Neuropeptide Y mitigates ER stress–induced neuronal cell death by activating the PI3K–XBP1 pathway

The unfolded protein response (UPR) is an evolutionarily conserved adaptive reaction that increases cell survival under endoplasmic reticulum (ER) stress conditions. ER stress–associated neuronal cell death pathways play roles in the pathogenesis of neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s disease. Neuropeptide Y (NPY) has an important role in neuroprotection against neurodegenerative diseases. In this study, we investigated whether NPY has a protective role in ER stress–induced neuronal cell death in SK-N-SH human neuroblastoma cells. An ER stress–inducing chemical, tunicamycin, increased the activities of caspase-3 and -4, whereas pretreatment with NPY decreased caspase-3 and -4 activities during the ER stress response. In addition, NPY suppressed the activation of three major ER stress sensors during the tunicamycin-induced ER stress response. NPY-mediated activation of PI3K increased nuclear translocation of XBP1s, which in turn induced expression of Grp78/BiP. Taken together, our data indicated that NPY plays a protective role in ER stress–induced neuronal cell death through activation of the PI3K–XBP1 pathway, and that NPY signaling can serve as therapeutic target for ER stress–mediated neurodegenerative diseases.     

Increased concentrations of circulating vitamin E in carriers of the apolipoprotein A5 gene - 1131T>C variant and associations with plasma lipids and lipid peroxidation

The aim of this study was to investigate the effects of the apolipoprotein A5 (APOA5) 1131T>C gene variant on vitamin E status and lipid profile. The gene variant was determined in 297 healthy nonsmoking men aged 20-75 years and recruited in the VITAGE Project. Effects of the genotype on vitamin E in plasma, LDL, and buccal mucosa cells (BMC) as well as on cholesterol and triglyceride (TG) concentrations in plasma and apolipoprotein A-I (apoA-I), apoB, apoE, apoC-III, and plasma fatty acids were determined. Plasma malondialdehyde concentrations as a marker of in vivo lipid peroxidation were determined. C allele carriers showed significantly higher TG, VLDL, and LDL in plasma, higher cholesterol in VLDL and intermediate density lipoprotein, and higher plasma fatty acids. Plasma alpha-tocopherol (but not gamma-tocopherol, LDL alpha- and gamma-tocopherol, or BMC total vitamin E) was increased significantly in C allele carriers compared with homozygote T allele carriers (P = 0.02), but not after adjustment for cholesterol or TG. Plasma malondialdehyde concentrations did not differ between genotypes. In conclusion, higher plasma lipids in the TC+CC genotype are efficiently protected against lipid peroxidation by higher alpha-tocopherol concentrations. Lipid-standardized vitamin E should be used to reliably assess vitamin E status in genetic association studies.     

The Fatty Acid Composition Characteristic of a Highly Migratory Fish,with Seasonal Variation of Docosahexaenoic Acid Content in Lipid of Bonito (Euthynnus pelamis)

Present address: Hagoromo Foods Corporation. 151, Shimazaki-cho, Shimizu-shi, Shizuoka 424-85. Japan.

The seasonal variation offatty acid composition in lipids of various organs and stomach contents of bonito (Euthynnus pelamis) was investigated. Although docosahexaenoic acid in the lipids of the stomach contents originating from their prey organisms varied from about 13% to 31%, it was the dominant unsaturated fatty acid and

accounted for more than 25% of the total fatty acids in the lipids of every organ of bonito in and out of season, and its seasonal variation was comparatively small.     

Chronic hypoxia upregulates adenosine 2a receptor expression in chromaffin cells via hypoxia inducible factor-2α: role in modulating secretion

Catecholamine (CAT) release from chromaffin tissue plays an essential role in the fetus which develops in a low O₂ environment (hypoxia). To address molecular mechanisms regulating CAT secretion in low O₂, we exposed a fetal chromaffin-derived cell line (MAH cells) to chronic hypoxia (CHox; 2% O₂, 24 h) and assessed gene expression using microarrays, quantitative RT-PCR, and western blot. CHox caused a dramatic ∼12× upregulation of adenosine A2a receptor (A2aR) mRNA, an effect critically dependent upon hypoxia-inducible factor (HIF)-2α which bound the promoter of the A2aR gene. In amperometric studies, acute hypoxia and high K⁺ (30 mM) evoked quantal CAT secretion that was enhanced after CHox, and further potentiated during simultaneous A2aR activation by adenosine. A2aR activation also enhanced stimulus-induced rise in intracellular Ca²⁺ in control, but not HIF-2α-deficient, MAH cells. Thus, A2aR, adenosine, and HIF-2α are key contributors to the potentiation of CAT secretion in developing chromaffin cells during chronic hypoxia.     

