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Rxivist combines biology preprints from bioRxiv and medRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 128,741 papers from 551,614 authors.

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in category pharmacology and toxicology

1,147 results found. For more information, click each entry to expand.

961: Nitric Oxide Synthase inhibition counteracts the stress-induced DNA methyltransferase 3b expression in the hippocampus of rats
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Posted 06 Aug 2020

Nitric Oxide Synthase inhibition counteracts the stress-induced DNA methyltransferase 3b expression in the hippocampus of rats
122 downloads bioRxiv pharmacology and toxicology

Izaque de Souza Maciel, Amanda Juliana Sales, Plinio C Casarotto, Eero Castrén, Caroline Biojone, Samia Regiane Lourenço Joca

It has been postulated that activation of NMDA receptors (NMDAr) and nitric oxide (NO) production in the hippocampus is involved in the behavioral consequences of stress. Stress triggers NMDAr-induced calcium influx in limbic areas, such as the hippocampus, which in turn activates neuronal NO synthase (nNOS). Inhibition of nNOS or NMDAr activity can prevent stress-induced effects in animal models, but the molecular mechanisms behind this effect are still unclear. In this study, cultured hippocampal neurons treated with NMDA or dexamethasone showed increased of DNA methyltransferase 3b (DNMT3b) mRNA expression, which was blocked by pre-treatment with nNOS inhibitor nω-propyl-L-arginine (NPA). In rats submitted to the Learned Helplessness paradigm (LH), we observed that inescapable stress increased of DNMT3b mRNA expression at 1h and 24h in the hippocampus. The NOS inhibitors 7-NI and aminoguanidine (AMG) decreased the number of escape failures in LH, and counteracted the changes in hippocampal DNMT3b mRNA induced in this behavioral paradigm. Altogether, our data suggest that NO produced in response to NMDAr activation following stress upregulates DNMT3b in the hippocampus. ### Competing Interest Statement The authors have declared no competing interest.

962: Cellular feedback to organotelluranes displays modulation of antioxidant proteins gene expression
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Posted 06 Jan 2021

Cellular feedback to organotelluranes displays modulation of antioxidant proteins gene expression
122 downloads bioRxiv pharmacology and toxicology

Felipe S. Pessoto, César H. Yokomizo, Rodrigo L. O. R. Cunha, Iseli L. Nantes-Cardoso

Organotelluranes, RT3 and RT4, are thiol reagents that induce mitochondrial transition pore (MTP) opening in the manner sensitive and insensitive to cyclosporin A. Although RT3 and RT4 promote glutathione depletion, paradoxically, they are also efficient antioxidant for membrane lipids. These antagonistic effects of these compounds elicited the challenging question of how the gene expression of antioxidant enzymes would respond to treatment with these compounds. The influence of RT3 and RT4 on the expression of antioxidant enzymes was investigated in cultured aortic smooth muscle cells (ASMC). RT-3 and RT4 promoted disruption of Ca2+ homeostasis, mitochondrial transmembrane potential ({Delta}{Psi}), and cell death in a dose-dependent manner. The cell death mechanisms responded qualitatively to the increase of the organotellurane concentration and changed from the predominance of apoptosis to necrosis. RT3 and RT4 increased significantly the expression of thioredoxin. RT3 increased also the expression of glutaredoxin and glutathione peroxidase, slightly the expression of catalase without significant effects on SOD expression. The results are consistent with GSH and protein thiol depletion and discussed on basis of the mechanism of cell toxicity exhibited by these compounds. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

963: Cardiac toxicity predictions: Safety pharmacologists correlate with the CiPA model
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Posted 12 Jun 2020

Cardiac toxicity predictions: Safety pharmacologists correlate with the CiPA model
121 downloads bioRxiv pharmacology and toxicology

Hitesh B. Mistry, Jaimit Parikh

There has been a lot of interest and publicity regarding the use of a complex biophysical model within drug development for predicting the TdeP risk of new compounds. Throughout the development of the complex model numerous groups have shown that a simple linear mechanistic model explains the predictive behaviour of complex mechanistic models. That is the input-output relationship is almost linear even when complex kinetic assays are used. We hypothesized that given this linear relationship that scientist would be able to predict the outcome of the biophysical model. The objective of this pilot study was to assess the feasibility of such an analysis but also assess the initial degree of correlation. A set of 15 compounds with diverse ion-channel blocking against 4 ion-channel currents, IKr, ICaL, INa and INaL, was generated. Safety pharmacologists across numerous companies were approached and asked to categorize the TdeP risk of these compounds using only the % block depicted via a bar chart into one of 3 categories: Risk, No-risk or Unsure. 12 scientists participated in the study, of which 11 correlated strongly with the model (11 person ROC AUC range: 0.86-1, 7 scientists had a value >0.9). The combined prediction of all scientists also correlated strongly with the model. These results highlight that the linear input-output relationship can indeed be predicted by the scientist. A future study exploring the degree of correlation with a wider group of scientists and wider set of compounds would be required to get a more precise estimate of the correlation. We hope this initial exploratory study will encourage the community to pursue this idea. ### Competing Interest Statement The authors have declared no competing interest.

