Articles: oligonucleotides.
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Journal of lipid research · Mar 2016
ReviewAntisense inhibition of apolipoprotein (a) to lower plasma lipoprotein (a) levels in humans.
Epidemiological, genetic association, and Mendelian randomization studies have provided strong evidence that lipoprotein (a) [Lp(a)] is an independent causal risk factor for CVD, including myocardial infarction, stroke, peripheral arterial disease, and calcific aortic valve stenosis. Lp(a) levels >50 mg/dl are highly prevalent (20% of the general population) and are overrepresented in patients with CVD and aortic stenosis. These data support the notion that Lp(a) should be a target of therapy for CVD event reduction and to reduce progression of aortic stenosis. ⋯ In cynomolgus monkeys, a second generation apo(a) ASO, ISIS-APO(a)Rx, significantly reduced hepatic apo(a) mRNA expression and plasma Lp(a) levels by >80%. Finally, in a phase I study in normal volunteers, ISIS-APO(a)Rx ASO reduced Lp(a) levels and their associated OxPL levels up to 89 and 93%, respectively, with minimal effects on other lipoproteins. ISIS-APO(a)Rx represents the first specific and potent drug in clinical development to lower Lp(a) levels and may be beneficial in reducing CVD events and progression of calcific aortic valve stenosis.
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Anesthesia and analgesia · Jan 2016
Inhibition of Mitochondrial Fission Protein Reduced Mechanical Allodynia and Suppressed Spinal Mitochondrial Superoxide Induced by Perineural Human Immunodeficiency Virus gp120 in Rats.
Mitochondria play an important role in many cellular and physiologic functions. Mitochondria are dynamic organelles, and their fusion and fission regulate cellular signaling, development, and mitochondrial homeostasis. The most common complaint of human immunodeficiency virus (HIV)-sensory neuropathy is pain on the soles in patients with HIV, but the exact molecular mechanisms of HIV neuropathic pain are not clear. In the present study, we investigated the role of mitochondrial dynamin-related protein 1 (Drp1, a GTPase that mediates mitochondrial fission) in the perineural HIV coat glycoprotein gp120-induced neuropathic pain state. ⋯ These data suggest that mitochondrial division plays a substantial role in the HIV gp120-related neuropathic pain state through mitochondrial reactive oxygen species and provides evidence for a novel approach to treating chronic pain in patients with HIV.
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Current drug metabolism · Jan 2016
ReviewSmad7 and its Potential as Therapeutic Target in Inflammatory Bowel Diseases.
The etiology of Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD) in humans, is still unknown, but evidence suggests that genetic and environmental factors interact to promote an excessive immune response that leads to tissue damage. Defects in the counter-regulatory mechanisms are also supposed to make a major contribution to the amplification and maintenance of the IBD-related inflammatory response. One such a mechanism involves TGF-β1, a cytokine synthesized by both immune and non-immune cells in the gut, which is essential in the maintenance of immune homeostasis. In both CD and UC, active inflammation occurs in areas characterized by enhanced production of TGF-β1 and reduced ability of this cytokine to activate Smad-associated signaling and suppress inflammatory pathways. The defective TGF-β1 activity is due to elevated levels of Smad7, an intracellular protein that inhibits TGF-β1-associated Smad signaling. ⋯ Data indicate that, in IBD, high Smad7 contributes to sustain detrimental immune responses and knockdown of this molecule can help attenuate the ongoing mucosal inflammation in patients with such disorders.
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Animals models have played an important role in enhancing our understanding of the pathogenesis of pulmonary arterial hypertension (PAH). Dysregulation of the profile of microRNAs (miRNAs) has been demonstrated in human tissues from PAH patients and in animal models. In this study, we measured miRNA levels in the monocrotaline (MCT) rat model of PAH and examined whether blocking a specific dysregulated miRNA not previously reported in this model, attenuated PAH. We also evaluated changes in miRNA expression in lung specimens from MCT PAH rats overexpressing human prostacyclin synthase, which has been shown to attenuate MCT PAH. ⋯ Inhibition of miR-223 did not attenuate MCT PAH, whereas human prostacyclin synthase overexpression restored miRNA levels in MCT PAH to levels detected in naïve rats. These data may establish a paradigm linking attenuation of PAH to restoration of BMPR2 signaling.
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Custom synthesis of transcription activator-like effector (TALE) genes has relied upon plasmid libraries of pre-fabricated TALE-repeat monomers or oligomers. Here we describe a novel synthesis method that directly incorporates annealed synthetic oligonucleotides into the TALE-repeat units. ⋯ In addition, this novel oligonucleotide-based method can readily accommodate design changes to the TALE repeats. We demonstrated an increased gene targeting efficiency against a genomic site containing a potentially methylated cytosine by incorporating non-conventional repeat variable di-residue (RVD) sequences.