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Results 961 through 980 out of 1084

in category pharmacology and toxicology

 

961: Yeast grown in continuous culture systems can detect mutagens with improved sensitivity relative to the Ames test

Joseph Y Ong, Julia T Pence et al.

104 downloads (posted 15 Jun 2020)

Continuous culture systems allow for the controlled growth of microorganisms over a long period of time. Here, we develop a novel test for mutagenicity that involves growing yeast in continuous culture systems exposed to low levels of mutagen for a period of weeks. In contrast, most microorganism-based tests for mutagenicity expose the potential mutagen to the biological reporter at a high concentration of mutagen for a short period of time. Our test improves upon the sensitivity of the well-established Ames test by at least 20-fold for each of two mutagens that act by different mechanisms (the intercalator ethidium bromide and alkylating agent methylmethane sulfonate). To conduct the tests, cultures were grown in small, inexpensive continuous culture systems in media containing (potential) mutagen, and the resulting mutagenicity of the added compound was assessed via two methods: a canavanine-based plate assay and whole genome sequencing. In the canavanine-based plate assay, we were able to detect a clear relationship between the amount of mutagen and the number of canavanine-resistant mutant colonies over a period of one to three weeks of exposure. Whole genome sequencing of yeast grown in continuous culture systems exposed to MMS demonstrated that quantification of mutations is possible by identifying the number of unique variants across each strain but with lower sensitivity than the plate-based assay. In conclusion, we propose yeast grown in continuous culture systems can provide an improved and more sensitive test for mutagenicity.

https://rxivist.org/papers/87527
https://doi.org/10.1101/2020.06.15.152371

962: Eurycomanone regulates lipid metabolism by activating the cAMP/PKA pathway

Jiang zhihui, Haote Han et al.

103 downloads (posted 20 Aug 2020)

Eurycoma longifolia Jack (ELJ) contains mainly alkaloids, and quassinoids, which are the main active ingredients. Eurycomanone (EN), one of the most common quassinoids, is said to have beneficial effects on lipid and glucose metabolism. In this study, we investigated the effects of EN on lipolysis by establishing a high-fat animal model in vivo and evaluated its efficacy as a lipolytic and anti-fatty liver agent. Oil red O staining showed morphological changes of 3T3-L1 preadipocytes after EN treatment and confirmed the...

https://rxivist.org/papers/95139
https://doi.org/10.1101/2020.08.20.258855

963: Characterization, and Anti-microbial Properties of Zinc Oxide Nanoparticles Synthesized Using Citrus sinensis (L.) Osbeck Peel Extract

Dharma Prasad Khanal, Sadikshya Aryal et al.

103 downloads (posted 14 Oct 2020)

Background: Citrus sinensis (L.) Osbeck peels are usually discarded as wastes; however, they are rich sources of Vitamin C, fibre, and many nutrients including phenolics and flavonoids which are also good antioxidant agents. This study aimed to examine phytochemical composition, antioxidant capabilities, cytotoxicity of C. sinensis (L.) Osbeck peel extract and and to compare the antibacterial activity with zinc nanoparticles of Citrus sinensis (L.) Osbeck peels with its extract. GC-MS analysis of the compounds present i...

https://rxivist.org/papers/96199
https://doi.org/10.1101/2020.10.13.337022

964: Antimalarial drugs lose their activity with a slight drop in pH

Tomohisa Kitagawa, Atsushi Mastumoto et al.

103 downloads (posted 05 Aug 2020)

Antimalarial drugs have antimicrobial, antiviral, antimalarial and immunosuppressive activities, although the mechanisms remain unknown. Quinacrine (QC) increases the antimicrobial activity against yeast exponentially with a pH-dependent increase in the cationic amphiphilic drug (CAD) structure. CAD-QC localizes in membranes and induces glucose starvation by noncompetitively inhibiting glucose uptake. A logarithmic increase in antimicrobial activity with pH-dependent CAD formation was also observed for chloroquine, indi...

https://rxivist.org/papers/93549
https://doi.org/10.1101/2020.08.04.237255

965: Inhibition of inositol-requiring enzyme 1α RNase activity protects pancreatic beta cell and improves diabetic condition in insulin mutation-induced diabetes

Oana Herlea-Pana, Venkateswararao Eeda et al.