964: Chronic Developmental Lead Exposure increases μ-Opiate Receptor Levels in the Adolescent Rat Brain
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Posted 20 Apr 2020

Chronic Developmental Lead Exposure increases μ-Opiate Receptor Levels in the Adolescent Rat Brain
121 downloads bioRxiv pharmacology and toxicology

Damaris Albores-Garcia, Jennifer L McGlothan, Zoran Bursac, Tomás R Guilarte

Opioid use and abuse has reached epidemic proportion in the United States resulting in a significant number of deaths due to overdose. While environmental factors are implicated in opioid addiction, less is known about the role of exposure to environmental pollutants on the brain opioid system. Human and preclinical studies have suggested an association between childhood lead (Pb2+) intoxication and proclivity to substance abuse and delinquent behavior. Opioid receptors are involved in the biological effects of opioids and other drugs of abuse. In this study, we examine the effect of chronic developmental Pb2+ exposure on m-opioid receptor (MOR) levels in the rat brain using [3H]-D-Ala2-MePhe4-Gly-ol5 enkephalin ([3H]-DAMGO) quantitative receptor autoradiography. Our results indicate that chronic developmental Pb2+ exposure increases the levels of [3H]-DAMGO specific binding to MOR in several limbic regions of the brain in male and female rats during the pre-adolescence (PN14) and early-adolescence (PN28) period. These changes were less pronounced in late-adolescence (PN50) and adult (PN120) animals. Our findings are important because the pre-adolescence and early adolescence period is a time in which there is higher engagement in reward and drug-seeking behaviors in humans. In summary, we show that chronic exposure to Pb2+ an ubiquitous and well-known environmental contaminant and neurotoxicant, alters MOR levels in brain regions associated with addiction circuits in the adolescent period with important implications to opioid drug use and abuse. ### Competing Interest Statement The authors have declared no competing interest.

965: Human ES and iPS Cells Display Less Drug Resistance Than Differentiated Cells, and Naïve-State Induction Further Decreases Drug Resistance
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Posted 17 Aug 2020

Human ES and iPS Cells Display Less Drug Resistance Than Differentiated Cells, and Naïve-State Induction Further Decreases Drug Resistance
121 downloads bioRxiv pharmacology and toxicology

Yulia Panina, Junko Yamane, Kenta Kobayashi, Hideko Sone, Wataru Fujibuchi

Pluripotent stem cells (PSCs) possess unique characteristics that distinguish them from other cell types. Human embryonic stem (ES) cells are recently gaining attention as a powerful tool for human toxicity assessment without the use of experimental animals, and an embryonic stem cell test (EST) was introduced for this purpose. However, human PSCs have not been thoroughly investigated in terms of drug resistance or compared with other cell types or cell states, such as naive state, to date. Aiming to close this gap in research knowledge, we assessed and compared several human PSC lines for their resistance to drug exposure. Firstly, we report that RIKEN-2A human induced pluripotent stem (iPS) cells possessed approximately the same sensitivity to selected drugs as KhES-3 human ES cells. Secondly, both ES and iPS cells were several times less resistant to drug exposure than other non-pluripotent cell types. Finally, we showed that iPS cells subjected to naive-state induction procedures exhibited a sharp increase in drug sensitivity. Upon passage of these naive-like cells in non-naive PSC culture medium, their sensitivity to drug exposure decreased. We thus revealed differences in sensitivity to drug exposure among different types or states of PSCs and, importantly, indicated that naive-state induction could increase this sensitivity.

