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Deficiency in docosahexaenoic acid (DHA) is associated with impaired visual and neurological development, cognitive decline, macular degeneration, and other neurodegenerative diseases. DHA is concentrated in phospholipids of the brain and retina, with photoreceptor cells having the highest DHA content of all cell membranes. The discovery that neuroprotectin D1 (NPD1 ; 10R, 17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid) is a bioactive mediator of DHA sheds light on the biological importance of this fatty acid. In oxidative stress-challenged human retinal pigment epithelial (RPE) cells, human brain cells, or brain ischemia-reperfusion, NPD1 synthesis is enhanced as a response for sustaining homeostasis. Thus, neurotrophins, Abeta peptide (A[beta])42, calcium ionophore A23187, interleukin-1 beta (IL-1[beta]), or DHA supply enhances NPD1 synthesis. NPD1, in turn, upregulates the antiapoptotic proteins of the Bcl-2 family and decreases the expression of proapoptotic Bcl-2 family members. In human neural cells, DHA attenuates A[beta]42 secretion, resulting in concomitant formation of NPD1. NPD1 repressed A[beta]42-triggered activation of proinflammatory genes and upregulated the antiapoptotic genes encoding Bcl-2, Bcl-xl, and BfI-1(A1) in human brain cells in culture. Overall, NPD1 signaling regulates brain and retinal cell survival via the induction of antiapoptotic and neuroprotective gene- expression programs that suppress A[beta]42-induced neurotoxicity and other forms of cell injury. These in turn support homeostasis during brain and retinal aging, counteract inflammatory signaling, and downregulate events that support the initiation and progression of neurodegenerative disease. doi: 10.3945/jn.109.114884

Methoxyacetic acid (MAA) is a primary metabolite of ester phthalates that are used in production of consumer products and pharmaceutical products. MAA causes embryo malformation and spermatocyte death through inhibition of histone deacetylases (HDACs). Little is known about MAA's effects on cancer cells. In this study, two immortalized human normal prostatic epithelial cell lines (RWPE-1 and pRNS-1-1) and four human prostate cancer cell lines (LNCaP, C4-2B, PC-3, and DU-145) were treated with MAA at different doses and for different time periods. Cell viability, apoptosis, and cell cycle analysis were performed using flow cytometry and chemical assays. Gene expression and binding to DNA were assessed using real-time PCR, Western blot, and chromatin immunoprecipitation analyses. We found that MAA dose-dependently inhibited prostate cancer cell growth through induction of apoptosis and cell cycle arrest at G1 phase. MAA-induced apoptosis was due to down-regulation of the anti-apoptotic gene baculoviral inhibitor of apoptosis protein repeat containing 2 (BIRC2, also named cIAP1), leading to activation of caspases 7 and 3 and turning on the downstream apoptotic events. MAA-induced cell cycle arrest (mainly G1 arrest) was due to up-regulation of p21 expression at the early time and down-regulation of cyclin-dependent kinase 4 (CDK4) and CDK2 expression at the late time. MAA up-regulated p21 expression through inhibition of HDAC activities, independently of p53/p63/p73. These findings demonstrate that MAA suppresses prostate cancer cell growth by inducing growth arrest and apoptosis, which suggests that MAA could be used as a potential therapeutic drug for prostate cancer.

As part of an effort to synthesize a dendronized cellulose, we have synthesized a trifunctional aminoamide derivative, which is the first generation of a dendron substituent. We anticipate that a dendronized cellulose would have applications in complexing metals and could be employed as an adjuvant for drugs. The trifunctional aminoamide substituent was introduced by coupling di-tert-butyl 4-[2-(tert-butoxycarbonyl)ethyl]-4-aminoheptanedicarboxylate, BA, directly to a (carboxymethyl)cellulose (CMC) backbone and converting the tert-butyl ester peripheral groups to aminoamide substituents by use of N,N-dimethyl-1,3-propanediamine. Confirmation of the proposed chemical structure of the intermediates as well as the water-soluble aminoamide derivative (CMCBADMPDA) was obtained by Fourier transform infrared (FT-IR) and NMR spectroscopy. The degree of substitution (DS) was determined to be 0.40 +/- 0.01 by thermogravimetric analysis. Typical weight average molecular weight (M(w)), molecular weight distribution (MWD), and molecular size of the dendronized polymers were found to be 97,000, 1.7, and 17.4 nm for derivatives of a CMC with corresponding M(w), MWD, and root-mean-square radius (RMS) of 230 000, 3.2, and 24 nm. A differential refractive index (dn/dc) for the aminoamide derivative measured in aqueous 0.40 N ammonium acetate-0.01 N NaOH was found to be 0.1473. The intrinsic viscosity of the dendronized cellulose decreased significantly when compared with that of CMC, that is, 0.40 dL/g relative to 5.60 dL/g. The hydrophobicity of the CMCBADMPDA microenvironment in aqueous solution was probed by evaluating the relative fluorescence intensities of the I(373)/I(384) pyrene bands; a slightly more hydrophobic environment was observed.