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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.

1081: Targeting influenza at the topologically conserved substructures
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Posted 26 Oct 2020

Targeting influenza at the topologically conserved substructures
80 downloads bioRxiv pharmacology and toxicology

BHUVANESWARI KAKUNURI

H9N2 avian influenza virus is a low pathogenic endemic strain in the domestic poultry of most of the Asian countries. Attempts have extensively failed in eradicating its diverse strains. To find the drug against the evolutionarily conserved substructures, the target protein sequence is analyzed through sequence and modelled structure for mapping the structurally conserved topology. The available drugs are screened against the deciphered topological map through the predicted ADMET and drug-likelihood scores. This study helps to build a theoretical framework to make the foremost potent drug. ### Competing Interest Statement The authors have declared no competing interest.

1082: Transdermal patch containing physostigmine and procyclidine protects rhesus monkeys against VX intoxication
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Posted 17 Oct 2020

Transdermal patch containing physostigmine and procyclidine protects rhesus monkeys against VX intoxication
80 downloads bioRxiv pharmacology and toxicology

Youngjo Song

VX is an organophosphate cholinesterase inhibitor known as a chemical warfare agent. This study was designed 1) to determine the acute toxicity of VX in male rhesus monkeys by subcutaneous administration, 2) to evaluate the efficacy of a transdermal patch containing physostigmine and procyclidine. The median lethal dose (LD50) of the subcutaneous injection of VX was 15.409 ug/kg, which was calculated using the up-and-down dose selection procedure based on deaths occurring within 48 h. To test the efficacy of the transdermal patch, rhesus monkeys were treated with a patch (5x5 cm2) alone or in combination with post-exposure therapy comprising atropine plus 2-pralidoxime (2-PAM), and then administered subcutaneous injection of VX at various doses. The rhesus monkeys pretreated with the patch alone were 100% protected against 1.5xLD50 of VX, while the rhesus monkeys treated with the patch, atropine, and 2-PAM were 100% protected against 50xLD50 of VX. This study demonstrated that patch pretreatment in conjunction with atropine and 2-PAM treatment is an effective regimen against high doses of VX. ### Competing Interest Statement The authors have declared no competing interest.

1083: Regeneration of lung epithelial cells by Fullerene C60 nanoformulation: A possible treatment strategy for acute respiratory distress syndrome (ARDS)
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Posted 10 Sep 2020

Regeneration of lung epithelial cells by Fullerene C60 nanoformulation: A possible treatment strategy for acute respiratory distress syndrome (ARDS)
80 downloads bioRxiv pharmacology and toxicology

Nabodita Sinha, Ashwani Kumar Thakur

Acute respiratory distress syndrome (ARDS) involves death of lung epithelial cells. ARDS is a leading reason behind mortality in respiratory infections. Here we show a proof-of-concept that a Fullerene nanoformulation can be used for the regeneration of cells treated with apoptosis-inducing molecules, suggeting its potential for ARDS therapy. ### Competing Interest Statement The authors have declared no competing interest.

1084: Novel insights into the mode of action of 1,4-dioxane using a systems screening approach
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Posted 28 Dec 2020

Novel insights into the mode of action of 1,4-dioxane using a systems screening approach
80 downloads bioRxiv pharmacology and toxicology

Georgia Charkoftaki, Jaya Prakash Golla, Alvaro Santos-Neto, David J Orlicky, Rolando Garcia-Milian, Ying Chen, Nicholas J.W. Rattray, Yuping Cai, Yewei Wang, Colin T Shern, Varvara Mironova, Yensheng Wang, Caroline H. Johnson, David C. Thompson, Vasilis Vasiliou

1,4-Dioxane (1,4-DX) is an environmental contaminant found in drinking water throughout the United States (US). While it is a suspected liver carcinogen, there is no federal or state maximum contaminant level for 1,4-DX in drinking water. Very little is known about the mechanisms by which this chemical elicits liver carcinogenicity. In the present study, female BDF-1 mice were exposed to 1,4-DX (0, 50, 500 and 5,000 mg/L) in their drinking water for one or four weeks, to explore the toxic effects. Histopathological studies and a multi-omics approach (transcriptomics and metabolomics) were performed to investigate potential mechanisms of toxicity. Immunohistochemical analysis of the liver revealed increased H2AX{gamma}-positive hepatocytes (a marker of DNA double strand breaks), and an expansion of precholangiocytes (reflecting both DNA damage and repair mechanisms) after exposure. Liver transcriptomics revealed 1,4-DX-induced perturbations in signaling pathways predicted to impact the oxidative stress response, detoxification, and DNA damage. Liver, kidney, feces and urine metabolomic profiling revealed no effect of 1,4-DX exposure, and bile acid quantification in liver and feces similarly showed no effect of exposure. We speculate that the results may be reflective of DNA damage being counterbalanced by the repair response, with the net result being a null overall effect on the systemic biochemistry of the exposed mice. Our results show a novel approach for the investigation of environmental chemicals that do not elicit cell death but have activated the repair systems in response to 1,4-DX exposure.

