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in category pharmacology and toxicology

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

1001: Acetylation of L-leucine switches its carrier from the L-amino acid transporter (LAT) to organic anion transporters (OAT)
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Posted 13 Nov 2020

Acetylation of L-leucine switches its carrier from the L-amino acid transporter (LAT) to organic anion transporters (OAT)
86 downloads bioRxiv pharmacology and toxicology

G.C. Churchill, Michael Strupp, Tatiana Bremova-Ertl, Mallory Factor, M. Patterson, F.M. Platt, A. Galione

N-acetyl-DL-leucine is an analogue of the alpha amino acid leucine with a chiral stereocenter. The active L-enantiomer of the racemate is currently under development for rare neurological disorders. Here we present evidence that a selective recognition of N-acetyl-L-leucine versus L-leucine by different uptake transporters significantly contributes to the therapeutic effects of N-acetyl-L-leucine. A previous study of the pharmacokinetics of racemic N-acetyl-DL-leucine and N-acetyl-L-leucine revealed D-L enantiomer competition and saturation kinetics, best explained by carrier-mediated uptake. The strategy we used was to first analyze the physicochemical properties associated with good oral bioavailable drugs and how these are alerted by N-acetylation by comparing N-acetyl-L-leucine with L-leucine. Using in silico computational chemistry we found that N-acetylation has a profound impact on certain physicochemical properties that can rationalize why N-acetyl-L-leucine is drug-like compared to L-leucine. Our calculations show that at physiological pH, L-leucine is a zwitterion, whereas N-acetyl-L-leucine is present as mainly an anion. Specifically, N-acetylation removes a charge from the nitrogen at physiological pH and N-acetyl-L-leucine is an anion that is then a substrate for the organic anion transporters. We examined N-acetyl-L-leucine uptake in human embryonic kidney cells overexpression candidate organic anion transporters (OAT) and pharmacological inhibitors. We found that N-acetyl-L-leucine is a translocated substrate for OAT1 and OAT3 with low affinity (Km ~10 mM). In contrast, L-leucine is known to be transported by the L-type Amino Acid Transporter (LAT) with high affinity (Km ~0.2 mM) and low capacity. The clinical consequence is that L-leucine uptake becomes saturated at 50-fold lower concentration than N-acetyl-L-leucine. These results demonstrate a mechanism of action that explains why N-acetyl-L-leucine is effective as a drug and L-leucine itself is not. ### Competing Interest Statement GCC is a cofounder, shareholder and consultant to IntraBio. MS is a shareholder to IntraBio, and consultant for Abbott, Actelion, AurisMedical, Heel, IntraBio and Sensorion; he has received speaker's honoraria from Abbott, Actelion, Auris Medical, Biogen, Eisai, Grunenthal, GSK, Henning Pharma, Interacoustics, Johnson & Johnson, MSD, Otometrics, Pierre-Fabre, TEVA, UCB. TBE received honoraria for lecturing from Actelion and Sanofi Genzyme. MF is a co-founder, shareholder, and Chairman of IntraBio. MCP is a shareholder of IntraBio, and has received consulting fees, honoraria and research grants from Actelion Pharmaceuticals Ltd. and Biomarin. FMP is a cofounder, shareholder, and consultant to IntraBio and consultant to Actelion and Orphazyme. AG is a cofounder, shareholder and consultant to IntraBio. IntraBio owns patents EP3359146 and EP3416631 (related to treatment of lysosomal storage disorders and neurodegenerative diseases with acetyl-Leucine and its analogues). IntraBio has pending patent applications EP19174007.5, EP3482754, PCT/US2018/056420, PCT/US2018/018420, PCT/IB2018/054676, PCT/IB2019/051214, PCT/IB2017/054928, PCT/GB2017/051090, PCT/IB2017/054929, USPTO 62/812,987, USPTO 62/842,296, USPTO 62/888,894, USPTO 62/895,144, USPTO 62/868,383, USPTO 62/931,003, USPTO 62/960,637, and PCT/IB2019/060525 relating to treatment of lysosomal storage disorders, neurodegenerative diseases and neurodegeneration with acetyl-leucine and its analogues.

