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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 125,186 papers from 537,576 authors.

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in category pharmacology and toxicology

1,084 results found. For more information, click each entry to expand.

941: 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
112 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.

942: Reanalysis of in vivo drug synergy validation study rules out synergy in most cases
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Posted 13 Nov 2020

Reanalysis of in vivo drug synergy validation study rules out synergy in most cases
111 downloads bioRxiv pharmacology and toxicology

Olaf van Tellingen, Renee de Menezes

In a recent paper in Nature Communications, Narayan et al described the development of an in silico method to predict synergy of drug combinations, validated in vivo using 5 different models for 5 different drug pairs. The published analysis of the in vivo experimental data used the Chou and Talalay Combination Index, which ignores important aspects of the study design, including, but not limited to the variability between individual mice and the longitudinal nature of the data. Furthermore, the original publication reported the Combination Index as static numbers without properly accounting for experimental variability. When 95% confidence intervals are recalculated using bootstrapping methods, 4 out of 5 drug pairs do not show a statistically significant synergistic effect. Three models (originally figures 5A, B and E) are subject to severe inaccuracies in the data handling and reporting. In one model, (originally figure 5D), the data better supports an additive effect between drugs rather than synergy. As the Chou and Talalay Combination Index is poorly suited to this data, we applied mixed-effects models fitted to the longitudinal tumor growth data as an alternative means of estimating synergy. The results support the findings from the bootstrapping analysis, namely that the majority of the drug pairs do not achieve a synergistic effect. We conclude that the in vivo validation of the in silico method to predict synergy of drug combinations as proposed by Narayan et al has a negative outcome when analyzed with appropriate statistical methods. ### Competing Interest Statement OvT: None RM was recently recruited as group leader of the Biostatistics Centre of the Netherlands Cancer Institute. Before this she was a biostatistician at the VUmc, which is the institute of Narayan and colleagues. RM is a coauthor of the paper under discussion, but she was not involved in the analyses of the in vivo data.

943: Continuous administration of the p38α inhibitor neflamapimod during the subacute phase after transient ischemia-induced stroke in the rat promotes dose-dependent functional recovery accompanied by increase in brain BDNF protein level
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Posted 29 Apr 2020

Continuous administration of the p38α inhibitor neflamapimod during the subacute phase after transient ischemia-induced stroke in the rat promotes dose-dependent functional recovery accompanied by increase in brain BDNF protein level
111 downloads bioRxiv pharmacology and toxicology

John Alam, Michael Krakovsky, Ursula Germann, Aharon Levy

There is unmet need for effective stroke therapies. Numerous neuroprotection attempts for acute cerebral ischemia have failed and there is growing interest in developing therapies that widen the treatment initiation window and promote functional recovery through increasing synaptic plasticity. The p38α mitogen-activated protein kinase is an already proven target for acute experimental stroke intervention and was hypothesized to also contribute to neuroinflammation-mediated impairment of recovery during the subacute phase. Neflamapimod, an orally bioavailable, brain-penetrant, potent and selective small molecule p38α inhibitor was evaluated as a subacute phase stroke treatment to promote recovery in this research study. Neflamapimod administration at two clinically relevant dose levels was initiated outside of the previously characterized neuroprotection window of less than 24 hours after stroke for p38α inhibitors to rats after transient middle cerebral artery occlusion. Continuous administration of neflamapimod, starting at 48 hours after reperfusion, significantly improved behavioral outcomes assessed by the modified neurological severity score at four- and six-weeks post stroke in a dose-dependent manner. Neflamapimod also demonstrated beneficial effects on additional measures of sensory and motor function and resulted in a dose-related increase in the terminal brain-derived neurotrophic factor protein level in both the injured and uninjured brain hemisphere. Variable interleukin-1β levels were detected in the injured brain hemisphere at study termination in a subset of the animals within every test group, implying ongoing, chronic inflammation, however, no clear neflamapimod effect on interleukin-1β production was observable. The dose-related in vivo efficacy of neflamapimod offers the possibility of both expanding the window for initiation of therapy after stroke and for improving recovery after a completed stroke. Since neflamapimod is already in mid-stage clinical trials for Alzheimer's disease and related dementias, the current results make it especially attractive for evaluation in a proof-of-concept clinical trial as therapeutic to promote recovery after ischemic stroke.

