An octopamine receptor confers selective toxicity of amitraz on honeybees and Varroa mites

The Varroa destructor mite is a devastating parasite of Apis mellifera honeybees. They can cause colonies to collapse by spreading viruses and feeding on the fat reserves of adults and larvae. Amitraz is used to control mites due to its low toxicity to bees; however, the mechanism of bee resistance to amitraz remains unknown. In this study, we found that amitraz and its major metabolite potently activated all four mite octopamine receptors. Behavioral assays using Drosophila null mutants of octopamine receptors identified one receptor subtype Octβ2R as the sole target of amitraz in vivo. We found that thermogenetic activation of octβ2R-expressing neurons mimics amitraz poisoning symptoms in target pests. We next confirmed that the mite Octβ2R was more sensitive to amitraz and its metabolite than the bee Octβ2R in pharmacological assays and transgenic flies. Furthermore, replacement of three bee-specific residues with the counterparts in the mite receptor increased amitraz sensitivity of the bee Octβ2R, indicating that relative insensitivity of their receptor is the major mechanism for honeybees to resist amitraz. The present findings have important implications for resistance management and the design of safer insecticides that selectively target pests while maintaining low toxicity to non-target pollinators.

Download Full-text

In vivo activity and low toxicity of the second-generation antimicrobial peptide DGL13K

PLoS ONE ◽

10.1371/journal.pone.0216669 ◽

2019 ◽

Vol 14 (5) ◽

pp. e0216669 ◽

Cited By ~ 11

Author(s):

Sven-Ulrik Gorr ◽

Craig M. Flory ◽

Robert J. Schumacher

Keyword(s):

Antimicrobial Peptide ◽

Second Generation ◽

Low Toxicity

Download Full-text

Construction of hollow polydopamine nanoparticle based drug sustainable release system and its application in bone regeneration

International Journal of Oral Science ◽

10.1038/s41368-021-00132-6 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Lu Wang ◽

Shuwei Liu ◽

Chunxia Ren ◽

Siyuan Xiang ◽

Daowei Li ◽

...

Keyword(s):

Bone Regeneration ◽

Bone Defect ◽

Load Capacity ◽

Good Prospect ◽

Alizarin Red ◽

Drug Load ◽

Load Rate ◽

Low Toxicity

AbstractNanomaterial-based drug sustainable release systems have been tentatively applied to bone regeneration. They, however, still face disadvantages of high toxicity, low biocompatibility, and low drug-load capacity. In view of the low toxicity and high biocompatibility of polymer nanomaterials and the excellent load capacity of hollow nanomaterials with high specific surface area, we evaluated the hollow polydopamine nanoparticles (HPDA NPs), in order to find an optimal system to effectively deliver the osteogenic drugs to improve treatment of bone defect. Data demonstrated that the HPDA NPs synthesized herein could efficiently load four types of osteogenic drugs and the drugs can effectively release from the HPDA NPs for a relatively longer time in vitro and in vivo with low toxicity and high biocompatibility. Results of qRT-PCR, ALP, and alizarin red S staining showed that drugs released from the HPDA NPs could promote osteogenic differentiation and proliferation of rat bone marrow mesenchymal stem cells (rBMSCs) in vitro. Image data from micro-CT and H&E staining showed that all four osteogenic drugs released from the HPDA NPs effectively promoted bone regeneration in the defect of tooth extraction fossa in vivo, especially tacrolimus. These results suggest that the HPDA NPs, the biodegradable hollow polymer nanoparticles with high drug load rate and sustainable release ability, have good prospect to treat the bone defect in future clinical practice.

Download Full-text

Selection of the First 99mTc-Labelled Somatostatin Receptor Subtype 2 Antagonist for Clinical Translation—Preclinical Assessment of Two Optimized Candidates

Pharmaceuticals ◽

10.3390/ph14010019 ◽

2020 ◽

Vol 14 (1) ◽

pp. 19

Author(s):

Melpomeni Fani ◽

Viktoria Weingaertner ◽

Petra Kolenc Peitl ◽

Rosalba Mansi ◽

Raghuvir H. Gaonkar ◽

...

