERV-W ENV/syncytin-1 expression levels by flow cytometry as well as by qPCR. Patients with relapsing MS forms showed significantly higher pHERV-W ENV/syncytin-1 protein and gene expression levels than HD. Progressive MS patients also showed significantly higher protein and gene expression levels than both HD and relapsing MS patients. Regarding antiviral antibodies titers, anti-HHV-6A/B IgM levels were positively correlated with pHERV-W ENV/syncytin-1 protein expression levels in patients with relapsing MS, while in the progressive forms patients this correlation was found with anti-HHVA/B IgG levels. Therefore, pHERV-W ENV could be involved in MS pathogenesis, playing a role in relapsing and progressive forms. Besides, anti-HHV-6A/B antibodies positively correlated with pHERV-W ENV expression. Further studies are needed to better understand this possible relationship.

Human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) persist as life-long infections alternating between latency and lytic replication. Human endogenous retroviruses (HERVs), via integration into the host genome, represent genetic remnants of ancient retroviral infections. Both show similar epigenetic silencing while dormant, but can reactivate in response to cell signaling cues or triggers that, for gammaherpesviruses, result in productive lytic replication. Given their co-existence with humans and shared epigenetic silencing, we asked if HERV expression might be linked to lytic activation of human gammaherpesviruses. We found ERVW-1 mRNA, encoding the functional HERV-W envelope protein Syncytin-1, along with other repeat class elements, to be elevated upon lytic activation of EBV. Knockdown/knockout of ERVW-1 reduced lytic activation of EBV and KSHV in response to various lytic cycle triggers. In this regard, reduced expression of immediate early proteins ZEBRA and RTA for EBV and KSHV, respectively, places Syncytin-1's influence on lytic activation mechanistically upstream of the latent-to-lytic switch. Conversely, overexpression of Syncytin-1 enhanced lytic activation of EBV and KSHV in response to lytic triggers, though this was not sufficient to induce lytic activation in the absence of such triggers. Syncytin-1 is expressed in replicating B cell blasts and lymphoma-derived B cell lines where it appears to contribute to cell cycle progression. Together, human gammaherpesviruses and B cells appear to have adapted a dependency on Syncytin-1 that facilitates the ability of EBV and KSHV to activate lytic replication from latency, while promoting viral persistence during latency by contributing to B cell proliferation. [ABSTRACT FROM AUTHOR]

Background: Human Syncytin-1 is a placentally-expressed cell surface glycoprotein of retroviral origin. After interaction with ASCT2, its cellular receptor, Syncytin-1 triggers cell–cell fusion and formation of a multinuclear syncytiotrophoblast layer of the placenta. The ASCT2 receptor is a multi-spanning membrane protein containing a protruding extracellular part called region C, which has been suggested to be a retrovirus docking site. Precise identification of the interaction site between ASCT2 and Syncytin-1 is challenging due to the complex structure of ASCT2 protein and the background of endogenous ASCT2 gene in the mammalian genome. Chicken cells lack the endogenous background and, therefore, can be used to set up a system with surrogate expression of the ASCT2 receptor. Results: We have established a retroviral heterologous chicken system for rapid and reliable assessment of ectopic human ASCT2 protein expression. Our dual-fluorescence system proved successful for large-scale screening of mutant ASCT2 proteins. Using this system, we demonstrated that progressive deletion of region C substantially decreased the amount of ASCT2 protein. In addition, we implemented quantitative assays to determine the interaction of ASCT2 with Syncytin-1 at multiple levels, which included binding of the soluble form of Syncytin-1 to ASCT2 on the cell surface and a luciferase-based assay to evaluate cell–cell fusions that were triggered by Syncytin-1. Finally, we restored the envelope function of Syncytin-1 in a replication-competent retrovirus and assessed the infection of chicken cells expressing human ASCT2 by chimeric Syncytin-1-enveloped virus. The results of the quantitative assays showed that deletion of the protruding region C did not abolish the interaction of ASCT2 with Syncytin-1. Conclusions: We present here a heterologous chicken system for effective assessment of the expression of transmembrane ASCT2 protein and its interaction with Syncytin-1. The system profits from the absence of endogenous ASCT2 background and implements the quantitative assays to determine the ASCT2-Syncytin-1 interaction at several levels. Using this system, we demonstrated that the protruding region C was essential for ASCT2 protein expression, but surprisingly, not for the interaction with Syncytin-1 glycoprotein. [ABSTRACT FROM AUTHOR]

