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Visualization of endogenous G proteins on endosomes and other organelles bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-17 Wonjo Jang, Kanishka Senarath, Sumin Lu, Nevin A Lambert
Classical G protein-coupled receptor (GPCR) signaling takes place in response to extracellular stimuli and involves receptors and heterotrimeric G proteins located at the plasma membrane. It has recently been established that GPCR signaling can also take place from intracellular membrane compartments, including endosomes that contain internalized receptors and ligands. While the mechanisms of GPCR
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Germline cis variant determines epigenetic regulation of the anti-cancer drug metabolism gene dihydropyrimidine dehydrogenase (DPYD) bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-16 Ting Zhang, Alisa Ambrodji, Huixing Huang, Kelly J Bouchonville, Amy S Etheridge, Remington E Schmidt, Brianna M Bembenek, Zoey B Temesgen, Zhiquan Wang, Federico Innocenti, Deborah Stroka, Robert B Diasio, Carlo R Largiadèr, Steven M Offer
Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression
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Benchmarking organ-specific responses to therapies in tissues differentiated from Cystic Fibrosis patient derived iPSCs bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-14 Abdelkader Daoud, Sunny Xia, Onofrio Laselva, Jia Xin Jiang, Christine Bear
Cystic Fibrosis (CF) is a life-shortening disease that is caused by mutations in the CFTR gene, a gene that is expressed in multiple organs. There are several primary tissue models of CF disease, including nasal epithelial cultures and rectal organoids, that are effective in reporting the potential efficacy of mutation-targeted therapies called CFTR modulators. However, there is the well-documented
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Direct inhibitors of InhA with efficacy similar or superior to isoniazid in novel drug regimens for tuberculosis bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-14 Lourdes Encinas, Si-Yang Li, Joaquin Rullas-Trincado, Rokeya Tasneen, Sandeep TYAGI, Heena Soni, adolfo garcia-perez, Jin Lee, Rubén González del Río, Jaime De Mercado, Verónica Sousa, Izidor Sosi?, Stanislav Gobec, Alfonso Mendoza-Losana, Paul J Converse, Khisimuzi Mdluli, Nader Fotouhi, David BARROS-AGUIRRE, Eric L. Nuermberger
Isoniazid is an important first-line medicine to treat tuberculosis (TB). Isoniazid resistance increases the risk of poor treatment outcomes and development of multidrug resistance, and is driven primarily by mutations involving katG, encoding the pro-drug activating enzyme, rather than its validated target, InhA. The chemical tractability of InhA has fostered efforts to discover direct inhibitors
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Silver nanoparticles can be sampled by ultrafiltration probe but elution into & recovery from plasma and DPBS differs in vitro bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-13 Marije Risselada, Robyn R Mc Cain, Miriam G Bates, Makensie Anderson
We compared 1) the influence of elution fluid on rate, pattern, and completeness of silver nanoparticle (AgNP) elution, and 2) ultrafiltration (UF) probe and direct sampling in vitro. Six specimens (2.5ml of 0.02mg/ml 10nm AgNP and 5.0ml of 30% poloxamer 407) contained in a dialysis tube (12-14kDa pores) were placed in 100ml Dulbecco’s Phosphate Buffered Saline (DPBS) (n=3) or canine plasma (n=3) for
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AlphaFold2 structures template ligand discovery bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-13 Jiankun Lyu, Nicholas Kapolka, Ryan Gumpper, Assaf Alon, Liang Wang, Manish Jain, Ximena Alvarez, Kensuke Sakamoto, Yoojoong Kim, Jeffrey DiBerto, Kuglae Kim, Tia Tummino, Sijie Huang, John Irwin, Olga Tarkhanova, Yurii Moroz, Georgios Skiniotis, Andrew Kruse, Brian Shoichet, Bryan Roth
AlphaFold2 (AF2) and RosettaFold have greatly expanded the number of structures available for structure-based ligand discovery, even though retrospective studies have cast doubt on their direct usefulness for that goal. Here, we tested unrefined AF2 models prospectively, comparing experimental hit-rates and affinities from large library docking against AF2 models vs the same screens targeting experimental
