Association of HLA-DRB1 alleles with status of antibodies to hepatitis B surface and e antigen.

Antigen presentation by HLA class II molecules to CD4+ T cells is an essential step for generating antibodies to hepatitis B antigens. In this study, we investigated the association between the HLA-DRB1 gene and the status of antibodies to hepatitis B surface and e antigens. Our results revealed a significant association between the status of anti-HBsAg and HLA-DRB1*04:03 (OR = 4.11, 95% CI = 1.50-10.84, p = 0.005, Padj. = 0.05) as well as HLA-DRB1*15:01 (OR = 1.74, 95% CI = 1.20-2.50, p = 0.002, Padj. = 0.045). MHC II binding predictions and in silico docking demonstrated strong binding affinity of HBsAg peptides to these two HLA-DRB1 molecules. Conversely, the status of anti-HBeAg was inversely associated with HLA-DRB1*14:54 (OR = 0.34, 95% CI = 0.18-0.64, p = 0.001, Padj. = 0.011), and in silico analysis revealed weak binding affinity of HBeAg peptides to HLA-DRB1*14:54. In conclusion, these findings support the involvement of HLA-DRB1 in humoral immunity against HBV infection.

Fatal multiple acyl-CoA dehydrogenase deficiency caused by ETFDH gene mutation: A case report.

BACKGROUND: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a disease of rare autosomal recessive disorder. There are three types of MADD. Type I is a neonatal-onset form with congenital anomalies. Type II is a neonatal-onset form without congenital anomalies. Type III is considered to a milder form and usually responds to riboflavin. However, late-onset form could also be fatal and not responsive to treatments. CASE SUMMARY: We report a severe case of a young man with onset type III MADD induced by drugs and strenuous exercise characterized by rhabdomyolysis and liver dysfunction. Urine analysis indicated 12 out of 70 kinds of organic acids like glutaric acid-2 were detected. Serum analysis in genetic metabolic diseases revealed 24 out of 43 tested items were abnormal, revealing the elevation of several acylcarnitines and the reduction of carnitine in the patient. By next generation sequencing technology for gene sequencing related to fatty acid oxidation and carnitine cycle defects, a rare ETFDH gene variant was identified: NM_004453:4:C.1448C>T(p.Pro483 Leu). The patient was diagnosed with late-onset GAII. He was not responsive to riboflavin and progressively worsened into multiple organ failure that finally led to death. CONCLUSION: Type III MADD can also be fatal and not responsive to treatments.

The synergistic effect of curcumin and mitoquinol mesylate on cognitive impairment and the neuropathology of Alzheimer's disease.

Given the complexity and heterogeneity of Alzheimer's disease (AD) pathology, targeted monotherapy drugs may not be effective. Therefore, synergistic combination therapy of curcumin and Mito Q was proposed and evaluated in a triple-transgenic AD model mice (3 × Tg-AD mice). The cognitive ability was assessed using behavioral tests and typical pathological changes were observed through Western blotting and histological analysis. The results demonstrated a significant enhancement in cognitive ability along with the mitigation of typical AD pathological features such as Aß aggregation, tau phosphorylation, and synaptic damage. Notably, the combination therapy demonstrated superior efficacy over individual drugs alone. These findings provide valuable insights for optimizing the development of AD drugs.

Se-methylselenocysteine ameliorates mitochondrial function by targeting both mitophagy and autophagy in the mouse model of Alzheimer's disease.

Background: Alzheimer's disease (AD) exerts tremendous pressure on families and society due to its unknown etiology and lack of effective treatment options. Our previous study had shown that Se-methylselenocysteine (SMC) improved the cognition and synaptic plasticity of triple-transgenic AD (3 × Tg-AD) mice and alleviated the related pathological indicators. We are dedicated to investigating the therapeutic effects and molecular mechanisms of SMC on mitochondrial function in 3 × Tg-AD mice. Methods: Transmission electron microscopy (TEM), western blotting (WB), mitochondrial membrane potential (ΔΨm), mitochondrial swelling test, and mitochondrial oxygen consumption test were used to evaluate the mitochondrial morphology and function. Mitophagy flux and autophagy flux were assessed with immunofluorescence, TEM and WB. The Morris water maze test was applied to detect the behavioral ability of mice. Results: The destroyed mitochondrial morphology and function were repaired by SMC through ameliorating mitochondrial energy metabolism, mitochondrial biogenesis and mitochondrial fusion/fission balance in 3 × Tg-AD mice. In addition, SMC ameliorated mitochondria by activating mitophagy flux via the BNIP3/NIX pathway and triggering autophagy flux by suppressing the Ras/Raf/MEK/ERK/mTOR pathway. SMC remarkably increased the cognitive ability of AD mice. Conclusions: This research indicated that SMC might exert its therapeutic effect by protecting mitochondria in 3 × Tg-AD mice.