Background: Both internal and external risk factors can accelerate the progression of breast cancer which is the reason why clinicians have tried to find new biomarkers for this health problem. Human endogenous retrovirus-W (HERV-W) can be one of these biomarkers, as it has been mentioned that some genes of this virus are able to have either higher or lower expression in numerous cancerous cells. In this study, we aimed to compare HERV-W envelope expression in breast cancer tissues and normal ones since its effects on this malignancy have not been clear., Materials and Methods: We collected 46 breast cancer tissues and their normal adjacent ones. After extracting the RNA of breast samples, we evaluated the expression of HERV-W envelope syncytin-1 and 2 using quantitative real-time polymerase chain reaction (PCR) in different kinds of breast cancer stages., Results: Data showed that more than 13% of patients had a family history of breast cancer; moreover, approximately half of the tissues were estrogen receptor or progesterone receptor positive. Lymph node metastasis was seen in 52% of the patients, and about 40% of tumors were larger than 2 cm. Real-time PCR showed that syncytin-1 and 2 had upward regulation with (* P < 0.05) and (** P < 0.01), respectively., Conclusion: As the expression of HERV-W Env (syncytin-1, syncytin-2) was higher in breast cancerous tissues in comparison with normal ones, we believe that these genes may have a role to play in monitoring patients suffering from this type of cancer. However, further studies are needed to confirm this hypothesis., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Research in Medical Sciences.)

Background A key step in embryo implantation is the adhesion to and invasion of the endometrium by the blastocyst trophectoderm. The envelope proteins of HERV-W and -FRD (human endogenous retrovirus-W and -FRD), syncytin-1 and syncytin-2, are mainly distributed in the placenta, and play important roles in the development of the placenta. The placenta originates from the trophectoderm of the blastocyst. It is unclear whether the envelope proteins of HERV-W and -FRD have an effect on the development of the trophectoderm and whether they have any association with the implantation of the blastocyst. Methods The whole-genome amplification products of the human blastocyst trophectoderm were used to measure the copy number of syncytin-1 and syncytin-2 using real time qPCR. In addition, clinical data associated with the outcome of pregnancies was collected, and included age, body mass index (BMI), basic follicle stimulating hormone(bFSH), rate of primary infertility and oligo-astheno-teratospermia, the thickness of the endometrium on the day of endometrial transformation, the levels of estrogen and progestin on the transfer day, the days and the morphological scores of the blastocysts. The expression of mRNA and the copy numbers of syncytin-1 and syncytin-2 in H1 stem cells, and in differentiated H1 cells, induced by BMP4, were measured using real time qPCR. Results The relative copy number of syncytin-1 in the pregnant group (median: 424%, quartile: 232%–463%, p 0.05), 3.36 (quartile: 0.85–14.80, p > 0.05), 10.85 (quartile: 3.39–24.46, p

pHERV-W ENV and syncytin-1, the envelope proteins of the human endogenous retrovirus W family (HERV-W), have been proposed as etiological factors for MS development. In addition, herpesviruses, such as the Epstein-Barr virus (EBV) and the human herpesvirus 6A/B (HHV-6A/B), have been also strongly associated with the disease. This work aims to study the possible link between viral loads and antibody titers against EBV and HHV-6A/B and the pHERV-W ENV/syncytin-1 protein/gene expression. For this purpose, we conducted a 12-month longitudinal study involving 98 RRMS patients. Peripheral blood samples were obtained from each patient. Serum antibody titers against EBV and HHV-6A/B were determined by ELISA, while viral loads were analyzed using qPCR. HLA MS-related alleles were also genotyped. pHERV-W ENV/syncytin-1 protein and gene expression levels in immune cells were assessed by flow cytometry and qPCR, respectively. We found that the 12-month variation of the pHERV-W ENV gene expression levels positively correlated with the variation of the EBV viral load, especially in those patients with high baseline EBV loads. Therefore, these results could support previous studies pointing to the transactivation of pHERV-W ENV by EBV. However, further studies are needed to better understand this possible relationship.