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Deoxynivalenol induced inflammation and increased the adherence of entero-invasive Escherichia coli to intestinal epithelial cells via modulation of mucin and pro-inflammatory cytokine production bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-13 Murphy LY Wan, Vanessa A Co, Paul C Turner, Shah P Nagendra, Hani El-Nezami
Deoxynivalenol (DON) is a mycotoxin that commonly occurs in crops. It was hypothesized that DON could trigger intestinal inflammation and increase the susceptibility of intestinal epithelial cells (IECs) to pathogen infection. Accordingly, the aim of this study was to investigate the effects of DON on intestinal susceptibility to pathogen infection. Semiconfluent Caco-2 cells were exposed to DON followed
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Karanjin alters gene expression through ERα: a preliminary study bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-13 Gaurav Bhatt, Latha Rangan, Anil Mukund Limaye
Karanjin is an abundant furanoflavonoid-constitutent of pongamia oil. Among several biological actions of karanjin, the antiproliferative effect of karanjin has gained traction in the recent years; raising speculations about its anticancer potential. In the backdrop of partial estrogen-like alteration of gene expression by karanjin in ERα positive MCF-7 breast cancer cells, we present preliminary evidences
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Metabolomic analysis of the effect of endocannabinoid metabolism inhibition in ovalbumin-induced allergic airway inflammation in Guinea pigs bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-13 Reshed Abohalaka, Yasemin Karaman, Tuba Recber, Sevgen Celik Onder, Emirhan Nemutlu, Turgut Emrah Bozkurt
Background and aims: Asthma manifests as a multifaceted airway inflammation. The therapeutic potential of targeting endocannabinoids in mitigating asthma remains incompletely elucidated. Therefore, we aim to scrutinize metabolic alterations, deepen our comprehension of the endocannabinoids therapeutic role, and discern novel biomarkers for monitoring allergic airway inflammation. Methods: Guinea pigs
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A randomized, controlled, two–center preclinical trial assessing the efficacy of a new benzodiazepine–dihydropyridine hybrid molecule (JM–20) in rodent models of ischemic stroke bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-13 Jeney Ramírez-Sánchez, André Rex, Sarah McCann, Daniel Schulze, Maylin Wong-Guerra, Luis A Fonseca-Fonseca, Enrique García-Alfonso, Ailín Ramírez-Abreu, Ricardo Limonta, Monika Dopatka, Larissa Mosch, Yanier Núňez-Figueredo, Ulrich Dirnagl
JM–20 is a novel multifunctional benzodiazepine molecule with potent neuroprotective effects in rat focal cerebral ischemia. To confirm previous results obtained in single laboratories with small sample sizes, and to provide robust preclinical evidence base for a potential clinical development in stroke, we have performed a two–center preclinical trial with sufficiently large group sizes to detect
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Predicting nanocarrier permeation across the human intestine in vitro: Model matters bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-12 Nathalie Jung, Jonas Schreiner, Florentin Baur, Sarah Vogel-Kindgen, Maike Windbergs
For clinical translation of oral nanocarriers, simulation of the complex intestinal microenvironment is crucial to evaluate interactions and transport across the intestinal mucosa for predicting the drug's bioavailability. However, permeation studies are often conducted using simplistic cell culture models, overlooking key physiological factors such as tissue composition, morphology, and additional
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Sclerostin blockade inhibits bone resorption through PDGF receptor signaling in osteoblast lineage cells bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-12 Cyril Thouverey, Pierre Apostolides, Julia Brun, Joseph Caverzasio, Serge Ferrari
While sclerostin-neutralizing antibodies (Scl-Ab) transiently stimulate bone formation by activating Wnt signaling in osteoblast lineage cells, they exert sustained inhibition of bone resorption, suggesting an alternate signaling pathway by which Scl-Ab control osteoclast activity. Since sclerostin can activate platelet-derived growth factor receptors (PDGFRs) in osteoblast lineage cells in vitro and
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Application of mechanistic multiparameter optimization and large scale in vitro to in vivo pharmacokinetics correlations to small molecule therapeutic projects bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-11 Fabio Broccatelli, Vijayabhaskar Veeravalli, Daniel Cashion, Javier L Baylon, Franco Lombardo, Lei Jia
