GluN2A: a promising target for developing novel antidepressants.

BACKGROUND: Depression is a heterogeneous disorder with high morbidity and disability rates that poses serious problems in regard to mental health care. It is now well established that N-methyl D-aspartate receptors (NMDARs) modulators are being increasingly explored as potential therapeutic options for treating depression, although relatively little is known about their mechanisms of action. NMDARs are glutamate-gated ion channels that are ubiquitously expressed in the central nervous system (CNS) and they have been shown to play key roles in excitatory synaptic transmission. GluN2A, the predominant Glu2N subunit of functional NMDARs in neurons, is involved in various physiological processes in the CNS and is associated with diseases such as anxiety, depression, and schizophrenia. However, the role of GluN2A in the pathophysiology of depression has not yet been elucidated. METHODS: We reviewed several past studies in order to better understand the function of GluN2A in depression. Additionally, we also summarized the pathogenesis of depression based on the regulation of GluN2A expression, particularly its interaction with neuroinflammation and neurogenesis, which has received considerable critical attention and is highly implicated in the onset of depression. RESULTS: These evidences suggest that GluN2A overexpression impairs structural and functional synaptic plasticity, which contributes to the development of depression. Consequently, this knowledge is vital for the development of selective antagonists targeting GluN2A subunits using pharmacological and molecular methods. CONCLUSIONS: Specific inhibition of GluN2A NMDAR subunit is resistant to chronic stress-induced depressive-like behaviors, making them promising targets for the development of novel antidepressants.

Knockdown of LINC01087 inhibits gastric cancer malignant behavior by regulating the miR-135a-5p/CAAP1 axis.

Long noncoding RNAs play important roles in the occurrence and development of many malignant cancers. This study focuses on the effects of LINC01087 on gastric cancer and its underlying mechanism. In the present study, LINC01087 and CAAP1 were found to be upregulated, and miR-135a-5p was diminished in gastric cancer specimens and cells. Inhibition of LINC01087 resulted in cell proliferation inhibition and induced cell apoptosis through the intrinsic apoptosis signaling pathway, as evidenced by the activation of caspase-3 and caspase-9. An investigation of the signaling pathway revealed that the effects on proliferation and apoptosis following LINC01087 knockdown were mediated by suppression of CAAP1. Furthermore, application of a miR-135a-5p inhibitor or overexpression of CAAP1 could attenuate the apoptotic effect achieved by LINC01087 inhibition, confirming the involvement of miR-135a-5p/CAAP1 signaling in the occurrence of gastric cancer. In conclusion, the LINC01087/miR-135a-5p/CAAP1 axis modulates gastric cancer tumorigenesis and pathogenesis and presents new insight into gastric cancer targeted therapy.

New Staging Model for Radiation-based Hepatocellular Carcinoma Treatment: A National Multicenter Study.

Background and Aims: The study aimed to create a new staging model for radiotherapy-based treatment for prognostic hepatocellular carcinoma (HCC) classification. Methods: The training cohort comprised 658 patients receiving stereotactic body radiotherapy and external validation cohort comprised 533 patients receiving three-dimensional conformal radiotherapy and intensity-modulated radiotherapy. We established a modified staging system as follows: stage I, solitary nodule without macrovascular invasion, or 2-3 nodules no more than 3.0 cm apart, and performance status (PS) 0-2 (Ia: ALBI-1 grade; Ib: ALBI-2 or 3 grade); stage II: 2-3 nodules with any one nodule more than 3.0-cm apart, or ≥4 nodules, and performance status 0-2 (IIa: ALBI-1 grade; IIb: ALBI-2 grade); stage III: macrovascular invasion, regional lymph node metastasis or distant metastasis, and performance status 0-2 (IIIa: ALBI-1 grade; IIIb: ALBI-2 grade); stage IV: performance status 3-4, or performance status 0-2 with ALBI-3 grade. We analyzed long-term overall survival based on different stages. Results: The staging model showed an excellent ability to discriminate patients according to four stages and seven substages with notably different curves in the training and validation cohort. The median survival decreased from stages I to IV with 63.0 months in stage I (not reached in Ia, and 53.0 months in Ib), 24.0 months in stage II (28.0 months in IIa, and 22.0 months in IIb), 11.0 months in stage III (18.0 months in IIIa, and 9.0 months in IIIb), and less than 9.0 months in stage IV in the training cohort. Conclusions: The modified staging model may provide an alternative for clinical radiation oncologists.