1085: Rejuveinix Reverses Severe Inflammatory Lung Damage in a Mouse Model of Fatal Sepsis
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Posted 02 Jan 2021

Rejuveinix Reverses Severe Inflammatory Lung Damage in a Mouse Model of Fatal Sepsis
80 downloads bioRxiv pharmacology and toxicology

Fatih Uckun, Ibrahim H. Ozercan, Cemal Orhan, Marcus Gitterle, Kazim Sahin

We set out to determine if our anti-sepsis drug candidate Rejuveinix (RJX) can effectively treat systemic inflammation in a mouse model of sepsis when used at a dose level that is >10-times lower than its maximum tolerated dose (MTD) for human subjects. Our findings obtained in the LPS-GalN mouse model of fatal sepsis provide experimental evidence that RJX exhibits potent single-agent anti-inflammatory activity and reverses very severe inflammatory lung injury when used therapeutically, thereby significantly improving the survival outcome. These findings demonstrate the clinical impact potential of RJX for the treatment of severe sepsis.

1086: Computational ligands to VKORC1s and CYPs. Could they predict new anticoagulant rodenticides?
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Posted 22 Jan 2021

Computational ligands to VKORC1s and CYPs. Could they predict new anticoagulant rodenticides?
80 downloads bioRxiv pharmacology and toxicology

Azucena Bermejo-Nogales, Jose M Navas, Julio Coll

Anticoagulant-resistance in rodents and anticoagulant off-target effects are some of the world-wide problems of increasing concern. To search for new anticoagulant rodenticide candidates we have computationally explored some of the rat genes previously implicated in resistance to actual anticoagulants. In particular, we searched among hundreds of anticoagulant-similar chemotypes those binding rat wild-type VKORC1 (the best-known anticoagulant target, a Vitamin K-recycling enzyme), VKORC1L1 (a VKORC1-related enzyme), Cytochrome P450 CYP enzymes (some of the most important enzymes implicated in detoxification) and anticoagulant-resistant VKORC1-mutants (to minimize propensity to resistance). Results predicted new VKORC1 leads with binding-scores in the low nM range (high binding-affinities) predicting hydroxycoumarin- and naphtoquinone-like chemotypes. We then selected top-leads with additional high binding-scores to more than three anticoagulant-related CYPs, suggesting minimal detoxification rates and therefore maximal anticoagulation expectatives. A downsized list of top top-leads maintaining VKORC1 low-binding scores to anticoagulant resistant mutants, was finally proposed for experimental validation. The combination of different rat targets for computational studies, could be used to search for unrelated chemotypes, for reduction of off-target environmental anticoagulant impacts, and/or as new tools to explore anticoagulant molecular mechanisms.

1087: Sex reversal and ontogeny under climate change and chemical pollution: are there interactions between the effects of elevated temperature and a xenoestrogen on early development in agile frogs?
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Posted 31 Dec 2020

Sex reversal and ontogeny under climate change and chemical pollution: are there interactions between the effects of elevated temperature and a xenoestrogen on early development in agile frogs?
80 downloads bioRxiv pharmacology and toxicology

Zsanett Mikó, Edina Nemesházi, Nikolett Ujhegyi, Viktória Verebélyi, János Ujszegi, Andrea Kásler, Réka Bertalan, Nóra Vili, Zoltán Gál, Orsolya I. Hoffmann, Attila Hettyey, Veronika Bókony