High-resolution estimation of near-surface ozone concentration and population exposure risk in China.

Considering the spatial and temporal effects of atmospheric pollutants, using the geographically and temporally weighted regression and geo-intelligent random forest (GTWR-GeoiRF) model and Sentinel-5P satellite remote sensing data, combined with meteorological, emission inventory, site observation, population, elevation, and other data, the high-precision ozone concentration and its spatiotemporal distribution near the ground in China from March 2020 to February 2021 were estimated. On this basis, the pollution status, near-surface ozone concentration, and population exposure risk were analyzed. The findings demonstrate that the estimation outcomes of the GTWR-GeoiRF model have high precision, and the precision of the estimation results is higher compared with that of the non-hybrid model. The downscaling method enhances estimation results to some extent while addressing the issue of limited spatial resolution in some data. China's near-surface ozone concentration distribution in space shows obvious regional and seasonal characteristics. The eastern region has the highest ozone concentrations and the lowest in the northeastern region, and the wintertime low is higher than the summertime high. There are significant differences in ozone population exposure risks, with the highest exposure risks being found in China's eastern region, with population exposure risks mostly ranging from 0.8 to 5.

Fatal toxic epidermal necrolysis associated with sinomenine in a patient with primary membranous nephropathy.

Sinomenine (SIN), the alkaloid monomer extracted from Sinomenium acutum, is a kind of non-steroidal anti-inflammatory drug widely used in China to treat rheumatoid arthritis (RA) and various glomerular diseases. It has various pharmacological effects such as anti-inflammatory, analgesic, and anti-tumor. As a strong histamine-releasing agent, SIN has drawn increasing attention in regards to its side effects such as allergic, gastrointestinal, and circulatory systemic reactions. In this report, we first described a patient with primary membranous nephropathy (PMN) who was treated with oral intake of SIN and developed medicine-induced toxic epidermal necrolysis (TEN) and subsequently died of septic multi-organ failure. The present case report intends to demonstrate the underestimated side effects of SIN that can eventually lead to death.

Zinc exacerbates tau-induced Alzheimer-like pathology in C57BL/6J mice.

The pathogenesis of Alzheimer's disease (AD) is highly complex and multifactorial. Compared with Aß, the pathological changes associated with tau are more related to the clinical symptoms and more indicative of the severity of AD. Studies have shown that the direct interaction between tau and Zn2+ plays an important role in tau toxicity, however, the mechanism by which Zn2+ contributes to tau-induced neurotoxicity is not fully understood. Our previous studies have found that Zn2+ bound to the third repeat unit of the microtubule-binding domain of tau (R3) with moderate affinity and induced R3 to form oligomers, thus increased the toxicity of R3 to nerve cells. Here, we demonstrated that Zn2+ binding to R3 (Zn2++R3) significantly reduced cognitive ability and increased blood lipid and glucose levels of C57BL/6J mice. In addition, Zn2++R3, not Zn2+ or R3 alone, markedly enhanced the endogenous Aß and tau pathology and damaged the neurons of C57BL/6J mice. The study suggests that the main reason for the toxicity of Zn2+ may be the formation of Zn2+ and tau complex. Thus, preventing the combination of Zn2+ and tau may be a potential strategy for AD treatment. Furthermore, as the C57BL/6J mice injected with Zn2++R3 complex showed behavioral deficits, deposition of Aß plaques and tau tangles, and the death of neurons within 45 days. Thus, they can be considered as a fast sporadic AD or other tauopathies mouse model.

Targeting G-quadruplexes in an ageing epigenetic regulator promoter for rescuing mitochondrial dysfunction in Alzheimer's disease.

Here, we provide an out-of-the-box G-quadruplex (G4) targeting-based strategy for rescuing mitochondrial dysfunction in Alzheimer's disease. We predict and verify the presence of G4s within the promoter of an ageing epigenetic regulator BAZ2B. G4-specific ligands targeting BAZ2B G4s could significantly down-regulate the BAZ2B expression and relieve mitochondrial dysfunction. Therefore, this work may provide a new way of rescuing mitochondrial dysfunction in AD by targeting G4s in a specific ageing epigenetic regulator promoter.

