Showing papers by "Gang Wang published in 2008"
TL;DR: PCSK9 targeting with RNAi therapeutics as an approach to specifically lower LDLc is validated, paving the way for the development of PCSK9-lowering agents as a future strategy for treatment of hypercholesterolemia.
Abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low density lipoprotein receptor (LDLR) protein levels and function. Loss of PCSK9 increases LDLR levels in liver and reduces plasma LDL cholesterol (LDLc), whereas excess PCSK9 activity decreases liver LDLR levels and increases plasma LDLc. Here, we have developed active, cross-species, small interfering RNAs (siRNAs) capable of targeting murine, rat, nonhuman primate (NHP), and human PCSK9. For in vivo studies, PCSK9 and control siRNAs were formulated in a lipidoid nanoparticle (LNP). Liver-specific siRNA silencing of PCSK9 in mice and rats reduced PCSK9 mRNA levels by 50-70%. The reduction in PCSK9 transcript was associated with up to a 60% reduction in plasma cholesterol concentrations. These effects were shown to be mediated by an RNAi mechanism, using 5'-RACE. In transgenic mice expressing human PCSK9, siRNAs silenced the human PCSK9 transcript by >70% and significantly reduced PCSK9 plasma protein levels. In NHP, a single dose of siRNA targeting PCSK9 resulted in a rapid, durable, and reversible lowering of plasma PCSK9, apolipoprotein B, and LDLc, without measurable effects on either HDL cholesterol (HDLc) or triglycerides (TGs). The effects of PCSK9 silencing lasted for 3 weeks after a single bolus i.v. administration. These results validate PCSK9 targeting with RNAi therapeutics as an approach to specifically lower LDLc, paving the way for the development of PCSK9-lowering agents as a future strategy for treatment of hypercholesterolemia.
686 citations
TL;DR: It is shown that tissue plasminogen activator (tPA), a serine protease implicated in NMDA receptor signaling, is required for the flow increase evoked by somatosensory stimulation, and the evidence suggests that tPA controls NMDA-dependent nitric oxide synthesis by influencing the phosphorylation state of neuronal Nitric oxide synthase.
Abstract: The increase in blood flow evoked by synaptic activity is essential for normal brain function and underlies functional brain imaging signals. Nitric oxide, a vasodilator released by NMDA receptor activation, is critical for the flow increase, but the factors linking NMDA receptor activity to nitric oxide-dependent hyperemia are poorly understood. Here, we show that tissue plasminogen activator (tPA), a serine protease implicated in NMDA receptor signaling, is required for the flow increase evoked by somatosensory stimulation. tPA acts by facilitating neuronal nitric oxide release, but this effect does not involve enhancement of NMDA currents or the associated intracellular Ca2+ rise. Rather, the evidence suggests that tPA controls NMDA-dependent nitric oxide synthesis by influencing the phosphorylation state of neuronal nitric oxide synthase. These findings unveil a previously unrecognized role of tPA in vital homeostatic mechanisms coupling NMDA receptor signaling with nitric oxide synthesis and local cerebral perfusion.
87 citations
TL;DR: The data demonstrate that BK channels play an important role in regulating proliferation of human ovarian cancer cells and may induce apoptosis through induction of p21(Cip1) expression in a p53-dependent manner and NS1619 inhibits the proliferation of A2780 cells in a dosage and time dependent manner.
50 citations
TL;DR: Observations suggest that an increase in AT(1) receptors in female RVLM neurons is counterbalanced by a reduction in p47 levels, such that ANG II-induced ROS production does not differ between females and males.
Abstract: Sex differences may play a significant role in determining the risk of hypertension. Bulbospinal neurons in the rostral ventrolateral medulla (RVLM) are involved in the tonic regulation of arterial...
37 citations
Patent•
18 Mar 2008TL;DR: In this paper, the authors present a process and reagents for oligonucleotide synthesis and purification, which are useful for activating phosphoramidites in oligonuclear synthesis and for preparing a phosphorothioate by treating a phosphite with a sulfur transfer reagent.
Abstract: The present invention relates to processes and reagents for oligonucleotide synthesis and purification. One aspect of the present invention relates to compounds useful for activating phosphoramidites in oligonucleotide synthesis. Another aspect of the present invention relates to a method of preparing oligonucleotides via the phosphoramidite method using an activator of the invention. Another aspect of the present invention relates to sulfur-transfer agents. In a preferred embodiment, the sulfur-transfer agent is a 3-amino-1,2,4-dithiazolidine-5-one. Another aspect of the present invention relates to a method of preparing a phosphorothioate by treating a phosphite with a sulfur-transfer reagent of the invention. In a preferred embodiment, the sulfur-transfer agent is a 3-amino-1,2,4-dithiazolidine-5-one. Another aspect of the present invention relates to compounds that scavenge acrylonitrile produced during the deprotection of phosphate groups bearing ethylnitrile protecting groups. In a preferred embodiment, the acrylonitrile scavenger is a polymer-bound thiol. Another aspect of the present invention relates to agents used to oxidize a phosphite to a phosphate. In a preferred embodiment, the oxidizing agent is sodium chlorite, chloroamine, or pyridine-N-oxide. Another aspect of the present invention relates to methods of purifying an oligonucleotide by annealing a first single-stranded oligonucleotide and second single-stranded oligonucleotide to form a double-stranded oligonucleotide; and subjecting the double-stranded oligonucleotide to chromatographic purification. In a preferred embodiment, the chromatographic purification is high-performance liquid chromatography.
2 citations
Patent•
14 Apr 2008TL;DR: In this paper, a sulfur-transfer reaction reagent for the synthesis and purification of an oligonucleotide was proposed, which was embodied with 3-amino-1,2,4-dithiazolidine-5-one.
Abstract: PROBLEM TO BE SOLVED: To provide a process and a reaction reagent for use in the synthesis and purification of an oligonucleotide. SOLUTION: The invention relates to a sulfur-transfer reaction reagent. The reagent is preferably embodied with 3-amino-1,2,4-dithiazolidine-5-one. The invention, in another aspect, relates to a preparation method for a phosphorothioate by treating a phosphite with the reagent, preferably with 3-amino-1,2,4-dithiazolidin-5-one as the reagent. COPYRIGHT: (C)2009,JPO&INPIT
Patent•
14 Apr 2008TL;DR: In this paper, a method for removing amino protective groups from oligonucleotide was proposed, which consisted of mixing a polyamine, PEHA, PEG-NH 2, a short PEG NH 2, cycloalkylamine, a cyclo-cyclo-alkylamide, a hydroxycycloalkyamine, hydroxyamine, K 2 CO 3 /MeOH microwave, a thio-alkylamines, thiolated amine, β-amino-ethyl-sulfonic acid, or sodium sulphate of β-
Abstract: PROBLEM TO BE SOLVED: To provide a method for removing amino protective groups from oligonucleotide. SOLUTION: The method comprises mixing a polyamine, PEHA, PEG-NH 2 , a short PEG-NH 2 , a cycloalkylamine, a hydroxycycloalkylamine, a hydroxyamine, K 2 CO 3 /MeOH microwave, a thioalkylamine, a thiolated amine, β-amino-ethyl-sulfonic acid or sodium sulphate of β-amino-ethylsulfonic acid, with an oligonucleotide having amide protective groups. COPYRIGHT: (C)2008,JPO&INPIT