Computational chemistry and machine learning are used in drug discovery to predict target-specific and pharmacokinetic properties of molecules. Multiparameter optimization (MPO) functions are used to summarize multiple properties into a single score, aiding compound prioritization. However, over-reliance on subjective MPO functions risks reinforcing human bias. Mechanistic modeling approaches based
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Pharmacological inhibition of macrophage triglyceride biosynthesis pathways does not improve Mycobacterium tuberculosis control in infected mice bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-11 Jennie Ruelas Castillo, Valentina Guerrini, Darla Quijada, Styliani Karanika, Pranita Neupane, Harley Harris, Andrew Garcia, Babajide Shenkoya, Addis Yilma, Hannah Bailey, Rehan Khan, Mathangi Gopalakrishnan, Maria Laura Gennaro, Petros C Karakousis
Triglyceride rich macrophages (foam cells) are a hallmark of necrotic granulomas in tuberculosis, and multiple antimicrobial functions are down-regulated in these cells. In this study, we assessed the ability of two different compounds to reduce triglyceride content and intracellular burden in Mycobacterium tuberculosis (Mtb)-infected macrophages: A-922500 (DGATi), an inhibitor of diacylglycerol acyltransferase
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The protective roles of Eugenol on type 1 diabetes mellitus through NRF2 mediated oxidative stress pathway bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-11 Yalan Jiang, Pingping He, Ke Sheng, Yongmiao Peng, Huilan Wu, Songwei Qian, Weiping Ji, Xiaoling Guo, Xiaoou Shan
Type 1 diabetes mellitus (T1DM), known as insulin-dependent diabetes mellitus, is characterized by persistent hyperglycemia caused by damage to the pancreatic β cells and an absolute insulin deficiency, which will affect multiple organs and has a poor prognosis. Oxidative stress and apoptosis play a major role in the progression of T1DM. Eugenol (EUG) is a natural compound with anti-inflammatory, anti-oxidant
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Air-liquid interface exposure of A549 human lung cells to characterize the hazard potential of a gaseous bio-hybrid fuel blend bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-11 Jonas Daniel, Ariel A. Schönberger Alvarez, Pia te Heesen, Bastian Lehrheuer, Stefan Pischinger, Henner Hollert, Martina Roß-Nickoll, Miaomiao Du
Gaseous and semi-volatile organic compounds emitted by the transport sector contribute to air pollution and have adverse effects on human health. To reduce harmful effects to the environment as well as to humans, renewable and sustainable bio-hybrid fuels are explored and investigated in the cluster of excellence “The Fuel Science Center” at RWTH Aachen University. However, data on the effects of bio-hybrid
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Off-target depletion of plasma tryptophan by allosteric inhibitors of BCKDK bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-11 Caitlyn E Bowman, Michael D Neinast, Cholsoon Jang, Jiten Patel, Megan C Blair, Emily T Mirek, William O Jonsson, Qingwei Chu, Lauren Merlo, Laura Mandik-Nayak, Tracy G Anthony, Joshua D Rabinowitz, Zolt Arany
The activation of branched chain amino acid (BCAA) catabolism has garnered interest as a potential therapeutic approach to improve insulin sensitivity, enhance recovery from heart failure, and blunt tumor growth. Evidence for this interest relies in part on BT2, a small molecule that promotes BCAA oxidation and is protective in mouse models of these pathologies. BT2 and other analogs allosterically
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Effects of access condition on substance use disorder-like phenotypes in male and female rats self-administering MDPV or cocaine bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-08 Michelle R Doyle, Nina M Beltran, Mark SA Bushnell, Maaz Syed, Valeria Acosta, Marisa Desai, Kenner C Rice, Katie M Serafine, Georgianna G Gould, Lynette C Daws, Gregory T Collins
Substance use disorder (SUD) is a heterogeneous disorder, where severity, symptoms, and patterns of substance use vary across individuals. Yet, when rats are allowed to self-administer drugs such as cocaine under short-access conditions, their behavior tends to be well-regulated and homogeneous in nature; though individual differences can emerge when rats are provided long- or intermittent-access to
