Niemann-Pick C1 Like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis

Niemann-Pick C1 Like 1 (NPC1L1) is a protein localized in jejunal enterocytes that is critical for intestinal cholesterol absorption. The uptake of intestinal phytosterols and cholesterol into absorptive enterocytes in the intestine is not fully defined on a molecular level, and the role of NPC1L1 in maintaining whole body cholesterol homeostasis is not known. NPC1L1 null mice had substantially reduced intestinal uptake of cholesterol and sitosterol, with dramatically reduced plasma phytosterol levels. The NPC1L1 null mice were completely resistant to diet-induced hypercholesterolemia, with plasma lipoprotein and hepatic cholesterol profiles similar to those of wild type mice treated with the cholesterol absorption inhibitor ezetimibe. Cholesterol/cholate feeding resulted in down-regulation of intestinal NPC1L1 mRNA expression in wild type mice. NPC1L1 deficiency resulted in up-regulation of intestinal hydroxymethylglutaryl-CoA synthase mRNA and an increase in intestinal cholesterol synthesis, down-regulation of ABCA1 mRNA, and no change in ABCG5 and ABCG8 mRNA expression. NPC1L1 is required for intestinal uptake of both cholesterol and phytosterols and plays a major role in cholesterol homeostasis. Thus, NPC1L1 may be a useful drug target for the treatment of hypercholesterolemia and sitosterolemia.     

Ecology and migration patterns of solitary red locusts,Nomadacris septemfasciata (Serville) (Orthoptera: Acrididae) in southwestern Madagascar

Red locusts frequently cause crop damage in Madagascar. This problem has worsened in recent years, likely due to the intensive deforestation that is under way. Little is known about this locust In Madagascar, contrary to continental Africa. Several studies have been carried out in southwestern Madagascar, where locust damage is regularly reported, with the aim of determining the cause of recent outbreaks and improving control strategies—they included surveys of rural inhabitants and an analysis of over 25 years of archival data at the Centre national antiacridien (Malagasy locust control centre). The results revealed several zones between which the red locust—a single-generation species that undergoes imaginal diapause in the dry season—seasonally migrates on a northeast to southwest track, and vice versa, depending on rainfall and wind patterns. The migration dynamics and interannual variations associated with rainfall irregularity certainly partially account for the recurrence of red locust outbreaks in Madagascar.     

Laboratory and field investigation of a mixture of Metarhizium acridum and Neem seed oil against the Tree Locust Anacridium melanorhodon melanorhodon (Orthoptera: Acrididae)

The in vitro compatibility of Metarhizium acridum strain IMI 330189 with different concentrations of Neem seed oil Azadirachta indica A. Juss. was investigated under laboratory conditions. Water, diesel and ground nut oil dilutions of M. acridum were inoculated into semi-synthetic culture medium with Neem oil and incubated for 10 days at 20, 28, and 34°C. Fungus vegetative growth and conidia production were estimated and compatibility calculated according to the in vitro classification model [T]. Field tests were also conducted during two successive years, where fourth instar nymphs of the Tree Locust, Anacridium melanorhodon melanorhodon, were sprayed with Metarhizium, Metarhizium/Neem mixture, Neem, or Malathion, on a plantation of Acacia senegal. Samples of the treated nymphs were taken 24 h after application, placed in cages and their mortality observed daily for 3 weeks. The compatibility test revealed that at 28°C, all Neem concentrations below 2% were compatible with M. acridum and concentrations of 2 and 2.5% were moderately toxic, while at 20°C, 1.0% Neem was not compatible with the fungus. In the field, Metarhizium+Neem resulted in 74 and 92% mortality during two successive years compared to 64 and 83% for Metarhizium alone. These findings clearly reveal that Neem concentration on the mixture could be increased to just under 1.0% Neem without negative impact on the fungus and that mixing Metarhizium with small quantities of Neem oil accelerates locust mortality and increases efficacy.     