1002: JQ-1 ameliorates schistosomiasis liver fibrosis by suppressing JAK2 and STAT3 activation
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Posted 04 Aug 2020

JQ-1 ameliorates schistosomiasis liver fibrosis by suppressing JAK2 and STAT3 activation
85 downloads bioRxiv pharmacology and toxicology

Han Ding, Jiaming Tian, Xuhan Yang, Yongsheng Ji, Saeed El-Ashram, Xin Hou, Cuiping Ren, Jijia Shen, Fengchun Liu

Schistosomiasis is a serious parasitic infection caused by Schistosoma . The parasite deposits eggs in the host liver, causing inflammation that activates hepatic stellate cells (HSCs), which leads to liver fibrosis. Currently, there is no effective therapy for liver fibrosis; thus, treatments are urgently needed. Therefore, in the present study, mice infected with Schistosoma japonicum were treated with JQ-1, a small-molecule bromodomain inhibitor with reliable anti-tumor and anti-inflammatory activities. The fibrotic area of the liver measured by computer-assisted morphometric analysis and the expression levels of the cytoskeletal protein alpha smooth muscle actin (α-SMA) and of collagen assessed by quantitative PCR and immunohistochemistry were significantly decreased in the liver following JQ-1 treatment compared with vehicle-treated controls. Total RNA was extracted from the liver of JQ-1–treated Schistosoma- infected mice for RNA- sequencing analysis. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that JQ-1 affected biological processes and the expression of cellular components known to play key roles in HSC transdifferentiation into myofibroblasts. In vitro treatment with JQ-1 of JS-1 cells, a mouse HSC line, indicated that JQ-1 significantly inhibited JS-1 proliferation but had no effect on JS-1 activity, senescence, or apoptosis. Western blot results showed that JQ-1 inhibited the expression of phosphorylated JAK2 and phosphorylated STAT3 without altering expression levels of these non-phosphorylated proteins. Taken together, these findings suggested that JQ-1 treatment ameliorated S. japonicum egg–induced liver fibrosis, at least in part, by suppressing HSC activation and proliferation through the inhibition of JAK2/STAT3 signaling. These results lay a foundation for the development of novel approaches to treat and control liver fibrosis caused by S. japonicum .

1003: EP3 signaling is decoupled from regulation of glucose-stimulated insulin secretion in β-cells compensating for obesity and insulin resistance
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Posted 11 Jul 2020

EP3 signaling is decoupled from regulation of glucose-stimulated insulin secretion in β-cells compensating for obesity and insulin resistance
85 downloads bioRxiv pharmacology and toxicology

Michael D. Schaid, Jeffrey M. Harrington, Grant M. Kelly, Sophia M. Sdao, Matthew J. Merrins, Michelle E. Kimple

Of the β-cell signaling pathways altered by non-diabetic obesity and insulin resistance, some are adaptive while others actively contribute to β-cell failure and demise. Cytoplasmic calcium (Ca2+) and cyclic AMP (cAMP), which control the timing and amplitude of insulin secretion, are two important signaling intermediates that can be controlled by stimulatory and inhibitory G protein-coupled receptors. Previous work has shown the importance of the cAMP-inhibitory EP3 receptor in the beta-cell dysfunction of type 2 diabetes. To examine alterations in β-cell cAMP during diabetes progression we utilized a β-cell specific cAMP biosensor in tandem with islet Ca2+ recordings and insulin secretion assays. Three groups of C57BL/6J mice were used as a model of the progression from metabolic health to type 2 diabetes: wildtype, normoglycemic LeptinOb, and hyperglycemic LeptinOb. Here, we report robust increases in β-cell cAMP and insulin secretion responses in normoglycemic Leptinob mice as compared to wild-type: an effect that was lost in islets from hyperglycemic Leptinob mice, despite elevated Ca2+ duty cycle. Yet, the correlation of EP3 expression and activity to reduce cAMP levels and Ca2+ duty cycle with reduced insulin secretion only held true in hyperglycemic LeptinOb mice. Our results suggest alterations in beta-cell EP3 signaling may be both adaptive and maladaptive and define β-cell EP3 signaling as much more nuanced than previously understood. ### Competing Interest Statement The authors have declared no competing interest.

1004: In vivo Evaluation and in silico Prediction of the Toxicity of Drepanoalpha Hard capsules
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Posted 04 Dec 2020

In vivo Evaluation and in silico Prediction of the Toxicity of Drepanoalpha Hard capsules
84 downloads bioRxiv pharmacology and toxicology

Benjamin Z. Gbolo, K. N. Ngbolua, Damien S. T. Tshibangu, Patrick B. Memvanga, Dorothée D. Tshilanda, Aristote Matondo, Jason T. Kilembe, Bienvenu M. Lebwaze, Amandine Nachtergael, Pius T. Mpiana, Pierre Duez