Anthropogenic environmental change poses a special threat to species in which genetic sex determination can be overwritten by the thermal and chemical environment. Endocrine disrupting chemicals as well as extreme temperatures can induce sex reversal in such species, with wide-ranging consequences for fitness, demography, population viability and evolution. Despite accumulating evidence suggesting that chemical and thermal effects may interact in ecological contexts, little is known about their combined effects on sex reversal. Here we assessed the simultaneous effects of high temperature (masculinizing agent) and 17-ethinylestradiol (EE2), a widespread xenoestrogen (feminizing agent), on sexual development and fitness-related traits in agile frogs (Rana dalmatina). We exposed tadpoles to a six-days heat wave (30 {degrees}C) and/or an ecologically relevant concentration of EE2 (30 ng/L) in one of three consecutive larval periods, and diagnosed sex reversals two months after metamorphosis using species-specific markers for genetic sexing. We found that high temperature induced female-to-male sex reversal, decreased survival, delayed metamorphosis, decreased body mass at metamorphosis, and increased the proportion of animals that had no fat bodies, while EE2 had no effect on these traits. Simultaneous exposure to heat and EE2 had non-additive effects on juvenile body mass, which were dependent on treatment timing and further complicated by a negative effect of sex reversal on body mass. These results show that environmentally relevant exposure to EE2 does not diminish the masculinizing effects of high temperature. Instead, our findings on growth suggest that climate change and chemical pollution may have complex consequences for individual fitness and population persistence in species with environment-sensitive sex determination.

1088: EVALUATION OF ANTI-BACTERIAL AND ANTHELMINTIC ACTIVITIES OF BARK OF PLANT CASSIA FISTULA Linn.
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Posted 19 Oct 2020

EVALUATION OF ANTI-BACTERIAL AND ANTHELMINTIC ACTIVITIES OF BARK OF PLANT CASSIA FISTULA Linn.
79 downloads bioRxiv pharmacology and toxicology

Anant Nayabaniya, Samyam Aryal, Bibek Dahal, Hemanta Khanal, Anil K. Gupta

This study deals with phytochemical screening and evaluation of anti-bacterial and anthelmintic activities of the bark extracts of Cassia fistula L. The extraction with different solvents - methanol, acetone, distilled water - had been carried out. The anti-bacterial assay was done against two gram +ve and two gram -ve bacteria by agar cup diffusion method. The anthelmintic activity was done on Pheretima posthuma (earthworm) by recording the paralyzing and death time under different concentrations. Methanolic extract showed the maximum activity on both fronts be it anti-bacterial or anthelmintic. The extract was effective only against gram +ve bacteria. Among Staphylococcus aureus and Streptococci faecalis, the former was more susceptible. The activity against gram -ve bacteria was not found. In case of anthelmintic activity, the concentration of 50 mg/ml was effective and near to the paralyzing and death time as recorded for the 10 mg/ml concentration of the standard Albendazole. However, aqueous extract was more effective than the acetone extract. ### Competing Interest Statement The authors have declared no competing interest.

1089: Chemical composition and insecticidal activity of Aeollanthus pubescens Benth leaf essential oil on the malaria vector Anopheles gambiae (Diptera: Culicidae).
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Posted 26 Nov 2020

Chemical composition and insecticidal activity of Aeollanthus pubescens Benth leaf essential oil on the malaria vector Anopheles gambiae (Diptera: Culicidae).
78 downloads bioRxiv pharmacology and toxicology

Roméo Barnabé Bohounton, Luc Djogbenou, Oswald Yédjinnavênan Djihinto, Oronce Sedjro-Ludolphe Dedome, Pierre Marie Sovegnon, Bruno Barea, Aristide Adomou, Pierre Villeneuve, Fidèle Paul Tchobo

The use of synthetic insecticides is responsible for many cases of resistance in insects. Therefore, the use of natural molecules of ecological interest with insecticidal properties turns out to be an alternative approach to the use of synthetic insecticides. This study aims at investigating the larvicidal, adulticidal activity and the composition of the essential oil of Aeollanthus pubescens Benth on the major malaria vector Anopheles gambiae. The leaves of Aeollanthus pubescens were collected in the South of the Republic of Benin. Three reference strains of Anopheles gambiae s.s. such as Kisumu, Kiskdr and Acerkis were used. The chemical composition of the essential oil was analysed by gas chromatography coupled to mass spectrometry. Larvae were exposed to the essential oil extract for 24 h. Adult mosquitoes were exposed to the fragment nets coated with the essential oil for 3 min. Larval mortality and adult survivorship were monitored. Fourteen components were identified representing 98.31% of the total of oil. The major components were carvacrol (51.06 %), thymyle acetate (14.01 %) and ?-terpinene (10.60 %). The essential oil has remarkable larvicidal properties with LC50 of 29.26, 22.65, and 28.37 ppm respectively on Kisumu, Acerkis and Kiskdr strains. With the fragment net treated at 165 {micro}g/cm2, the KDT50 of both Acerkis (1.71 s, p < 0.001) and Kiskdr (2.67 s, p < 0.001) individuals were significantly lower than that of Kisumu (3.77 s). The lifespan of the three mosquito strains decreased respectively to one day for Kisumu (p < 0.001), two days for Acerkis (p < 0.001) and three days for Kiskdr (p < 0.001) compared to their control. Our findings show that the Aeollanthus pubescens essential oil is an efficient larvicide and adulticide against malaria vector Anopheles gambiae. This bioinsecticidal activity is a promising discovery for the control of the resistant malaria-transmitting vectors.