Background: Endometrial carcinoma (EC) is the most common and lethal malignancy worldwide. Syncytin-1 is expressed in multiple types of cancer. However, the expression -pattern and potential mechanism of syncytin-1 and its clinical significance in EC remain unclear. Materials and methods: We analyzed 130 primary EC specimens from Binzhou Medical University to investigate the clinical role of syncytin-1 in EC by using different advanced pathological stages of EC tissues. Kaplan–Meier analysis was used to measure the overall survival of EC patients. Syncytin-1 expression was analyzed by Western blot assays in HECCL-1 and RL-95-2 cells. Cell proliferation, cycle, migration, and invasion abilities were detected by cell counting kit-8, flow cytometry, and transwell assays. AKT and epithelial-mesenchymal transition (EMT)-related genes were assessed by Western blot assays in HECCL-1 and RL-95-2 cells. Results: Syncytin-1 was upregulated in EC tissues and cells and was related to clinical stages, expression of ER, Ki-67, and overall survival of EC. Functional research revealed that overexpression of syncytin-1 can promote cell proliferation, cell cycle progression, and the migration and invasion of EC cells. Suppression of syncytin-1 expression also inhibited cell proliferation and apoptosis in vitro. The expression of syncytin-1 substantially improved the expression levels of EMT-related genes (vimentin, E-cadherin, slug, and ZEB1) but significantly decreased those of epithelial markers (N-cadherin and snail). In addition, we found that syncytin-1 was not correlated with AKT-related genes (total-AKT, p-AKT, and vinculin). Conclusion: Our results suggested that syncytin-1 may promote aggressive behavior and can serve as a novel prognostic biomarker for EC. Our study provides new insights into the regulatory mechanism of EMT signaling. [ABSTRACT FROM AUTHOR]

Human endogenous retroviruses (HERVs) comprise approximately 8% of the human genome. Recent studies have considered HERVs as potential pathogenic factors. The majority of HERV genes are mutated and not capable of encoding functional proteins; regardless, some HERV genes, such as HERV-W envelope (env) glycoprotein, are known to have intact open reading frames. The HERV-W element on 7q21.2, which encodes a protein referred to as Syncytin-1, participates in human placental morphogenesis and can activate a pro-inflammatory and autoimmune cascade. Neuropsychological disorders are typically linked to inflammatory abnormalities. In this study, we review that Syncytin-1 has been increasingly involved in the development of neuropsychological disorders, such as schizophrenia and multiple sclerosis (MS). This study also presents inflammation imbalances in schizophrenia and MS. More importantly, we discuss the potential role and molecular mechanisms by which Syncytin-1 regulates inflammatory abnormalities in neuropsychological diseases. In summary, Syncytin-1 activity may represent a novel molecular pathogenic mechanism in neuropyschological diseases, such as schizophrenia and MS.

Human endogenous retroviruses (HERVs) comprise approximately 8% of the human genome. Recent studies have considered HERVs as potential pathogenic factors. The majority of HERV genes are mutated and not capable of encoding functional proteins; regardless, some HERV genes, such as HERV-W envelope (env) glycoprotein, are known to have intact open reading frames. The HERV-W element on 7q21.2, which encodes a protein referred to as Syncytin-1, participates in human placental morphogenesis and can activate a pro-inflammatory and autoimmune cascade. Neuropsychological disorders are typically linked to inflammatory abnormalities. In this study, we review that Syncytin-1 has been increasingly involved in the development of neuropsychological disorders, such as schizophrenia and multiple sclerosis (MS). This study also presents inflammation imbalances in schizophrenia and MS. More importantly, we discuss the potential role and molecular mechanisms by which Syncytin-1 regulates inflammatory abnormalities in neuropsychological diseases. In summary, Syncytin-1 activity may represent a novel molecular pathogenic mechanism in neuropyschological diseases, such as schizophrenia and MS. [ABSTRACT FROM AUTHOR]

Objective To investigate the change in the expression of Syncytin-1 in the non-small-cell lung cancer (NSCLC) tissues and its relationship with prognosis of patients. Methods Thirty NSCLC patients were selected, and the expression of Syncytin-1 in the NSCLC tissues and adjacent tissues was detected and compared by immunohistochemistry. We used the 25% positive rate of Syncytin-1 as the boundary. The positive cell rate 多 25% was Syncytin-1 high expression group， and the positive cell rate < 25 % was Syncytin-1 low expression group， and there were 19 and 11 cases in the two groups， respectively. Thirteen cases survived ( 5-year survival group)， and 17 cases died within 5 years ( 5-year death group) . The rate of Syncytin-1 positive cells in the two groups was compared. The Kaplan-Meier survival curve was used to calculate the survival rate，and the Cox proportional hazard regression model was used to analyze the risk factors for death. Results The rates of Syncytin-1 positive cells in the NSCLC tissues and adjacent tissues were 35. 41% ± 0. 22% and 2. 17% ±0.03%，respectively，and significant difference was found between these two groups ( P < 0. 01); the rates of Syncytin-1 positive cells in the 5-year survival group and 5-year death group were 23. 30% ± 0. 16% and 44. 67% 土 0.21% , respectively, and significant difference was found between these two groups (P <0.01). Kaplan-Meier survival curve analysis showed that the survival time of the Syncytin-1 high expression group was significantly lower than that of the Syncytin-1 low expression group， and the difference between the two groups was significant ( P < 0. 01 ) . Through multivariate analysis of Cox proportional hazard model， Syncytin-1 positive cell rate and clinical stage were risk factors for NSCLC death (all P <0.05). Conclusion The level of Syncytin-1 expression in the NSCLC tissues increases, and its high expression is related to the poor prognosis. [ABSTRACT FROM AUTHOR]