Effect of long-term temperature stress on the intestinal microbiome of an invasive snail.

The gut microbiome is vital to the physiological and biochemical functions of the host, and changes in the composition of these microbial communities may affect growth and adaptability to the environment. Pomacea canaliculata is an invasive freshwater snail which has become a serious agricultural pest. Temperature adaptation is considered an important reason for the widespread distribution of this species. To date, the contribution of the gut microbes to host fitness of P. canaliculata during long-term temperature stress is not well understood. In this study, the morphological changes and intestinal microbiome of P. canaliculata under long-term stress at low temperature (15°C) and high temperature (35°C) were investigated with laboratory experiments. Compared with control group (25°C), the alpha diversity increased and pathogenic bacteria enriched changed under high and low temperature stress. The effect of high temperature stress on the intestinal microbiome of P. canaliculata was more significant than that of low temperature stress. A sustained high temperature environment led to an increase in the abundance of pathogenic bacteria, such as Aeromonas and Enterobacter, and a decrease in the abundance of immune-related bacteria such as Bacteroidetes, Firmicutes, and Lactococcus. These intestine microbiome changes can increase the risk of diseases like intestinal inflammation, and lead to more deaths at high temperature environments. In addition, with the extension of stress time from 14 to 28 days, the beneficial bacteria such as Bacteroidetes, Firmicutes, and Lactococcus were significantly enriched, while potential pathogenic bacteria such as Pseudomonas, Acinetobacter, Shivalella, and Flavobacterium decreased, suggesting that intestinal microbiota may play an important role in host response to heat stress. These results are consistent with previously reported results that the survival rate of both male and female P. canaliculata no longer significantly reduced after 21 days of high temperature stress, suggesting that the surviving P. canaliculata had gradually adapted to high temperature environments under long-term high temperature stress.

Ebselen Interferes with Alzheimer's Disease by Regulating Mitochondrial Function.

(1) Background: With unknown causes and no effective treatment available, Alzheimer's disease (AD) places enormous pressure on families and society. Our previous study had shown that Ebselen at a high concentration (10.94 µM) improved the cognition of triple-transgenic AD (3×Tg-AD) mice and alleviated the related pathological indicators but showed toxicity to the mice. Here, we dedicated to study the therapeutic effect and molecular mechanism of Ebselen at a much lower concentration on 3×Tg-AD mice. (2) Methods: Various behavioral experiments were applied to detect the behavioral ability of mice. Western blot, thioflavin T staining and a transmission electron microscope were used to evaluate the pathology of AD mice. The mitochondrial membrane potential and respiration were assessed with the corresponding assay kit. (3) Results: Ebselen remarkably increased cognitive ability of AD mice, eliminated ß-Amyloid (Aß) oligomers and recovered the synaptic damage in AD mice brain. In addition, the destroyed mitochondrial morphologies and function were repaired by Ebselen through ameliorating mitochondrial energy metabolism, mitochondrial biogenesis and mitochondrial fusion/fission balance in N2a-SW cells and brain tissues of AD mice. (4) Conclusions: This research indicated that Ebselen might exert its therapeutic effect via protecting mitochondria in AD.

Glycometabolism change during Burkholderia pseudomallei infection in RAW264.7 cells by proteomic analysis.

Burkholderia pseudomallei is a Gram-negative intracellular bacterium that causes melioidosis, a life-threatening disease. The interaction of B. pseudomallei with its host is complicated, and cellular response to B. pseudomallei infection is still largely unknown. In this study, we aimed to determine host-cell responses to B. pseudomallei at the proteomics level. We performed proteomic profiling of B. pseudomallei HNBP001-infected mouse macrophage RAW264.7 cells to characterize the cellular response dynamics during infection. Western blot analysis was utilized for the validation of changes in protein expression. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted using the clusterProfiler R package. Compared with the negative control (NC) group, 811 common proteins varied over time, with a cut-off level of two fold change and an adjusted P-value less than 0.05. The bioinformatics analysis revealed that the proteins significantly changed in the B. pseudomallei HNBP001 infection group (Bp group) were enriched in glycometabolism pathways, including glycolysis, fructose and mannose metabolism, pentose phosphate pathway, galactose metabolism, and carbon metabolism. Western blot analysis verified three selected proteins involved in glycometabolism pathways, namely PGM1, PKM, and PGK1 were increase over time post the infection. Furthermore, in vitro functional analysis revealed an increased glucose uptake and decreased ATP production and O-GlcNAcylation in the Bp group compared with control group, suggesting that B. pseudomallei HNBP001 infection induces changes in glycometabolism in RAW264.7 cells. These results indicate that glycometabolism pathways change in RAW264.7 cells post B. pseudomallei HNBP001 infection, providing important insights into the intimate interaction between B. pseudomallei and macrophages.

