Interactions of DEET and Novel Repellents With Mosquito Odorant Receptors

2020 ◽  
Vol 57 (4) ◽  
pp. 1032-1040
Author(s):  
Gariel G Grant ◽  
Rachel R Estrera ◽  
Narendra Pathak ◽  
C Dennis Hall ◽  
Maia Tsikolia ◽  
...  
Keyword(s):  
Electrophysiological Study ◽  
Odorant Receptors ◽  
Xenopus Laevis Oocytes ◽  
Dependent Manner ◽  
The Novel ◽  
Biological Assays ◽  
Insect Repellents ◽  
Anopheles Gambiae Giles ◽  
Chemical Groups ◽  
Dose Dependent

Abstract The carboxamide N,N-di-ethyl-meta-toluamide (DEET) is the most effective and widely used insect repellent today. However, drawbacks concerning the efficacy and the safety of the repellent have led to efforts to design new classes of insect repellents. Through quantitative structure–activity relationships, chemists have discovered two chemical groups of novel repellents: the acylpiperidines and the carboxamides, with the acylpiperidines generally more potent in biological assays. Although the exact mechanism of action of DEET and other repellents has not yet been thoroughly elucidated, previous research shows that the activity of insect odorant receptors are inhibited in the presence of repellents. The present electrophysiological study employs two-electrode voltage clamp with Xenopus laevis oocytes expressing AgOR2/AgOrco and AgOR8/AgOrco receptors to assess the effects of the novel repellents on Anopheles gambiae Giles (Insecta: Diptera: Culicidae) mosquito odorant receptors. The novel acylpiperidines and carboxamides reversibly inhibited (12–91%) odorant-evoked currents from both AgOR2/AgOrco and AgOR8/AgOrco receptors in a dose-dependent manner at all tested concentrations (30 μM to 1 mM). Furthermore, all the novel agents were more potent inhibitors of the receptors than DEET, with the acylpiperidines producing on average greater inhibition than the carboxamides. Interestingly, there was a correlation (r2 = 0.72) between the percentage inhibition of AgOR2/AgOrco receptor currents and protection times of the acylpiperidines. Our results add to existing evidence that the repellency of a compound is linked to its ability to disrupt the insect olfactory system and that the acylpiperidines could represent a class of more effective alternatives to the current gold standard, DEET.

scholarly journals Nesfatin-1 Suppresses Cardiac L-type Ca2+ Channels Through Melanocortin Type 4 Receptor and the Novel Protein Kinase C Theta Isoform Pathway

2015 ◽  
Vol 36 (2) ◽  
pp. 555-568 ◽  
Author(s):  
Jiaoqian Ying ◽  
Yuan Zhang ◽  
Shan Gong ◽  
Zhigang Chang ◽  
Xiaofeng Zhou ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Ventricular Myocytes ◽  
Dependent Manner ◽  
The Novel ◽  
Inotropic Effects ◽  
Kinase C ◽  
Melanocortin 4 Receptor ◽  
Dose Dependent ◽  
Ca2 Channels

Background/Aims: Nesfatin-1 (NF-1), an anorexic nucleobindin-2 (NUCB2)-derived hypothalamic peptide, acts as a peripheral cardiac modulator and it can induce negative inotropic effects. However, the mechanisms underlying these effects in cardiomyocytes remain unclear. Methods: Using patch clamp, protein kinase assays, and western blot analysis, we studied the effect of NF-1 on L-type Ca2+ currents (ICa,L) and to explore the regulatory mechanisms of this effect in adult ventricular myocytes. Results: NF-1 reversibly decreased ICa,L in a dose-dependent manner. This effect was mediated by melanocortin 4 receptor (MC4-R) and was associated with a hyperpolarizing shift in the voltage-dependence of inactivation. Dialysis of cells with GDP-β-S or anti-Gβ antibody as well as pertussis toxin pretreatment abolished the inhibitory effects of NF-1 on ICa,L. Protein kinase C (PKC) antagonists abolished NF-1-induced responses, whereas inhibition of PKA activity or intracellular application of the fast Ca2+-chelator BAPTA elicited no such effects. Application of NF-1 increased membrane abundance of PKC theta isoform (PKCθ), and PKCθ inhibition abolished the decrease in ICa,L induced by NF-1. Conclusion: These data suggest that NF-1 suppresses L-type Ca2+ channels via the MC4-R that couples sequentially to the βγ subunits of Gi/o-protein and the novel PKCθ isoform in adult ventricular myocytes.

scholarly journals Sodium Iodate Selectively Injuries the Posterior Pole of the Retina in a Dose-Dependent Manner: Morphological and Electrophysiological Study