Current approaches to the treatment of Parkinson’s Disease

Parkinson’s Disease (PD) is the second most common neurodegenerative disorder. Clinical approaches to manage PD include symptomatic therapies, serving to compensate for the effects of dopaminergic neuronal deficits, as well as more recently a move toward disease modification, with the goal of slowing or stopping disease progression. This perspective surveys the approved therapies for PD treatment as well as provides a view of the ongoing clinical approaches aimed at improving outcomes for PD patients.     

A novel vascular-targeting peptide for gastric cancer delivers low-dose TNFα to normalize the blood vessels and improve the anti-cancer efficiency of 5-fluorouracil

Various vascular-targeted agents fused with tumor necrosis factor α (TNFα) have been shown to improve drug absorption into tumor tissues and enhance tumor vascular function. TCP-1 is a peptide selected through in vivo phage library biopanning against a mouse orthotopic colorectal cancer model and is a promising agent for drug delivery. This study further investigated the targeting ability of TCP-1 phage and peptide to blood vessels in an orthotopic gastric cancer model in mice and assessed the synergistic anti-cancer effect of 5-fluorouracil (5-FU) with subnanogram TNFα targeted delivered by TCP-1 peptide. In vivo phage targeting assay and in vivo colocalization analysis were carried out to test the targeting ability of TCP-1 phage/peptide. A targeted therapy for improvement of the therapeutic efficacy of 5-FU and vascular function was performed through administration of TCP-1/TNFα fusion protein in this model. TCP-1 phage exhibited strong homing ability to the orthotopic gastric cancer after phage injection. Immunohistochemical staining suggested that and TCP-1 phage/TCP-1 peptide could colocalize with tumor vascular endothelial cells. TCP-1/TNFα combined with 5-FU was found to synergistically inhibit tumor growth, induce apoptosis and reduce cell proliferation without evident toxicity. Simultaneously, subnanogram TCP-1/TNFα treatment normalized tumor blood vessels. Targeted delivery of low-dose TNFα by TCP-1 peptide can potentially modulate the vascular function of gastric cancer and increase the drug delivery of chemotherapeutic drugs.     

Synergistic effect on anti-methicillin-resistant Staphylococcus aureus among combinations of α-mangostin-rich extract,lawsone methyl ether and ampicillin

α-Mangostin-rich extract (AME) exhibited satisfactory inhibitory activities against all tested MRSA strains, with minimum inhibitory concentrations (MICs) of 7·8–31·25 µg ml⁻¹, whereas lawsone methyl ether (LME) and ampicillin revealed weak antibacterial activity with MICs of 62·5–125 µg ml⁻¹. However, the combination of AME and LME showed synergistic effects against all tested MRSA strains with fractional inhibitory concentration index (FICI) values of 0·008–0·009, while the combination of AME and ampicillin, as well as LME and ampicillin produced synergistic effects with FICIs of 0·016–0·257. A time-kill assay against MRSA (DMST 20654 strain) revealed a 6-log reduction in CFU per ml, which completely inhibited bacterial growth for the combinations of AME and LME, AME and ampicillin, and LME and ampicillin at a 8-h incubation, while those against MRSA (2468 strain) were at 10-h incubation. The combination of α-mangostin and LME as well as the combinations of each compound with ampicillin synergized the alteration of membrane permeability. In addition, α-mangostin, LME and ampicillin inhibited the biofilm formation of MRSA. These findings indicated that the combinations of AME and LME or each of them in combination with ampicillin had enhanced antibacterial activity against MRSA. Therefore, these compounds might be used as the antibacterial cocktails for treatment of MRSA.     

Structural analysis and antioxidative properties of mutan (water-insoluble glucan) and carboxymethyl mutan from Streptococcus mutans

Streptococcus mutans (MTCC 497) was grown anaerobically in acidic Brain heart infusion (BHI) medium with 15 % sucrose to produce cell-bound and extracellular water-insoluble polysaccharide mutan. Fourier transformed infrared (FTIR) and ¹³C NMR studies revealed a mixed linkage of α-1−3 and α-1–6 mutan with a production yield of 1.8 g/L. Mutan has a branched structure with a molecular weight (M_w) of 5654 Da. Water-insoluble mutan was carboxymethylated at 0.93 degrees of substitution. FTIR spectra with characteristic peaks at 1603 cm⁻¹ and 1418 cm⁻¹ due to symmetric and asymmetric vibrations of the COO- group confirmed carboxymethylation. Thermal gravimetric analysis showed that native mutan and carboxymethyl mutan exhibited higher thermal stability. Carboxymethylation enhanced solubility and antioxidative radical-scavenging activity. The in-vitro antioxidative radical scavenging analysis revealed 52 % and 47 % inhibition of DPPH and ABTS radicals.