TNIP2 mediates GRß-promoted inflammation and is associated with severity of major depressive disorder.

In depression, continual activation of the hypothalamic-pituitaryadrenal (HPA) axis with excess cortisol release leads to impair sensitivity of the glucocorticoid receptor (GR) and increase activity of the pro-inflammatory immune responses. Aberrant expression of GR has been associated with inflammation in patients with major depressive disorder (MDD). Our previous studies showed that the aberrant expression of TNFAIP3 gene, which encodes the NF-κB regulatory protein A20, TNFAIP3-associated proteins and Toll-like receptors (TLRs) are involved in inflammation-associated depression. However, the link between desensitization of GR actions and negative regulation of the TLRs-mediated inflammatory pathway in MDD is yet to be established. Here, we examined the association of depression severity, measured via the 17-item Hamilton Depression Rating Scale (HAMD-17), with the mRNA expression profiling of GRα, GRß, TNFAIP3-interacting proteins (TNIP), including TNIP1, TNIP2, and TNIP3, and TNFAIP3-like proteins, such as cezanne1, cezanne2, trabid, and valosin-containing protein p97/p47 complex-interacting protein p135 (VCIP135), in monocytes from 69 patients with MDD and 42 healthy controls. Herein we found the mRNA expressions of GRß and TNIP2 were significantly higher in monocytes from patients with MDD. Notably, TNIP2 level was positively correlated with the GRß expression and severity of depression, as determined via Pearson's correlation analysis. Mechanistically, we demonstrated that overexpression of GRß promotes the mRNA levels of TNIP2 and tumor necrosis factor alpha (TNF-α) in human monocytes. The promoting effect of GRß on TNF-α expression was partially attenuated upon depletion of TNIP2, suggesting that TNIP2 was required for GRß-mediated enhancement of TNF-α levels. Together, these results suggest that activation of GRß/TNIP2/TNF-α axis may induce inflammation in MDD patients and targeting this newly identified pathway may help in the development of better therapeutic approaches to reduce the development of MDD.

Novel Biomarkers of Alzheimer's Disease: Based Upon N-methyl-D-aspartate Receptor Hypoactivation and Oxidative Stress.

Early detection and prevention of Alzheimer's disease (AD) is important. The current treatment for early AD is acetylcholine esterase inhibitors (AChEIs); however, the efficacy is poor. Besides, AChEI did not show efficacy in mild cognitive impairment (MCI). Beta-amyloid (A) deposits have been regarded to be highly related to the pathogenesis of AD. However, many clinical trials aiming at the clearance of A deposits failed to improve the cognitive decline of AD, even at its early phase. There should be other important mechanisms unproven in the course of AD and MCI. Feasible biomarkers for the diagnosis and treatment response of AD are lacking to date. The N-methyl-D-aspartate receptor (NMDAR) activation plays an important role in learning and memory. On the other hand, oxidative stress has been regarded to contribute to aging with the assumption that free radicals damage cell constituents and connective tissues. Our recent study found that an NMDAR enhancer, sodium benzoate (the pivotal inhibitor of D-amino acid oxidase [DAAO]), improved the cognitive and global function of patients with early-phase AD. Further, we found that peripheral DAAO levels were higher in patients with MCI and AD than healthy controls. We also found that sodium benzoate was able to change the activity of antioxidant. These pieces of evidence suggest that the NMDAR function is associated with anti-oxidation, and have potential to be biomarkers for the diagnosis and treatment response of AD.

D2 dopamine receptor gene (DRD2) Taq1A (rs1800497) affects bone density.

Schizophrenia patients are susceptible to lower bone mineral density (BMD). However, studies exploring the genetic effects are lacking. Genes that affect the activity of antipsychotics may be associated with BMD, particularly in patients receiving long-term antipsychotic treatment. We aimed to explore the relationship between the dopamine receptor D2 (DRD2) gene Taq1A (rs1800497) polymorphism and BMD in chronic schizophrenia patients. We recruited schizophrenia patients (n = 47) and healthy controls (n = 39) from a medical center in Taiwan and collected data that may affect BMD. Patients' BMD was measured by dual-energy X-ray absorptiometer (DEXA). DRD2 rs1800497 was genotyped through polymerase chain reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Among all participants, subjects with DRD2 rs1800497(T;T) allele had lower DEXA T score and DEXA Z score compared to those with rs1800497(C;T) and rs1800497(C;C) alleles (p = 0.008, 0.003, respectively). In schizophrenia patients, subjects with rs1800497(T;T) allele also had lower DEXA Z score compared to the other two alleles (p = 0.045). Our findings suggest that individuals with the DRD2 rs1800497(T;T) had lower BMD than those with the rs1800497(C;T) and rs1800497(C;C) genotypes. Therefore, genes should be considered as one of the risk factors of lower BMD.