87 research outputs found
Dual Hypocretin Receptor Antagonism Is More Effective for Sleep Promotion than Antagonism of Either Receptor Alone
The hypocretin (orexin) system is involved in sleep/wake regulation, and antagonists of both hypocretin receptor type 1 (HCRTR1) and/or HCRTR2 are considered to be potential hypnotic medications. It is currently unclear whether blockade of either or both receptors is more effective for promoting sleep with minimal side effects. Accordingly, we compared the properties of selective HCRTR1 (SB-408124 and SB-334867) and HCRTR2 (EMPA) antagonists with that of the dual HCRTR1/R2 antagonist almorexant in the rat. All 4 antagonists bound to their respective receptors with high affinity and selectivity in vitro. Since in vivo pharmacokinetic experiments revealed poor brain penetration for SB-408124, SB-334867 was selected for subsequent in vivo studies. When injected in the mid-active phase, SB-334867 produced small increases in rapid-eye-movement (REM) and non-REM (NR) sleep. EMPA produced a significant increase in NR only at the highest dose studied. In contrast, almorexant decreased NR latency and increased both NR and REM proportionally throughout the subsequent 6 h without rebound wakefulness. The increased NR was due to a greater number of NR bouts; NR bout duration was unchanged. At the highest dose tested (100 mg/kg), almorexant fragmented sleep architecture by increasing the number of waking and REM bouts. No evidence of cataplexy was observed. HCRTR1 occupancy by almorexant declined 4β6 h post-administration while HCRTR2 occupancy was still elevated after 12 h, revealing a complex relationship between occupancy of HCRT receptors and sleep promotion. We conclude that dual HCRTR1/R2 blockade is more effective in promoting sleep than blockade of either HCRTR alone. In contrast to GABA receptor agonists which induce sleep by generalized inhibition, HCRTR antagonists seem to facilitate sleep by reducing waking βdriveβ
Xanthone, benzophenone and bioflavonoid accumulation in Cyclopia genistoides (L.) Vent. (honeybush) shoot cultures grown on membrane rafts and in a temporary immersion system
Site of Allergic Airway Narrowing and the Influence of Exogenous Surfactant in the Brown Norway Rat
Background: The parameters RN (Newtonian resistance), G (tissue damping), and H (tissue elastance) of the constant phase model of respiratory mechanics provide information concerning the site of altered mechanical properties of the lung. The aims of this study were to compare the site of allergic airway narrowing implied from respiratory mechanics to a direct assessment by morphometry and to evaluate the effects of exogenous surfactant administration on the site and magnitude of airway narrowing. Methods: We induced airway narrowing by ovalbumin sensitization and challenge and we tested the effects of a natural surfactant lacking surfactant proteins A and D (InfasurfH) on airway responses. Sensitized, mechanically ventilated Brown Norway rats underwent an aerosol challenge with 5 % ovalbumin or vehicle. Other animals received nebulized surfactant prior to challenge. Three or 20 minutes after ovalbumin challenge, airway luminal areas were assessed on snap-frozen lungs by morphometry. Results: At 3 minutes, RN and G detected large airway narrowing whereas at 20 minutes G and H detected small airway narrowing. Surfactant inhibited RN at the peak of the early allergic response and ovalbumin-induced increase in bronchoalveolar lavage fluid cysteinyl leukotrienes and amphiregulin but not IgE-induced mast cell activation in vitro. Conclusion: Allergen challenge triggers the rapid onset of large airway narrowing, detected by RN and G, and subsequen
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Concurrent evaluation of cytokines improves the accuracy of antibodies against Mycobacterium tuberculosis antigens in the diagnosis of active tuberculosis
Data availability statement: All the important data relevant to this study was reported in the manuscript. Any additional data will be made available upon request from the corresponding author.Copyright Β© 2022 The Authors. Background:
Antibodies against mycobacterial proteins are highly specific, but lack sensitivity, whereas cytokines have been shown to be sensitive but not very specific in the diagnosis of tuberculosis (TB). We assessed combinations between antibodies and cytokines for diagnosing TB.