1090: Characterizing the relationship between the chemical structures of drugs and their activities on primary cultures of pediatric solid tumors
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Posted 02 Nov 2020

Characterizing the relationship between the chemical structures of drugs and their activities on primary cultures of pediatric solid tumors
78 downloads bioRxiv pharmacology and toxicology

Saw Simeon, Ghita Ghislat, Pedro Ballester

Better drugs are required to manage pediatric cancers. A high-throughput screen of drugs in primary cultures derived from orthotopic patient-derived xenografts (O-PDX) of pediatric solid tumours has been recently published. Here we analyzed these data sets to find out whether it is possible to leverage them for identifying new drug leads in a phenotypic manner. We found that drugs bearing a higher number of heterocyclic rings, two carbon-hetero bonds and halogens are associated to submicromolar potency in alveolar rhabdomyosarcoma and osteosarcoma O-PDXs. Furthermore, Murcko scaffolds 1-cyclopentyl-octahydro-1H-indene and tetradecahydroanthracene can be utilized as starting scaffolds to selectively optimize potency against osteosarcoma since drugs bearing this scaffold displayed superior O-PDX culture potency. Lastly, we have generated QSAR (Quantitative Structure-Activity Relationship) models able to predict the potency of drugs on each O-PDX tumor. To permit their use to guide drug repositioning on these 30 O-PDX cell cultures, we are providing a user-friendly web server implementing these QSAR models at https://rnewbie.shinyapps.io/Shobek-master ### Competing Interest Statement The authors have declared no competing interest.

1091: Protein kinases mediate anti-inflammatory effects of cannabidiol and estradiol against high glucose in cardiac sodium channels
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Posted 24 Nov 2020

Protein kinases mediate anti-inflammatory effects of cannabidiol and estradiol against high glucose in cardiac sodium channels
78 downloads bioRxiv pharmacology and toxicology

Mohamed A Foouda, Peter Ruben

Background and purpose: Cardiovascular anomalies are predisposing factors for diabetes-induced morbidity and mortality. Recently, we showed that high glucose induces changes in the biophysical properties of Nav1.5 that could be strongly correlated to diabetes-induced arrhythmia. However, the mechanisms underlying hyperglycemia-induced inflammation, and how inflammation provokes cardiac arrhythmia, are not well understood. We hypothesized that inflammation could mediate the high glucose-induced biophyscial changes on Nav1.5 through protein phosphorylation by protein kinases A and C. We also hypothesized that this signaling pathway is, at least partly, involved in the cardiprotective effects of CBD and E2. Experimental approach: To test these ideas, we used Chinese hamster ovarian (CHO) cells transiently co-transfected with cDNA encoding human Nav1.5 -subunit under control, a cocktail of inflammatory mediators or 100 mM glucose conditions (for 24 hours). We used electrophysiological experiments and action potential modelling. Key Results: Inflammatory mediators, similar to 100 mM glucose, right shifted the voltage dependence of conductance and steady state fast inactivation and increased persistent current leading to computational prolongation of action potential (hyperexcitability) which could result in long QT3 arrhythmia. In addition, activators of PK-A or PK-C replicated the inflammation-induced gating changes of Nav1.5. Inhibitors of PK-A or PK-C, CBD or E2 mitigated all the potentially deleterious effects provoked by high glucose/inflammation. Conclusions and implications: These findings suggest that PK-A and PK-C may mediate the anti-inflammatory effects of CBD and E2 against high glucose-induced arrhythmia. CBD, via Nav1.5, may be a cardioprotective therapeutic approach in diabetic postmenopausal population.

