Effects of the ApoE genotype on cognitive function in aging mice fed with a high-fat diet and the protective potential of n-3 polyunsaturated fatty acids.

The ApoE4 allele is the strongest genetic determinant for Alzheimer's disease (AD), while obesity is a strong environmental risk for AD. The modulatory effect of the ApoE genotype on aging-related cognitive function in tandem with a high-fat diet (HFD) remains uncertain. This study aimed to elucidate the effects of ApoE3/ApoE4 genotypes in aged mice exposed to a HFD, and the benefits of n-3 polyunsaturated fatty acids (PUFAs) from fish oil. Remarkably, the HFD led to weight gain and lipid accumulation, more pronounced in ApoE3 mice, while ApoE4 mice experienced exacerbated cerebral insulin resistance, neuroinflammation, and oxidative stress. Critically, n-3 PUFAs modulated the cerebral insulin signaling via the IRS-1/AKT/GLUT4 pathway, mitigated microglial hyperactivity, and reduced IL-6 and MDA levels, thereby counteracting cognitive deficits. These findings highlight the contrasting impacts of ApoE genotypes on aging mice exposed to a HFD, supporting n-3 PUFAs as a strategic nutritional intervention for brain health, especially for ApoE4 carriers.

Regulation of TREM2 expression by transcription factor YY1 and its protective effect against Alzheimer's disease.

TREM2 encoding the transmembrane receptor protein TREM2 is a risk gene of Alzheimer's disease (AD), and the impairment of TREM2 functions in microglia due to mutations in TREM2 may significantly increase the risk of AD by promoting AD pathologies. However, how the expression of TREM2 is regulated and the transcription factors required for TREM2 expression are largely unknown. By luciferase assay, DNA pull-down, and in silico predictions, we identified Yin Yang 1(YY1) as a binding protein of the minimal promoter of the TREM2 gene, and the binding was further confirmed by EMSA and DNA pull-down assay. shRNA-mediated YY1 silencing significantly reduced the activity of the TREM2 minimal promoter and TREM2 protein levels in the microglial cell line BV2 and the neuroblastoma Neuro2A. Furthermore, we found that the levels of TREM2 and YY1 were both downregulated in lipopolysaccharide-treated BV2 cells and in the brain of AD model mice. These results demonstrated that YY1 plays a crucial role in the regulation of TREM2 expression. Our study suggests that microglial YY1 could be targeted to maintain TREM2 expression for AD prevention and therapy.

Effects of Stratified Vitamin D Supplementation in Middle-Aged and Elderly Individuals with Vitamin D Insufficiency.

The incidence of vitamin D deficiency is high globally, and vitamin D supplementation draws particular attention. The objective of this study was to investigate the effects of stratified vitamin D supplementation in middle-aged and elderly individuals with vitamin D insufficiency in Beijing. A total of 448 subjects aged over 40 years old were selected from a community in Beijing. Among them, 100 middle-aged and elderly people with vitamin D insufficiency were randomly selected on a voluntary basis. They were further divided into control group and intervention group. The control group received health education and lifestyle guidance, and the intervention group received lifestyle guidance and vitamin D supplementation for nine months. The doses were stratified as follows: for vitamin D insufficiency, oral vitamin D3 supplement was given at 5000 IU/w; for mild vitamin D deficiency, oral vitamin D3 supplement was given at 10 000 IU/w; for severe vitamin D deficiency, oral vitamin D3 supplement was given at 15 000 IU/w. Safety evaluation was conducted after three-month treatment. The intervention group consisted of 8%, 62%, and 30% of cases who had vitamin D insufficiency, mild vitamin D deficiency, and severe vitamin D deficiency, respectively, which were similar with the control group. It showed that the blood 25(OH)D level increased significantly in the intervention group, from 14.30±4.30 ng/ml to 33.62±6.99 ng/ml (p<0.001), in contrast to insignificant change in the control group. Stratified vitamin D supplementation effectively increased the blood 25(OH)D level, as well as the number of cases with corrected vitamin D insufficiency or deficiency.

Ursolic acid alleviates inflammation and against diabetes­induced nephropathy through TLR4­mediated inflammatory pathway.

Ursolic acid (UA) is a triterpenoid isolated from Chinese herbal medicine. It is extensively distributed in the plant kingdom in at least 63 Chinese herbal medicines of 26 families. UA has multiple bioactivities, including anti­viral hepatitis, antitumor, anti­oxidation, anti­bacterium and anti­inflammation. The aim of this in vitro study was to examine the effects of UA on diabetes­induced nephropathy and its possible mechanism. In mice with diabetes­induced nephropathy, UA increased the body weight, reduced kidney/body weight index, protected kidney cells, alleviated inflammation [tumor necrosis factor (TNF)­α, interleukin (IL)­1ß, IL­6 and IL­18 levels] and kidney cell damage. It was also indicated that UA suppressed Toll­like receptor 4 (TLR4), myeloid differentiation factor 88 and nuclear factor­κB protein expression in mice with diabetes­induced nephropathy. The inhibition of TLR4 increased the anti­inflammation of UA on inflammation in rat with diabetes­induced nephropathy through the TLR4 signaling pathway. In conclusion, UA alleviates inflammation and inhibits diabetes­induced nephropathy through a TLR4­mediated inflammatory pathway. The present findings indicated that UA may be a possible therapeutic agent against diabetic nephropathy.