944: 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
111 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.

945: 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
110 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.

946: Development of nano-emulsions based on Ayapana triplinervis for the control of Aedes aegypti larvae
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Posted 09 Jul 2020

Development of nano-emulsions based on Ayapana triplinervis for the control of Aedes aegypti larvae
110 downloads bioRxiv pharmacology and toxicology

Alex Bruno Lobato Rodrigues, Rosany Martins Lopes, Érica Menezes Rabelo, Rosana Tomazi, Lizandra Lima Santos, Lethícia Barreto Brandão, Cleidjane Gomes Faustino, Ana Luzia Ferreira Farias, Cleydson Breno Rodrigues dos Santos, Patrick de Castro Cantuária, Allan Kardec Ribeiro Galardo, Sheylla Susan Moreira da Silva de Almeida

Ayapana triplinervis is a plant species used in traditional medicine and in mystical-religious rituals by traditional communities in the Amazon. The aim of this study is to evaluate the larvicidal activity against A. aegypti of nano-emulsions containing essential oils from A. triplinervis morphotypes, and acute oral toxicity in non-target organism. Essential oils were identified and nano-emulsions were prepared using the low energy method. The mortality test of A. aegypti larvae was performed according to the protocol recommended by the World Health Organization, and toxicity in non-target mammals was performed according to the OECD. Phytochemical analyses indicated the major compounds (E)-Caryophyllene (45.93%) and Thymohydroquinone Dimethyl Ether (32.93%) in morphotype A, and in morphotype B, Thymohydroquinone Dimethyl Ether (84.53%) was found. Morphotype A essential oil nano-emulsion showed a particle size of 101.400 ± 0.971 nm (PdI = 0.124 ± 0.009 and ZP = -19,300 ± 0.787 mV). Morphotype B essential oil nano-emulsion had a particle size of 104.567 ± 0.416 nm (PdI = 0.168 ± 0.016 and ZP = -27,700 ± 1,307 mV). Histomorphological analyses showed the presence of inflammatory cells in the liver of animals treated with morphotype A essential oil nano-emulsion (MAEON) and morphotype B essential oil nano-emulsion (MBEON). Congestion and the presence of transudate with leukocyte infiltration in the lung of animals treated with MAEON were observed. The nano-emulsions containing essential oils of A. triplinervis morphotypes showed an effective nanobiotechnological product in the chemical control of A. aegypti larvae and safe for non-target mammals.

947: Consequences of a short-term exposure to a sub lethal concentration of CdO nanoparticles on key life history traits in the fruit fly (Drosophila melanogaster)
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Posted 16 Jul 2020

Consequences of a short-term exposure to a sub lethal concentration of CdO nanoparticles on key life history traits in the fruit fly (Drosophila melanogaster)
110 downloads bioRxiv pharmacology and toxicology

Samar El Kholy, John P. Giesy, Yahya Al Naggar

Nanoparticles of cadmium oxide (CdO NPs) are among the most common industrial metal oxide nanoparticles. Early adulthood (F0) fruit flies (D. melanogaster) were exposed for 7 days to a sub lethal concentration (0.03 mg CdO NPs/ml, which was 20% of the LC50), spiked into food media to test for long term-effects over time and beyond their direct exposure on key life history traits. Effects on survival, developmental time, eclosion rate, fecundity and negative geotaxis performance were assessed. Potential effects on ultrastructure of mid gut cells were also investigated by use of electron microscopy. All studied life history traits, as well as climbing behavior were adversely affected by exposure to CdO NPs. In non-exposed progeny (F1) of adult flies (F0), a blistered wing phenotype was also observed. Lysis of nuclear and rough endoplasmic reticulum (rER) membranes, mitochondrial swelling and lysis were among the most common cellular alterations observed in midgut cells of F0 flies exposed to CdO NPs. Genes encoding for metallothionein (MTn A-D) were significantly upregulated in both parent flies (F0) and their progeny (F1) after exposure of F0 flies to CdO NPs, compared to unexposed, control flies, a result which indicated potential, long-term effects. Taken together, these results suggest that short-term exposure to a sublethal concentration of CdO NPs is sufficient to cause long-lasting, harmful effects on fruit flies. ### Competing Interest Statement The authors have declared no competing interest.

