19 research outputs found
Synthesis of 5-(6-hydroxy-7H-purine-8-ylthio)- 2-(N-hydroxyformamido)pentanoic acid
We have developed a synthetic route for the preparation of a hybrid bisubstrate small molecule based on a nucleoside. A prototype compound was designed and docked into the catalytic domain of the AdSS enzyme bridging the region between the magnesium center of the protein to the nucleoside region. The synthesis involves coupling a brominated peptide fragment capable of complexing magnesium to a thiolated nucleoside to obtain the hybrid model compound
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Small molecule NPT-440-1 inhibits ionic flux through Aβ1-42 pores: Implications for Alzheimer's disease therapeutics.
Increased levels of soluble amyloid-beta (Aβ) oligomers are suspected to underlie Alzheimer's disease (AD) pathophysiology. These oligomers have been shown to form multi-subunit Aβ pores in bilayers and induce uncontrolled, neurotoxic, ion flux, particularly calcium ions, across cellular membranes that might underlie cognitive impairment in AD. Small molecule interventions that modulate pore activity could effectively prevent or ameliorate their toxic activity. Here we examined the efficacy of a small molecule, NPT-440-1, on modulating amyloid pore permeability. Co-incubation of B103 rat neuronal cells with NPT-440-1 and Aβ1-42 prevented calcium influx. In purified lipid bilayers, we show that a 10-15min preincubation, prior to membrane introduction, was required to prevent conductance. Thioflavin-T and circular dichroism both suggested a reduction in Aβ1-42 β-sheet content during this incubation period. Combined with previous studies on site-specific amino acid substitutions, these results suggest that pharmacological modulation of Aβ1-42 could prevent amyloid pore-mediated AD pathogenesis
Small molecule NPT-440-1 inhibits ionic flux through Aβ1-42 pores: Implications for Alzheimer's disease therapeutics.
Increased levels of soluble amyloid-beta (Aβ) oligomers are suspected to underlie Alzheimer's disease (AD) pathophysiology. These oligomers have been shown to form multi-subunit Aβ pores in bilayers and induce uncontrolled, neurotoxic, ion flux, particularly calcium ions, across cellular membranes that might underlie cognitive impairment in AD. Small molecule interventions that modulate pore activity could effectively prevent or ameliorate their toxic activity. Here we examined the efficacy of a small molecule, NPT-440-1, on modulating amyloid pore permeability. Co-incubation of B103 rat neuronal cells with NPT-440-1 and Aβ1-42 prevented calcium influx. In purified lipid bilayers, we show that a 10-15min preincubation, prior to membrane introduction, was required to prevent conductance. Thioflavin-T and circular dichroism both suggested a reduction in Aβ1-42 β-sheet content during this incubation period. Combined with previous studies on site-specific amino acid substitutions, these results suggest that pharmacological modulation of Aβ1-42 could prevent amyloid pore-mediated AD pathogenesis
Novel therapeutic strategy for neurodegeneration by blocking Aβ seeding mediated aggregation in models of Alzheimer's disease
Aβ accumulation plays a central role in the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that the process of Aβ nucleated polymerization is essential for Aβ fibril formation, pathology spreading and toxicity. Therefore, targeting this process represents an effective therapeutic strategy to slow or block disease progression. To discover compounds that might interfere with the Aβ seeding capacity, toxicity and pathology spreading, we screened a focused library of FDA-approved drugs in vitro using a seeding polymerization assay and identified small molecule inhibitors that specifically interfered with Aβ seeding-mediated fibril growth and toxicity. Mitoxantrone, bithionol and hexachlorophene were found to be the strongest inhibitors of fibril growth and protected primary cortical neuronal cultures against Aβ-induced toxicity. Next, we assessed the effects of these three inhibitors in vivo in the mThy1-APPtg mouse model of AD (8-month-old mice). We found that mitoxantrone and bithionol, but not hexachlorophene, stabilized diffuse amyloid plaques, reduced the levels of Aβ42 oligomers and ameliorated synapse loss, neuronal damage and astrogliosis. Together, our findings suggest that targeting fibril growth and Aβ seeding capacity constitutes a viable and effective strategy for protecting against neurodegeneration and disease progression in AD
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Hypoestoxide reduces neuroinflammation and α-synuclein accumulation in a mouse model of Parkinson's disease.
BackgroundDeposition of α-synuclein and neuroinflammation are key pathological features of Parkinson's disease (PD). There is no cure for the disease; however, targeting the pathological features might be available to modulate the disease onset and progression. Hypoestoxide (HE) has been demonstrated as a NF-κB modulator, thereby acting as a potential anti-inflammatory and anti-cancer drug.MethodsIn order to assess the effect of HE in a mouse model of PD, mThy1-α-syn transgenic mice received intraperitoneal (IP) injections of either vehicle or HE (5 mg/kg) daily for 4 weeks.ResultsTreatment of HE decreased microgliosis, astrogliosis, and pro-inflammatory cytokine gene expression in α-syn transgenic mice. HE administration also prevented the loss of dopaminergic neurons and ameliorated motor behavioral deficits in the α-syn transgenic mice, and α-synuclein pathology was significantly reduced by treatment of HE. In addition, increased levels of nuclear phosphorylated NF-κB in the frontal cortex of α-syn transgenic mice were significantly reduced by HE administration.ConclusionsThese results support the therapeutic potential of HE for PD and other α-synuclein-related diseases
Recognition of Dextran–Superparamagnetic Iron Oxide Nanoparticle Conjugates (Feridex) via Macrophage Scavenger Receptor Charged Domains
Dextran-coated superparamagnetic iron oxide nanoparticles
(dextran–SPIO
conjugates) offer the attractive possibility of enhancing MRI imaging
sensitivity so that small or diffuse lesions can be detected. However,
systemically injected SPIOs are rapidly removed by macrophages. We
engineered embryonic cells (HEK293T) to express major macrophage scavenger
receptor (SR) subtypes including SR-AI, MARCO, and endothelial receptor
collectin-12. These SRs possess a positively charged collagen-like
(CL) domain and they promoted SPIO uptake, while the charge neutral
lipoprotein receptor SR-BI did not. In silico modeling indicated a
positive net charge on the CL domain and a net negative charge on
the cysteine-rich (CR) domain of MARCO and SR-AI. In vitro experiments
revealed that CR domain deletion in SR-AI boosted uptake of SPIO 3-fold,
while deletion of MARCO’s CR domain abolished this uptake.
These data suggest that future studies might productively focus on
the validation and further exploration of SR charge fields in SPIO
recognition
Additional file 1: of Hypoestoxide reduces neuroinflammation and α-synuclein accumulation in a mouse model of Parkinson’s disease
Hypoestoxide reduces human α-synuclein accumulation in a mouse model of PD. Mice brain sections were inmmunostained against human α-synuclein (Syn211 antibody) or C-terminal of human α-synuclein (Syn105 antibody). a Immunofluorescence analysis of human α-synuclein in the frontal cortex of non-tg and α-syn-tg mice treated with either vehicle or hypoestoxide. (n = 5 per group; unpaired t test; *p < 0.05). Error bars represent ± SEM. b Fluorescence intensity against human α-synuclein was analyzed in frontal cortex of the brains. c Immunohistochemical analysis of C-terminal of human α-synuclein in the frontal cortex of non-tg and α-syn-tg mice. d Optical density analysis for C-terminal of α-synuclein in frontal cortex. (n = 5 per group; unpaired t test; **p < 0.01). Error bars represent ± SEM. Scale bars = 250 μm (low magnification) and 25 μm (high magnification). (TIF 13692 kb