Mesoionic pyrido[1,2-a]pyrimidinones: Discovery of dicloromezotiaz as a lepidoptera insecticide acting on nicotinic acetylcholine receptors1,2

A novel class of mesoionic pyrido[1,2-a]pyrimidinones has been discovered with exceptional insecticidal activity controlling a number of insect species. In this communication, we report the part of the optimization program that led to the identification of dicloromezotiaz as a potent insecticide to control a broad range of lepidoptera. Our efforts in discovery, synthesis, structure-activity relationship elucidation, and biological activity evaluation are also presented.     

A potent synthetic LXR agonist is more effective than cholesterol loading at inducing ABCA1 mRNA and stimulating cholesterol efflux.

The LXR nuclear receptors are intracellular sensors of cholesterol excess and are activated by various oxysterols. LXRs have been shown to regulate multiple genes of lipid metabolism, including ABCA1 (formerly known as ABC1). ABCA1 is a lipid pump that effluxes cholesterol and phospholipid out of cells. ABCA1 deficiency causes extremely low high density lipoprotein (HDL) levels, demonstrating the importance of ABCA1 in the formation of HDL. The present work shows that the acetyl-podocarpic dimer (APD) is a potent, selective agonist for both LXRalpha (NR1H3) and LXRbeta (NR1H2). In transient transactivation assays, APD was approximately 1000-fold more potent, and yielded approximately 6-fold greater maximal stimulation, than the widely used LXR agonist 22-(R)-hydroxycholesterol. APD induced ABCA1 mRNA levels, and increased efflux of both cholesterol and phospholipid, from multiple cell types. Gas chromatography-mass spectrometry measurements demonstrated that APD stimulated efflux of endogenous cholesterol, eliminating any possible artifacts of cholesterol labeling. For both mRNA induction and stimulation of cholesterol efflux, APD was found to be more effective than was cholesterol loading. Taken together, these data show that APD is a more effective LXR agonist than endogenous oxysterols. LXR agonists may therefore be useful for the prevention and treatment of atherosclerosis, especially in the context of low HDL levels.     

Fluorogenic substrates for high-throughput measurements of endothelial lipase activity

Endothelial lipase (EL) has been shown to be a critical determinant for high density lipoprotein cholesterol levels in vivo; therefore, assays that measure EL activity have become important for the discovery of small molecule inhibitors that specifically target EL. Here, we describe fluorescent Bodipy-labeled substrates that can be used in homogeneous, ultra-high-throughput kinetic assays that measure EL phospholipase or triglyceride lipase activities. Triton X-100 detergent micelles and synthetic HDL particles containing Bodipy-labeled phospholipid or Bodipy-labeled triglyceride substrates were shown to be catalytic substrates for EL, LPL, and HL. More importantly, only synthetic HDL particles containing Bodipy-labeled triglyceride were ideal substrates for EL, LPL, and HL in the presence of high concentrations of human or mouse serum. These data suggest that substrate presentation is a critical factor when determining EL activity in the presence of serum.     

New cytotoxic benzosuberene analogs. Synthesis,molecular modeling and biological evaluation

In this Letter we describe the synthesis and biological evaluation of new benzosuberene analogs with structural modifications on the B-ring. The focus was initially to probe the chemical space around the B-ring C-8 position. This position was readily available for derivatization chemistry using our recently developed new synthesis for this compound class. Furthermore, we describe two new B-ring analogs, one containing a diene and the other a cyclic ether group. Both new analogs show excellent potencies in tumor cell proliferation assays. In addition, we describe molecular modeling studies that provide a binding rationale for reference compound 8 in the colchicine binding site using the known colchicine crystal structure. We also examine whether the cell based potency data obtained with selected new analogs are supported by modeling results.     

Mesoionic pyrido[1,2-a]pyrimidinones: Discovery of triflumezopyrim as a potent hopper insecticide1

A novel class of mesoionic pyrido[1,2-a]pyrimidinones has been discovered with exceptional insecticidal activity controlling a number of insect species. In this communication, we report the part of the optimization program which led to the discovery of triflumezopyrim as a highly potent insecticide controlling various hopper species. Our efforts in discovery, synthesis, structure-activity relationship elucidation, and biological activity evaluation are also presented.