103 downloads (posted 31 Aug 2020)

Proinsulin misfolding in the endoplasmic reticulum (ER) plays an important role in β-cell dysfunction and death and the pathogenesis of mutant INS -gene-induced diabetes of youth (MIDY). There is no effective treatment for MIDY except the insulin administration. Here, we found that the ER stress sensor inositol-requiring enzyme 1α (IRE1α) was activated in the Akita mice, a mouse model of MIDY. Normalization of IRE1α RNase hyperactivity by pharmacological inhibitors significantly ameliorated the hyperglycemic conditions ...

https://rxivist.org/papers/100896
https://doi.org/10.1101/2020.08.30.274381

966: Diazepam attenuates the effects of cocaine on locomotion, 50-kHz ultrasonic vocalizations and phasic dopamine release in the nucleus accumbens of rats

William N. Sanchez Luna, Jose A. Pochapski et al.

102 downloads (posted 14 Oct 2020)

Background and Purpose : Currently, no effective drug exists to treat cocaine use disorders, which affect millions of people worldwide. Benzodiazepines are potential therapeutic candidates, as microdialysis and voltammetry studies have shown that they can decrease dopamine release in the nucleus accumbens of rodents. In addition, we have recently shown that diazepam blocks the increase in dopamine release and the affective marker 50-kHz ultrasonic vocalizations (USV) induced by DL-amphetamine in rats. Experimental Appro...

https://rxivist.org/papers/96165
https://doi.org/10.1101/2020.10.13.338343

967: Qualitative and quantitative bioanalytical methods validation of aristolochic acid DNA adducts and application in human formalin-fixed paraffin-embedded hepatocellular carcinoma tissues

Wang xin, Song jinping et al.

102 downloads (posted 21 Aug 2020)

Mutation signature of aristolochic acid (AA) found in urothelial or hepatocellular carcinoma causes public concern about the cancer risk of AA. In contrast, direct evidence based on the reliable bioanalytical method for the exposure of AA is still lacking and not universal. Here, we strictly complied with the qualitative and quantitative guidance for forensic toxicological analysis: In the sample preprocessing, DNA from formalin-fixed and paraffin-embedded (FFPE) tissues was digested to single nucleotide by a series of ...

https://rxivist.org/papers/95223
https://doi.org/10.1101/2020.08.20.260331

968: Health professionals’ over estimation of knowledge on snakebite management, a threat to survival of snake bite victims - A cross-sectional study in Ghana

Evans Paul Kwame Ameade, Isaac Bonney et al.

101 downloads (posted 03 Sep 2020)

Background According to the World Health Organization, snakebites, a common occupational hazard in developing countries accounts an annual loss of between 81,000 and 139, 000 lives following 5 million of bites of which 2.7 million results in envenomation. Since snakebite associated morbidity and mortality is more prevalent in agriculture economies such as Ghana, health professionals should be optimally knowledgeable on how to manage incidence of snakebites. Lack of knowledge or overestimation of a professional’s knowled...

https://rxivist.org/papers/100381
https://doi.org/10.1101/2020.09.02.280586

969: PDE1 inhibition modulates Cav1.2 channel to stimulate cardiomyocyte contraction

Grace K Muller, Joy Song et al.

100 downloads (posted 05 Nov 2020)

Rationale: Cyclic adenosine monophosphate (cAMP) activation of protein kinase A (PKA) stimulates excitation-contraction coupling, increasing cardiac contractility. This is clinically leveraged by beta-adrenergic stimulation (β-ARs) or phosphodiesterase-3 inhibition (PDE3i), though both approaches are limited by arrhythmia and chronic myocardial toxicity. Phosphodiesterase-1 inhibition (PDE1i) also augments cAMP and was recently shown in rabbit cardiomyocytes to augment contraction independent of β-AR stimulation or bloc...

https://rxivist.org/papers/103179
https://doi.org/10.1101/2020.11.05.368852

970: Cytoprotective effects of combination of gypenosides and Costus pictus D.Don extract in BRIN-BD11 β-cells

Chinmai Patibandla, Mark James Campbell et al.