This study was carried out in order to investigate the safety of Drepanoalpha hard capsules, a phytomedicine used for the management of sickle cell disease in the Democratic Republic of Congo, by acute and sub-acute administration in Guinea pigs. The hard capsules were dissolved in normal saline solution (NaCl 9{per thousand}). The animals were randomly selected, marked and divided into 2 groups of 5 animals each (3 males and 2 females) for acute toxicity and 4 groups of 3 animals each for sub-acute toxicity. They received by gavage a single dose of 5000 mg/ kg of body weight (B.W.) of Drepanoalpha hard capsules for acute toxicity and 125 mg/ kg, 250 mg/ kg and 500 mg/ kg of B.W. twice daily for 28 days for sub-acute toxicity. Normal saline solution was used as control. Hematological, biochemical and histopathological analyses were performed and the behavior of the animals was observed after treatment. The results showed that the median lethal dose (LD50) is greater than 5000 mg/ kg of B.W., and the relative weights of vital organs (kidney, liver, lungs, and heart) collected from Guinea pigs at the end of treatment on D14 (acute toxicity) and D28 (sub-acute toxicity) did not undergone significant changes (p>0.05). The results of haematological (Red Blood Cells, White Blood Cells, Haemoglobin, Haematocrit) and biochemical (ALT, AST, Albumin, Total Protein) tests did not show significant differences between control and test groups (0.05 for acute toxicity), while the histopathological study revealed no damage to the various organs excised. In conclusion, the results confirm the safety of Drepanoalpha, as shown in previous studies in rats and Guinea pigs using lyophilizate and decoction. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/411124v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1e3e05borg.highwire.dtl.DTLVardef@19e7755org.highwire.dtl.DTLVardef@ac7990org.highwire.dtl.DTLVardef@160efbf_HPS_FORMAT_FIGEXP M_FIG C_FIG

1005: Cycle network model of Prostaglandin H Synthase-1
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Posted 12 Aug 2020

Cycle network model of Prostaglandin H Synthase-1
83 downloads bioRxiv pharmacology and toxicology

Alexey Goltsov, Maciej Swat, Kirill Peskov, Yuri Kosinsky

The kinetic model of Prostaglandin H Synthase-1 (PGHS-1) was developed to investigate its complex network kinetics and non-steroidal anti-inflammatory drugs (NSAIDs) efficacy in different in vitro and in vivo conditions. To correctly describe the complex mechanism of PGHS-1 catalysis, we developed a microscopic approach to modelling of intricate network dynamics of 35 intraenzyme reactions among 24 intermediate states of the enzyme. The developed model quantitatively describes interconnection between cyclooxygenase and peroxidase enzyme activities; substrate (arachidonic acid, AA) and reducing cosubstrate competitive consumption; enzyme self-inactivation; autocatalytic role of AA; enzyme activation threshold, and synthesis of intermediate PGG2 and final PGH2 products under wide experimental conditions. In the paper we provided the detailed description of the enzyme catalytic cycle, model calibration based on a series of in vitro kinetic data and model validation using experimental data on the regulatory properties of PGHS-1. The validated model of PGHS-1 with a unified set of kinetic parameters is applicable for in silico screening and prediction of the inhibition effects of NSAIDs and their combination on the balance of pro-thrombotic (thromboxane) and anti-thrombotic (prostacyclin) prostaglandin biosynthesis in platelets and endothelial cells expressing PGHS-1. ### Competing Interest Statement The authors have declared no competing interest.

1006: Predicting the Disposition of the Antimalarial Drug Artesunate and its Active Metabolite Dihydroartemisinin Using Physiologically-Based Pharmacokinetic Modeling
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Posted 29 Oct 2020

Predicting the Disposition of the Antimalarial Drug Artesunate and its Active Metabolite Dihydroartemisinin Using Physiologically-Based Pharmacokinetic Modeling
83 downloads bioRxiv pharmacology and toxicology

Ryan Arey, Brad Reisfeld

Artemisinin-based combination therapies (ACTs) have proven to be effective in helping to combat the global malaria epidemic. To optimally apply these drugs, information about their tissue-specific disposition is required. Physiologically-based pharmacokinetic (PBPK) modeling is a useful technique for predicting these pharmacokinetic behaviors. In this study, a whole-body PBPK model was developed to simulate the time-dependent tissue concentrations of artesunate (AS) and its active metabolite, dihydroartemisinin (DHA). The model was developed for both rats and humans and incorporated drug metabolism of the parent compound and major metabolite. Model calibration was conducted using data from the literature in a Bayesian framework and model verification was assessed using separate sets of data. Results showed good agreement between model predictions and the validation data, demonstrating the capability of the model in predicting the blood, plasma, and tissue pharmacokinetics of AS and DHA. It is expected that such a tool will be useful in characterizing the disposition of these chemicals and ultimately improve dosing regimens by enabling a quantitative assessment of the tissue-specific drug levels critical in the evaluation of efficacy and toxicity.