Keyword(s):

Protein Binding ◽

Somatostatin Receptor ◽

Somatostatin Receptors ◽

Preclinical Study ◽

Clinical Translation ◽

Hek293 Cells ◽

Neuroendocrine Neoplasms ◽

Receptor Subtype ◽

Selection Of

Recently, radiolabelled antagonists targeting somatostatin receptors subtype 2 (SST2) in neuroendocrine neoplasms demonstrated certain superior properties over agonists. Within the ERA-PerMED project “TECANT” two 99mTc-Tetramine (N4)-derivatized SST2 antagonists (TECANT-1 and TECANT-2) were studied for the selection of the best candidate for clinical translation. Receptor-affinity, internalization and dissociation studies were performed in human embryonic kidney-293 (HEK293) cells transfected with the human SST2 (HEK-SST2). Log D, protein binding and stability in human serum were assessed. Biodistribution and SPECT/CT studies were carried out in nude mice bearing HEK-SST2 xenografts, together with dosimetric estimations from mouse-to-man. [99mTc]Tc-TECANT-1 showed higher hydrophilicity and lower protein binding than [99mTc]-TECANT-2, while stability was comparable. Both radiotracers revealed similar binding affinity, while [99mTc]Tc-TECANT-1 had higher cellular uptake (>50%, at 2 h/37 °C) and lower dissociation rate (<30%, at 2 h/37 °C). In vivo, [99mTc]Tc-TECANT-1 showed lower blood values, kidney and muscles uptake, whereas tumour uptake was comparable to [99mTc]Tc-TECANT-2. SPECT/CT imaging confirmed the biodistribution results, providing the best tumour-to-background image contrast for [99mTc]Tc-TECANT-1 at 4 h post-injection (p.i.). The estimated radiation dose amounted to approximately 6 µSv/MBq for both radiotracers. This preclinical study provided the basis of selection of [99mTc]Tc-TECANT-1 for clinical translation of the first 99mTc-based SST2 antagonist.

Download Full-text

Galanin-receptor ligand M40 peptide distinguishes between putative galanin-receptor subtypes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.90.23.11287 ◽

1993 ◽

Vol 90 (23) ◽

pp. 11287-11291 ◽

Cited By ~ 86

Author(s):

T Bartfai ◽

U Langel ◽

K Bedecs ◽

S Andell ◽

T Land ◽

...

Keyword(s):

Spinal Cord ◽

Binding Sites ◽

Receptor Subtype ◽

Receptor Subtypes ◽

Galanin Receptor ◽

Flexor Reflex ◽

Receptor Ligand ◽

Insulinoma Cells ◽

Galanin Receptors

The galanin-receptor ligand M40 [galanin-(1-12)-Pro3-(Ala-Leu)2-Ala amide] binds with high affinity to [mono[125I]iodo-Tyr26]galanin-binding sites in hippocampal, hypothalamic, and spinal cord membranes and in membranes from Rin m5F rat insulinoma cells (IC50 = 3-15 nM). Receptor autoradiographic studies show that M40 (1 microM) displaces [mono[125I]iodo-Tyr26]galanin from binding sites in the hippocampus, hypothalamus, and spinal cord. In the brain, M40 acts as a potent galanin-receptor antagonist: M40, in doses comparable to that of galanin, antagonizes the stimulatory effects of galanin on feeding, and it blocks the galaninergic inhibition of the scopolamine-induced acetylcholine release in the ventral hippocampus in vivo. In contrast, M40 completely fails to antagonize both the galanin-mediated inhibition of the glucose-induced insulin release in isolated mouse pancreatic islets and the inhibitory effects of galanin on the forskolin-stimulated accumulation of 3',5'-cAMP in Rin m5F cells; instead M40 is a weak agonist at the galanin receptors in these two systems. M40 acts as a weak antagonist of galanin in the spinal flexor reflex model. These results suggest that at least two subtypes of the galanin receptor may exist. Hypothalamic and hippocampal galanin receptors represent a putative central galanin-receptor subtype (GL-1-receptor) that is blocked by M40. The pancreatic galanin receptor may represent another subtype (GL-2-receptor) that recognizes M40, but as a weak agonist. The galanin receptors in the spinal cord occupy an intermediate position between these two putative subtypes.