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[225Ac]Ac/[89Zr]Zr-labeled N4MU01 radioimmunoconjugates as theranostics against nectin-4 positive triple negative breast cancer bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-08 Hanan Babeker, Fabrice Ngoh Njotu, Jessica Pougoue Ketchemen, Anjong Florence Tikum, Alireza Doroudi, Emmanuel Nwangele, Maruti Uppalapati, Humphrey Fonge
Purpose: Nectin-4 is an overexpressed biomarker in 60-70% of triple-negative breast cancer (TNBC), and an ideal target for radiotherapy and PET imaging. In this study, we have developed theranostic radioimmunoconjugates (RICs) based on a fully-human anti-nectin-4 antibody, N4MU01. We characterized and evaluated the efficacy of these RICs for applications in molecular imaging and radiotherapy of aggressive
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Large- and Small-Animal Studies of Safety, Pharmacokinetics (PK), and Biodistribution of Inflammasome-Targeting Nanoligomer in the Brain and Other Target Organs bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-07 Sydney Risen, Breonna Kusick, Sadhana Sharma, Vincenzo Gilberto, Stephen Brindley, Mikayla Aguilar, Jared Brown, Stephanie McGrath, Anushree Chatterjee, Julie Moreno, Prashant Nagpal
Immune malfunction or misrecognition of healthy cells and tissue, termed autoimmune disease, is implicated in more than 80 disease conditions and multiple other secondary pathologies. While pan-immunosuppressive therapies like steroids offer some relief for systemic inflammation for some organs, many patients never achieve remission and such drugs do not cross the blood-brain barrier making them ineffective
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Hyaluronidase impacts exposures of long-acting injectable paliperidone palmitate in rodent models bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-06 Henry Pertinez, Amit Kaushik, Paul Curley, Usman Arshad, Eman El-Khateeb, Si-Yang Li, Rokeya Tasneen, Joanne Sharp, Edyta Kijak, Joanne Herriott, Megan Neary, Michael Noe, Charles Flexner, Eric Nuermberger, Andrew Owen, Nicole C. Ammerman
A significant challenge in the development of long-acting injectable drug formulations, especially for anti-infective agents, is delivering an efficacious dose within a tolerable injection volume. Co-administration of the extracellular matrix-degrading enzyme hyaluronidase can increase maximum tolerable injection volumes but is untested for this benefit with long-acting injectable formulations. One
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Salidroside and its in vivo metabolite tyrosol could act directly on dopamine D2 receptors: a study using RNAseq combined with Connectivity Map analysis bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-06 Jizhou Zhang, Chang Jiang, Jing Han
Salidroside is an active ingredient in traditional Chinese medicine such as Rhodiola. Its in vivo metabolite, tyrosol, exist in olive oil and red wine. For a long time, clinical practice and research have shown that both of them have many pharmacological activities, but their targets have not reached unanimous conclusion. The present study proposed that dopamine D2 receptor (DRD2) may be the target
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Investigating the mode of action for wasting produced by tetrachlorodibenzo-p-dioxin (TCDD) in rats using transcriptomics: Evidence for roles of AHR and ARNT in circadian cycling bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-06 Melvin E Andersen, Rasim Barutcu, Michael B Black, Joshua Harrill
Single, high doses of TCDD in rats caused wasting, a progressive loss of 30 to 50% body weight and death within several weeks. To identify pathway perturbations at or near doses causing wasting, we examined differentially gene expression (DGE) and pathway enrichment in centrilobular (CL) and periportal (PP) regions of female rat livers following 6 dose levels of TCDD, 0, 3, 22, 100, 300, and 1000 ng/kg/day
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Investigating the mode of action for liver toxicity and wasting-like responses produced by high dose exposures to longer chain perfluoroacid substances (PFAS) using high throughput transcriptomics bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-06 Rasim Barutcu, Michael Black, Melvin E Andersen
Single doses of perfluoro-n-decanoic acid (PFDA) cause wasting, a progressive loss of 30 to 50% body weight, increasing liver/body weight ratios, and death within several weeks (Olson and Andersen, 1983). Repeat high doses of perfluorooctane sulfonate (PFOS) produce a subset of these responses in rats and monkeys. The mode of action (MOA) of these wasting-like syndromes is not clear, nor is it understood