1007: A novel and potent thrombolytic fusion protein consisting of anti-insoluble fibrin antibody and mutated urokinase
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Posted 08 Sep 2020

A novel and potent thrombolytic fusion protein consisting of anti-insoluble fibrin antibody and mutated urokinase
83 downloads bioRxiv pharmacology and toxicology

Shingo Hanaoka, Shinji Saijou, Yasuhiro Matsumura

Because the risk of thromboembolism increases with age, as well as due to infectious diseases, safer and more effective thrombolytic agents are in greater demand. Tissue plasminogen activator (tPA) is currently used clinically because it has higher binding specificity for insoluble fibrin (IF) than urokinase (UK), but even pro-tPA has catalytic activity in places other than IF. Meanwhile, UK has the advantage that it is specifically activated on IF, but it only binds IF weakly. Unlike the anti-IF monoclonal antibody (mAb) established in the past, our anti-IF mAb recognizes a pit structure formed only in IF. Here, we developed a new mAb against the pit, 1101, that does not affect coagulation or fibrinolysis, and prepared a fusion protein of UK with humanized 1101 Fab to transport UK selectively to IF. In IF-containing lesions, UK is cleaved by plasmin at two sites, Lys158/Ile159 and Lys135/Lys136. Cleavage of the former leads to activation of UK; however, because activated UK is linked by S-S bonds before and after cleavage, it is not released from the fusion. Cleavage at the latter site causes UK to leave the fusion protein; hence, we mutated Lys135/Lys136 to Gly135/Gly136 to prevent release of UK. This engineered UK-antibody fusion, AMU1114, significantly decreased the systemic side effects of UK in vivo . In a mouse thrombus formation experiment, the vascular patency rate was 0% (0/10) in the control, 50% (5/10) in the tPA, and 90% (9/10) in the AMU1114 treatment group. These data support future clinical development of AMU1114. ### Competing Interest Statement Y.M. is co-founder, shareholder, and Board Member of RIN Institute, Inc., a venture company spun out from the National Cancer Center, Japan. S.H. and S.S. are employees of RIN Institute, Inc.

1008: An exploratory analysis of the current chemical regulations and guidelines from the perspective of endocrine disrupting chemicals using public resources
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Posted 08 Oct 2020

An exploratory analysis of the current chemical regulations and guidelines from the perspective of endocrine disrupting chemicals using public resources
83 downloads bioRxiv pharmacology and toxicology

Bagavathy Shanmugam Karthikeyan, Janani Ravichandran, S. R. Aparna, Areejit Samal

The regulatory assessment of endocrine disrupting chemicals (EDCs) is complex due to the lack of a standardized definition of EDCs and validated testing criteria. In spite of these challenges, there is growing scientific interest in EDCs which has resulted in the rapid expansion of published literature on endocrine disruption upon chemical exposure. Here, we explore how academic research leading to curated knowledgebases can inform current chemical regulations on EDCs. To this end, we present an updated knowledgebase, DEDuCT 2.0, containing 792 potential EDCs with supporting evidence from 2218 research articles. Thereafter, we study the distribution of potential EDCs across several chemical lists that reflect guidelines for use or regulations. Further, to understand the scale of possible exposure to the potential EDCs present in chemical lists, we compare them with high production volume chemicals. Notably, we find many potential EDCs are in use across various product categories such as ‘Food additives and Food contact materials’ and ‘Cosmetics and household products’. Several of these EDCs are also produced or manufactured in high volume across the world. Lastly, we illustrate using an example how diverse information in curated knowledgebases such as DEDuCT 2.0 can be helpful in the risk assessment of EDCs. In sum, we highlight the need to bridge the gap between academic and regulatory aspects of chemical safety, as a step towards the better management of environment and health hazards such as EDCs. ### Competing Interest Statement Some of the compiled data on potential EDCs was previously submitted as a compilation to the copyright office, Government of India. Based on this copyright application, the authors were granted a literary copyright (L-79979/2019) by the Government of India and the copyright owner is the authors' institution, The Institute of Mathematical Sciences, Chennai, India.

1009: Accelerated tissue repair through cell proliferative effect by a size controlled aqueous based Fullerene C60 nanoformulation
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Posted 03 Jul 2020

Accelerated tissue repair through cell proliferative effect by a size controlled aqueous based Fullerene C60 nanoformulation
82 downloads bioRxiv pharmacology and toxicology

Nabodita Sinha, Avinash Y. Gahane, Ashwani Kumar Thakur

We have developed Fullerene-C60 nanoformulations containing discrete sized nanoparticles by dispersing the concentration range of Fullerene. Small-sized particles are cytotoxic while larger ones are cell proliferative. The cell proliferative property is used for tissue repair in cellular and animal wound models. ### Competing Interest Statement The authors have declared no competing interest.

