Browsing by Subject "Azetidines"
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Item Open Access JAK inhibitor blocks COVID-19 cytokine-induced JAK/STAT/APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids.(JCI insight, 2022-06) Nystrom, Sarah E; Li, Guojie; Datta, Somenath; Soldano, Karen L; Silas, Daniel; Weins, Astrid; Hall, Gentzon; Thomas, David B; Olabisi, Opeyemi ACOVID-19 infection causes collapse of glomerular capillaries and loss of podocytes, culminating in a severe kidney disease called COVID-19-associated nephropathy (COVAN). The underlying mechanism of COVAN is unknown. We hypothesized that cytokines induced by COVID-19 trigger expression of pathogenic APOL1 via JAK/STAT signaling, resulting in podocyte loss and COVAN phenotype. Here, based on 9 biopsy-proven COVAN cases, we demonstrated for the first time, to the best of our knowledge, that APOL1 protein was abundantly expressed in podocytes and glomerular endothelial cells (GECs) of COVAN kidneys but not in controls. Moreover, a majority of patients with COVAN carried 2 APOL1 risk alleles. We show that recombinant cytokines induced by SARS-CoV-2 acted synergistically to drive APOL1 expression through the JAK/STAT pathway in primary human podocytes, GECs, and kidney micro-organoids derived from a carrier of 2 APOL1 risk alleles, but expression was blocked by a JAK1/2 inhibitor, baricitinib. We demonstrate that cytokine-induced JAK/STAT/APOL1 signaling reduced the viability of kidney organoid podocytes but was rescued by baricitinib. Together, our results support the conclusion that COVID-19-induced cytokines are sufficient to drive COVAN-associated podocytopathy via JAK/STAT/APOL1 signaling and that JAK inhibitors could block this pathogenic process. These findings suggest JAK inhibitors may have therapeutic benefits for managing cytokine-induced, APOL1-mediated podocytopathy.Item Open Access Oral sazetidine-A, a selective α4β2* nicotinic receptor desensitizing agent, reduces nicotine self-administration in rats.(Pharmacology, biochemistry, and behavior, 2019-04) Rezvani, Amir H; Wells, Corinne; Slade, Susan; Xiao, Yingxian; Kellar, Kenneth J; Levin, Edward DSazetidine-A selectively desensitizes α4β2 nicotinic receptors and also has partial agonist effects. We have shown that subcutaneous acute and repeated injections as well as chronic infusions of sazetidine-A significantly reduce intravenous (IV) nicotine self-administration in rats. To further investigate the promise of sazetidine-A as a smoking cessation aid, it is important to determine sazetidine-A effects with oral administration and the time-effect function for its action on nicotine self-administration. Young adult female Sprague-Dawley rats were trained to self-administer IV nicotine at the benchmark dose of 0.03 mg/kg/infusion dose in an operant FR1 schedule in 45-min sessions. After five sessions of training, they were tested for the effects of acute oral doses of sazetidine-A (0, 0.3, 1 and 3 mg/kg) given 30 min before testing. To determine the time-effect function, these rats were administered 0 or 3 mg/kg of sazetidine-A 1, 2, 4 or 23 h before the onset of testing. Our previous study showed that with subcutaneous injections, only 3 mg/kg of sazetidine-A significantly reduced nicotine self-administration, however, with oral administration of sazetidine-A lower dose of 1 mg/kg was also effective in reducing nicotine intake. A similar effect was seen in the time-effect study with 3 mg/kg of oral sazetidine-A causing a significant reduction in nicotine self-administration across all the time points of 1, 2, 4 or 23 h after oral administration. These results advance the development of sazetidine-A as a possible aid for smoking cessation by showing effectiveness with oral administration and persistence of the effect over the course of a day.Item Open Access α4β2 Nicotinic receptor desensitizing compounds can decrease self-administration of cocaine and methamphetamine in rats.(European journal of pharmacology, 2019-02) Levin, Edward D; Rezvani, Amir H; Wells, Corinne; Slade, Susan; Yenugonda, Venkata M; Liu, Yong; Brown, Milton L; Xiao, Yingxian; Kellar, Kenneth JSazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a selective α4β2 nicotinic receptor desensitizing agent and partial agonist. Sazetidine-A has been shown in our previous studies to significantly reduce nicotine and alcohol self-administration in rats. The question arises whether sazetidine-A would reduce self-administration of other addictive drugs as well. Nicotinic receptors on the dopaminergic neurons in the ventral tegmental area play an important role in controlling the activity of these neurons and release of dopamine in the nucleus accumbens, which is critical mechanism for reinforcing value of drugs of abuse. Previously, we showed that the nonspecific nicotinic antagonist mecamylamine significantly reduces cocaine self-administration in rats. In this study, we acutely administered systemically sazetidine-A and two other selective α4β2 nicotinic receptor-desensitizing agents, VMY-2-95 and YL-2-203, to young adult female Sprague-Dawley rats and determined their effects on IV self-administration of cocaine and methamphetamine. Cocaine self-administration was significantly reduced by 0.3 mg/kg of sazetidine-A. In another set of rats, sazetidine-A (3 mg/kg) significantly reduced methamphetamine self-administration. VMY-2-95 significantly reduced both cocaine and methamphetamine self-administration with threshold effective doses of 3 and 0.3 mg/kg, respectively. In contrast, YL-2-203 did not significantly reduce cocaine self-administration at the same dose range and actually significantly increased cocaine self-administration at the 1 mg/kg dose. YL-2-203 (3 mg/kg) did significantly decrease methamphetamine self-administration. Sazetidine-A and VMY-2-95 are promising candidates to develop as new treatments to help addicts successfully overcome a variety of addictions including tobacco, alcohol as well as the stimulant drugs cocaine and methamphetamine.