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Disease Modifying Osteoarthritis Drug Discovery Using A Temporal Phenotypic Reporter In Primary Human Chondrocytes bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-05 Maria A Cruz, Scott Gronowicz, Makan Karimzadeh, Kari Martyniak, Ramapaada Medam, Thomas J Kean
Osteoarthritis is a significant and growing problem with no disease modifying drugs in the clinic. Current screening platforms typically use 2D culture, immortalized or non-human cells in a hyperoxic environment. To challenge this paradigm and identify new drugs, we engineered primary human chondrocytes with a secreted luciferase reporter under the control of the articular cartilage marker, type II
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Next Generation Neuropeptide Y Receptor Small Molecule Agonists Inhibit Mosquito Biting Behavior bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-05 Emely V. Zeledon, Leigh A. Baxt, Tanweer A. Khan, Mayako Michino, Michael Miller, David J. Huggins, Caroline S. Jiang, Leslie B. Vosshall, Laura B. Duvall
Female Aedes aegypti mosquitoes can spread disease-causing pathogens when they bite humans to obtain blood nutrients required for egg production. Following a complete blood meal, host-seeking is suppressed until eggs are laid. Neuropeptide Y-like Receptor 7 (NPYLR7) plays a role in endogenous host-seeking suppression and previous work identified small molecule NPYLR7 agonists that suppress host-seeking
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Synthesis and Biological Assessment of Chalcone and Pyrazoline Derivatives as novel inhibitor for ELF3-MED23 Interaction bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-05 Soo-Yeon Hwang, Kyung-Hwa Jeon, Hwa-Jong Lee, Inhye Moon, Sehyun Jung, Seul-Ah Kim, Hyunji Jo, Seojeong Park, Misun Ahn, Soo-Yeon Kwak, Younghwa Na, Youngjoo Kwon
HER2 overexpression significantly contributes to the aggressive nature and recurrent patterns observed in various solid tumors, notably gastric cancers. Trastuzumab, HER2-targeting monoclonal antibody drug, has shown considerable clinical success, however, readily emerging drug resistance emphasizes the pressing need for improved interventions in HER2-overexpressing cancers. To address this, we proposed
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Identification of bazedoxifene for the treatment of LGMD R2 by high throughput screening. bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-04 Celine Bruge, Nathalie Bourg, Emilie PELLIER, Johana Tournois, Jerome Polentes, Manon BENABIDES, Noella Grossi, Anne Bigot, Anthony Brureau, Isabelle Richard, Xavier Nissan
LGMD R2 is a rare genetic disorder characterized by progressive proximal muscle weakness and wasting caused by a recessive loss of function of dysferlin, a transmembrane protein controlling plasma membrane repair in skeletal muscles. We report here the development of an in vitro high-throughput assay using immortalized myoblasts and monitored reallocation of an aggregated mutant form of dysferlin (DYSFL1341P)
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Pharmacological Characterization of SDX-7320/Evexomostat: a Novel Methionine Aminopeptidase Type 2 Inhibitor with Anti-Tumor and Anti-Metastatic Activity bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-03 Peter Cornelius, Benjamin A Mayes, John S Petersen, David J Turnquist, Pierre J Dufour, James M Shanahan, Bradley J Carver
Methionine aminopeptidase type 2 (MetAP2) is a ubiquitous, evolutionarily conserved metalloprotease fundamental to protein biosynthesis which catalyzes removal of the N-terminal methionine residue from nascent polypeptides. MetAP2 is an attractive target for cancer therapeutics based upon its over-expression in multiple human cancers, the importance of MetAP2-specific substrates whose biological activity
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The atypical antipsychotic lurasidone positively modulates the gut microbiota in rats: A comparative study to olanzapine bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-03 Srinivas Kamath, Alexander Hunter, Kate Collins, Anthony Wignall, Paul Joyce
Antipsychotics like olanzapine are associated with significant metabolic dysfunction, attributable to gut microbiota dysbiosis. A recent notion that most psychotropics are detrimental to the gut microbiota has arisen from consistent findings of metabolic adverse effects. However, unlike olanzapine, the metabolic effects of lurasidone are conflicting, with most reports observing weight loss rather than