2010 ◽  
Vol 35 (11) ◽  
pp. 1819-1827 ◽  
Author(s):  
Anna Machalińska ◽  
Wojciech Lubiński ◽  
Patrycja Kłos ◽  
Miłosz Kawa ◽  
Bartłomiej Baumert ◽  
...  
Keyword(s):  
Electrophysiological Study ◽  
Posterior Pole ◽  
Dependent Manner ◽  
Sodium Iodate ◽  
Dose Dependent

scholarly journals Anticonvulsant effects of nimodipine alone and combination with phenytoin on MES induced seizures

2018 ◽  
Vol 7 (6) ◽  
pp. 1160
Author(s):  
Raina Jain ◽  
Ashish Jain
Keyword(s):  
Synergistic Effect ◽  
Anticonvulsant Activity ◽  
Hind Limb ◽  
Channel Blockers ◽  
Dependent Manner ◽  
The Novel ◽  
Antiepileptic Activity ◽  
Effective Doses ◽  
Dose Dependent ◽  
Anticonvulsant Effects

Background: To evaluate the anticonvulsant activity of Nimodipine alone and in combination with Phenytoin, in MES induced seizures.Methods: The study was conducted in mice and MES seizure was induced by Techno electroconvulsometer. In first part of study, animals were treated with Nimodipine (20mg/kg i.p. and 40mg/kg i.p.) and Phenytoin (0.5 mg/100g i.p. and 1.0mg/100g i.p.), MES was induced and durations of various phases were noted. Duration of Tonic hind limb extension (THLE) was taken as index for antiepileptic activity. In second part, the animals were treated with combination of sub effective doses of Nimodipine (20mg/kg i.p.) and Phenytoin (0.5mg/100g i.p.), MES was induced and durations of various phases were noted.Results: Nimodipine produced significant antiepileptic activity, in dose dependent manner. Phenytoin produced significant antiepileptic effect in dose of 1.0mg/100g but failed to produce any such effect in dose of 0.5mg/100g, when administered alone. But when sub effective doses.Of Nimodipine and Phenytoin were combined, a synergistic effect was seen.Conclusions: Nimodipine possess significant antiepileptic activity, alone, as well as it potentiates the antiepileptic effect of Phenytoin, suggesting the novel application of already proven safe and efficacious calcium channel blockers.

The novel antiviral properties of brassicasterol against human adenovirus

2021 ◽  
Author(s):  
Peifeng Yu ◽  
Dan Lou ◽  
Lifeng Qi ◽  
Zewei Chen
Keyword(s):  
Dna Replication ◽  
Epithelial Cells ◽  
Viral Entry ◽  
Human Adenovirus ◽  
Airway Epithelial Cells ◽  
Dependent Manner ◽  
The Novel ◽  
Airway Epithelial ◽  
Infected Cells ◽  
Dose Dependent

Aim: To investigate whether brassicasterol has inhibitory effects against adenovirus (AdV). Materials and methods: The antiviral effects of brassicasterol against AdV 3 and 7 were tested in human airway epithelial cells. Brassicasterol cytotoxicity was assessed by WST-1 assay. AdV DNA was quantified by qPCR. Results: Brassicasterol inhibited AdV 3 and 7 infection of airway epithelial cells in a dose-dependent manner. Similarly, brassicasterol also inhibited AdV 3 and 7 production in infected cells. No apparent cytotoxicity of brassicasterol was detected. Further study showed that brassicasterol inhibited AdV DNA replication, but had no impact on viral entry of cells and viral genome import to nucleus. Conclusion: Brassicasterol exerts anti-AdV effects probably through the inhibition of viral DNA replication.

Small Molecule Inhibitors of USP1 Target ID1 Degradation in Leukemic Cells and Cause Cytotoxicity

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2906-2906
Author(s):  
Helena Mistry ◽  
Grace Hsieh ◽  
Sara Buhrlage ◽  
Min Huang ◽  
Eunmi Park ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Dependent Manner ◽  
The Novel ◽  
Dose Dependent