966: Lipophilic Nanocrystal Prodrug-Release Defines the Extended Pharmacokinetic Profiles of a Year-Long Cabotegravir
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Posted 19 Jan 2021

Lipophilic Nanocrystal Prodrug-Release Defines the Extended Pharmacokinetic Profiles of a Year-Long Cabotegravir
120 downloads bioRxiv pharmacology and toxicology

Nagsen Gauram, JoEllyn M. McMillan, Devendra Kumar, Aditya N Bade, Qiaoyu Pan, Tanmay A Kulkarni, Wenkuan Li, Nathan A. Smith, Bhagya L Dyavar Shetty, Brady Sillman, Adam Szlachetka, Benson J Edagwa, Howard E. Gendelman, Yazen Alnouti

A single, once every eight-week cabotegravir (CAB) long-acting parenteral is more effective than daily oral emtricitabine and tenofovir disoproxil fumarate in preventing human immunodeficiency virus type one (HIV-1) transmission. Extending CAB dosing to a yearly injectable can advance efforts leading to the elimination of viral transmission. The current submission adds rigor, reproducibility and mechanistic insights for the extended apparent half-life of a yearlong antiretroviral injectable. Pharmacokinetic (PK) profiles of a nanoformulated fatty acid ester CAB prodrug (named NM2CAB) were affirmed at two academic and one contract research laboratory. PK profiles showed plasma CAB levels at or above the protein-adjusted 90% inhibitory concentration for up to one year after a single dose. Measures of drug biodistribution demonstrated sustained native drug at the muscle injection site and in lymphoid tissues (spleen and lymph nodes). The results paralleled NM2CAB uptake and retention in human macrophages. NM2CAB nanocrystals were stable in blood, tissue and liver homogenates. The long apparent drug half-life followed pH-dependent slow prodrug release in weeks from the nanocrystal. In contrast, solubilized prodrug was hydrolyzed in hours in plasma and tissues recorded from multiple mammalian species at basic pH. No measurable toxicities were recorded. These results, taken together, affirm the pharmacological mechanistic properties of a year-long nanoformulated CAB prodrug supporting the established protocol design for formulation safety, rigor and reproducibility.

967: Improving drug safety predictions by reducing poor analytical practices
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Posted 28 Sep 2020

Improving drug safety predictions by reducing poor analytical practices
120 downloads bioRxiv pharmacology and toxicology

Stanley E. Lazic, Dominic Williams

Predicting the safety of a drug from preclinical data is a major challenge in drug discovery, and progressing an unsafe compound into the clinic puts patients at risk and wastes resources. In drug safety pharmacology and related fields, methods and analytical decisions known to provide poor predictions are common and include creating arbitrary thresholds, binning continuous values, giving all assays equal weight, and multiple reuse of information. In addition, the metrics used to evaluate models often omit important criteria and models' performance on new data are often not assessed rigorously. Prediction models with these problems are unlikely to perform well, and published models suffer from many of these issues. We describe these problems in detail, demonstrate their negative consequences, and propose simple solutions that are standard in other disciplines where predictive modelling is used. ### Competing Interest Statement The authors have declared no competing interest.

968: Silencing NADPH-Cytochrome P450 reductase affects imidacloprid susceptibility, fecundity, and embryonic development in Leptinotarsa decemlineata
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Posted 01 Oct 2020

Silencing NADPH-Cytochrome P450 reductase affects imidacloprid susceptibility, fecundity, and embryonic development in Leptinotarsa decemlineata
120 downloads bioRxiv pharmacology and toxicology

Timothy W Moural, Liping Ban, Jonathan A. Hernandez, Meixiang Wu, Chaoyang Zhao, Subba R. Palli, Andrei Alyokhin, Fang Zhu

The Colorado potato beetle (CPB) is a prominent insect pest of potatoes, tomatoes and eggplants all over the world, however, the management of CPB remains a challenging task for more than one hundred years. We have successfully developed bacteria-expressed dsRNA-mediated feeding RNA interference (RNAi) approach in our previous study. A critical step towards field management of CPB via feeding RNAi is to identify effective and environmentally safe target genes. NADPH-Cytochrome P450 reductase (CPR) plays a central role in cytochrome P450 action. The full length Leptinotarsa decemlineata CPR ( LdCPR ) cDNA was isolated from an imidacloprid resistant population. The LdCPR gene was ubiquitously expressed in all stages tested but showed an increase in expression during the early stage of embryonic development. The bacteria-expressed dsRNA-mediated feeding RNAi of LdCPR in adults caused systemic knock down expression of the gene coding for LdCPR in both adults and their eggs. Suppression of LdCPR expression increased susceptibility of imidacloprid in resistant beetles, as well as a significant decrease of fecundity in female beetles (29% less eggs/day) and the hatching rate (47%) of their eggs. These data suggest that LdCPR plays important roles in insecticide detoxification and biosynthetic pathways of endogenous compounds and may serve as an essential target to control CPB. HIGHLIGHTS ### Competing Interest Statement The authors have declared no competing interest.