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Ultrasonic Cigarettes: Chemicals and Cytotoxicity are Similar to Heated-Coil Pod-Style Electronic Cigarettes bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-03 Esther E. Omaiye, Wentai Luo, Kevin J. McWhirter, James F. Pankow, Prue Talbot
Our purpose was to test the hypothesis that ultrasonic cigarettes (u-cigarettes), which operate at relatively low temperatures, produce aerosols that are less harmful than heated-coil pod-style electronic cigarettes (e-cigarettes). The major chemicals in SURGE u-cigarette fluids and aerosols were quantified, their cytotoxicity and cellular effects were assessed, and a Margin of Exposure risk assessment
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Bio-guided isolation of a new sesquiterpene from Artemisia cina with anthelmintic activity against Haemonchus contortus L3 infective larvae bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-01 Luis David Arango-De la Pava, Manasés González-Cortázar, Alejandro Zamilpa, Jorge Alfredo Cuéllar-Ordaz, Héctor Alejandro de la Cruz-Cruz, Rosa Isabel Higuera-Piedrahita, Raquel López-Arellano
Haemonchus contortus is a blood-feeding gastrointestinal parasite that impacts grazing sheep, causing economic losses in animal production and presenting anthelmintic resistance, requiring alternative antiparasitic treatments, including the exploration of plant-based anthelmintics. Artemisia cina (Asteraceae) is a plant whose n-hexane (n-HE) and ethyl acetate extract (EAE) exhibits anthelmintic activity
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The effect of enriched versus inadequate housing conditions on eucalyptus smoke-induced cardiovascular dysfunction in mice bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-01 Molly Harmon, Michelle Fiamingo, Sydnie Toler, Kaleb Lee, Yongho Kim, Brandi Martin, M Ian Gilmour, Aimen Farraj, Mehdi Hazari
Living conditions play a major role in health and well-being, particularly for the cardiovascular and pulmonary systems. Depleted housing contributes to impairment and development of disease, but how it impacts body resiliency during exposure to environmental stressors is unknown. This study examined the effect of depleted (DH) versus enriched housing (EH) on cardiopulmonary function and subsequent
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Xylazine enhances the tranq, but not the fentanyl dope bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-01 Celsey St. Onge, Jeremy Canfield, Allison Ortiz, Jon Sprague, Matthew Banks
The adulteration of illicit fentanyl with the alpha-2 agonist xylazine has been designated an emerging public health threat. The clinical rationale for combining fentanyl with xylazine is currently unclear, and the inability to study fentanyl/xylazine interactions in humans warrants the need for preclinical research. We studied fentanyl and xylazine pharmacokinetic and pharmacodynamic interactions
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Evaluation of common in vitro assays for the prediction of oral bioavailability and hepatic metabolic clearance in humans bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-03-01 Urban Fagerholm
Introduction: Intrinsic hepatic metabolic clearance (CLint) measured with human hepatocytes, apparent intestinal permeability (Papp) obtained using the Caco-2 model, unbound fraction in plasma (fu) and blood-to-plasma concentration ratio (Cbl/Cpl) are commonly used for predicting the hepatic clearance (CLH) and oral bioavailability (F) of drug candidates in humans. The primary objective was to select
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Curcumin and turmeric extract inhibit SARS-CoV-2 pseudovirus cell entry and Spike mediated cell fusion bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-29 Endah Puji Puji Septisetyani, Dinda Lestari, Komang Alit Paramitasari, Pekik Wiji Prasetyaningrum, Ria Fajarwati Kastian, Khairul Anam, Adi Santoso, Kartini Eriani
Turmeric extract (TE) with curcumin as its main active ingredient has been studied as a potential COVID-19 therapeutic. Curcumin has been studied in silico and in vitro against a naive SARS-CoV-2 virus, yet little is known about TE's impact on SARS-CoV-2 infection. Moreover, no study reveals the potential of both curcumin and TE on the inhibition of SARS-CoV-2 cell-to-cell transmission. Here, we investigated