100 downloads (posted 07 Sep 2020)

Ethnopharmacological Relevance Gypenosides and Costus pictus D.Don are used as an anti-diabetic herbal remedy in China and India respectively. However, the synergistic effect of these two extracts on β-cell protection is not yet elucidated. Introduction In Type 2 diabetes mellitus (T2DM), pro-inflammatory cytokines and lipotoxicity are known causes of pancreatic β-cell dysfunction and impaired insulin secretion and eventually β-cell death. Thus, any cytoprotective drug supplements can protect the β-cell and may help in...

https://rxivist.org/papers/100114
https://doi.org/10.1101/2020.09.07.286435

971: Development of an orally-administrable tumor vasculature-targeting therapeutic using annexin A1-binding D-peptides

Motohiro Nonaka, Hideaki Mabashi-Asazuma et al.

98 downloads (posted 12 Oct 2020)

IF7 peptide, which binds to the annexin A1 (ANXA1) N-terminal domain, functions as a tumor vasculature-targeted drug delivery vehicle after intravenous injection. To enhance IF7 stability in vivo , we undertook mirror-image peptide phage display using a synthetic D-peptide representing the Anxa1 N-terminus as target. Peptide sequences were identified, synthesized as D-amino acids, and designated as dTIT7, which was shown to bind the ANXA1 N-terminus. Whole body imaging of mouse brain tumors modeled with near infrared fl...

https://rxivist.org/papers/96350
https://doi.org/10.1101/2020.10.12.335851

972: Genetic ablation of serotonin receptor 2B improves aortic valve hemodynamics in a high-cholesterol diet mouse model

J. Ethan Joll, Cyndi Clark et al.

98 downloads (posted 18 Aug 2020)

Calcific aortic valve disease (CAVD) is a deadly disease that is rising in prevalence due to population aging. While the disease is complex and poorly understood, one well-documented driver of valvulopathy is serotonin agonism. Both serotonin overexpression, as seen with carcinoid tumors and drug-related agonism, such as with Fenfluramine use, are linked with various diseases of the valves. Thus, the objective of this study was to determine if genetic ablation or pharmacological antagonism of the 5-HT 2B serotonin recep...

https://rxivist.org/papers/94909
https://doi.org/10.1101/2020.08.18.255414

973: Where and how does d-amphetamine act to reveal antipsychotic-induced dopamine supersensitivity in rats?

Alice Servonnet, Florence Allain et al.

98 downloads (posted 09 Sep 2020)

Antipsychotic treatment can produce a dopamine supersensitive state. In both schizophrenia patients and rodents, this is linked to antipsychotic treatment failure. In rodents, dopamine supersensitivity is often confirmed by an exaggerated behavioural response to the indirect monoamine agonist, d-amphetamine, after discontinuation of antipsychotic treatment. Here we investigated where and how d-amphetamine acts to trigger behavioural expression of dopamine supersensitivity, as this could uncover pathophysiological mechan...

https://rxivist.org/papers/99890
https://doi.org/10.1101/2020.09.08.287664

974: Pathway-extended gene expression signatures integrate novel biomarkers that improve predictions of patient responses to kinase inhibitors

Ashis J. Bagchee-Clark, Eliseos J Mucaki et al.

98 downloads (posted 15 Nov 2020)

Cancer chemotherapy responses have been related to multiple pharmacogenetic biomarkers, often for the same drug. This study utilizes machine learning to derive multi-gene expression signatures that predict individual patient responses to specific tyrosine kinase inhibitors, including erlotinib, gefitinib, sorafenib, sunitinib, lapatinib and imatinib. Support Vector Machine learning was used to train mathematical models that distinguished sensitivity from resistance to these drugs using a novel systems biology-based appr...

https://rxivist.org/papers/104094
https://doi.org/10.1101/2020.11.13.381798

975: Quantifying synergy in the bioassay-guided fractionation of natural product extracts

Micah Dettweiler, Lewis Marquez et al.