969: Vanilloids Hamper Caenorhabditis elegans Response to Noxious Heat
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Posted 11 Sep 2020

Vanilloids Hamper Caenorhabditis elegans Response to Noxious Heat
119 downloads bioRxiv pharmacology and toxicology

Bruno Nkambeu, Jennifer Ben Salem, Francis Beaudry

Eugenol, a known vanilloid, was frequently used in dentistry as a local analgesic in addition, antibacterial and neuroprotective effects were also reported. Eugenol, capsaicin and many vanilloids are interacting with the transient receptor potential vanilloid 1 (TRPV1) in mammals and are activated by noxious heat. The pharmacological manipulation of the TRPV1 has been shown to have therapeutic value. Caenorhabditis elegans (C. elegans) express TRPV orthologs (e.g. OCR-2, OSM-9) and it is a commonly used animal model system to study nociception as it displays a well-defined and reproducible nocifensive behavior. After exposition to vanilloid solutions, C. elegans wild type (N2) and mutants were placed on petri dishes divided in quadrants for heat stimulation. Thermal avoidance index was used to phenotype each tested C. elegans experimental groups. The results showed that eugenol, vanillin and zingerone can hamper nocifensive response of C. elegans to noxious heat (32C - 35C) following a sustained exposition. Also, the effect was reversed 6h post exposition. Furthermore, eugenol and vanillin did not target specifically the OCR-2 or OSM-9 but zingerone did specifically target the OCR-2 similarly to capsaicin. Further structural and physicochemical analyses were performed. Key parameters for quantitative structure-property relationships (QSPR), quantitative structure-activity relationships (QSAR) and frontier orbital analyses suggest similarities and dissimilarities amongst the tested vanilloids and capsaicin in accordance with the relative anti-nociceptive effects observed. ### Competing Interest Statement The authors have declared no competing interest.

970: Carbon dots deposition in adult bones reveal areas of growth, injury and regeneration
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Posted 14 Oct 2020

Carbon dots deposition in adult bones reveal areas of growth, injury and regeneration
119 downloads bioRxiv pharmacology and toxicology

Rachel DuMez, Esmail Miyanji, Lesly Corado-Santiago, Bryle Barrameda, Yiqun Zhou, Sajini D Hettiarachchi, Roger Leblanc, Isaac Skromne

C-dots synthesized from carbon nanopowder (oxidation, hydrothermal) are particularly attractive theragnostic agents for bone-related injuries and disease due to their bright fluorescence and high binding affinity and specificity for bones, as demonstrated in a larval animal model. Larval bone development, however, is significantly different from the bone growth, repair and regeneration processes occurring in adults. Using adult zebrafish, we investigated C-dots interactions with adult skeletal structures. Upon injection, C-dots were observed at the surface of bones, at sites of appositional growth. In regenerating bones, C-dots were observed at the core and on the surface of the bones depending on the age of the tissue. C-dots deposition occurred within 30 min of delivery and it was highly selective. Importantly, their deposition did not interfere with bone regeneration or the animals health. Together, these properties establish C-dots as novel tools for the diagnostic and treatment of adult bone-related injuries and diseases. ### Competing Interest Statement The authors have declared no competing interest.

971: Automated identification of multinucleated germ cells with U-Net
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Posted 20 Feb 2020

Automated identification of multinucleated germ cells with U-Net
119 downloads bioRxiv pharmacology and toxicology

Samuel Bell, Andras Zsom, Justin Conley, Daniel Spade

Phthalic acid esters (phthalates) are male reproductive toxicants, which exert their most potent toxicity during a critical window of sensitivity in fetal development. In the fetal rat, exposure to phthalates reduces testosterone biosynthesis, alters the development of seminiferous cords and other male reproductive tissues, and induces the formation of abnormal multinucleated germ cells (MNGs). Identification of MNGs is a time-intensive process, and it requires specialized training to identify MNGs in histological sections. As a result, MNGs are not routinely quantified in phthalate toxicity experiments. In order to speed up and standardize this process, we have developed an improved method for automated detection of MNGs. Using hand-labeled histological section images with human-identified MNGs, we trained a convolutional neural network with a U-Net architecture to identify MNGs on unlabeled images. With unseen hand-labeled images not used in model training, we assessed the performance of the model, using five different configurations of the data. On average, the model reached near human accuracy, and in the best model, it exceeded it. The use of automated image analysis will allow data on this histopathological endpoint to be more readily collected for analysis of phthalate toxicity. Our trained model application code is available for download at github.com/brown-ccv/mngcount.