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The effect of molnupiravir and nirmatrelvir on SARS-CoV-2 genome diversity in infected and immune suppressed mice bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-28 Rebekah Penrice-Randal, Eleanor G Bentley, Parul Sharma, Adam Kirby, I'ah Donovan-Banfield, Anja Kipar, Daniele F Mega, Chloe Bramwell, Joanne Sharp, Andrew Owen, Julian A Hiscox, James P Stewart
Objectives: Immunocompromised individuals are susceptible to severe COVID-19 and potentially contribute to the emergence of variants with altered pathogenicity due to persistent infection. This study investigated the impact of immunosuppression on SARS-CoV-2 infection in k18-hACE2 mice and the effectiveness of antiviral treatments in this context. Methods: Mice were immunosuppressed using cyclophosphamide
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Large library docking for cannabinoid-1 receptor agonists with reduced side effects bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-28 Tia A. Tummino, Christos Iliopoulos-Tsoutsouvas, Joao M. Braz, Evan S. O'Brien, Reed M. Stein, Veronica Craik, Ngan K. Tran, Suthakar Ganapathy, Fangyu Liu, Yuki Shiimura, Fei Tong, Thanh C. Ho, Dmytro S. Radchenko, Yurii S. Moroz, Sian Rodriguez Rosado, Karnika Bhardwaj, Jorge Benitez, Yongfeng Liu, Herthana Kandasamy, Claire Normand, Meriem Semache, Laurent Sabbagh, Isabella Glenn, John J. Irwin
Large library docking can reveal unexpected chemotypes that complement the structures of biological targets. Seeking new agonists for the cannabinoid-1 receptor (CB1R), we docked 74 million tangible molecules, prioritizing 46 high ranking ones for de novo synthesis and testing. Nine were active by radioligand competition, a 20% hit-rate. Structure-based optimization of one of the most potent of these
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Prenatal Stress Alters Transcription of NMDA-Type Glutamate Receptors in the Hippocampus. bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-28 Tristram G Buck, Erbo Dong, Alessandro Guidotti, Monsheel Sodhi
Prenatal stress damages the development of the cortico-hippocampal circuit in the brain and increases the risk for neurological disorders associated with deficits of social behavior, including schizophrenia. Accumulating evidence indicates that the NMDA-type glutamate receptor plays an important role in social cognition and stress-induced pathology in the hippocampus. In this study we have tested the
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Association of Macular Pigment Density with Plasma Macular Carotenoids levels, And lipids in Indian patients with early Age-Related Macular Degeneration bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-27 Senthilkumari Srinivasan, Anand Rajendran, Bala Panneerselvam, Mohammed Sithiq Uduman
Purpose: The objective of the present study was to investigate the relationship of macular pigment optical density (MPOD) with plasma carotenoids [(L) and (Z)] and serum lipids in South Indian young healthy volunteers and patients with early AMD. Methods: Two hundred and fourteen (N= 214) study participants (Healthy control group (N) = 178; Early AMD group (N) = 36) were enrolled after getting their
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Silicon-rhodamine functionalized evocalcet probes (EvoSiR) potently and selectively label calcium sensing receptors (CaSR) in vitro, in vivo and ex vivo bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-25 Daniel Batora, Jerome P Fischer, Reto M Kaderli, Mate Varga, Martin Lochner, Jurg Gertsch
The calcium sensing receptor (CaSR) is a ubiquitously expressed G-protein coupled receptor (GPCR) that regulates extracellular calcium signals via the parathyroid glands. CaSR has recently also been implicated in non-calcitropic pathophysiologies like asthma, gut inflammation and cancer. To date, molecular tools that enable the bioimaging of CaSR in tissues are lacking. Based on in silico analyses
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Ovarian disrupting effects and mechanisms of long- and short-chain per- and polyfluoroalkyl substances in mice bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-25 Pawat Pattarawat, Tingjie Zhan, Yihan Fan, Jiyang Zhang, Hilly Yang, Ying Zhang, Sarahna Moyd, Nataki C. Douglas, Magrit Urbanek, Brian Buckley, Joanna Burdette, Qiang Zhang, Ji-Yong Julie Kim, Shuo Xiao