97 downloads (posted 23 Jun 2020)

Mixtures of drugs often have greater therapeutic value than any of their constituent drugs alone, and such combination therapies are widely used to treat diseases such as cancer, malaria, and viral infections. However, developing useful drug mixtures is challenging due to complex interactions between drugs. Natural substances can be fruitful sources of useful drug mixtures because secondary metabolites produced by living organisms do not often act in isolation in vivo. In order to facilitate the study of interactions wi...

https://rxivist.org/papers/88569
https://doi.org/10.1101/2020.06.23.166686

976: Effects of salvianolic acid A on β-amyloid mediated toxicity in Caenorhabditis elegans model of Alzheimer's disease

Chee Wah Yuen, Mardani Abdul Halim et al.

97 downloads (posted 14 Apr 2020)

Alzheimers disease (AD) is a brain disease attributed to the accumulation of extracellular senile plaques comprising β-amyloid peptide (Aβ). In this study, a transgenic Caenorhabditis elegans containing the human beta amyloid Aβ42 gene which exhibited paralysis when expressed, was used to study the anti-paralysis effect of salvianolic acid A. Various concentrations ranging from 1 μg/ml to 100 μg/ml of salvianolic acid A were tested and exhibited the highest effect on the worm at the concentration of 100 μg/ml. For anti-...

https://rxivist.org/papers/79821
https://doi.org/10.1101/2020.04.13.040170

977: Cytoplasmic aggregation of uranium in human dopaminergic cells after continuous exposure to soluble uranyl at non-cytotoxic concentrations

Asuncion Carmona, Francesco Porcaro et al.

95 downloads (posted 16 Jul 2020)

Uranium exposure can lead to neurobehavioral alterations in particular of the monoaminergic system, even at non-cytotoxic concentrations. However, the mechanisms of uranium neurotoxicity after non-cytotoxic exposure are still poorly understood. In particular, imaging uranium in neurons at low intracellular concentration is still very challenging. We investigated uranium intracellular localization by means of synchrotron X-ray fluorescence imaging with high spatial resolution (< 300 nm) and high analytical sensitivity (<...

https://rxivist.org/papers/91290
https://doi.org/10.1101/2020.07.16.205831

978: Chronic high glyphosate exposure delays individual worker bee (Apis mellifera L.) development under field conditions

Richard Odemer, Abdulrahim T. Alkassab et al.

95 downloads (posted 10 Jul 2020)

The ongoing debate about glyphosate-based herbicides (GBH) and their implications for beneficial arthropods give rise to controversy. This research was carried out to cover possible sublethal GBH effects on brood and colony development, adult survival, and overwintering success of honey bees (Apis mellifera L.) under field conditions. Residues in bee relevant matrices such as nectar, pollen and plants were measured in addition. To address these questions, we adopted four independent study approaches. For brood effects a...

https://rxivist.org/papers/90645
https://doi.org/10.1101/2020.07.08.194530

979: Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo

Katharina Ernst, Ann-Katrin Mittler et al.

95 downloads (posted 25 Sep 2020)

Whooping cough is caused by Bordetella pertussis that releases pertussis toxin (PT) which comprises enzyme A-subunit PTS1 and binding/transport B-subunit. After receptor-mediated endocytosis, PT reaches the endoplasmic reticulum from where unfolded PTS1 is transported to the cytosol. PTS1 ADP-ribosylates G-protein α-subunits resulting in increased cAMP signaling. Here, the role of target cell chaperones Hsp90, Hsp70, cyclophilins and FK506-binding proteins for cytosolic PTS1-uptake is characterized in detail. PTS1 speci...

https://rxivist.org/papers/98245
https://doi.org/10.1101/2020.09.24.303321

980: Mutations associated with pyrethroid resistance in Varroa mites, a parasite of honey bees, are widespread across the USA

Anabel Millán-Leiva, Óscar Marín et al.

94 downloads (posted 28 Nov 2020)

BACKGROUND: Managed honey bees are key pollinators of many crops and play an essential role in the United States food production. For more than 10 years, beekeepers in the US have been reporting high rate of colony losses. One of the drivers of this colony loss is the parasitic mite Varroa destructor. Preserving healthy honey bee colonies in the US is dependent on a successful control of this mite. The pyrethroid tau-fluvalinate (Apistan(R)) was among the first synthetic varroacide registered in the US. With over 20 yea...

https://rxivist.org/papers/119288
https://doi.org/10.1101/2020.11.27.401927