1010: Effects of gypenosides on enteroendocrine L-cell function and GLP-1 secretion
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Posted 07 Sep 2020

Effects of gypenosides on enteroendocrine L-cell function and GLP-1 secretion
82 downloads bioRxiv pharmacology and toxicology

Chinmai Patibandla, Erin Campbell, Xinhua Shu, Angus M Shaw, Sharron Dolan, Steven Patterson

Glucagon-like peptide 1 (GLP-1) is an incretin hormone produced in gut L-cells, which regulates postprandial glucose-dependent insulin secretion, also known as the incretin effect. GLP-1 secretion may be reduced in type 2 diabetes mellitus, impacting on glycaemic regulation. Thus, methods to enhance endogenous GLP-1 secretion by use of natural GLP-1 secretagogues may improve glucose control in diabetes. Gypenosides (GYP) extracted from the plant Gynostemma Pentaphyllum (Jiaogulan) are known for their glucose-lowering effects both in vitro and in vivo , although their effect on GLP-1 secretion is unknown. Our results showed that GYP enhanced cell viability and significantly upregulated antioxidant gene Nrf2, Cat and Ho-1 expression. GYP did not affect glucokinase expression but downregulated proglucagon gene expression over 24h, although, cellular GLP-1 content was unchanged. Prohormone convertase 1 (Pcsk1) gene expression was unchanged by GYP over 24h, although protein levels were significantly downregulated, while prohormone convertase 2 (Pcsk2) mRNA and protein levels were significantly upregulated. Acute exposure to gypenosides enhanced calcium uptake and GLP-1 release from GLUTag cells both at low and high glucose concentrations. These results suggest that anti-diabetic properties of gypenosides are partly linked to their ability to stimulate GLP-1 secretion. Gypenosides enhance antioxidant gene expression and may protect L-cells from excess oxidative stress. ### Competing Interest Statement The authors have declared no competing interest. * GLP-1 : Glucagon-like peptide-1 GYP : Gypenosides T2DM : Type 2 diabetes mellitus Ncx : Sodium/Calcium exchange channel Sglt1 : Sodium/glucose cotransporter 1 Gcg : Glucagon Gck : Glucokinase Pc1 : Prohormone convertase-1 Pc2 : Prohormone convertase-2 Nrf2 : Nuclear factor erythroid 2-related factor 2 NFkb1 : Nuclear factor Kappa b1 Cat : Catalase Ho-1 : Heme oxygenase-1 MTT : 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

1011: Genome-Wide Mapping of Cisplatin Damaged Gene Loci
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Posted 28 Jul 2020

Genome-Wide Mapping of Cisplatin Damaged Gene Loci
82 downloads bioRxiv pharmacology and toxicology

Luyu Qi, Qun Luo, Yan Xu, Wanchen Yu, Xingkai Liu, Yanyan Zhang, Feifei Jia, Tiantian Fang, Shijun Wang, Xiangjun Li, Yao Zhao, Fuyi Wang

Cisplatin is a DNA targeting anticancer drug, yet its damaged gene loci have remained unclear. In the present work, combining affinity isolation and high throughput sequencing, we genome-widely mapped 17729 gene loci containing platination lesions, which mainly function as enzymes, transcription regulators, transporters and kinases, and of which 445 genes account for 71% of potential gene targets for cancer therapy reported in the literature. The most related core signaling pathway, disease and tissue toxicity of 7578 genes with an enrichment fold (EFG) of >12, where EFG refers to the ratio of total read counts of a gene detected in cells with and without cisplatin treatment, are sperm motility, cancer and hepatotoxicity with association P values of < 1*10^-22. Among 616 kinase genes damaged by cisplatin, 427 are protein kinases which account for 82% of putative protein kinases, suggesting that cisplatin may act as broad-spectrum protein kinase inhibitor. Western Blot assays verified that expression of 8 important protein kinase genes was significantly reduced due to cisplatin damage. SPAG9 is closely related to 147 of 361 cancer diseases which the cisplatin damaged genes are associated with and was severely damaged by cisplatin. Given SPAG9 abundantly expresses JIP-4, a upstream mediator of protein kinase signaling, in testis, it may be responsible for the high sensitivity of testicular cancer to cisplatin, thus being a potential therapeutic target for precise treatment of testicular cancer. These findings provide novel insights into better understanding in molecular mechanism of anticancer activity and toxicity of cisplatin, more importantly inspire further studies in prioritizing gene targets for precise treatment of cancers. ### Competing Interest Statement The authors have declared no competing interest.

1012: Prohibitin protects against cigarette smoke extract-induced cell apoptosis in cultured human pulmonary microvascular endothelial cells
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Posted 01 May 2020

Prohibitin protects against cigarette smoke extract-induced cell apoptosis in cultured human pulmonary microvascular endothelial cells
81 downloads bioRxiv pharmacology and toxicology

Yating Peng, Zijing Zhou, Aiyuan Zhou, JiaXi Duan, Hong Peng, Ruoyun Ouyang, Yan Chen, Ping Chen