972: The Lonidamine Derivative H2-Gamendazole Reduces Cyst Formation in Polycystic Kidney Disease
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Posted 09 Sep 2020

The Lonidamine Derivative H2-Gamendazole Reduces Cyst Formation in Polycystic Kidney Disease
118 downloads bioRxiv pharmacology and toxicology

Shirin V. Sundar, Xia Zhou, Brenda S. Magenheimer, Gail A. Reif, Darren Wallace, Gunda I. Georg, Sudhakar R. Jakkaraj, Joseph S. Tash, Alan S.L. Yu, Xiaogang Li, James Calvet

Autosomal dominant polycystic kidney disease (ADPKD) is a debilitating renal neoplastic disorder with limited treatment options. It is characterized by the formation of large fluid-filled cysts that develop from kidney tubules through abnormal cell proliferation and cyst-filling fluid secretion driven by cAMP-dependent Cl− secretion. We have examined the effectiveness of the indazole carboxylic acid, H2-gamendazole (H2-GMZ), a derivative of lonidamine, to inhibit these processes and cyst formation using in vitro and in vivo models of ADPKD. H2-GMZ was effective in rapidly blocking forskolin-induced, Cl−-mediated short-circuit currents in human ADPKD cells at 1 μM and it significantly inhibited both cAMP- and EGF-induced proliferation of ADPKD cells with an IC50 of 5-10 μM. Western blot analysis of H2-GMZ-treated ADPKD cells showed decreased phosphorylated ERK and hyperphosphorylated Rb levels. H2-GMZ treatment also decreased ErbB2, Akt, and Cdk4, consistent with inhibition of the chaperone Hsp90, and reduced the levels of the CFTR Cl− channel. H2-GMZ-treated ADPKD cultures contained a higher proportion of smaller cells with fewer and smaller lamellipodia and decreased cytoplasmic actin staining, and they were unable to accomplish wound closure even at low H2-GMZ concentrations, consistent with an alteration in the actin cytoskeleton and decreased cell motility. Studies using mouse metanephric organ cultures showed that H2-GMZ inhibited cAMP-stimulated cyst growth and enlargement. In vivo , H2-GMZ (20mg/kg) was effective in slowing postnatal cyst formation and kidney enlargement in the Pkd1 flox/flox : Pkhd1-Cre mouse model. Thus, H2-GMZ treatment decreases Cl− secretion, cell proliferation, cell motility, and cyst growth. These properties, along with its reported low toxicity, suggest that H2-GMZ might be an attractive candidate for treatment of ADPKD. ### Competing Interest Statement Dr. Shirin V. Sundar is currently employed by Otsuka Pharmaceutical Development and Commercialization, Inc.

973: The narrow-spectrum anthelmintic oxantel is a potent agonist of a novel acetylcholine receptor subtype in whipworms
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Posted 17 Sep 2020

The narrow-spectrum anthelmintic oxantel is a potent agonist of a novel acetylcholine receptor subtype in whipworms
118 downloads bioRxiv pharmacology and toxicology

Tina V. A. Hansen, Susanna Cirera, Cédric Neveu, Kirstine Calloe, Dan A. Klaerke, Richard J Martin

In the absence of efficient alternative strategies, the control of parasitic nematodes, impacting human and animal health, mainly relies on the use of broad-spectrum anthelmintic compounds. Unfortunately, most of these drugs have a limited single-dose efficacy against infections caused by the whipworm, Trichuris . These infections are of both human and veterinarian importance. However, in contrast to a wide range of parasitic nematode species, the narrow-spectrum anthelmintic oxantel has a high efficacy on Trichuris spp . Despite this knowledge, the molecular target(s) of oxantel within Trichuris is still unknown. In the distantly related pig roundworm, Ascaris suum , oxantel has a small, but significant effect on the recombinant homomeric N icotine-sensitive ionotropic acetylcholine receptor ( N -AChR) made up of five ACR-16 subunits. Therefore, we hypothesized that in whipworms, a putative homolog of an ACR-16 subunit, can form a functional oxantel-sensitive receptor. Using the pig whipworm T. suis as a model, we identified and cloned a novel ACR-16-like receptor subunit and successfully expressed the corresponding homomeric channel in Xenopus laevis oocytes. Electrophysiological experiments revealed this receptor to have distinctive pharmacological properties with oxantel acting as a full agonist, hence we refer to the receptor as an O -AChR subtype. Pyrantel activated this novel O -AChR subtype moderately, whereas classic nicotinic agonists surprisingly resulted in only minor responses. We demonstrated that the novel Tsu- ACR-16-like receptor is indeed a target for oxantel and is more responsive to oxantel than the ACR-16 receptor from A. suum . These finding most likely explain the high sensitivity of whipworms to oxantel, and highlights the importance of the discovery of additional distinct receptor subunit types within Trichuris that can be used as valuable screening tools to evaluate the effect of new synthetic or natural anthelmintic compounds. Author Summary The human whipworm, Trichuris trichiura , is an intestinal parasitic nematode infecting approximately 289.6 million people globally, primarily children living in developing countries. Chronic T. trichiura infection may cause dysentery, growth stunting and decreased cognitive performance. Whipworm infections are notoriously difficult to control with most available anthelmintics, including those commonly used in mass drug administration programs. Recently performed randomised controlled trials with whipworm-infected humans, have reported superior efficacies of oxantel, a classic, narrow-spectrum anthelmintic, developed for the treatment of Trichuris infections. Despite this knowledge, the molecular target(s) of oxantel within the whipworm has not been identified. In this study, we used the whipworm from pigs as a model and identified a receptor, which was explored using the Xenopus oocyte expression system. We demonstrated that this receptor is highly responsive to oxantel, and therefore a major target of oxantel within Trichuris . In addition, we discovered that this receptor-type is distinctive and only present in the ancient group of parasitic nematodes, Clade I, which also includes the important zoonotic parasite Trichinella . Our findings, explain the specific mode of action of oxantel and open the way for additional characterization of similar receptor subtypes in other medically or veterinary important parasitic nematodes of Clade I.