Schizophrenia is a devastating psychiatric disorder that impacts on social functioning and quality of life, and there is accumulating evidence that inflammation is a potential pathogenic mechanism of schizophrenia. However, the mechanism of inflammation possibly occurred in schizophrenia has not been well understood. The endogenous retroviral protein syncytin-1 and inflammatory marker CRP are both abnormally expressed in schizophrenia patients. CRP is one of the markers of bacterial infection generally. Less clear is whether virus or viral protein can trigger the activation of CRP. Here, we detected a robust increase of the levels of syncytin-1 and CRP in schizophrenia patients, and displayed a positive correlation and marked consistency between expressions of syncytin-1 and CRP in schizophrenia patients. Furthermore, overexpression of syncytin-1 significantly elevated the levels of CRP, TLR3, and IL-6 in both human microglia and astrocytes. TLR3 deficiency impaired the expressions of CRP and IL-6 induced by syncytin-1. Importantly, we observed a cellular co-localization and a direct interaction between syncytin-1 and TLR3. Additionally, knockdown of IL-6 inhibited the syncytin-1-induced CRP expression. Thus, the totality of these results showed that viral protein syncytin-1 could trigger the activation of CRP, which might explain the elevated CRP in sterile inflammation and exhibit a novel mechanism for regulation of inflammation by syncytin-1 in schizophrenia. [ABSTRACT FROM AUTHOR]

Syncytin-1 , a human endogenous retroviral envelope gene ( HERVW1 ), is specifically expressed in placental trophoblasts and mediates the formation of syncytiotrophoblasts through a fusogenic activity. Syncytin-1 expression deficiency has been repeatedly observed in preeclamptic/IUGR placentas. Previous gene knockout studies indicated that in mice, complete syncytin-A null mouse embryos died in utero between 11.5 and 13.5 days of gestation. However, the complete knockout model could not fully recapitulate the mid- to third-trimester, time-specific syncytin-1 deficiency in preeclampsia patients. To construct a preeclampsia model and to better investigate the function of syncytin in placental development, we created a mouse inducible knockout model of syncytin-1A gene. It was found that the disruption of syncytin-A at E11.5 to E17.5 is associated with significant morphological changes in placentas and fetuses. Moreover, syncytin-A disruption led to extensive vasculature abnormalities in the labyrinth, with irregular distribution and reduced number of fetal microvessels. Moreover, Syncytin-A knockout affected neovascularization-related gene expression in labyrinth and the maternal plasma level of sVEGFR-1, and a dramatic increase of sFlt-1/PlGF ratio. These findings indicate that syncytin-A may be involved in the placenta angiogenesis and potentially, the development of preeclampsia. The new model could be a useful tool for studying the pathogenesis and management of preeclampsia. [ABSTRACT FROM AUTHOR]

A hypothesis is formulated on viral interaction between HHV-6A and EBV as a pathogenic mechanism in Multiple Sclerosis (MS). Evidence of molecular and genetic mechanisms suggests a link between HHV-6A infection and EBV activation in the brain of MS patients leading to intrathecal B-cell transformation. Consequent T-cell immune response against the EBV-infected cells is postulated as a pathogenic basis for inflammatory lesion formation in the brain of susceptible individuals. A further link between HHV-6A and EBV involves their induction of expression of the human endogenous retrovirus HERV-K18-encoded superantigen. Such virally induced T-cell responses might secondarily also lead to local autoimmune phenomena. Finally, research recommendations are formulated for substantiating the hypothesis on several levels: epidemiologically, genetically, and viral expression in the brain. [ABSTRACT FROM AUTHOR]

Human endogenous retroviruses (HERVs) have evolved from exogenous retroviruses and account for approximately 8% of the human genome. A growing number of findings suggest that the abnormal expression of HERV genes is associated with schizophrenia, multiple sclerosis, endometriosis, breast cancer, bladder cancer and other diseases. HERV-W env (syncytin-1) is a membrane glycoprotein which plays an important role in placental development. It includes embryo implantation, fusion of syncytiotrophoblasts and of fertilized eggs, and immune response. The abnormal expression of syncytin-1 is related to placental development-related diseases such as preeclampsia, infertility, and intrauterine growth restriction, as well as tumors such as neuroblastoma, endometrial cancer, and endometriosis. This review mainly focused on the molecular interactions of syncytin-1 in placental development-related diseases and tumors, to explore whether syncytin-1 can be an emerging biological marker and potential therapeutic target., (© 2023. The Author(s).)