Prohibitin is an evolutionarily conserved and ubiquitously expressed protein in eukaryocyte. It mediate many important roles in cell survival, apoptosis, autophagy and senescence. In the present study, we aimed to explore the role of prohibitin in cigarette smoke extract (CSE)-induced apoptosis of human pulmonary microvascular endothelial cells (HPMECs). For this purpose, HPMECs were trasfected with prohibitin and challenged with CSE. Our results showed that CSE exposure inhibited prohibitin expression in a dose-dependent manner in HPMECs. Overexpression of prohibitin could protect cell from CSE-induced injury by inhibiting CSE-induced cell apoptosis, inhibiting reactive oxygen species (ROS) production, increase mitochondrial membrane potential, increase the content of mitochondrial transcription factor A (mtTFA), IKKα/β phosphorylation and IκB-α degradation. CSE decreases prohibitin expression in endothelial cells and restoration of prohibitin expression in these cells can protect against the deleterious effects of CSE on mitochondrial and cells. We identified prohibitin is a novel regulator of endothelial cell apoptosis and survival in the context of cigarette smoke exposure.

1013: Discovery of a Novel, Selective and Short-Acting Skeletal Myosin II Inhibitor
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Posted 29 Jul 2020

Discovery of a Novel, Selective and Short-Acting Skeletal Myosin II Inhibitor
81 downloads bioRxiv pharmacology and toxicology

Laszlo Radnai, Matthew Surman, Madalyn Hafenbreidel, Erica J Young, Rebecca F Stremel, Li Lin, Paolo Pasetto, Xiaomin Jin, Mackenzie Geedy, Joni-Rae Partridge, Aagam Patel, Michael Conlon, James R. Sellers, Michael D Cameron, Gavin Rumbaugh, Patrick R Griffin, Theodore M. Kamenecka, Courtney A. Miller

Myosin IIs, actin-based motors that utilize the chemical energy of ATP to generate force, have potential as therapeutic targets. Their heavy chains differentiate the family into muscle (skeletal [SkMII], cardiac, smooth) and nonmuscle myosin IIs. Despite therapeutic potential for muscle disorders, no SkMII-specific inhibitor has been reported and characterized. Here we present the discovery, synthesis and characterization of 'skeletostatins', novel derivatives of the pan-myosin II inhibitor blebbistatin, with selectivity within the myosin IIs for SkMII. In addition, the skeletostatins bear improved potency, solubility and photostability, without cytotoxicity. Based on its optimal in vitro profile, Skeletostatin 1's in vivo tolerability, efficacy and pharmacokinetics were determined. Skeletostatin 1 was well-tolerated in mice, impaired motor performance, and had an excellent muscle to plasma ratio. Skeletostatins are useful probes for basic research and a strong starting point for drug development. ### Competing Interest Statement The authors have declared no competing interest.

1014: Measuring mutagenicity in ecotoxicology: A case study of Cd exposure in Chironomus riparius
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Posted 02 Nov 2020

Measuring mutagenicity in ecotoxicology: A case study of Cd exposure in Chironomus riparius
81 downloads bioRxiv pharmacology and toxicology

Halina Binde Doria, Ann-Marie Waldvogel, Markus Pfenninger

Existing mutagenicity tests for metazoans lack the direct observation of enhanced germline mutation rates after exposure to anthropogenic substances, therefore being inefficient. Cadmium (Cd) is a metal described as a mutagen in mammalian cells and listed as a group 1 carcinogenic and mutagenic substance. But Cd mutagenesis mechanism is not yet clear. Therefore, in the present study, we propose a method coupling short-term mutation accumulation (MA) lines with subsequent whole genome sequencing (WGS) and a dedicated data analysis pipeline to investigate if chronic Cd exposure on Chironomus riparius can alter the rate at which de novo point mutations appear. Results show that Cd exposure did not affect the basal germline mutation rate nor the mutational spectrum in C. riparius, thereby arguing that exposed organisms might experience a range of other toxic effects before any mutagenic effect may occur. We show that it is possible to establish a practical and easily implemented pipeline to rapidly detect germ cell mutagens in a metazoan test organism. Furthermore, our data implicate that it is questionable to transfer mutagenicity assessments based on in vitro methods to complex metazoans. ### Competing Interest Statement The authors have declared no competing interest.

1015: The effect of combined treatment of vitamin C and loperamide on intestinal sodium and potassium ion ATPase, alkaline phosphatase and lipid peroxidation on castor oil induced diarrheal rats.
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Posted 13 Nov 2020

The effect of combined treatment of vitamin C and loperamide on intestinal sodium and potassium ion ATPase, alkaline phosphatase and lipid peroxidation on castor oil induced diarrheal rats.
80 downloads bioRxiv pharmacology and toxicology