Human-derived decellularized extracellular matrix scaffold incorporating autologous bone marrow stem cells from patients with congenital heart disease for cardiac tissue engineering.

BACKGROUND: Stem cells are used as an alternative treatment option for patients with congenital heart disease (CHD) due to their regenerative potential, but they are subject to low retention rate in the injured myocardium. Also, the diseased microenvironment in the injured myocardium may not provide healthy cues for optimal stem cell function. OBJECTIVE: In this study, we prepared a novel human-derived cardiac scaffold to improve the functional behaviors of stem cells. METHODS: Decellularized extracellular matrix (ECM) scaffolds were fabricated by removing cells of human-derived cardiac appendage tissues. Then, bone marrow c-kit+ progenitor cells from patients with congenital heart disease were seeded on the cardiac ECM scaffolds. Cell adhesion, survival, proliferation and cardiac differentiation on human cardiac decellularized ECM scaffold were evaluated in vitro. Label-free mass spectrometry was applied to analyze cardiac ECM proteins regulating cell behaviors. RESULTS: It was shown that cardiac ECM scaffolds promoted stem cell adhesion and proliferation. Importantly, bone marrow c-kit+ progenitor cells cultured on cardiac ECM scaffold for 14 days differentiated into cardiomyocyte-like cells without supplement with any inducible factors, as confirmed by the increased protein level of Gata4 and upregulated gene levels of Gata4, Nkx2.5, and cTnT. Proteomic analysis showed the proteins in cardiac ECM functioned in multiple biological activities, including regulation of cell proliferation, regulation of cell differentiation, and cardiovascular system development. CONCLUSION: The human-derived cardiac scaffold constructed in this study may help repair the damaged myocardium and hold great potential for tissue engineering application in pediatric patients with CHD.

Hydrogen-rich water ameliorates neuropathological impairments in a mouse model of Alzheimer's disease through reducing neuroinflammation and modulating intestinal microbiota.

Hydrogen exhibits the potential to treat Alzheimer's disease. Stereotactic injection has been previously used as an invasive method of administering active hydrogen, but this method has limitations in clinical practice. In this study, triple transgenic (3×Tg) Alzheimer's disease mice were treated with hydrogen-rich water for 7 months. The results showed that hydrogen-rich water prevented synaptic loss and neuronal death, inhibited senile plaques, and reduced hyperphosphorylated tau and neurofibrillary tangles in 3×Tg Alzheimer's disease mice. In addition, hydrogen-rich water improved brain energy metabolism disorders and intestinal flora imbalances and reduced inflammatory reactions. These findings suggest that hydrogen-rich water is an effective hydrogen donor that can treat Alzheimer's disease. This study was approved by the Animal Ethics and Welfare Committee of Shenzhen University, China (approval No. AEWC-20140615-002) on June 15, 2014.

Septicemic Melioidosis Detection Using Support Vector Machine with Five Immune Cell Types.

Melioidosis, caused by Burkholderia pseudomallei (B. pseudomallei), predominantly occurs in the tropical regions. Of various types of melioidosis, septicemic melioidosis is the most lethal one with a mortality rate of 40%. Early detection of the disease is paramount for the better chances of cure. In this study, we developed a novel approach for septicemic melioidosis detection, using a machine learning technique-support vector machine (SVM). Several SVM models were built, and 19 features characterized by the corresponding immune cell types were generated by Cell type Identification Estimating Relative Subsets Of RNA Transcripts (CIBERSORT). Using these features, we trained a binomial SVM model on the training set and evaluated it on the independent testing set. Our findings indicated that this model performed well with means of sensitivity and specificity up to 0.962 and 0.979, respectively. Meanwhile, the receiver operating characteristic (ROC) curve analysis gave area under curves (AUCs) ranging from 0.952 to 1.000. Furthermore, we found that a concise SVM model, built upon a combination of CD8+ T cells, resting CD4+ memory T cells, monocytes, M2 macrophages, and activated mast cells, worked perfectly on the detection of septicemic melioidosis. Our data showed that its mean of sensitivity was up to 0.976 while that of specificity up to 0.993. In addition, the ROC curve analysis gave AUC close to 1.000. Taken together, this SVM model is a robust classification tool and may serve as a complementary diagnostic technique to septicemic melioidosis.