1092: Quantitative proteomics reveals the protective effects of ESD against osteoarthritis via attenuating inflammation and modulating immune response
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Posted 15 Jul 2020

Quantitative proteomics reveals the protective effects of ESD against osteoarthritis via attenuating inflammation and modulating immune response
78 downloads bioRxiv pharmacology and toxicology

Ying Hao, Yang Wu, Shanglong Wang, Chungguo Wang, Sihao Qu, Li Li, Guohua Yu, Zimin Liu, Zhen Zhao, Pengcheng Fan, Zengliang Zhang, Yuanyuan Shi

Epimedium, Salvia miltiorrhiza, and Dioscorea nipponica Makino (ESD) have been combined to treat osteoarthritis (OA) for a long time. In this study we used quantitative proteomics to find the protective effects of ESD against OA and possible mechanism. After papain-induced OA rats model established ESD was intragastrically administrated to rats for four weeks. Label-free quantitative proteomics was used to screen the comprehensive protein profiling changes in both OA and ESD groups. After stringent filtering, 62 proteins were found to be significantly up-regulated and 208 proteins were down-regulated in OA model compared with sham-operated control. Functional analysis revealed that these OA up-regulated proteins were enriched in the activation of humoral immunity response, complement activation, leukocyte mediated immunity, acute inflammatory, endocytosis regulation, and proteolysis regulation. ESD partially recovered the protein profiling changes in OA model. The effects of ESD were also assessed by measurement of behavioral activity and pathologic changes in the joints. ESD showed protective effects in suppressing inflammation, releasing joint pain, and attenuating cartilage degradation. Our study presented that ESD as a potential candidate to alleviate OA damage by reducing inflammation and modulating of immune system.

1093: Pharmacologic inhibition of Protein Kinase C α and Protein Kinase C β halts renal function decline indirectly, by blunting hyperphagia, and directly reduces adiposity in the ZSF1 rat model of type 2 diabetes
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Posted 03 Dec 2020

Pharmacologic inhibition of Protein Kinase C α and Protein Kinase C β halts renal function decline indirectly, by blunting hyperphagia, and directly reduces adiposity in the ZSF1 rat model of type 2 diabetes
78 downloads bioRxiv pharmacology and toxicology

Ju Wang, Agustin Casimiro-Garcia, Bryce G. Johnson, Jennifer Duffen, Michael Cain, Leigh Savary, Stephen Wang, Prashant Nambiar, Matthew Lech, Shanrong Zhao, Li Xi, Yutian Zhan, Jennifer Olson, James A. Stejskal, Hank Lin, Baohong Zhang, Robert Martinez, Katherine Masek-Hammerman, Franklin J. Schlerman, Ken Dower

Type 2 diabetes (T2D) and its complications can have debilitating, sometimes fatal consequences. Despite advances that address some of the metabolic aspects of T2D, for many patients these approaches do not sufficiently control the disease. As a result, an emerging therapeutic strategy is to target the pathobiological mechanisms downstream of T2D metabolic derangement that can result in organ damage, morbidity, and mortality in afflicted individuals. One such proposed mechanism involves the Protein Kinase C (PKC) family members PKC and PKC{beta}, which have been linked to diabetes-induced tissue damage to organs including the kidneys. To evaluate the therapeutic potential of dual inhibition of PKC and PKC{beta} in the context of T2D, we have evaluated a potent and orally bioavailable inhibitor, herein referred to as Cmpd 1, in the ZSF1 rat model of leptin-receptor deficiency, obesity-driven T2D. Therapeutic dosing of Cmpd 1 virtually halted renal function decline but did so indirectly by blunting the hyperphagia response of these animals. Beyond this clear but indirect effect, Cmpd 1 had direct and prominent effects on body weight and in liver and inguinal white adipose tissue (iWAT) when administered to ZSF1 obese rats.

1094: Protective effect of Morus macroura Miq. fruit extract against acetic acid-induced ulcerative colitis in rats: Involvement of miRNA-223 and TNFα/NFκB/NLRP3 inflammatory pathway
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Posted 22 Dec 2020

Protective effect of Morus macroura Miq. fruit extract against acetic acid-induced ulcerative colitis in rats: Involvement of miRNA-223 and TNFα/NFκB/NLRP3 inflammatory pathway
78 downloads bioRxiv pharmacology and toxicology

Rania M. Salama, Samar F. Darwish, Ismail El Shaffei, Noura F. Elmongy, Manal S. Afifi, Ghada A. Abdel-Latif

