Review Article Lgr4 in Ocular Development and Glaucoma

The leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4, also called GPR48) plays a key role in multiple developmental processes, and mice lacking Lgr4 display anterior segment dysgenesis leading to early-onset glaucomatous retinal ganglion cell loss as well as defective eyelid formation. This paper will review Lgr4 signaling and its regulation of the AxenfeldRieger syndrome gene Pitx2, a crucial developmental transcription factor. In addition, Wnt signaling plays an important role in eye development, with Norrin functioning to activate the Wnt receptor Frizzled 4 required for proper retinal vascularization. Recent discoveries identifying Lgr4 as a receptor for Norrin highlight the potential for Lgr4 function in retinal vascularization. Finally, several unanswered questions impeding a full understanding of Lgr4 in glaucoma are considered as avenues for further research

Lgr4 in Ocular Development and Glaucoma

The leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4, also called GPR48) plays a key role in multiple developmental processes, and mice lacking Lgr4 display anterior segment dysgenesis leading to early-onset glaucomatous retinal ganglion cell loss as well as defective eyelid formation. This paper will review Lgr4 signaling and its regulation of the Axenfeld-Rieger syndrome gene Pitx2, a crucial developmental transcription factor. In addition, Wnt signaling plays an important role in eye development, with Norrin functioning to activate the Wnt receptor Frizzled 4 required for proper retinal vascularization. Recent discoveries identifying Lgr4 as a receptor for Norrin highlight the potential for Lgr4 function in retinal vascularization. Finally, several unanswered questions impeding a full understanding of Lgr4 in glaucoma are considered as avenues for further research

Extracranial Artery Stenosis Is Associated With Total MRI Burden of Cerebral Small Vessel Disease in Ischemic Stroke Patients of Suspected Small or Large Artery Origins

Background and Purpose: Extracranial artery stenosis (ECAS) is related to individual imaging markers of cerebral small vessel disease (cSVD). However, little has been reported on the association between ECAS and the total burden of cSVD as assessed by magnetic resonance imaging (MRI). The purpose of this study was to investigate the relationship between ECAS and cSVD burden in patients with ischemic stroke of suspected small or large artery origin.Methods: We reviewed consecutive patients with ischemic stroke of suspected small or large artery origin who underwent color Doppler ultrasonography and brain MRI. Bilateral extracranial cerebral arteries including common carotid artery, internal carotid artery (ICA), and proximal vertebral artery (VA, ostium, V2–3 segments) were assessed using color Doppler ultrasonography. ECAS severity was classified as no/mild stenosis, moderate stenosis, severe stenosis, or occlusion. The total cSVD score was assessed by awarding one point according to the load of each of these cSVD markers as determined using MRI; lacunar infarction, white matter hyperintensities, cerebral microbleeds, and enlarged perivascular spaces. The relationship between ECAS severity and cSVD burden according to MRI was examined.Results: Two hundred and twenty one patients were included in this study (mean age 61 ± 12 years, 75.6% male). Hypertension, current smoking, hyperlipidaemia, and diabetic mellitus were frequent among the patients (67.4, 45.7, 43.9, and 36.7%, respectively), while the other vascular risk factors including previous stroke or TIA and alcohol excess were less frequent (19.0 and 15.4%, respectively). Patients with higher total cSVD burden was significantly older and had severer ECAS. The frequency of hypertension was significantly higher in patients with higher total cSVD burden. This analysis indicated that that increasing ECAS severity (from no stenosis through to 100%) was independently associated with increasing total cSVD score after adjusting for other vascular risk factors (odds ratio 1.76, 95% CI [1.16–2.69]).Conclusions: In this study, high levels of ECAS from ultrasound evidence were associated with coexisting advanced cerebral cSVD in ischemic stroke patients of suspected small or large artery origin. Further studies are required to determine if and how extracranial arterial imaging helps reduce cSVD burden or improves cognitive function

RETRACTED ARTICLE: Circular RNA hsa_circ_0001829 promotes gastric cancer progression through miR-155-5p/SMAD2 axis