Godswill Imolele Anthony, Paul Aondowase Iorhemba

Background: Diarrhea is distinguished by prevalence of bowel movement accompanied by a loose consistency of stools, resulting from hyper peristalsis of the small intestine or colon, Diarrhea is a major challenge among infants and growing children. The study was carried out to assess the result of combined treatment of vitamin C and loperamide on intestinal Na+, K+ - ATPase, alkaline phosphatase, and lipid peroxidation in castor oil induced diarrheal wistar rats. Method: A total of 18 wistar rats weighing 180-200g were randomly divided into 6 groups, (Group 1 Normal control no castor oil, no treatment administered, Group 2 Experimental control were given castor oil 3.0 ml/kg body weight with no treatment, Group 3 Standard control were given castor oil 3.0 ml/kg body weight + loperamide, Group 4 Treatment 1 were administered 3.0 ml/kg body weight + 25 mg/kg combined effect of vitamin C and loperamide, Group 5 Treatment 2 were administered 3.0 ml/kg body weight + 50 mg/kg combined effect of vitamin C and loperamide, and Group 6 were administered 3.0 ml/kg body weight + 100 mg/kg combined effect of vitamin C and loperamide) with 3 rats per group; the experiment lasted for 24 hours. The action of intestinal alkaline phosphatase, Na+, K+ -ATPase and malondialdehyde were determined. Result: Descriptive statistical analysis was adopted using SPSS version 20. Combined effect of vitamin C and loperamide significantly (p<0.05) lowered the elevated levels of malondialdehyde caused by castor oil induced diarrhea; the Na+, K+ - ATPase intestinal activity treatment with both vitamin C and loperamide significantly elevated the activity of Na+, K+ ATPase when compared with the normal control, but both treatments (loperamide alone and vitamin C plus loperamide were not significantly different (p<0.05) to themselves. However, at 50 mg/kg body weight of combined effect of vitamin C and loperamide it showed significant difference in the action of intestinal alkaline phosphatase. Conclusion: Findings of this study therefore, indicate that a combined effect of loperamide and vitamin C will be an effective therapeutic agent in the management of diarrhea by scavenging of free radicals generated in the cause of diarrheal to reduce lipid peroxidation. Therefore, combined effect of vitamin C and loperamide should be encouraged in the management of diarrhea. Further research should be directed towards assessing the therapeutic action of vitamin C only in the management of diarrhea. ### Competing Interest Statement The authors have declared no competing interest.

1016: Overexpressed microrna-129-5p reverses CCl4-Induced hepatic fibrosis by suppressing PEG3 expression and the NF-κB signaling pathway
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Posted 27 Nov 2020

Overexpressed microrna-129-5p reverses CCl4-Induced hepatic fibrosis by suppressing PEG3 expression and the NF-κB signaling pathway
79 downloads bioRxiv pharmacology and toxicology

Yinfeng Li, Shengtao Sun, Yunxia Ma

Hepatic fibrosis is a pathological process resulting from liver damage, which leads to the extracellular matrix (ECM) proteins accumulation in the liver. Considering that microRNA (miR)-129-5p has a vital effect in the gene expression regulation about fibrosis through transcriptional profiling, this study speculated whether miR-129-5p had potential to influence the progression of hepatic fibrosis. The hepatic fibrosis rat models induced by C-C motif chemokine ligand 4 (CCl4) were established. The pathological changes of the liver tissues were assayed with hematoxylin-eosin (HE) staining. Subsequently, gain- and loss-of-function analysis with miR-129-5p antagomir or shRNA against PEG3 was conducted to further investigate the molecular regulatory mechanism of miR-129-5p, with detection of the expression of NF-{kappa}B signaling pathway-related proteins and apoptosis-related factors. The serum samples of rats were analyzed by serological index analysis. The targeting of miR-129-5p to PEG3 was verified by dual-luciferase reporter gene assay. The detection of apoptosis in rats was measured by TUNEL staining. MiR-129-5p was poorly-expressed and PEG3 was highly-expressed in hepatic fibrosis. miR-129-5p could reduce the expression of PEG3. Next, upregulated miR-129-5p or downregulated PEG3 led to less obvious histological changes of liver cirrhosis and lowered apoptosis rate. Further, miR-129-5p regulated the activation of NF-{kappa}B signaling pathway via PEG3. The hepatic fibrosis induced by CCl4 can be reversed by upregulated miR-129-5p or downregulated PEG3 expression.