Tumor necrosis factor receptor (TNFR) activation and nuclear factor kappa B (NF{kappa}B) expression play a significant role in the activation of nod-like receptor pyrin domain-1 containing 3 (NLRP3) inflammasome inflammatory pathway, which is involved in the pathogenesis of ulcerative colitis (UC). Furthermore, miRNA-223 expression was shown to exert counter-regulatory effect on NLRP3 expression. Interestingly, polyphenols are attaining increased importance for their potential effectiveness in ameliorating certain diseases owing to their antioxidant and anti-inflammatory activity. In accord, our study attempted to investigate the effect of mulberry tree (Morus macroura) fruit extract (MFE) against acetic acid (AA)- induced UC in rats, which is not previously investigated, based on previous promising results for MFE in alleviating gastric ulcer in rats. First, total phenolic (TPC), total flavonoid (TFC), and total anthocyanin content (TAC) were determined in MFE. Then, MFE (300 mg/kg) and sulfasalazine (Sulfa), as a standard treatment (100 mg/kg), were given orally for seven days before intra-rectal induction of UC by AA (2 ml, 4% v/v) on day eight. The extent of UC was evaluated macroscopically and microscopically. Biochemically, the colonic TNFR1, NLRP3, p- NF{kappa}B p65, TNF, interleukin-1 beta (IL-1{beta}), IL-18 levels, miRNA-223 expression and caspase-1 activity were assayed. MFE significantly reduced macroscopic and microscopic scores, colonic levels of TNFR1, NLRP3, p-NF{kappa}B p65, TNF, IL-1{beta}, IL-18, and caspase-1 activity, and showed increased miRNA-223 expression, almost similarly to Sulfa effects. In conclusion, our study provided a novel impact for MFE against AA-induced UC in rats through affecting miRNA-223 expression and halting TNF/NF{kappa}B/NLRP3 inflammatory pathway.

1095: Metformin protects against insulin resistance induced by high uric acid in cardiomyocytes via AMPK signaling pathways in vitro and in vivo
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Posted 31 Jan 2021

Metformin protects against insulin resistance induced by high uric acid in cardiomyocytes via AMPK signaling pathways in vitro and in vivo
78 downloads bioRxiv pharmacology and toxicology

Zhenyu Jiao, Yingqun Chen, Yang Xie, Yanbing Li, Zhi Li

High uric acid (HUA) is associated with insulin resistance and abnormal glucose metabolism in cardiomyocytes. Metformin is a recognized agonist of AMP-activated protein kinase (AMPK) and an antidiabetic drug widely used for type 2 diabetes. It can play a cardioprotective role in many pathways. We investigated whether metformin protects against HUA-induced insulin resistance and abnormal glucose metabolism in cardiomyocytes. We exposed primary cardiomyocytes to HUA, and cellular glucose uptake was quantified by measuring the uptake of 2-NBDG, a fluorescent glucose analog, after insulin excitation. Treatment with metformin (10 mol/L) protected against HUA-inhibited glucose uptake induced by insulin in primary cardiomyocytes, as shown by fluorescence microscopy and flow cytometry analysis. HUA directly inhibited the phosphorylation of Akt and the translocation of glucose transporter type 4 (GLUT4) induced by insulin, which was blocked by metformin. Metformin promoted phosphorylation of AMPK, renewed HUA-inhibited glucose uptake induced by insulin and protected against insulin resistance in cardiomyocytes. As a result of these effects, in a mouse model of acute hyperuricemia, metformin improved insulin tolerance and glucose tolerance, accompanied by increased AMPK phosphorylation, Akt phosphorylation and translocation of GLUT4 in myocardial tissues. As expected, AICAR, another AMPK activator, had equivalent effects to metformin, demonstrating the important role of AMPK activation in protecting against insulin resistance induced by HUA in cardiomyocytes. Metformin protects against insulin resistance induced by HUA in cardiomyocytes and improves insulin tolerance and glucose tolerance in an acute hyperuricemic mouse model, along with the activation of AMPK. Consequently, metformin may be an important potential new treatment strategy for hyperuricemia-related cardiovascular disease.