Proliferation of Bifidobacterium L80 under different proportions of milk protein hydrolysate.

The intestinal microecological environment is critical to an infant's growth. For those infants consuming milk power, it is very important to improve the intestinal microecological environment to promote the healthy growth of infants. In this paper, Milk protein hydrolysate (MPH), consisting of different proportions of proteins and small molecule peptides (5:5, 4:6, 3:7, 2:8, 1:9) were added to infant formula powder (IFP). The effects of MFP-enriched IFP addition on proliferation and metabolism of Bifidobacterium L80 were studied. Compared with MPH-free IFP, MFP-enriched IFP with 1:9 of proteins to small molecule peptides significantly enhanced the proliferation of Bifidobacterium L80, resulting in higher cell density, greater viable counts and higher titratable acidity. MFP-enriched IFP increased the content of seven organic acids and H2O2 in the system, and improved the antibacterial activity to E. coli BL21. This study suggested that MPH could be an effective addition to infant formula powder to promote the growth of Bifidobacterium, so to improve the intestinal health of infants.

Genome-wide identification and functional analysis of the glutathione S-transferase (GST) family in Pomacea canaliculata.

Cold causes oxidative stress in living organisms, mainly caused by the accumulation of reactive oxygen species (ROS). In the antioxidant defense systems, Glutathione S-transferases (GSTs) play a vital role in the regulation of detoxification and redox balance of ROS. In this study, the P. canaliculata GST gene family were characterized using a genome-wide search of the conserved domain. Phylogenetic tree and domain composition analysis revealed that 30 PcGSTs belong to seven classes, including five in MAPEG, two in Mu, nine in Omega, 11 in Sigma, one in Rho, Theta and Alpha class, respectively. RNA-seq analysis revealed that most PcGSTs localized in mitochondria highly expressed in hepatopancreas, and most PcGSTs localized in cytoplasm highly expressed in kidney. A total of 12 PcGST genes were significantly up-regulated and PcGST12 was significantly down-regulated after cold acclimation. Ten PcGSTs were identified as DEGs under cold stress after cold acclimation. qRT-PCR revealed that the expression level of five PcGST genes were significantly varied during the cold acclimation. The present study investigated the characterization of the P. canaliculata GST gene family, extending our understanding of GST mediated cold acclimation and cold stress-response mechanisms in this invasive snail.

Whole Blood Transcriptome Analysis Reveals the Correlation between Specific Immune Cells and Septicemic Melioidosis.

Melioidosis is a serious infectious disease caused by the environmental Gram-negative bacillus Burkholderia pseudomallei. It has been shown that the host immune system, mainly comprising various types of immune cells, fights against the disease. The present study was to specify correlation between septicemic melioidosis and the levels of multiple immune cells. First, the genes with differential expression patterns between patients with septicemic melioidosis (B. pseudomallei) and health donors (control/healthy) were identified. These genes being related to cytokine binding, cell adhesion molecule binding, and MHC relevant proteins may influence immune response. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed 23 enriched immune response pathways. We further leveraged the microarray data to investigate the relationship between immune response and septicemic melioidosis, using the CIBERSORT analysis. Comparison of the percentages of 22 immune cell types in B. pseudomallei vs. control/healthy revealed that those of CD4 memory resting cells, CD8+ T cells, B memory cells, and CD4 memory activated cells were low, whereas those of M0 macrophages, neutrophils, and gamma delta T cells were high. The multivariate logistic regression analysis further revealed that CD8+ T cells, M0 macrophages, neutrophils, and naive CD4+ cells were strongly associated with the onset of septicemic melioidosis, and M2 macrophages and neutrophils were associated with the survival in septicemic melioidosis. Taken together, these data point to a complex role of immune cells on the development and progression of melioidosis.

A CTLA-4 blocking strategy based on Nanoboby in dendritic cell-stimulated cytokine-induced killer cells enhances their anti-tumor effects.

