Here we showed that a naturally occurring ether analog of lysophosphatidic acid, 1-O-octadecenyl-2-hydroxy-sn-glycero-3-phosphate (AGP), is a high affinity partial agonist of the peroxisome proliferator-activated receptor ␥ (PPAR␥ The peroxisome proliferator-activated receptors (PPARs) 2 are members of the nuclear receptor superfamily that are involved in the regulation of lipid metabolism, glucose homeostasis, cell differentiation, and motility (1-4). The nuclear receptor superfamily consists of several ligand-regulated transcription factors that include the steroid and thyroid hormone receptors, vitamin D 3 receptor, retinoic acid receptors, and the PPARs (5-7). The PPAR subfamily consists of three isoforms, PPAR␣, PPAR␤/␦, and PPAR␥. PPAR␥ has two isotypes, ␥ 1 and ␥ 2 , that differ by a 30-amino acid extension on the N terminus of PPAR␥ 2 . Genetic deletion of PPAR␥ 1 is embryonic lethal (8); however, deletion of PPAR␥ 2 causes minimal alterations in lipid metabolism (9). The effects of ligands on PPAR␥ and retinoid X receptor are mediated through their ligand binding domains (LBD), conserved regions of ϳ250 amino acids within the C-terminal half of the receptors (10). PPAR␥, like other PPAR isoforms, undergoes a conformational change that stabilizes the AF-2 helix upon binding of agonist. Upon activation, these isoforms heterodimerize with the retinoid X receptor and bind to the peroxisome proliferator-response element (PPRE) in the promoters of target genes (5-7, 11, 12).A number of natural ligands for PPAR␥ have been identified and include two main groups of compounds, fatty acids and phospholipids. PPAR␥ exhibits a modest preference for essential polyunsaturated fatty acids, including linoleic (13), linolenic (14), arachidonic (15), and eicosapentaenoic acids (16). PPAR␥ is also activated by the monounsaturated fatty acid oleic acid (17). Several oxidatively modified lipids bind to and activate PPAR␥, including 15-deoxy-⌬-prostaglandin J 2 (18, 19), 9-hydroxy-10,12-octadecadienoic acid, 13-hydroxy-10,12-octadecadienoic acid (20), the oxidized alkyl phospholipid hexadecyl azelaoyl phosphatidylcholine (21), and nitrolinoleic acid (22). Many of these endogenous molecules require high concentrations and are weak activators of PPAR␥, casting doubt about their physiological relevance as bona fide agonists. The thiozolidinedione (TZD) class of anti-diabetics, including rosiglitazone (Rosi), troglitazone, and pioglitazone, are full agonists with

Lung ischemia-reperfusion (I/R) injury remains one of the most common complications after various cardiopulmonary surgeries. The inflammation response triggered by the released damage-associated molecular patterns (DAMPs) aggravates lung tissue damage. However, little is known about the role of autophagy in the pathogenesis of lung I/R injury. Here, we report that a variety of inflammation-related and autophagy-associated genes are rapidly upregulated, which facilitate the inflammation response in a minipig lung I/R injury model. Left lung I/R injury triggered inflammatory cytokine production and activated the autophagy flux as evidenced in crude lung tissues and alveolar macrophages. This was associated with the release of DAMPs, such as high mobility group protein B1 (HMGB1) and heat shock protein 60 (HSP60). Indeed, treatment with recombinant HMGB1 or HSP60 induced autophagy in alveolar macrophages, whereas autophagy inhibition by knockdown of ATG7 or BECN1 markedly reduced DAMPtriggered production of inflammatory cytokines including IL-1β, TNF and IL12 in alveolar macrophages. This appeared to be because of decreased activation of MAPK and NF-κB signaling. Furthermore, knockdown of ATG7 or BECN1 inhibited Lys63 (K63)-linked ubiquitination of TNF receptor-associated factor 6 (TRAF6) in DAMP-treated alveolar macrophages. Consistently, treatment with 3-MA inhibited K63-linked ubiquitination of TRAF6 in I/R-injured lung tissues in vivo. Collectively, these results indicate that autophagy triggered by DAMPs during lung I/R injury amplifies the inflammatory response through enhancing K63-linked ubiquitination of TRAF6 and activation of the downstream MAPK and NF-κB signaling.

Guided by nuclear magnetic resonance (NMR) binding assays and computational docking studies, a series of 5, 5′ substituted Apogossypol derivatives was synthesized that resulted in potent pan-active inhibitors of anti-apoptotic Bcl-2 family proteins. Compound 8r inhibits the binding of BH3 peptides to Bcl-XL, Bcl-2, Mcl-1 and Bfl-1 with IC50 values of 0.76, 0.32, 0.28 and 0.73 μM, respectively. The compound also potently inhibits cell growth of human lung cancer and BP3 human B-cell lymphoma cell lines with EC50 values of 0.33 and 0.66 μM, respectively. Compound 8r shows little cytotoxicity against bax−/−bak−/− cells, indicating that it kills cancers cells via the intented mechanism. The compound also displays in vivo efficacy in transgenic mice in which Bcl-2 is overexpressed in splenic B-cells. Together with its improved chemical, plasma and microsomal stability relative to compound 2 (Apogossypol), compound 8r represents a promising drug lead for the development of novel apoptosis-based therapies for cancer.

More than two million American adults, or approximately one percent of the population 18 years or older, suffer from bipolar disorder. Current treatments include the so-called "mood stabilizers," lithium and valproic acid. Both are relatively dated drugs that are only partially effective and produce various undesirable side effects including weight gain. Based upon continued efforts to understand the molecular target for lithium, it now appears that specific inhibitors of the enzyme glycogen synthase kinase-3beta (GSK-3beta) may mimic the therapeutic action of mood stabilizers and might therefore allow for the design of improved drugs for treating patients with bipolar disorder as well as certain neurodegenerative disorders. Furthermore, the pro-apoptotic properties of the GSK-3 enzyme suggest the possible use of such inhibitors as neuroprotective agents. In fact, neuroprotection may contribute to the treatment of mood disorders. The present chemistry, modeling, and biology efforts have identified 3-benzofuranyl-4-indolylmaleimides as potent and relatively selective GSK-3beta inhibitors. The best ligand in this series (having a Ki value of 4.6 nM against GSK-3beta) was studied in a novel mouse model of mania that has recently been validated with several clinically effective mood stabilizers. This study presents the first demonstration of the efficacy of a GSK-3beta inhibitor in this mouse model of mania. Selective brain penetrable GSK-3 ligands like those described herein become valuable research tools in better defining the role of this multifaceted kinase in both physiological and pathophysiological events.