974: Varenicline rescues nicotine-induced decrease in motivation for sucrose reinforcement
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Posted 04 Jun 2020

Varenicline rescues nicotine-induced decrease in motivation for sucrose reinforcement
118 downloads bioRxiv pharmacology and toxicology

Erin Hart, Daniel Hertia, Scott T Barrett, Sergios Charntikov

Varenicline is one of the top medications used for smoking cessation and is often prescribed before termination of nicotine use. The effect of this combined nicotine and varenicline use on the reward system and motivation for primary reinforcement is underexplored. The goal of this study was to assess the effects of nicotine and varenicline on the consumption of sucrose. In Experiment 1, we first assessed the responding for sucrose after pretreatment with nicotine (0, 0.1, or 0.4 mg/kg) and varenicline (0.0, 0.1, 1.0 mg/kg) using a behavioral economics approach. The responding for sucrose was then assessed using a progressive ratio schedule of reinforcement after pretreatment with all possible combinations of nicotine and varenicline doses. In Experiment 2, rats were assessed for the consumption of sucrose in home cages after pretreatment with nicotine and varenicline. We found that a) nicotine decreased economic demand for sucrose, b) varenicline rescued nicotine-induced reduction in economic demand for sucrose, and c) history of varenicline treatment predicted responding for sucrose on a progressive ratio schedule of reinforcement where rats with a history of varenicline treatment responded significantly lower for sucrose across nicotine doses than rats that have not being exposed to varenicline. The results of Experiment 2 largely confirmed that nicotine decreases motivation for sucrose using a passive consumption protocol and that varenicline rescues this effect. Overall, these findings suggest that varenicline interacts with the effects of nicotine by restoring nicotine-induced reduction in motivation for appetitive rewards. ### Competing Interest Statement The authors have declared no competing interest.

975: Inhibition of inositol-requiring enzyme 1α RNase activity protects pancreatic beta cell and improves diabetic condition in insulin mutation-induced diabetes
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Posted 31 Aug 2020

Inhibition of inositol-requiring enzyme 1α RNase activity protects pancreatic beta cell and improves diabetic condition in insulin mutation-induced diabetes
117 downloads bioRxiv pharmacology and toxicology

Oana Herlea-Pana, Venkateswararao Eeda, Ram Babu Undi, Iulia Rus, Hui-Ying Lim, Weidong Wang

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 and increased serum insulin levels in Akita mice. These benefits were accompanied by a concomitant protection of functional β-cell mass, as shown by the suppression of β-cell apoptosis, increase in mature insulin production and reduction of proinsulin level. At the molecular level, we observed that the expression of genes associated with β-cell identity and function was significantly up-regulated and ER stress and its associated inflammation and oxidative stress were suppressed in islets from Akita mice treated with IRE1α RNase inhibitors. This study provides the first evidence of the in vivo efficacy of IRE1α RNase inhibition in Akita mice, pointing to the possibility of targeting IRE1α RNase as a therapeutic direction for the treatment of MIDY diabetes. ### Competing Interest Statement The authors have declared no competing interest.