BACKGROUND: Cytokine-induced killer cells induced with tumor antigen-pulsed dendritic cells (DC-CIK) immunotherapy is a promising strategy for the treatment of malignant tumors. However, itsefficacy isrestricted by the immunosuppression, which is mediated by the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) pathway. In order to overcome the negative co-stimulation from these T cells,we screened a nanobody targeted for CTLA-4 (Nb36) and blocked the CTLA-4 signaling with Nb36. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from healthy donors to beused to induce CIK cells in vitro, after which they were co-cultured with DC cells that had received tumor antigens. In addition, wetested whether blocking CTLA-4 signaling with Nb36 could promote in vitro DC-CIK cells proliferation, pro-inflammatory cytokine production and cytotoxicity,or not. For the in vivo experiments, we constructed a subcutaneously transplanted tumor model and placed it in NOD/SCID mice to verify the anti-tumor effect of this therapy. RESULTS: After stimulation with Nb36, the DC-CIK cells presented enhanced proliferation and production of IFN-γ in vitro, which strengthened the killing effect on the tumor cells. For the in vivo experiments, it was found that Nb36-treated DC-CIK cells significantly inhibited the growth of subcutaneously transplanted livercancer tumors, as well as reduced the tumor weight and prolonged the survival of tumor-bearing NOD/SCID mice. CONCLUSIONS: Ourfindings demonstrated that in response to CTLA-4 specific nanobody stimulation, DC-CIK cells exhibited a better anti-tumor effect. In fact, this Nb-based CTLA-4 blocking strategy achieved an anti-tumor efficacy close to that of monoclonal antibodies. Our findings suggest that DC-CIK cells + Nb36 have the potential totreatmalignant tumors through in vivo adoptive therapy.

Composition and diversity of gut microbiota in Pomacea canaliculata in sexes and between developmental stages.

BACKGROUND: The apple snail, Pomacea canaliculata, is one of the world's 100 worst invasive alien species and vector of some pathogens relevant to human health. METHODS: On account of the importance of gut microbiota to the host animals, we compared the communities of the intestinal microbiota from P. canaliculata collected at different developmental stages (juvenile and adult) and different sexes by using high-throughput sequencing. RESULTS: The core bacteria phyla of P. canaliculata gut microbiota included Tenericutes (at an average relative abundance of 45.7 %), Firmicutes (27.85 %), Proteobacteria (11.86 %), Actinobacteria (4.45 %), and Cyanobacteria (3.61 %). The female group possessed the highest richness values, whereas the male group possessed the lowest bacterial richness and diversity compared with the female and juvenile group. Both the developmental stages and sexes had important effects on the composition of the intestinal microbiota of P. canaliculata. By LEfSe analysis, microbes from the phyla Proteobacteria and Actinobacteria were enriched in the female group, phylum Bacteroidetes was enriched in the male group, family Mycoplasmataceae and genus Leuconostoc were enriched in the juvenile group. PICRUSt analysis predicted twenty-four metabolic functions in all samples, including general function prediction, amino acid transport and metabolism, transcription, replication, recombination and repair, carbohydrate transport and metabolism, etc. CONCLUSIONS: This study provided a general understanding of the diversity characteristics of intestinal microbial communities of P. canaliculata, and indicated that developmental stage and gender could both influence the intestinal microbes of P. canaliculata. Further study may focus on the interaction between the gut microbiota and their host.

Bis(ethylmaltolato)oxidovanadium (IV) alleviates neuronal apoptosis through regulating peroxisome proliferator-activated receptor γ in a triple transgenic animal model of Alzheimer's disease.

Endoplasmic reticulum stress (ER stress) plays a critical role in neuronal apoptosis along with the aggravation of Alzheimer's disease (AD). Nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor that is involved in regulating ER stress in Alzheimer's disease (AD), therefore, this protein could be a promising therapeutic target for AD. Vanadium compounds, such as vanadyl acetylacetonate, sodium metavanadate and bis(maltolato)oxovanadium, are well-known as puissant PPARγ modulators. Thus, we are curious whether bis(ethylmaltolato)oxidovanadium (IV) (BEOV) can ameliorate ER stress and subsequent neuronal apoptosis by regulating PPARγ in AD models. To this end, we determined the effect of BEOV on behavioral performance, ER stress and neuronal apoptosis in the triple transgenic mouse AD model (3×Tg-AD). Our results showed that BEOV improved cognitive abilities and reduced the ER stress- and apoptosis-associated proteins in the brains of 3×Tg-AD mice. In vitro administration of BEOV in primary hippocampal neurons and N2asw cells achieved similar results in repressing ER stress. In addition, cotreatment with GW9662 (an antagonist of PPARγ) effectively blocked these neuroprotective effects of BEOV, which provided strong evidence that PPARγ-dependent signaling plays a key role in protecting against ER stress and neuronal apoptosis in AD. In conclusion, our data demonstrated that BEOV alleviated neuronal apoptosis triggered by ER stress by regulating PPARγ in a 3×Tg-AD model.