1096: DIETARY MONOTERPENOIDS AS A NEW CLASS OF ALLOSTERIC HUMAN ARYL HYDROCARBON RECEPTOR ANTAGONISTS
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Posted 01 Dec 2020

DIETARY MONOTERPENOIDS AS A NEW CLASS OF ALLOSTERIC HUMAN ARYL HYDROCARBON RECEPTOR ANTAGONISTS
77 downloads bioRxiv pharmacology and toxicology

Karolina Poulikova, Iveta Zuvalova, Barbora Vyhlidalova, Kristyna Krasulova, Eva Jiskrova, Radim Vrzal, Sandhya Kortagere, Martina Kopecna, David Kopecny, Marek Sebela, Katharina Maria Rolfes, Thomas Haarmann-Stemmann, Sridhar Mani, Zdenek Dvorak

Carvones, the constituents of essential oils of dill, caraway, and spearmint, were reported to antagonize the human aryl hydrocarbon receptor (AhR); however, the exact molecular mechanism remains elusive. We show that carvones are non-competitive allosteric antagonists of the AhR that inhibit the induction of AhR target genes in a ligand-selective and cell type-specific manner. Carvones do not displace radiolabeled ligand from binding at the AhR, but they bind allosterically within the bHLH/PAS-A region of the AhR. Carvones did not influence a translocation of ligand-activated AhR into the nucleus. Carvones inhibited the heterodimerization of the AhR with its canonical partner ARNT and subsequent binding of the AhR to the promotor of CYP1A1. Interaction of carvones with potential off-targets, including ARNT and protein kinases, was refuted. This is the first report of a small dietary monoterpenoids as a new class of AhR non-competitive allosteric antagonists with the potential preventive and therapeutic application.

1097: Raspberry pi: Assessments of emerging organic chemicals by the predictive in silico methods
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Posted 17 Jan 2021

Raspberry pi: Assessments of emerging organic chemicals by the predictive in silico methods
77 downloads bioRxiv pharmacology and toxicology

Charli Deepak Arulanandam, Prathiviraj R, Rasiravathanahalli Kaveriyappan Govindarajan

Phthalic acid esters (PAEs) and bisphenols are used as plasticizers worldwide. During plastic production, use, deposition, and recycling these compounds contaminate the environment and affect environmental health. In this study, we investigated the toxicity of plasticizers by using in silico tools. None of the test compounds were found to be hERG blockers in multiclass predictions as evaluated by the Pred-hERG 4.1 tool. Among all tested compounds in Pred-Skin 2.0, only BBP, BCP, DBP, diethyl phthalate (DEP), DMP, DNHP, DNPP, DPP, DTDP, DUP, and ODP were non-skin sensitizers. Our results demonstrate that in silico tools provide a reliable, fast, and economic way to explore the toxicological effects of EOCs.

1098: Niclosamide Inhalation Powder Made by Thin-Film Freezing: Pharmacokinetic and Toxicology Studies in Rats and Hamsters
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Posted 27 Jan 2021

Niclosamide Inhalation Powder Made by Thin-Film Freezing: Pharmacokinetic and Toxicology Studies in Rats and Hamsters
77 downloads bioRxiv pharmacology and toxicology

Miguel O. Jara, Zachary N Warnken, Sawittree Sahakijpijarn, Chaeho Moon, Esther Y Maier, Dale J. Christensen, John J Koleng, Jay I Peters, Sarah D Hackman, Robert O Williams

In this work, we have developed and tested in vivo a dry powder form of niclosamide made by thin-film freezing (TFF) and administered it by inhalation to rats and hamsters. The niclosamide dry powder, suitable for inhalation, is being developed as a therapeutic agent against COVID-19 infection. Niclosamide, a poorly water-soluble drug, is an interesting drug candidate because it was approved over 60 years ago for use as an anthelmintic medication, but recent studies demonstrated its potential as a broad-spectrum antiviral with a specific pharmacological effect against SARS-CoV-2 infection. In the past, clinical trials for other indications were terminated prior to completion due to low and highly variable oral bioavailability. In order to quickly address the current pandemic, targeting niclosamide directly to the lungs is rational to address the COVID-19 main clinical complications. Thin-film freezing technology was used to develop a niclosamide inhalation powder composition that exhibited acceptable aerosol performance with a fine particle fraction (FPF) of 86.0% and a mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of 1.11 microns and 2.84, respectively. This formulation not only proved to be safe after an acute three-day, multi-dose pharmacokinetic study in rats as evidenced by histopathology analysis, but also was able to achieve lung concentrations above the required IC50 and IC90 levels for at least 24 h after a single administration in a Syrian hamster model. To conclude, we successfully developed a niclosamide dry powder inhalation formulation by thin-film freezing for further scale-up and clinical testing against the COVID-19 infection. This approach overcomes limitations of niclosamide of poor oral bioavailability by targeting the drug directly to the primary site of infection, the lungs.