Abstract Background Accumulating evidences have shown that circular RNAs (circRNAs) play important roles in regulating the pathogenesis of cancer. However, the role of circRNAs in gastric cancer (GC) remains largely unclear. Methods In this study, we identified a novel upregulated circRNA, hsa_circ_0001829, in chemically induced malignant transformed human gastric epithelial cells using RNA-seq. Subsequent qRT-PCR and ISH assays were performed to detect the expression level of hsa_circ_0001829 in GC cell lines and tissues. Functional roles of hsa_circ_0001829 in GC were then explored by loss- and gain-of- function assays. Bioinformatic prediction and luciferase assay were used to investigate potential mechanisms of hsa_circ_0001829. Finally, the mice xenograft and metastasis models were constructed to assess the function of hsa_circ_0001829 in vivo. Results We found that hsa_circ_0001829 was significantly upregulated in GC tissues and cell lines. Loss- and gain-of- function assays showed that hsa_circ_0001829 promotes GC cells proliferation, migration and invasion, and the affected cell cycle progression and apoptosis rates may account for the effect of hsa_circ_0001829 on GC proliferation. In addition, bioinformatic prediction and luciferase assay showed that hsa_circ_0001829 acts as a molecular sponge for miR-155-5p and that SMAD2 was a target gene of miR-155-5p; moreover, hsa_circ_0001829 sponges miR-155-5p to regulate SMAD2 expression and hsa_circ_0001829 promotes GC progression through the miR-155-5p–SMAD2 pathway. Finally, suppression of hsa_circ_0001829 expression inhibited tumor growth and aggressiveness in vivo. Conclusion Taken together, our findings firstly demonstrated a novel oncogenic role of hsa_circ_0001829 in GC progression through miR-155-5p–SMAD2 axis, and our study may offer novel biomarkers and therapeutic targets for GC

Identification of prostate-specific G-protein coupled receptor as a tumor antigen recognized by CD8(+) T cells for cancer immunotherapy.

Prostate cancer is the most common cancer among elderly men in the US, and immunotherapy has been shown to be a promising strategy to treat patients with metastatic castration-resistant prostate cancer. Efforts to identify novel prostate specific tumor antigens will facilitate the development of effective cancer vaccines against prostate cancer. Prostate-specific G-protein coupled receptor (PSGR) is a novel antigen that has been shown to be specifically over-expressed in human prostate cancer tissues. In this study, we describe the identification of PSGR-derived peptide epitopes recognized by CD8(+) T cells in an HLA-A2 dependent manner.Twenty-one PSGR-derived peptides were predicted by an immuno-informatics approach based on the HLA-A2 binding motif. These peptides were examined for their ability to induce peptide-specific T cell responses in peripheral blood mononuclear cells (PBMCs) obtained from either HLA-A2(+) healthy donors or HLA-A2(+) prostate cancer patients. The recognition of HLA-A2 positive and PSGR expressing LNCaP cells was also tested. Among the 21 PSGR-derived peptides, three peptides, PSGR3, PSGR4 and PSGR14 frequently induced peptide-specific T cell responses in PBMCs from both healthy donors and prostate cancer patients. Importantly, these peptide-specific T cells recognized and killed LNCaP prostate cancer cells in an HLA class I-restricted manner.We have identified three novel HLA-A2-restricted PSGR-derived peptides recognized by CD8(+) T cells, which, in turn, recognize HLA-A2(+) and PSGR(+) tumor cells. The PSGR-derived peptides identified may be used as diagnostic markers as well as immune targets for development of anticancer vaccines

Regulation of bone formation and remodeling by G-protein-coupled receptor 48

G-protein-coupled receptor (GPCR) 48 (Gpr48; Lgr4), a newly discovered member of the glycoprotein hormone receptor subfamily of GPCRs, is an orphan GPCR of unknown function. Using a knockout mouse model, we have characterized the essential roles of Gpr48 in bone formation and remodeling. Deletion of Gpr48 in mice results in a dramatic delay in osteoblast differentiation and mineralization, but not in chondrocyte proliferation and maturation, during embryonic bone formation. Postnatal bone remodeling is also significantly affected in Gpr48-/- mice, including the kinetic indices of bone formation rate, bone mineral density and osteoid formation, whereas the activity and number of osteoclasts are increased as assessed by tartrate-resistant acid phosphatase staining. Examination of the molecular mechanism of Gpr48 action in bone formation revealed that Gpr48 can activate the cAMP-PKA-CREB signaling pathway to regulate the expression level of Atf4 in osteoblasts. Furthermore, we show that Gpr48 significantly downregulates the expression levels of Atf4 target genes/proteins, such as osteocalcin (Ocn; Bglap2), bone sialoprotein (Bsp; Ibsp) and collagen. Together, our data demonstrate that Gpr48 regulates bone formation and remodeling through the cAMP-PKA-Atf4 signaling pathway