976: Transgenerational inheritance of abnormal spermatogenesis with Igf2/H19 epigenetic alteration in CD1 mouse induced by in utero arsenic exposure
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Posted 18 Apr 2020

Transgenerational inheritance of abnormal spermatogenesis with Igf2/H19 epigenetic alteration in CD1 mouse induced by in utero arsenic exposure
117 downloads bioRxiv pharmacology and toxicology

Guoying Yin, Liting Xia, Yaxing Hou, Yaoyan Li, Deqing Cao, Yanan Liu, Jingshan Chen, Juan Liu, Liwen Zhang, Qiaoyun Yang, Qiang Zhang, Naijun Tang

Developmental exposure to environmental toxicants can induce transgenerational reproductive disease phenotypes through epigenetic mechanisms. However, little is known about the transgenerational effects of arsenic exposure. We hypothesize that prenatal arsenic exposure may result in impaired spermatogenesis in subsequent generations of male mice. To test our hypothesis, we treated pregnant CD-1 (F0) mice with drinking water containing sodium arsenite (85 ppm) from days 8 to 18 of gestation. Male offspring were bred with untreated female mice until the F3 generation was produced. Our results revealed that transient exposure of the F0 gestating female to arsenic can result in decreased sperm quality and histological abnormalities in testes of male offspring in the F1 and F3 generations. The overall methylation status of Igf2 DMR2 and H19 DMR was significantly lower in the arsenic-exposed group than that of the control group in both F1 and F3 generations. The relative mRNA expression levels of Igf2 and H19 in arsenic-exposed males were significantly higher than in the control males in both F1 and F3 generations. This study indicates that ancestral exposure to arsenic may result in transgenerational inheritance of an impaired spermatogenesis phenotyping involving both epigenetic alterations and the abnormal expression of Igf2 and H19. ### Competing Interest Statement The authors have declared no competing interest.

977: Alleviatory effects of Danshen, Salvianolic acid A and Salvianolic acid B on PC12 neuronal cells and Drosophila melanogaster model of Alzheimer's disease.
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Posted 14 May 2020

Alleviatory effects of Danshen, Salvianolic acid A and Salvianolic acid B on PC12 neuronal cells and Drosophila melanogaster model of Alzheimer's disease.
117 downloads bioRxiv pharmacology and toxicology

Florence Hui Ping Tan, Andrew Chung Jie Ting, Nazalan Najimudin, Nobumoto Watanabe, Ghows Azzam

Alzheimer's disease (AD) is the most common form of neurodegenerative disorder worldwide. Its pathogenesis involves the hallmark aggregation of amyloid-beta (Aβ). Of all the Aβ oligomers formed in the brain, Aβ42 has been found to be the most toxic and aggressive. Despite this, the mechanism behind this disease remains elusive. With the ability to utilize various genetic manipulations, Drosophila melanogaster is ideal in analysing not only cellular characteristics, but also physiological and behavioural traits of human neurodegenerative diseases. Danshen water extract (DWE), obtained from the root of Salvia miltiorrhiza Bunge, was found to have a vast array of beneficial properties. In this study, DWE, and its major components, Salvianolic acid A (SalA) and Salvianolic acid B (SalB) were tested for their abilities to ameliorate Aβ42's effects. DWE, SalA and SalB were confirmed to be able to reduce fibrillation of Aβ42. As Aβ42 causes neurodegeneration on neurons, DWE, SalA and SalB were tested on Aβ42-treated PC12 neuronal cells and were shown to increase cell viability. DWE and its components were then tested on the Drosophila melanogaster AD model and their rescue effects were further characterized. When human Aβ42 was expressed, the Drosophila exhibited degenerated eye structures known as the rough eye phenotype (REP), reduced lifespan and deteriorated locomotor ability. Administration of DWE, SalA and SalB partially reverted the REP, increased the age of AD Drosophila and improved most of the mobility of AD Drosophila . In conclusion, DWE and its components may have therapeutic potential for AD patients and possibly other forms of brain diseases. ### Competing Interest Statement The authors have declared no competing interest.