Download Full-text

161. Development of a Novel Low Toxicity and High Efficiency PEI-Based Nanopolymer for Gene Delivery In Vitro and In Vivo

Molecular Therapy ◽

10.1016/s1525-0016(16)38519-7 ◽

2009 ◽

Vol 17 ◽

pp. S64 ◽

Cited By ~ 2

Keyword(s):

Gene Delivery ◽

High Efficiency ◽

Low Toxicity

Download Full-text

Evaluation of Paclitaxel Nanocrystals In Vitro and In Vivo

Drug Research ◽

10.1055/s-0043-119461 ◽

2017 ◽

Vol 68 (04) ◽

pp. 205-212 ◽

Cited By ~ 1

Author(s):

Wanqing Li ◽

Zhiguo Li ◽

Lisha Wei ◽

Aiping Zheng

Keyword(s):

Drug Concentration ◽

Antitumor Effects ◽

High Drug ◽

High Drug Concentration ◽

Low Toxicity ◽

Nanoparticle Drug Delivery ◽

Antitumor Evaluation ◽

Mcf 7

AbstractWe created a novel paclitaxel (PTX) nanoparticle drug delivery system and compared this to acommercial injection preparation to evaluate the antitumor effects for both formulations in vivo and in vitro.PTXnanocrystals were 194.9 nm with potential of −29.6 mV. Cytotoxicity tests indicated that both formulations had similar effects and cytotoxicity was dose- and time-dependent.Pharmacodynamics indicated that the drug concentration at the tumor was greater with PTX nanocrystals compared to commercial injection (P<0.01) and that drug accumulated more and for a longer duration. In vivo antitumor evaluation indicated significant antitumor effects and low toxicity of PTX nanocrystals. Moreover, bioimaging indicated that the PTX retention time in MCF-7-bearing mice was longer, especially at the tumor site, and this high drug concentration was maintained for a long time.Overall, PTX nanocrystalsare feasible and superior to traditional injection formulation chemotherapy.

Download Full-text

Graphene: Insights on Biological, Radiochemical and Ecotoxicological Aspects

Journal of Biomedical Nanotechnology ◽

10.1166/jbn.2021.3006 ◽

2021 ◽

Vol 17 (1) ◽

pp. 131-148

Author(s):

Xing Haixia ◽

Aline Oliveira da Silva de Barros ◽

Francisco do Vale Chaves e Mello ◽

Fan Sozzi-Guo ◽

Cristina Müller ◽

...

Keyword(s):

Graphene Oxide ◽

Graphene Quantum Dots ◽

Covalent Bonds ◽

Cell Internalization ◽

Functional Density Theory ◽

Ecotoxicological Evaluation ◽

Plasmatic Membrane ◽

Low Toxicity ◽

The Impact

Graphene, including graphene quantum dots, its oxide and unoxidized forms (pure graphene) have several properties, like fluorescence, electrical conductivity, theoretical surface area, low toxicity, and high biocompatibility. In this study, we evaluated genotoxicity (in silico analysis using the functional density theory-FDT), cytotoxicity (human glioblastoma cell line), in vivo pharmacokinetics, in vivo impact on microcirculation and cell internalization assay. It was also radiolabeled with lutetium 177 (177Lu), a beta emitter radioisotope to explore its therapeutic use as nanodrug. Finally, the impact of its disposal in the environment was analyzed using ecotoxicological evaluation. FDT analysis demonstrated that graphene can construct covalent and non-covalent bonds with different nucleobases, and graphene oxide is responsible for generation of reactive oxygen species (ROS), corroborating its genotoxicity. On the other hand, non-cytotoxic effect on glioblastoma cells could be demonstrated. The pharmacokinetics analysis showed high plasmatic concentration and clearance. Topical application of 0.1 and 1 mg/kg of graphene nanoparticles on the hamster skinfold preparation did not show inflammatory effect. The cell internalization assay showed that 1-hour post contact with cells, graphene can cross the plasmatic membrane and accumulate in the cytoplasm. Radio labeling with 177Lu is possible and its use as therapeutic nanosystem is viable. Finally, the ecotoxicity analysis showed that A. silina exposed to graphene showed pronounced uptake and absorption in the nauplii gut and formation of ROS. The data obtained showed that although being formed exclusively of carbon and carbon-oxygen, graphene and graphene oxide respectively generate somewhat contradictory results and more studies should be performed to certify the safety use of this nanoplatform.

Download Full-text