Optimal stereotactic body radiotherapy dosage for hepatocellular carcinoma: a multicenter study.

BACKGROUND: The optimal dose and fractionation scheme of stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) remains unclear due to different tolerated liver volumes and degrees of cirrhosis. In this study, we aimed to verify the dose-survival relationship to optimize dose selection for treatment of HCC. METHODS: This multicenter retrospective study included 602 patients with HCC, treated with SBRT between January 2011 and March 2017. The SBRT dosage was classified into high dose, moderate dose, and low dose levels: SaRT (BED10 ≥ 100 Gy), SbRT (EQD2 > 74 Gy to BED10 < 100 Gy), and ScRT (EQD2 < 74 Gy). Overall survival (OS), progression-free survival (PFS), local control (LC), and intrahepatic control (IC) were evaluated in univariable and multivariable analyses. RESULTS: The median tumor size was 5.6 cm (interquartile range [IQR] 1.1-21.0 cm). The median follow-up time was 50.0 months (IQR 6-100 months). High radiotherapy dose correlated with better outcomes. After classifying into the SaRT, SbRT, and ScRT groups, three notably different curves were obtained for long-term post-SBRT survival and intrahepatic control. On multivariate analysis, higher radiation dose was associated with improved OS, PFS, and intrahepatic control. CONCLUSIONS: If tolerated by normal tissue, we recommend SaRT (BED10 ≥ 100 Gy) as a first-line ablative dose or SbRT (EQD2 ≥ 74 Gy) as a second-line radical dose. Otherwise, ScRT (EQD2 < 74 Gy) is recommended as palliative irradiation.

Protective effect of eNOS overexpression against ischemia/reperfusion injury in small-for-size liver transplantation.

Ischemia/reperfusion (I/R) injury can occur during small-for-size liver transplantation, resulting in delayed graft function and decreased long-term graft survival. The aim of the present study was to evaluate the effects of genetic overexpression of endothelial nitric oxide synthase (eNOS) in protecting hepatocytes against I/R injury in a rat model of small-for-size liver transplantation. L02 liver cells were transfected with the eNOS gene using an adenovirus (Ad-eNOS). eNOS expression was detected using quantitative polymerase chain reaction and western blot analysis. To evaluate the effect of eNOS overexpression, L02 cells were placed in a hypoxic environment for 12 h and immediately transferred to an oxygen-enriched atmosphere. For in vivo testing, rats pretreated with Ad-eNOS or control underwent small-for-size liver transplantation. At 6 h after reperfusion, the bile quantity, serum transaminase and nitric oxide (NO) levels, and histological outcomes were evaluated. Cell apoptosis was assessed by flow cytometry or TUNEL assay. In vitro, Ad-eNOS prevented apoptosis in L02 cells with an increase in the level of NO in culture supernatant. In vivo, Ad-eNOS pre-treatment significantly increased bile production, improved abnormal transaminase levels, diminished apoptosis among liver cells, and decreased hepatocellular damage at 6 h after I/R injury. The eNOS-mediated renal protective effects might be associated with the downregulation of tumor necrosis factor-α and a reduction in macrophage activation in the early stage of reperfusion in small-for-size liver allografts. eNOS-derived NO production significantly attenuates hepatic I/R injury. Thus, eNOS overexpression constitutes a promising therapeutic approach to prevent liver I/R injury following small-for-size liver transplantation.