Abstract ID1 (inhibitor of DNA-binding-1) is a member of the helix-loop-helix family of transcriptional regulatory proteins. The ID-family of proteins (ID1-ID4) inhibit the DNA binding of transcription factors which regulate cellular differentiation and proliferation. Accordingly, deregulation of ID proteins has been observed in many cancer types including leukemia. High levels of ID1 expression are found in primary acute myeloid leukemia (AML) samples and correlate with poor prognosis. ID1 is also identified as a common downstream target of the oncogenic tyrosine kinases, BCR-ABL, TEL-ABL and FLT3-ITD. In addition, Id1 has been shown to promote a myeloproliferative disease in mice, and knockdown of ID1 expression inhibits leukemic cell growth. Therefore, ID1 is an excellent candidate for targeted therapy in leukemia. However, suitable drugs to target ID1 have not been developed to date. ID1 is normally polyubiquitinated and degraded by the proteasome. Recently, it has been shown that USP1, a ubiquitin specific protease, deubiquitinates ID1 and rescues it from proteasome degradation. Inhibition of USP1 therefore offers a new avenue to target ID1 in cancer. Here, using a Ubiquitin-Rhodamine-based high throughput screen, we identified small molecule inhibitors of USP1 and investigated their therapeutic potential for leukemia. These inhibitors blocked the deubiquitinating enzyme activity of USP1 in vitro in a dose-dependent manner with an IC50 in the nanomolar range, and also targeted the enzyme activity of native USP1. To determine the cellular consequences of USP1 inhibition, we exposed leukemic cells to micromolar concentrations of the inhibitors and evaluated ID1 levels and survival. USP1 inhibitors promoted the degradation of ID1 and, concurrently, inhibited the growth (>90% inhibition in 24 hrs) of chronic myelogenous leukemia (CML) and AML cell lines with induction of apoptosis in a dose dependent manner. The EC50 of the inhibitors for the leukemic cell growth inhibition was approximately 1.07 μM ± 0.08 (95% Confidence Limits). Interestingly, exposure to low doses of USP1 inhibitor for 5 days in culture resulted in erythroid differentiation of K562 leukemic cells. A known USP1 inhibitor, Pimozide, also promoted ID1 degradation and inhibited growth of leukemic cells (>90% inhibition in 48 hrs), though at a higher drug concentrations as compared to the novel USP1 inhibitors. Importantly, the novel USP1 inhibitors promoted ID1 degradation and exhibited cytotoxicity (>90% death in 48 hrs) in primary AML patient-derived leukemic cells. Notably, siRNA-mediated knockdown of USP1 in K562 leukemic cells resulted in growth inhibition, increased apoptosis and cell cycle arrest. Collectively, our results demonstrate that the novel small molecule inhibitors of USP1 promote ID1 degradation and are cytotoxic to leukemic cells. The identification of USP1 inhibitors therefore opens up a new approach for leukemia therapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Mutations in the Nonstructural Protein 3A Confer Resistance to the Novel Enterovirus Replication Inhibitor TTP-8307

2009 ◽  
Vol 53 (5) ◽  
pp. 1850-1857 ◽  
Author(s):  
Armando M. De Palma ◽  
Hendrik Jan Thibaut ◽  
Lonneke van der Linden ◽  
Kjerstin Lanke ◽  
Ward Heggermont ◽  
...  
Keyword(s):  
Rna Synthesis ◽  
Nonstructural Protein ◽  
Dependent Manner ◽  
Drug Resistant ◽  
The Novel ◽  
Amino Acid Mutation ◽  
Hydrophobic Domain ◽  
Efficient Replication ◽  
Drug Resistant Phenotype ◽  
Dose Dependent

ABSTRACT A novel compound, TTP-8307, was identified as a potent inhibitor of the replication of several rhino- and enteroviruses. TTP-8307 inhibits viral RNA synthesis in a dose-dependent manner, without affecting polyprotein synthesis and/or processing. Drug-resistant variants of coxsackievirus B3 were all shown to carry at least one amino acid mutation in the nonstructural protein 3A. In particular, three mutations located in a nonstructured region preceding the hydrophobic domain (V45A, I54F, and H57Y) appeared to contribute to the drug-resistant phenotype. This region has previously been identified as a hot sport for mutations that resulted in resistance to enviroxime, the sole 3A-targeting enterovirus inhibitor reported thus far. This was corroborated by the fact that TTP-8307 and enviroxime proved cross-resistant. It is hypothesized that TTP-8307 and enviroxime disrupt proper interactions of 3A(B) with other viral or cellular proteins that are required for efficient replication.

scholarly journals Insulin-like effects of vanadate on glucose uptake and on maturation in Xenopus laevis oocytes.

1991 ◽  
Vol 2 (4) ◽  
pp. 317-327 ◽  
Author(s):  
P Hainaut ◽  
S Giorgetti ◽  
A Kowalski ◽  
E Van Obberghen
Keyword(s):  
Xenopus Laevis ◽  
Glucose Uptake ◽  
Xenopus Laevis Oocytes ◽  
Dependent Manner ◽  
Intact Cells ◽  
Igf I ◽  
Dose Dependent ◽  
Fold Stimulation ◽  
Indirect Action ◽  
Stimulation Of