948: Depressive-like behaviors induced by somatostatin-positive GABA neuron silencing are rescued by alpha 5 GABA-A receptor potentiation
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Posted 06 Oct 2020

Depressive-like behaviors induced by somatostatin-positive GABA neuron silencing are rescued by alpha 5 GABA-A receptor potentiation
109 downloads bioRxiv pharmacology and toxicology

Corey Fee, Thomas D. Prevot, Keith Misquitta, Daniel E Knutson, Guanguan Li, Prithu Mondal, James M Cook, Mounira Banasr, Etienne Sibille

Introduction: Deficits in somatostatin-positive gamma-aminobutyric acid interneurons (SST+ cells) are associated with major depressive disorder (MDD) and a causal link between SST+ cell dysfunction and depressive-like deficits has been proposed, based on rodent studies showing that chronic stress induces a low SST+ GABA cellular phenotype across corticolimbic brain regions, that lowering Sst, SST+ cell, or GABA functions induces depressive-like behaviors, and that disinhibiting SST+ cell functions has antidepressant effects. Recent studies found that compounds preferentially potentiating receptors mediating SST+ cell functions with alpha5-GABA-A receptor positive allosteric modulators (alpha5-PAMs) achieved antidepressant-like effects. Together, evidence suggests that SST+ cells regulate mood and cognitive functions that are disrupted in MDD and that rescuing SST+ cell function may represent a promising therapeutic strategy. Methods: We developed a mouse model with chemogenetic silencing of brain-wide SST+ cells and employed behavioral characterization 30 min after acute or sub-chronic silencing to identify contributions to behaviors related to MDD. We then assessed whether an alpha5-PAM, GL-II-73, could rescue behavioral deficits induced by SST+ cell silencing. Results: Brain-wide SST+ cell silencing induced features of stress-related illnesses, including elevated neuronal activity and plasma corticosterone levels, increased anxiety- and anhedonia-like behaviors, and impaired short-term memory. GL-II-73 led to antidepressant-like improvements among all behavioral deficits induced by brain-wide SST+ cell silencing. Conclusion: Our data validate SST+ cells as regulators of mood and cognitive functions, support a role for SST+ cell deficits in depressive-like behaviors, and demonstrate that bypassing low SST+ cell function via alpha5-PAM represents a targeted antidepressant strategy. ### Competing Interest Statement Funding and Disclosure C.F. and T.P. were supported by CAMH Discovery Fund fellowships. C.F. also received an Ontario Graduate Scholarship during the studies. M.B. is supported by a NARSAD young investigator award from the Brain & Behavior Research Foundation (#24034) and the CAMH Discovery Seed Fund and the Canadian Institutes of Health Research (PJT-165852). E.S. was supported by the Brain & Behavior Research Foundation (#25637) and Canadian Institutes of Health Research (PJT-153175). The project was also supported by the Campbell Family Mental Health Research Institute. D.K., G.L., P.M., J.C., E.S., M.B. and T.P. are co-inventors or listed on U.S. patent applications that cover GABAergic ligands and/or their use in brain disorders. E.S. is co-Founder of Alpha Cog, a biotech company developing ligands, including GL-II-73, as procognitive therapeutics. C.F. and K.M. have no conflicts-of-interest to disclose. Acknowledgements We acknowledge the hard work of CAMH institutional animal facility staff for their assistance in breeding, genotyping, and maintaining colonies. Special thanks to K.F., G.F., and K.D. Special thanks to Dr. Bryan Roth for providing DREADD vectors (Addgene #44362) and Drs. Gradinaru and Deverman for the AAV-PHP.eB serotype technology. Thanks also to the Penn Vector Core for packaging and production of AAV-PHP.eB serotype control viruses (Addgene #50459).

