A series of substituted 2-benzyl-3-aryl-7-trifluoromethylindazoles were prepared as LXR modulators. These compounds were partial agonists in transactivation assays when compared to 1 (T0901317) and were slightly weaker with respect to potency and efficacy on LXRalpha than on LXRbeta. Lead compounds in this series 12 (WAY-252623) and 13 (WAY-214950) showed less lipid accumulation in HepG2 cells than potent full agonists 1 and 3 (WAY-254011) but were comparable in efficacy to 1 and 3 with respect to cholesterol efflux in THP-1 foam cells, albeit weaker in potency. Compound 13 reduced aortic lesion area in LDLR knockout mice equivalently to 3 or positive control 2 (GW3965). In a 7-day hamster model, compound 13 showed a lesser propensity for plasma TG elevation than 3, when the compounds were compared at doses in which they elevated ABCA1 and ABCG1 gene expression in duodenum and liver at equal levels. In contrast to results previously published for 2, the lack of TG effect of 13 correlated with its inability to increase liver fatty acid synthase (FAS) gene expression, which was up-regulated 4-fold by 3. These results suggest indazoles such as 13 may have an improved profile for potential use as a therapeutic agent.

The influence of submucosal neurons on ion transport in the guinea pig distal colon was examined in muscle-stripped sheets of submucosa-mucosa set up in Ussing flux chambers. Spontaneous variations in potential differences (PD) and short-circuit current occurred ranging from positive currents associated with luminal negative PDs to negative currents with luminal positive PDs. Basal current in both groups was reduced by mucosal amiloride. In tissues with positive or negative short-circuit currents, unidirectional mucosal-to-serosal sodium fluxes were greater than serosal-to-mucosal fluxes and small net absorptive fluxes were present. Little or no chloride secretory flux was present. Electrical stimulation of submucosal neurons evoked a tetrodotoxin-sensitive increase in short-circuit current in tissues with positive or negative short-circuit currents. This was due to an increase in net chloride flux and little change in net sodium flux or residual flux. The increase in net chloride flux was due almost entirely to an increase in serosal-to-mucosal chloride flux and was associated with an increase in total tissue conductance. The stimulus-evoked response was reduced by atropine. These results suggest that stimulation of submucosal neurons that innervate the distal colonic epithelium evokes a large chloride secretory response that is due in part to release of acetylcholine at neuro-enterocyte junctions.

In third-, fourth-, and fifth-instar larvae of the cabbage looper moth, Trichoplusia ni, the activities of the antioxidant enzymes, superoxide dismutase (SOD*), catalase (CAT), glutathione peroxidase (GPOX), and glutathione reductase (GR) were examined using 850 g supernatants of wholebody homogenates. The enzyme activities, expressed as units mg-' protein m i n -I at 25OC ranged as follows: SOD, 0.67-2.13 units; CAT, 180.5-307.5 units; GPOX, none detectable; and GR, 0.40-1.19 units. There was a similar pattern of changes for SOD and CAT activities with larval ontogeny, but not for GR. The cabbage looper apparently uses SOD and CAT to form a "defensive team" effective against endogenously produced superoxide anion (02'). Glutathione may serve as an antioxidant for the destruction of any organic/ lipid peroxides formed, and GSH oxidized to glutathione disulfide would be recycled by GR. Bioassays against pro-oxidant compounds (exogenous sources of (023 show high sensitivity of mid-fifth instars to the linear furanocoumarin, 8-methoxypsoralen (xanthotoxin) primarily from photoactivation (320-380 nm), and auto-oxidation of the flavonoid, quercetin. The LCsos are 0.0004 and 0.0045% (wlw) concentration of xanthotoxin and quercetin, respectively. Both pro-oxidants have multiple target sites for lethal action and, in this context, the role of antioxidant enzymes is discussed.Key words: cabbage looper, catalase, glutathione peroxidase, glutathione reductase, superoxide dismutase *Abbreviations: CAT = catalase; GPOX = glutathione peroxidase; GR = glutathione reductase; 302 = ground state oxygen; -0OH = hydroperoxy radical; *OH = hydroxyl radical; LOOH = lipid (organic peroxides); Idp = log dose-probit; RCR = relative consumption rate; RGR = relative growth rate; lo2 = singlet oxygen; 02-= superoxide anion; SOD = superoxide dismutase; 3S = triplet excited sensitizer.

The black swallowtail butterfly larvae, Papilio polyxenes, are specialist feeders that have adapted to feeding on plants containing high levels of prooxidant allelochemicals. Third, fourth, and fifth instar larvae were tested for their antioxidant enzyme activities, superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPOX), using 850-g supernatants from whole-body homogenates. The overall antioxidant enzyme profile for P. polyxenes was high compared to other insects, with activities ranging as follows: SOD, 1.1-7.5; CAT, 124-343; GR, 1.0-7.5; and GPOX, 0 units.To determine whether these antioxidant enzymes were inducible, P. poly xenes larvae were given a prooxidant challenge by dipping parsley leaves (their diet in the initial studies) in solutions of quercetin, such that the leaves became coated with this prooxidant flavonoid. Mid-fifth instar larvae fed on quercetin-coated leaves were assayed for antioxidant enzyme activities as was previously done with the larvae fed the standard diet. Food consumption and quercetin intake were monitored. SOD activity was increased almost twofold at the highest quercetin concentration tested. CAT and GR activity, on the other hand, were inhibited by increased quercetin consumption, with GR activity completely inhibited at the highest quercetin concentration after 12 h of feeding. GPOX activity, not present in control insects, was also not inducible by a quercetin challenge. These studies point out the key role that the antioxidant enzymes play in insect defenses against plant prooxidants.

Administration of dehydroepiandrosterone (DHEA), or its sulfated form (DHEAS), controls hyperglycemia in diabetic rodents without directly altering insulin sensitivity. We show that DHEAS enhanced glucose-stimulated insulin secretion when administered in vivo to rats or in vitro to ␤-cell lines, without changing cellular insulin content. Insulin secretion increased from 3 days of steroid exposure in vitro, suggesting that DHEAS did not directly activate the secretory processes. DHEAS selectively increased the ␤-cell mRNA expression of acyl CoA synthetase-2 and peroxisomal acyl CoA oxidase in a time-dependent manner. Although DHEAS is a peroxisomal proliferator, it did not alter the mRNA expression of peroxisomal proliferator-activated receptor (PPAR) ␣ or ␤, or enhance the activity of transfected PPAR ␣, ␤, or ␥ in vitro. Thus, DHEAS directly affected the ␤-cell to enhance glucose-stimulated insulin secretion and increased the mRNA expression of specific ␤-cell mitochondrial and peroxisomal lipid metabolic enzymes. This effect of DHEAS on insulin secretion may contribute to the amelioration of hyperglycemia seen in various rodent models of diabetes. Diabetes 49