Methods:
Immuoglubulin (Ig) A and IgM antibody titres against selected mycobacterial antigens including Apa, NarL, Rv3019c, PstS1, LAM, βKit 1β (MTP64 and Tpx)β, and βKit 2β (MPT64, Tpx and 19 kDa) were evaluated by ELISA in plasma samples obtained from individuals under clinical suspicion for TB. Combinations between the antibody titres and previously published cytokine responses in the same participants were assessed for diagnosing active TB.
Results:
Antibody responses were more promising when used in combination (AUC of 0.80), when all seven antibodies were combined. When anti-βKit 1β-IgA levels were combined with five host cytokine biomarkers, the AUC increased to 97% (92β100%) with a sensitivity of 95% (95% CI, 73β100%), and specificity of 88.5% (95% CI, 68.7β97%) achieved after leave-one-out cross validation.
Conclusion:
When used in combination, IgA titres measured with ELISA against multiple Mycobacterium tuberculosis antigens may be useful in the diagnosis of TB. However, diagnostic accuracy may be improved if the antibodies are used in combination with cytokines.This work was part of the EDCTP1 programme supported by the European Union (grant number IP_2009_32040, AE-TBC; awarded to GW). The project was also supported by the South African Government through the National Research Foundation (NRF, awarded to NC) and the South African Medical Research Council (SAMRC, postgraduate scholarship to RJ)
Consequences of fragmentation for the ability to adapt to novel environments in experimental Drosophila metapopulations
Phosphonium ylide-catalyzed cyclotrimerization of ethyl propynoate
NatuurwetenskappeChemie & PolimeerwetenskapPlease help us populate SUNScholar with the post print version of this article. It can be e-mailed to: [email protected]
Rooibos (Aspalathus linearis), honeybush (Cyclopia intermedia) and cancer bush (Sutherlandia frutescens subsp. microphylla) protect against tobacco-specific mutagenesis in vitro
Antimutagenesis studies against the tobacco-specific mutagens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-oxide, 4 (methyl-nitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), were conducted using hot water aqueous extracts of rooibos (Aspalathus linearis), honeybush (Cyclopia intermedia), and cancer bush (Sutherlandia frutescens). Aqueous extracts of both βfermentedβ and βunfermentedβ (green) rooibos and honeybush were included, while extracts of green and black teas (Camellia sinensis) served as benchmarks. A polyphenol-enriched methanol extract of unfermented rooibos (RgM) was included to further elucidate the possible role of rooibos polyphenols. Studies were performed in the presence of the metabolic activation against Salmonella typhimurium tester strain TA1535, using the standard plate incorporation and micro-suspension, pre-incubation assays. The mutagenic effects of NNK against the strain TA1535 was best demonstrated using the standard plate incorporation assay, while a higher mutagenicity was demonstrated for NNAL using the micro-suspension, pre-incubation method. Black tea and RgM exhibited the highest protection against NNK-induced mutagenesis followed by the aqueous extracts of rooibos β₯ green tea β₯ honeybush β₯ cancer bush. Black tea, green tea, RgM and unfermented rooibos were the most effective against NNAL-induced mutagenesis, followed by fermented rooibos. The two honeybush extracts exhibited similar, but the weakest protective response. When considering the amount of total polyphenols (TPP) incorporated in the plate incorporation assay, cancer bush exhibited similar protection to that of fermented and unfermented honeybush against NNK mutagenesis. The involvement of specific polyphenol-cytochrome P450 (CYP450) interactions is likely to be involved in the protection against tobacco-related mutagenesis. Polyphenol constituents of rooibos, honeybush and cancer bush could play an important role in the protection against mutagenesis induced by the major tobacco-specific carcinogens
Food ingredient extracts of <i>Cyclopia subternata</i> (Honeybush): Variation in phenolic composition and antioxidant capacity
NatuurwetenskappeBiochemiePlease help us populate SUNScholar with the post print version of this article. It can be e-mailed to: [email protected]
Variation in phenolic content and antioxidation activity of fermented rooibos herbal tea infusions: Role of production season and quality grade
NatuurwetenskappeChemie & PolimeerwetenskapPlease help us populate SUNScholar with the post print version of this article. It can be e-mailed to: [email protected]
Acute assessment of an aspalathin-enriched green rooibos (<I>Aspalathus linearis</I>) extract with hypoglycemic potential
AgriwetenskappeVoedselwetenskapPlease help us populate SUNScholar with the post print version of this article. It can be e-mailed to: [email protected]
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