949: 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
108 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.

950: 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
108 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.

951: Combination of ipratropium bromide and salbutamol in children and adolescents with asthma: a meta-analysis
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Posted 31 Jul 2020

Combination of ipratropium bromide and salbutamol in children and adolescents with asthma: a meta-analysis
108 downloads bioRxiv pharmacology and toxicology

Hongzhen Xu, Lin Tong, Peng Gao, Yan Hu, Huijuan Wang, Zhimin Chen, Luo Fang

Background A combination of ipratropium bromide (IB) and salbutamol is commonly used to treat asthma in children and adolescents; however, there has been a lack of consistency in its usage in clinical practice. Objective To evaluate the efficacy and safety of IB + salbutamol in the treatment of asthma in children and adolescents. Methods The MEDLINE, Embase, and Cochrane Library as well as other Chinese biomedical databases (including China Biological Medicine Database, Chinese National Knowledge Infrastructure, Chongqing VIP, and Wanfang Chinese language bibliographic database) were systematically searched from the date of database inception to 02/09/2019 for randomized controlled trials in children and adolescents (≤18 years) with asthma who received IB + salbutamol or salbutamol alone. The primary outcomes included hospital admission and adverse events. A random effects model with a 95% confidence interval (CI) was used. Subgroup analysis was performed according to age, severity of asthma, and co-interventions with other asthma controllers. This study was registered with PROSPERO. Results Of the 637 studies that were identified, 55 met the inclusion criteria and involved 6396 participants. IB + salbutamol significantly reduced the risk of hospital admission compared with salbutamol alone (risk ratio [RR] 0.79; 95% CI 0.66–0.95; p = 0.01; I 2 = 40%). Subgroup analysis only showed significant difference in the risk of hospital admission in participants with severe asthma exacerbation (RR 0.71; 95% CI 0.60–0.85; p = 0.0001; I 2 = 0%) and moderate-to-severe exacerbation (RR 0.69; 95% CI 0.50–0.96; p = 0.03; I 2 = 3%). There were no significant differences in the risk of adverse events between IB + salbutamol group and salbutamol alone group (RR 1.77; 95% CI 0.63–4.98). Conclusion IB + salbutamol may be more effective than salbutamol alone for the treatment of asthma in children and adolescents, especially in those with severe and moderate to severe asthma exacerbation. Future prospective research on these subgroup population are needed.

952: 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
108 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.

953: Nicotine dosimetry and stability in Cambridge Filter PADs (CFPs) following different smoking regimen protocols and condition storage
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Posted 10 Sep 2020

Nicotine dosimetry and stability in Cambridge Filter PADs (CFPs) following different smoking regimen protocols and condition storage
107 downloads bioRxiv pharmacology and toxicology

Pietro Zuccarello, Sonja Rust, Massimo Caruso, Rosalia Emma, Roberta Pulvirenti, Claudia Favara, Riccardo Polosa, Giovanni Li Volti, Margherita Ferrante