Expression and Enzyme Activity of Catalase in Chilo suppressalis (Lepidoptera: Crambidae) Is Responsive to Environmental Stresses.

Catalase (CAT) is an important antioxidant enzyme that protects organisms against oxidative stresses by eliminating hydrogen peroxide. In this study, we cloned and characterized a full-length cDNA of CAT from Chilo suppressalis (CsCAT) and examined the influence of environmental stresses on CsCAT expression and enzyme activity. The cDNA contains a 1659-bp open reading frame encoding a polypeptide of 553 amino acids most closely related (90.14%) to Papilio polytes catalases. The CsCAT was expressed in all developmental stages with the highest expression in the fat body, and the CsCAT enzyme activity closely mirrored its observed mRNA expression patterns. The CsCAT mRNA was up-regulated when the larvae were exposed to high temperature (≥30 °C), insecticides (abamectin and chlorantraniliprole), chemicals (H2O2, CHP, CdCl2, and CuSO4), and a dead-end trap plant (vetiver grass), and the CsCAT enzyme activity again mirrored the observed CsCAT expression patterns. These results suggest that up-regulation of CsCAT may enhance the defense response of C. suppressalis by weakening the effects of environmental stresses, and provide insight into the role of CsCAT during development of C. suppressalis.

The proteasome inhibitor carfilzomib functions independently of p53 to induce cytotoxicity and an atypical NF-κB response in chronic lymphocytic leukemia cells.

PURPOSE: The proteasome consists of chymotrypsin-like (CT-L), trypsin-like, and caspase-like subunits that cleave substrates preferentially by amino acid sequence. Proteasomes mediate degradation of regulatory proteins of the p53, Bcl-2, and nuclear factor-κB (NF-κB) families that are aberrantly active in chronic lymphocytic leukemia (CLL). CLL remains an incurable disease, and new treatments are especially needed in the relapsed/refractory setting. We therefore investigated the effects of the proteasome inhibitor carfilzomib (CFZ) in CLL cells. EXPERIMENTAL DESIGN: Tumor cells from CLL patients were assayed in vitro using immunoblotting, real-time polymerase chain reaction, and electrophoretic mobility shift assays. In addition, a p53 dominant-negative construct was generated in a human B-cell line. RESULTS: Unlike bortezomib, CFZ potently induces apoptosis in CLL patient cells in the presence of human serum. CLL cells have significantly lower basal CT-L activity compared to normal B and T cells, although activity is inhibited similarly in T cells versus CLL. Co-culture of CLL cells on stroma protected from CFZ-mediated cytotoxicity; however, PI3K inhibition significantly diminished this stromal protection. CFZ-mediated cytotoxicity in leukemic B cells is caspase-dependent and occurs irrespective of p53 status. In CLL cells, CFZ promotes atypical activation of NF-κB evidenced by loss of cytoplasmic IκBα, phosphorylation of IκBα, and increased p50/p65 DNA binding, without subsequent increases in canonical NF-κB target gene transcription. CONCLUSIONS: Together, these data provide new mechanistic insights into the activity of CFZ in CLL and support phase I investigation of CFZ in this disease.

Comparative analysis of essential oil components of Evodia rutaecarpa (Juss.) Benth. var. officinalis (Dode) Huang and Evodia rutaecarpa (Juss.) Benth.

Essential oils from the fruit of two species of Evodia rutaecarpa from China (Evodia rutaecarpa (Juss.) Benth. var. officinalis (Dode) Huang and Evodia rutaecarpa (Juss.) Benth.) have been obtained by hydrodistillation and analysed by gas chromatography-mass spectrometry in order to discern the differences and similarities between the volatile chemical compositions of these species. More than 21 components were identified in essential oils of the studied plants. In the oil of E. rutaecarpa (Juss.) Benth. var. officinalis (Dode) Huang, the main essential oil ingredients were ß-myrcene (44.43%) and ß-pinene (39.88%). ß-pinene (72.82%), 1R-α-pinene (8.90%) and ß-myrcene (1.99%) were the major compounds in the oil of E. rutaecarpa (Juss.) Benth. The chemical compounds of the essential oils showed that there are only six common compounds between the two species.