978: Accelerated erythrocyte senescence causes dose-limiting anemia of antimalarial enolase inhibitors
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Posted 10 Oct 2020

Accelerated erythrocyte senescence causes dose-limiting anemia of antimalarial enolase inhibitors
117 downloads bioRxiv pharmacology and toxicology

Andrew J. Jezewski, Yu-Hsi Lin, Julie A. Reisz, Rachel Culp-Hill, Yasaman Barekatain, Victoria C Yan, Angelo D’Alessandro, Florian L Muller, Audrey R Odom John

Glycolysis controls cellular energy, redox balance, and biosynthesis. Antiglycolytic therapies are being investigated for obesity, cancer, aging, autoimmunity, and microbial diseases. Interrupting glycolysis is highly valued as a therapeutic strategy, because glycolytic disruption is generally tolerated in mammals. Unfortunately, anemia is a key dose-limiting side effect of these inhibitors and presents a major caveat to development of antiglycolytic therapies. We developed specific inhibitors of enolase (a critical enzyme in glycolysis) and validated their metabolic and cellular effects on human erythrocytes. Enolase inhibition increases erythrocyte susceptibility to oxidative damage that induces rapid and premature erythrocyte senescence, rather than direct hemolysis. We apply our model of red cell toxicity to address questions regarding erythrocyte glycolytic disruption in the context of malaria pathogenesis. Our study provides a framework for understanding red blood cell homeostasis under normal and disease states and clarifies the importance of erythrocyte reductive capacity. ### Competing Interest Statement The authors have declared no competing interest.

979: Pro-metaphase arrest, polyploidy, micronuclei, and mitotic abnormality inducing agents isolation from leaf aqueous extract of Clerodendrum viscosum Vent.
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Posted 01 Dec 2020

Pro-metaphase arrest, polyploidy, micronuclei, and mitotic abnormality inducing agents isolation from leaf aqueous extract of Clerodendrum viscosum Vent.
117 downloads bioRxiv pharmacology and toxicology

Sujit Roy, Lalit Mohan Kundu, Gobinda Chandra Roy, Manabendu Barman, Sanjib Ray

Clerodendrum viscosum is a traditionally used medicinal plant and the earlier reports indicate its leaf aqueous extract (LAECV) contains metaphase arresting, cell cycle delay, and mitotic abnormality inducing active principles. The present study aimed to isolate pro-metaphase arresting, polyploidy, micronuclei and mitotic abnormality inducing active principles of LAECV. The LAECV was successively fractionated as petroleum ether (PEF), chloroform (CHF), and ethyl acetate (EAF) fractions. All the extract fractions were tested for Allium cepa and Triticum aestivum root swelling and root growth inhibition analyses. The petroleum ether fraction was selected for further cytotoxicity analysis on A. cepa root tip cells and was processed for detection of the active principles through HPLC, LC-MS, GC-MS and IR analyses. The comparative seedlings' root growth and swelling patterns indicate the bioactive principles are effectively fractionated in PEF and GC-MS analysis revealed the presence of Clerodin (m/z 434.3), 15-hydroxy-14, 15-dihydroclerodin (m/z 452), 15-methoxy-14, 15-dihydroclerodin (m/z 466), and 14, 15-dihydroclerodin (m/z 436) with the retention time of 14.038, 14.103, 14.480 and 14.655 respectively. Thus the present study explores clerodane diterpenoids of LAECV as pro-metaphase arresting, polyploidy, micronuclei, and mitotic abnormality inducing active principles.

980: Modeling disease progression in newly diagnosed type 2 diabetes
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Posted 05 May 2020

Modeling disease progression in newly diagnosed type 2 diabetes
116 downloads bioRxiv pharmacology and toxicology

Kun Hao, Yanguang Cao

Type 2 diabetes (T2DM) is a progressive disease, which is primarily characterized by a decline in β-cell function and worsening of insulin resistance. Unfortunately, most interventions (lifestyle, diet, and therapeutic agents) for T2DM only provide a transient restoration of β-cell function and the progression is inevitable once it starts. To understand the natural progression of T2DM, a mechanistic model was developed to quantitatively characterize the dynamic interactions among β-cell function, plasma fasting glucose (PFG), fasting insulin (FI), and the degree of insulin resistance, starting from an early stage of T2DM over up to 8 years. The model was validated using clinical data to optimize the disease parameters. The restoration and deterioration rates of β-cell function were both predicted as 84.5 %/year and 1.10 /year for early stages of T2DM. The model predicted a positive correlation between the initial level of β-cell function at diagnosis and its maximum restoration potential, underscoring the importance of early diagnosis and intervention. After the treatment, β-cell function could be temporarily restored within several months, which has a long-term benefit in glycemic control. The maximal tolerated PFG level that permits β-cell function restoration was predicted to be around 8.33 nM; and the temporal restoration of β-cell function would be unlikely at a PFG level above this threshold. The intrinsic deterioration rates of β-cell function and insulin resistance were both critical factors for long-term glycemic control. In conclusion, our model provides a quantitative analysis of the natural disease progression in T2DM and yields insights into factors that are critical for long-term glycemic control. ### Competing Interest Statement The authors have declared no competing interest.

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