1017: Bridging the gap between in silico and in vivo: modeling opioid disposition in a kidney proximal tubule microphysiological system
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Posted 06 Dec 2020

Bridging the gap between in silico and in vivo: modeling opioid disposition in a kidney proximal tubule microphysiological system
79 downloads bioRxiv pharmacology and toxicology

Tomoki Imaoka, Weize Huang, Sara Shum, Dale W. Hailey, Shih-Yu Chang, Alenka Chapron, Catherine K Yeung, Jonathan Himmelfarb, Nina Isoherranen, Edward J. Kelly

Background: Opioid overdose, dependence, and addiction are a major public health crisis. Patients with chronic kidney disease (CKD) are at high risk of opioid overdose, therefore novel methods that provide accurate prediction of kidney clearance (CLr) and systemic disposition of opioids in CKD patients can facilitate the optimization of therapeutic regimens. Methods: We conducted prediction of kidney clearance and systemic disposition of morphine and its active metabolite morphine-6-glucuronide (M6G) in CKD patients using a vascularized human proximal tubule microphysiological system (VPT-MPS) coupled with a parent-metabolite full body physiologically-based pharmacokinetic (PBPK) model. Results: The VPT-MPS, populated with a human umbilical vein endothelial cell (HUVEC) channel and an adjacent human primary proximal tubular epithelial cells (PTEC) channel, successfully demonstrated secretory transport of morphine and M6G from the HUVEC channel into the PTEC channel in a time-dependent manner; transporter inhibitors decreased translocation by 74.3% and 63.6%, respectively. The in vitro data generated by VPT-MPS were incorporated into a mechanistic kidney model and parent-metabolite full body PBPK model to predict CLr and systemic disposition of morphine and M6G. The model successfully predicted CLr within 1.5-fold, and the plasma concentration-time profiles of morphine and M6G in both healthy subjects and CKD patients, with absolute average fold error values <1.5. Conclusions: A microphysiological system together with mathematical modeling successfully predicted kidney clearance and systemic disposition of opioids in CKD patients and healthy subjects.

1018: Neuroprotective mechanisms of red clover and soy isoflavones in Parkinson's disease models
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Posted 02 Dec 2020

Neuroprotective mechanisms of red clover and soy isoflavones in Parkinson's disease models
79 downloads bioRxiv pharmacology and toxicology

Aurélie de Rus Jacquet, Abeje Ambaw, Mitali Arun Tambe, Sin Ying Ma, Michael Timmers, Qing-Li Wu, James E Simon, George P McCabe, Mary Ann Lila, Riyi Shi, Jean-Christophe Rochet

Parkinsons disease (PD) is a neurodegenerative disorder characterized by nigrostriatal degeneration and the spreading of aggregated forms of the presynaptic protein -synuclein (aSyn) throughout the brain. PD patients are currently only treated with symptomatic therapies, and strategies to slow or stop the progressive neurodegeneration underlying the diseases motor and cognitive symptoms are greatly needed. The time between the first neurobiochemical alterations and the initial presentation of symptoms is thought to span several years, and early neuroprotective dietary interventions could delay the disease onset or slow PD progression. This study aimed at characterizing the neuroprotective effects of isoflavones, a class of dietary polyphenols found in soy products and in the medicinal plant red clover (Trifolium pratense). We found that isoflavone-rich extracts and individual isoflavones rescued the loss of dopaminergic neurons and the shortening of neurites in primary mesencephalic cultures exposed to two PD-related insults, the environmental toxin rotenone and an adenovirus encoding the A53T aSyn mutant. The extracts and individual isoflavones also activated the Nrf2-mediated antioxidant response in astrocytes via a mechanism involving inhibition of the ubiquitin-proteasome system, and they alleviated deficits in mitochondrial respiration. Furthermore, an isoflavone-enriched soy extract reduced motor dysfunction exhibited by rats lesioned with the PD-related neurotoxin 6-OHDA. These findings suggest that plant-derived isoflavones could serve as dietary supplements to delay PD onset in at-risk individuals and mitigate neurodegeneration in the brains of patients.

1019: 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.
79 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.

1020: Effect of pesticides and metals on zebrafish embryo development and larval locomotor activity
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Posted 05 Oct 2020

Effect of pesticides and metals on zebrafish embryo development and larval locomotor activity
79 downloads bioRxiv pharmacology and toxicology

Michael K. Richardson, Shaukat Ali

The zebrafish has been widely used as a predictive model in safety and toxicology. Low cost high-throughput screening can be achieved with this model, and the genome contains orthologues of the majority of human disease genes. However, previous studies indicate that the predictivity of the zebrafish model in toxicology varies between compound and compound class. We examined this issue by screening 24 compounds from two different compound classes, metals and biocides (pesticides/insecticides) for toxicity in the zebrafish model and looked at the effects on hatching, morphology and predictivity for mammalian toxicity. Wild-type zebrafish embryos were exposed to test compounds in 96-well plates for 96 hours starting at 24 hours post fertilization. Hatching was either delayed or accelerated depending on the compound. Three types of alteration in behavioural responses were noted: (i) hypoactivity; (ii) hyperactivity; and (iii) biphasic response (a dose-dependent shift between hypo- and hyperactivity). LC 50 of compounds was calculated and compared to published LD 50 values in rodents. The zebrafish-rodent values were poorly correlated for both metals and biocides. We conclude that, although the zebrafish is a good model for some aspects of toxicology, its predictivity for mammalian toxicity needs to be determined per compound class.

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