Recurrent spontaneous abortion (RSA) affects approximately 5 % of women of reproductive age worldwide. The etiology and pathogenesis of approximately 50 % of RSA cases currently remain unclear, which known as unexplained RSA (URSA). Syncytin-1, an envelope protein encoded by HERV-W gene, is essential for human embryonic development. The purpose of this study was to explore the correlation between syncytin-1 expression and URSA occurrence. The villi tissues of URSA patients and patients with voluntary termination of pregnancy for non-medical reasons in early pregnancy (Control group) were collected. Compared with the Control group, syncytin-1 was abnormally low expressed in URSA villus tissues, and the HERV-W gene promoter was hypermethylated. Compared with the control group, the global DNA methylation level and the expression level of DNA methylases in the villus tissues of the URSA group had no significant difference. In addition, compared with the Control group, URSA villus tissue showed obviously abnormal apoptosis. Overexpression of syncytin-1 promoted the proliferation of HTR-8 cells and inhibited their apoptosis; while knockdown of syncytin-1 inhibited cell proliferation and promoted cell apoptosis. URSA villus tissue exhibited hypermethylation of the HERV-W gene and down-regulation of syncytin-1 expression. Syncytin-1 has the potential to be a predictive and diagnostic biomarker for URSA. • Syncytin-1 is abnormally low expressed in URSA villus tissues. • Aberrantly hypermethylated HERV-W gene promoter in URSA villus tissue. • Syncytin-1 affects the apoptosis of villous cells. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs)─including exosomes and microvesicles─are involved in cell-cell communication. EVs encapsulate different types of molecules such as proteins or nucleotides and are long-lasting contenders for the establishment of personalized drug delivery systems. Recent studies suggest that the intrinsic capacities for uptake and cargo delivery of basic EVs might be too limited to serve as a potent delivery system. Here, we develop two synergistic methods to, respectively, control EV cargo loading and enhance EV cargo delivery through fusion without requirement for any viral fusogenic protein. Briefly, cargo loading is enabled through a reversible drug-inducible system that triggers the interaction between a cargo of interest and CD63, a well-established transmembrane EV marker. Enhanced cargo delivery is promoted by overexpressing Syncytin-1, an endogenous retrovirus envelop protein with fusogenic properties encoded by the human genome. We validate our bioengineered EVs in a qualitative and quantitative manner. Finally, we utilize this method to develop highly potent killer EVs, which contain a lethal toxin responsible for protein translation arrest and acceptor cell death. These advanced methods and future downstream applications may open promising doors in the manufacture of virus-free and EV-based delivery systems.

Introduction: Up to 20% of hydatidiform moles are followed by malignant transformation in gestational trophoblastic neoplasia and require chemotherapy. Syncytin-1 is involved in human placental morphogenesis and is also expressed in various cancers. We assessed the predictive value of the expression of Syncytin-1 and its interactants in the malignant transformation process of hydatidiform moles.Methods: Syncytin-1 glycoprotein was localized by immunohistochemistry in hydatidiform moles, gestational trophoblastic neoplasia and control placentas. The transcription levels of its locus ERVWE1, its interaction partners (hASCT1, hASCT2, TLR4 and DC-SIGN) and two loci (ERVFRDE1 and ERV3) involved the expression of other placental envelopes were assessed by real-time PCR.Results: Syncytin-1 glycoprotein was expressed in syncytiotrophoblast of hydatidiform moles with an apical enhancement when compared with normal placentas. Moles with further malignant transformation had a higher staining intensity of Syncytin-1 surface unit C-terminus but the transcription level of its locus ERVWE1 was not different from that of moles with further remission and normal placentas. hASCT1 and TLR4, showed lower transcription levels in complete moles when compared to normal placentas. ERVWE1, ERVFRDE1 and ERV3 transcription was down-regulated in hydatidiform moles and gestational trophoblastic neoplasia.Conclusions: Variations of Syncytin-1 protein localization and down-regulation of hASCT1 and TLR4 transcription are likely to reflect altered functions of Syncytin-1 in the premalignant context of complete moles. The reduced transcription in gestational trophoblastic diseases of ERVWE1, ERVFRDE1 and ERV3, which expression during normal pregnancy is differentially regulated by promoter region methylation, suggest a joint dysregulation mechanism in malignant context. [ABSTRACT FROM AUTHOR]