Arginine methylation is a critical post-translational modification that plays multifaceted biological functions. However, the manipulation of protein arginine methylation largely depends on genetic or pharmaceutic inhibition of the regulatory enzymes, protein arginine methyltransferases (PRMTs), or non-methylation substitution of corresponding arginine residue to lysine or alanine of protein of interest (POI), which inevitably affects other substrates, or disrupts the structure of POI. Thus, it urges an approach to specifically modulate the arginine methylation of a POI under physiological conditions. To this end, we report the discovery of a methylation tagging system (MeTAG), that enables targeted modification of protein arginine methylation. Through bridging the methyltransferase PRMT5 proximity to a POI, MeTAG facilitates the arginine methylation of POIs, including known arginine methylated proteins, androgen receptor (AR) and protein kinase B (AKT), as well as a neo-substrate E1A binding protein (p300), in a reversible and PRMT5-dependent manner. Moreover, MeTAG can regulate downstream signaling in a methylation dependent manner, leading to downregulation of PSMA mRNA level and activation of AKT. Therefore, MeTAG represents a feasible approach to modulate protein methylation and thereby perturbs protein function in biological and therapeutic contexts.

BACKGROUND: AND PURPOSE: Previous studies have explored the association between retinal vascular changes and cognitive impairment. The retinal vasculature shares some characteristics with the cerebral vasculature, and quantitative changes in it could indicate cognitive impairment. Hence, a comprehensive meta-analysis was performed to clarify the potential relationship between retinal vascular geometric changes and cognitive impairment. METHODS: Relevant databases were scrupulously and systematically searched for retinal vascular geometric changes including caliber, tortuosity, and fractal dimension (FD), and for cognitive impairment. The Newcastle-Ottawa Scale was used to evaluate the methodological quality of included studies. RevMan was used to perform the meta-analysis and detect publication bias. Sensitivity analyses were also performed. RESULTS: Five studies that involved 2,343 subjects were finally included in the meta-analysis. The results showed that there was no significant association between central retinal artery equivalents (Z=1.17) or central retinal venular equivalents (Z=1.74) and cognitive impairment (both p>0.05). Similarly, no significant difference was detected in retinal arteriolar tortuosity (Z=0.91) and venular tortuosity (Z=1.31) (both p>0.05). However, the retinal arteriolar FD (mean difference: −0.03, 95% CI: −0.05, −0.01) and venular FD (mean difference: −0.03, 95% CI: −0.05, −0.02) were associated with cognitive impairment. CONCLUSIONS A smaller retinal microvascular FD might be associated with cognitive impairment. Further large-sample and well-controlled original studies are required to confirm the present findings.

Metastasis is the leading cause of death in breast cancer patients. However, the mechanisms underlying metastasis are not well understood and there is no effective treatment in the clinic. Here, we demonstrate that in MMTV-PyMT, a highly malignant spontaneous breast tumor model, IL-25 (also called IL-17E) was expressed by tumor-infiltrating CD4 T cells and macrophages. An IL-25 neutralization antibody, while not affecting primary tumor growth, substantially reduced lung metastasis. Inhibition of IL-25 resulted in decreased type 2 T cells and macrophages in the primary tumor microenvironments, both reported to enhance breast tumor invasion and subsequent metastasis to the lung. Taken together, our data suggest IL-25 blockade as a novel treatment for metastatic breast tumor.
Animals ; Antibodies, Neoplasm ; pharmacology ; Antibodies, Neutralizing ; pharmacology ; Breast Neoplasms ; drug therapy ; genetics ; immunology ; CD4-Positive T-Lymphocytes ; immunology ; pathology ; Female ; Humans ; Interleukin-17 ; antagonists & inhibitors ; genetics ; immunology ; Interleukins ; antagonists & inhibitors ; genetics ; immunology ; Macrophages ; immunology ; pathology ; Mammary Neoplasms, Animal ; drug therapy ; genetics ; immunology ; Mice ; Neoplasm Metastasis ; Tumor Microenvironment ; drug effects ; genetics ; immunology

ObjectiveTo evaluate the association between Pro12Ala polymorphism in peroxisome proliferator activated receptorγ2 (PPARγ2) gene and gestational diabetes mellitus(GDM).Methods Publications on genetic association studies of PPARγ2 and GDM were searched using the PubMed database, The HuGE Navigator, China National Knowledge Infrastructure (CNKI), Wanfang database and VIP Science from the inception of the databases to December 1, 2014. Two reviewers independently selected literature according to the inclusion and exclusion criteria, extracted data and assessed the quality of the data using the Newcastle-Ottawa Scale (NOS) standard. Meta-analysis was performed using RevMan 5.3 software.ResultsOverall, 13 eligible articles were identified, including seven in English and six in Chinese, with a total of 2 787 GDM cases and 5 408 healthy controls. Quality assessment showed that the quality of the 13 articles was all good, with NOS≥5. (1) Pro12Ala polymorphism in PPARγ2 (allele Ala or genotype Ala/Ala or Pro/Ala) was shown to be highly associated with GDM occurrence on general evaluation, with anOR(95%CI) of 0.74(0.60-0.93) in the allele model and 0.79(0.65-0.96) in the dominant genetic model (P<0.05, respectively). (2) Pro12Ala polymorphism in PPARγ2 was shown to be highly associated with GDM occurrence in Asians in a stratification analysis of ethnicity in the populations included in the studies, with anOR(95%CI) of 0.61(0.48-0.79) in the allele model and 0.64(0.50-0.82) in the dominant genetic model (P<0.01, respectively). No correlation was found between the Pro12Ala polymorphism in PPARγ2 and GDM in the Caucasian population. (3) A meta-analysis of six Chinese studies showed that the Pro12Ala polymorphism in PPARγ2 was associated with the risk of GDM in the Chinese population, with anOR(95%CI) of 0.52 (0.36-0.73) in the allele model and 0.55(0.39-0.80) in the dominant genetic model (P<0.01, respectively). (4) No significant association was observed in the TaqMan allelic discrimination assay with anOR(95%CI) of 0.96(0.83-1.10) in the allele model and 0.95(0.81-1.11) in the dominant genetic model (P>0.05, respectively), although there was still a significant correlation in polymerase chain reaction-restriction fragment length polymorphism with anOR(95%CI) of 0.58(0.43-0.79) in the allele model and 0.62(0.45-0.85) in the dominant genetic model (P<0.01, respectively).ConclusionsThe Ala allele and the Ala/Ala or Pro/Ala genotypes of the Pro12Ala polymorphism in PPARγ2 can decrease the risk of GDM. However, there are differences in the results which are affected by the genotype analysis method or races.