Fermented mixed grain ameliorates chronic stress-induced depression-like behavior and memory deficit.

Fermented mixed grain (FG) has beneficial anti-cancer, antioxidant, and anti-inflammatory effects. In this study, we investigated the effects of FG on gut inflammation, brain dysfunction, and anxiety/depression-like behavior induced by unpredictable chronic mild stress (UCMS) in mice. Mice were administered mixed grain or FG for 3 weeks and were then exposed to UCMS for 4 weeks. FG administration ameliorated stress-induced anxiety/despair-like behavior. FG administration also prevented UCMS-induced memory impairment. Additionally, the mRNA levels of 5-HTR1A and IL-6 were restored to normal levels in the brains of FG-administered mice. FG administration also inhibited intestinal damage in stressed mice compared with that in the UCMS (without FG) group. These results suggest that FG can alleviate stress-induced intestinal damage, brain dysfunction, and cognitive impairment.

The comprehensive expression of BCL2 family genes determines the prognosis of diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a prevalent and aggressive non-Hodgkin's lymphoma, and 40% of patients succumb to death. Despite numerous clinical trials aimed at developing treatment strategies beyond the conventional R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen, there have been no positive results thus far. Although the selective BCL2 inhibitor venetoclax has shown remarkable efficacy in chronic lymphocytic leukemia, its therapeutic effect in DLBCL was limited. We hypothesized that the limited therapeutic effect of venetoclax in DLBCL may be attributed to the complex expression and interactions of BCL2 family members, including BCL2. Therefore, we aimed to comprehensively analyze the expression patterns of BCL2 family members in DLBCL. We analyzed 157 patients with de novo DLBCL diagnosed at Asan Medical Center and Ajou University Hospital. The mRNA expression levels of BCL2 family members were quantified using the NanoString technology. BCL2 family members showed distinct heterogeneous expression patterns both intra- and inter-patient. Using unsupervised hierarchical cluster analysis, we were able to classify patients with similar BCL2 family expression pattern and select groups with clear prognostic features, C1 and C6. In the group with the best prognosis, C1, the expression of pro-apoptotic and pro-apoptotic BH3-only group gene expressions were increased, while anti-apoptotic group expression was significantly increased in both C1 and C6. Based on this, we generated the BCL2 signature score using the expression of pro-apoptotic genes BOK and BCL2L15, and anti-apoptotic gene BCL2. The BCL2 signature score 0 had the best prognosis, score 1/2 had intermediate prognosis, and score 3 had the worst prognosis (EFS, p = 0.0054; OS, p = 0.0011). Multivariate analysis, including COO and IPI, showed that increase in the BCL2 signature score was significantly associated with poor prognosis for EFS, independent of COO and IPI. The BCL2 signature score we proposed in this study provides information on BCL2 family deregulation based on the equilibrium of pro-versus anti-apoptotic BCL2 family, which can aid in the development of new treatment strategies for DLBCL in the future.

Inhibition of REV-ERBs stimulates microglial amyloid-beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer's disease.

A promising new therapeutic target for the treatment of Alzheimer's disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the molecular clock in regulating amyloid-beta (Aß) pathology is still poorly understood. Here, we explored how the circadian repressors REV-ERBα and ß affected Aß clearance in mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels of the master clock protein BMAL1 and more rapidly phagocytosed fibrillary Aß1-42 (fAß1-42 ) than at CT12. BMAL1 directly drives transcription of REV-ERB proteins, which are implicated in microglial activation. Interestingly, pharmacological inhibition of REV-ERBs with the small molecule antagonist SR8278 or genetic knockdown of REV-ERBs-accelerated microglial uptake of fAß1-42 and increased transcription of BMAL1. SR8278 also promoted microglia polarization toward a phagocytic M2-like phenotype with increased P2Y12 receptor expression. Finally, constitutive deletion of Rev-erbα in the 5XFAD model of AD decreased amyloid plaque number and size and prevented plaque-associated increases in disease-associated microglia markers including TREM2, CD45, and Clec7a. Altogether, our work suggests a novel strategy for controlling Aß clearance and neuroinflammation by targeting REV-ERBs and provides new insights into the role of REV-ERBs in AD.

14-3-3γ Haploinsufficient Mice Display Hyperactive and Stress-sensitive Behaviors.

14-3-3γ plays diverse roles in different aspects of cellular processes. Especially in the brain where 14-3-3γ is enriched, it has been reported to be involved in neurological and psychiatric diseases (e.g. Williams-Beuren syndrome and Creutzfeldt-Jakob disease). However, behavioral abnormalities related to 14-3-3γ deficiency are largely unknown. Here, by using 14-3-3γ deficient mice, we found that homozygous knockout mice were prenatally lethal, and heterozygous mice showed developmental delay relative to wild-type littermate mice. In addition, in behavioral analyses, we found that 14-3-3γ heterozygote mice display hyperactive and depressive-like behavior along with more sensitive responses to acute stress than littermate control mice. These results suggest that 14-3-3γ levels may be involved in the developmental manifestation of related neuropsychiatric diseases. In addition, 14-3-3γ heterozygote mice may be a potential model to study the molecular pathophysiology of neuropsychiatric symptoms.

Clinical analysis of acute radiculopathy after osteoporotic lumbar compression fracture.

OBJECTIVE: The purpose of this study was to analyze the relationship between fracture pattern and the development of acute radiculopathy after osteoporotic lumbar compression fracture. METHODS: This study included 59 patients who underwent bone cement augmentation for osteoporotic compression fracture below the L2 level, which can lead to radiculopathic radiating pain. The patients were divided into two groups according to the presence of radiculopathy (group A : back pain only; group B : back pain with newly developed radiating pain). We categorized compression fractures into three types by the position of the fracture line. The incidence of newly developed radiculopathy was examined retrospectively for each compression fracture type. RESULTS: The overall incidence of newly developed leg pain (group B) was 25%, and the frequency increased with descending spinal levels (L2 : 0%, L3 : 22%, L4 : 43%, and L5 : 63%). The back pain-only group (group A) had mostly superior-type fractures. On the other hand, the back pain with radiculopathy group (group B) had mostly inferior-type fractures. Most patients in group B showed significant relief of leg pain as well as back pain after bone cement augmentation. CONCLUSION: The incidence of a newly developed, radiating pain after osteoporotic compression fractures increased gradually from the L3 to L5 levels. Most of these fractures were of the inferior type, and the bone cement augmentation procedures seemed to be sufficient for relief of both back and radiating pain.