Despite the growing numbers of studies with cigarettes and other electronic nicotine delivery products (ENDs), there is no standard covering nicotine dosimetry and its stability in various matrix. The aim of the present study was to provide a protocol to normalize nicotine concentration adsorbed in Cambridge Filter PADs (CFPs) and their storage method. Smoke/vapor generated by a reference tobacco cigarette (1R6F) and ENDs with different exposure regimes (ISO, HCI and CRM81) was collected in CFPs. For each exposure, some CFPs were analyzed at time zero, whereas the others were stored under different conditions for nicotine assessment after 30 days. Principal Component Analysis (PCA) was also performed to establish the best parameter for nicotine normalization. PCA showed the best correlation between nicotine in CFPs and TPM. Our results showed differences between products and puffing regimes, but storage of CFPs at −80°C was always effective in maintaining the nicotine content. In conclusion, this study highlights that different exposure regimens and products can affect the preservation of nicotine titer in CFPs and samples storage at −80°C may prevent the loss of nicotine. These conditions are recommended and should be adopted for Inter-laboratory comparison studies on ENDs to ensure harmonization between participating laboratories. ### Competing Interest Statement In relation to his work in the area of tobacco control and respiratory diseases, Riccardo Polosa has received lecture fees and research funding from Pfizer, Inc., GlaxoSmithKline plc, CV Therapeutics, NeuroSearch A/S, Sandoz, MSD, Boehringer Ingelheim, Novartis, Duska Therapeutics, and Forest Laboratories. He has also served as a consultant for Pfizer, Inc., Global Health Alliance for treatment of tobacco dependence, CV Therapeutics, NeuroSearch A/S, Boehringer Ingelheim, Duska Therapeutics, Forest Laboratories, ECITA (Electronic Cigarette Industry Trade Association, in the UK), and Health Diplomat (consulting company that delivers solutions to global health problems with special emphasis on harm minimization). Lecture fees from a number of European EC industry and trade associations (including Federation Interprofessionnelle de la VAPE in France and Federazione Italiana Esercenti Svapo Elettronico in Italy) were directly donated to vaper advocacy no-profit organizations. He is currently Head of the European Technical Committee for standardization on Requirements and test methods for emissions of electronic cigarettes (CEN/TC 437; WG4). He is also founder of the Center of Excellence for the acceleration of Harm Reduction at the University of Catania (CoEHAR), which has received a grant from the Foundation for a Smoke Free World to support 8 independent investigator-initiated research projects on tobacco harm reduction, and scientific advisor for LIAF, Lega Italiana Anti Fumo (Italian acronym for Italian Anti-Smoking League). Prof. Li Volti is currently elected Director of the Center of Excellence for the acceleration of HArm Reduction. All the other authors declare no conflicts of interest.

954: A novel saline-soluble, rapidly-metabolized RyR1 inhibitor rescues volatile anesthesia-induced death and environmental heat stroke in a mouse model relevant to malignant hyperthermia
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Posted 02 Jul 2020

A novel saline-soluble, rapidly-metabolized RyR1 inhibitor rescues volatile anesthesia-induced death and environmental heat stroke in a mouse model relevant to malignant hyperthermia
107 downloads bioRxiv pharmacology and toxicology

Toshiko Yamazawa, Takuya Kobayashi, Nagomi Kurebayashi, Masato Konishi, Satoru Noguchi, Takayoshi Inoue, Yukiko U. Inoue, Ichizo Nishino, Shuichi Mori, Hiroto Iinuma, Noriaki Manaka, Hiroyuki Kagechika, Arkady Uryas, Jose Adams, Jose R Lopez, Xiaochen Liu, Paul D. Allen, Sho Kakizawa, Keigo Ikeda, Bangzhong Lin, Kazuto Nunomura, Shinsaku Nakagawa, Takashi Sakurai, Takashi Murayama

Mutations in the type 1 ryanodine receptor (RyR1), a Ca2+ release channel in skeletal muscle, hyperactivate the channel to cause malignant hyperthermia (MH) and are implicated in severe heat stroke. Dantrolene, the only approved drug for MH, has the disadvantages of having very poor water solubility and long plasma half-life. We show here that a novel RyR1-selective inhibitor, 6,7-(methylenedioxy)-1-octyl-4-quinolone-3-carboxylic acid (Compound 1), effectively rescues MH and heat stroke in several mouse models relevant to MH. Compound 1 reduced resting intracellular Ca2+, inhibited halothane-induced Ca2+ release, suppressed caffeine-induced contracture in skeletal muscle, reduced sarcolemmal cation influx, and prevented or reversed the fulminant MH crisis by isoflurane anesthesia and heat stroke by environmental heat stress. Notably, Compound 1 has great advantages of better water solubility and rapid clearance in vivo over dantrolene. Compound 1 has the potential to be a promising new candidate for effective treatment of patients carrying RyR1 mutations. ### Competing Interest Statement The authors have declared no competing interest.