Vanadate, an inhibitor of phosphotyrosyl phosphatases that exerts insulin-like effects in intact cells, stimulated both maturation and glucose uptake in isolated Xenopus laevis oocytes. Vanadate enhanced the effects of insulin/IGF-I and progesterone on maturation in a dose-dependent manner, with an effective concentration of 750 microM and a maximum at 2 mM, whereas, in the absence of hormone, activation of maturation was seen at 10 mM vanadate. Further, vanadate at 2 mM increased glucose uptake, but this effect was not additive to that of the hormone. In cell-free systems, vanadate caused a 12-fold stimulation of autophosphorylation of the oocyte IGF-I receptor in the absence, but not in the presence, of IGF-I and inhibited largely, but not totally, receptor dephosphorylation induced by an extract of oocytes rich in phosphotyrosyl phosphatase activities. These effects were dose dependent, with effective concentrations of 50-100 microM and maxima at 2 mM. Moreover, using an acellular assay to study the effect of vanadate on the activation of maturation promoting factor (MPF), we found that vanadate at 2 mM stimulated the activation of the MPF H1 kinase. This suggests that vanadate did not prevent dephosphorylation of p34cdc2 on tyrosine residues. Vanadate thus exerted insulin-like effects in oocytes, including stimulation of maturation. These effects might result from a direct or indirect action of vanadate on the IGF-I receptor kinase and on MPF activity.

scholarly journals ANTICONVULSANT EFFECTS OF NIMODIPINE ALONE AND COMBINATION WITH PHENYTOIN ON MES INDUCED SEIZURES

2018 ◽  
Vol 10 (3) ◽  
pp. 44
Author(s):  
Jain Raina ◽  
Jain Ashish
Keyword(s):  
Synergistic Effect ◽  
Calcium Channel Blockers ◽  
Anticonvulsant Activity ◽  
Channel Blockers ◽  
Dependent Manner ◽  
The Novel ◽  
Antiepileptic Activity ◽  
Effective Doses ◽  
Dose Dependent ◽  
Anticonvulsant Effects

Objective: To evaluate the anticonvulsant activity of Nimodipine alone and in combination with Phenytoin, in MES induced seizures.Methods: The study was conducted in mice and MES seizure was induced by Techno electro-convulsometer. In the first part of the study, animals were treated with Nimodipine (20 mg/kg i. p. and 40 mg/kg i. p.) and Phenytoin (0.5 mg/100g i. p. and 1.0 mg/100g i. p.), MES was induced and durations of various phases were noted. Duration of Tonic hindlimb extension (THLE) was taken as an index for antiepileptic activity. In the second part, the animals were treated with a combination of sub effective doses of Nimodipine (20 mg/kg i. p.) and Phenytoin (0.5 mg/100g i. p.), MES was induced and durations of various phases were noted.Results: Nimodipine produced significant antiepileptic activity, in a dose-dependent manner. Phenytoin produced a significant antiepileptic effect in dose of 1.0 mg/100g, but failed to produce any such effect in a dose of 0.5 mg/100g, when administered alone. But when sub-effective doses. Of Nimodipine and Phenytoin were combined, a synergistic effect was seen.Conclusion: Nimodipine posses significant antiepileptic activity, alone, as well as it potentiates the antiepileptic effect of Phenytoin, suggesting the novel application of already proven safe and efficacious calcium channel blockers.

scholarly journals Restricted epithelial proliferation by lacritin via PKCα-dependent NFAT and mTOR pathways

2006 ◽  
Vol 174 (5) ◽  
pp. 689-700 ◽  
Author(s):  
Jiahu Wang ◽  
Ningning Wang ◽  
Jinling Xie ◽  
Staci C. Walton ◽  
Robert L. McKown ◽  
...  
Keyword(s):  
Phospholipase D ◽  
Cell Types ◽  
Secretory Cells ◽  
Dependent Manner ◽  
The Novel ◽  
Receptor Binding Domain ◽  
Epithelial Proliferation ◽  
Α Helix ◽  
Different Cell Types ◽  
Dose Dependent

Renewal of nongermative epithelia is poorly understood. The novel mitogen “lacritin” is apically secreted by several nongermative epithelia. We tested 17 different cell types and discovered that lacritin is preferentially mitogenic or prosecretory for those types that normally contact lacritin during its glandular outward flow. Mitogenesis is dependent on lacritin's C-terminal domain, which can form an α-helix with a hydrophobic face, as per VEGF's and PTHLP's respective dimerization or receptor-binding domain. Lacritin targets downstream NFATC1 and mTOR. The use of inhibitors or siRNA suggests that lacritin mitogenic signaling involves Gαi or Gαo–PKCα-PLC–Ca2+–calcineurin–NFATC1 and Gαi or Gαo–PKCα-PLC–phospholipase D (PLD)–mTOR in a bell-shaped, dose-dependent manner requiring the Ca2+ sensor STIM1, but not TRPC1. This pathway suggests the placement of transiently dephosphorylated and perinuclear Golgi–translocated PKCα upstream of both Ca2+ mobilization and PLD activation in a complex with PLCγ2. Outward flow of lacritin from secretory cells through ducts may generate a proliferative/secretory field as a different unit of cellular renewal in nongermative epithelia where luminal structures predominate.

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