1099: Modulation of Transient receptor potential melastatin 3 by protons through its intracellular binding sites
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Posted 08 Oct 2020

Modulation of Transient receptor potential melastatin 3 by protons through its intracellular binding sites
77 downloads bioRxiv pharmacology and toxicology

Md Zubayer Hossain Saad, Liuruimin Xiang, Yan-Shin Liao, Leah R Reznikov, Jianyang Du

Transient receptor potential melastatin 3 channel (TRPM3) is a calcium-permeable nonselective cation channel that plays an important role in modulating glucose homeostasis in the pancreatic beta cells. However, how TRPM3 is regulated under physiological and pathological conditions is poorly understood. In this study, we found that both intracellular and extracellular protons block TRPM3 through its intracellular binding sites. We demonstrated that external protons indirectly block TRPM3, whereas internal protons inhibit TRPM3 directly with an inhibitory pH50 of 6.9. We identified three titratable residues, D1059, D1062, and D1073, at the inner vestibule of the channel pore that contributes to pH sensitivity. The mutation of D1073Q reduces TRPM3 current intensity and pH sensitivity; Replacement of Asp 1073 by Gln 1073 changes the reduction of TRPM3 outward current by low external pH 5.5, from 62% in WT to 25% in D1073Q. These results indicate that D1073 is not only essential for intracellular pH sensitivity, but it is also crucial for TRPM3 channel gating. In addition, a single mutation of D1059 or D1062 enhances pH sensitivity. In summary, our findings provide a novel molecular determinant for pH regulation of TRPM3. The inhibition of TRPM3 by protons may indicate an endogenous mechanism governing TRPM3 gating and its physiological/ pathological functions. ### Competing Interest Statement The authors have declared no competing interest.

1100: BLOCKADE OF M4 MUSCARINIC RECEPTORS ON STRIATAL CHOLINERGIC INTERNEURONS NORMALIZES STRIATAL DOPAMINE RELEASE IN A MOUSE MODEL OF DYT1-TOR1A DYSTONIA
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Posted 18 Dec 2020

BLOCKADE OF M4 MUSCARINIC RECEPTORS ON STRIATAL CHOLINERGIC INTERNEURONS NORMALIZES STRIATAL DOPAMINE RELEASE IN A MOUSE MODEL OF DYT1-TOR1A DYSTONIA
76 downloads bioRxiv pharmacology and toxicology

Anthony M. Downs, Yuping Donsante, H.A. Jinnah, Ellen J. Hess

Trihexyphenidyl (THP), a non-selective muscarinic receptor (mAChR) antagonist, is the preferred oral pharmaceutical for the treatment of DYT1-TOR1A dystonia. A better understanding of the mechanism of action of THP is a critical step in the development of better therapeutics with fewer side effects. Using a mouse model of DYT1-TOR1A dystonia (Tor1a+/{Delta}E KI mice), we recently found that THP normalized striatal DA release, revealing a plausible mechanism of action for this compound. However, the exact mAChR subtypes that mediate this effect remain unclear. In this study we used a combination of a newly developed M4 subtype-selective mAChR antagonist and cell-type specific mAChR KO mice to determine which mAChR subtypes mediate the DA enhancing effects of THP. We determined that THP and the M4 subtype-selective mAChR antagonist enhance striatal DA release by blocking M4 mAChR on striatal cholinergic interneurons in Tor1a+/{Delta}E KI mice. However, in Tor1a+/+ mice THP increases striatal DA release through a combination of M1 and M4 mAChR, which reveals an alteration in M1 mAChR function in Tor1a+/{Delta}E KI mice. Taken together these data implicate a principal role for M4 mAChR located on striatal cholinergic interneurons in the mechanism of action of THP and suggest that M4-subtype selective mAChR antagonists may be more efficacious therapeutics for DYT1-TOR1A dystonia. SIGNIFICANCE STATEMENTTrihexyphenidyl, a non-selective muscarinic receptor antagonist, is the preferred oral therapeutic for DYT1-TOR1A dystonia, but it is poorly tolerated due to significant side effects. A better understanding of the mechanism of action of trihexyphenidyl is needed for the development of improved therapeutics. We recently found that trihexyphenidyl rescues the deficit in both striatal dopamine release and steady-state extracellular striatal dopamine concentrations in a mouse model of DYT1-TOR1A dystonia. However, the precise muscarinic receptor subtype(s) that mediate these effects are unknown. We used a newly developed M4 muscarinic receptor subtype-selective antagonist along with M1 and M4 muscarinic receptor knockout mice to determine the precise muscarinic receptor subtypes that mediate the dopamine-enhancing effects of trihexyphenidyl.

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