955: Cercosporamide inhibits bone morphogenetic protein receptor type I kinase activity in zebrafish
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Posted 31 May 2020

Cercosporamide inhibits bone morphogenetic protein receptor type I kinase activity in zebrafish
107 downloads bioRxiv pharmacology and toxicology

Jelmer Hoeksma, Gerard C.M. van der Zon, Peter ten Dijke, Jeroen den Hertog

Zebrafish models are well established tools for investigating underlying mechanisms of diseases. Here, we identified cercosporamide, a metabolite from the fungus Ascochyta aquiliqiae, as a potent bone morphogenetic protein (BMP) type I receptor kinase inhibitor through a zebrafish embryo phenotypic screen. The developmental defects in zebrafish, including lack of the ventral fin induced by cercosporamide was strikingly similar as the phenotypes caused by renowned small molecule BMP type I receptor kinase inhibitors and inactivating mutations in zebrafish BMP receptors. In mammalian cell-based assays, cercosporamide blocked BMP/SMAD-dependent transcriptional reporter activity and BMP-induced SMAD1/5-phosphorylation. Biochemical assays with a panel of purified recombinant kinases demonstrated that cercosporamide directly inhibited kinase activity of BMP type I receptors (also called activin receptor-like kinases (ALKs)). In mammalian cells, cercosporamide selectively inhibited constitutively active BMP type I receptor-induced SMAD1/5 phosphorylation. Importantly, cercosporamide rescued the developmental defects caused by constitutively active Alk2 in zebrafish embryos. Taken together, we believe cercosporamide may be the first of a new class of molecules with potential to be developed further for clinical use against diseases that are causally linked to overactivation of BMP receptor signaling, including Fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma.

956: 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
106 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.

957: 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
106 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.

958: In vitro activity evaluation of Lippia alba essential oil against Zika virus
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Posted 25 Jun 2020

In vitro activity evaluation of Lippia alba essential oil against Zika virus
105 downloads bioRxiv pharmacology and toxicology

Bernardo E. Quispe-Bravo, Lucas Augusto Sevilla Drozdek, Joe Hermosilla Jara, Ingrit Elida Collantes Díaz, Edison Luiz Durigon, Enrique Walter Mamani Zapana, Egma Marcelina Mayta Huatuco, Juan Samuel Sulca Herencia

The Zika virus (ZIKV) of the Flaviviridae family is an emerging virus that caused, between 2016 and 2018, serious public health problems in Latin America, affecting neonates with greater severity. The clinical spectrum includes Guillain-Barré syndrome, microcephaly and others neurodegenerative diseases. There is no antiviral treatment or vaccine against this virus, for that reason the antiviral properties of various plants are being studied. Lippia alba , locally known as “Prontoalivio”, is an aromatic shrub of the Verbenaceae family with a wide geographical distribution (especially in South and Central America) and is used in traditional medicine against fever, skin diseases and as a pain reliever. In this study, the antiviral activity of the essential oil of Lippia alba against ZIKV was evaluated in the Vero 76 cell line. Lippia alba was collected in the department of Amazonas, in the rainforest of Peru, and identified in the Museo de Historia Natural of the Universidad Nacional Mayor de San Marcos. The essential oil sample was obtained by steam hydrodistillation. The essential oil showed cytotoxicity to a concentration greater than or equal to 167 μg/mL in the Vero 76 cell line. The antiviral activity of essential oil against ZIKV (previously identified by real-time PCR and propagated in the C6/36 cell line) was evaluated using the plaque reduction test (PRP). The essential oil showed antiviral activity in concentrations from 8.02 μg/mL to 20.88 μg/mL, which represents a range between 59.44% to 85.56% of plaque reduction and may be considered as a candidate for antiviral studies against ZIKV.

959: 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
105 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.

960: Yeast grown in continuous culture systems can detect mutagens with improved sensitivity relative to the Ames test
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Posted 15 Jun 2020

Yeast grown in continuous culture systems can detect mutagens with improved sensitivity relative to the Ames test
104 downloads bioRxiv pharmacology and toxicology

Joseph Y Ong, Julia T Pence, David C Molik, Holly V. Goodson

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.

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