Background: The extensive use of per- and polyfluoroalkyl substances (PFAS) has led to environmental contamination and bioaccumulation. Previous research linked PFAS exposure to female reproductive disorders, but the mechanism remains elusive. Further, most studies focused on legacy long-chain PFOA and PFOS, yet the reproductive impacts of other long-chain PFAS and short-chain alternatives are rarely
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O6-Alkylguanine-DNA Alkyltransferase Maintains Genomic Integrity During Peroxynitrite-Mediated DNA Damage by Forming DNA-Protein Crosslinks bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-24 Shayantani Chakraborty, Gargi Mukherjee, Anindita Chakrabarty, Goutam Chowdhury
Inflammation is an early immune response against invading pathogens and damaged tissue. Although beneficial, uncontrolled inflammation leads to various diseases and may be fatal. Peroxynitrite (PN) is a major reactive nitrogen species (RNS) generated during inflammation. It produces various DNA lesions including labile 8-nitroguanine which spontaneously converts into abasic sites resulting in DNA strand
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The wide spectrum anti-inflammatory activity of andrographolide in comparison to NSAIDs: a promising therapeutic compound against the cytokine storm bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-22 Mitchell Low, Harsha Suresh, Xian Zhou, Deep Jyoti Bhuyan, Muhammad A. Alsherbiny, Cheang Khoo, Gerald Münch, Chun Guang Li
The challenges of the COVID-19 pandemic have highlighted an increasing clinical demand for safe and effective treatment options against an overzealous immune defence response, also known as the "cytokine storm". Andrographolide is a naturally derived bioactive compound with promising anti-inflammatory activity in many clinical studies. However, its cytokine-inhibiting activity, in direct comparison
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Human like severe hypertriglyceridemia in a high fat fed chicken model bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-22 Saranya K, Beniha JG, Deepshikha TK, Kriti Shanker, Vishnu R, Gopi Kadiyala, Uday Saxena
Cardiovascular disease (CVD) is the biggest cause of mortality globally. Controlling the risk factors for CVD such as blood cholesterol and triglycerides is the hallmark of primary prevention of CVD. There are several drugs to control cholesterol that are available but not many approaches to reducing triglycerides safely are available. High blood triglycerides or hypertriglyceridemia in humans is classified
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Alveolar macrophages play a key role in tolerance to ozone bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-21 Gregory Smith, Morgan Nalesnik, Robert Immormino, Jeremy Simon, Jack R Harkema, Jason R Mock, Timothy P Moran, Samir N. P. Kelada
Acute exposure to ozone (O3) causes pulmonary inflammation and injury in humans and animal models. In rodents, acute O3-induced inflammation and injury can be mitigated by pre-exposure to relatively low concentration O3, a phenomenon referred to as tolerance. While tolerance was described long ago, the underlying mechanisms are not known, though upregulation of antioxidants has been proposed. To identify
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Blockade of TREM2 ameliorates pulmonary inflammation and fibrosis by modulating sphingolipid metabolism bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-21 Xueqing Gu, Hanyujie Kang, Siyu Cao, Zhaohui Tong, Nan Song
Pulmonary fibrosis is a chronic interstitial lung disease involving systemic inflammation and abnormal collagen deposition. Dysregulations in lipid metabolism, such as macrophage-dependent lipid catabolism, have been recognized as critical factors for the development of pulmonary fibrosis. However, little is known about the signaling pathways involved and the key regulators. Here we found that triggering
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Steatotic liver disease induced by TCPOBOP-activated hepatic constitutive androstane receptor: Primary and secondary gene responses with links to disease progression bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-20 Ravi Sonkar, Hong Ma, David J. Waxman
Constitutive Androstane Receptor (CAR, Nr1i3), a liver nuclear receptor and xenobiotic sensor, induces drug, steroid and lipid metabolizing enzymes, stimulates liver hypertrophy and hyperplasia, and ultimately, hepatocellular carcinogenesis. The mechanisms linking early CAR responses to subsequent disease development are poorly understood. Here we show that exposure of CD-1 mice to TCPOBOP, a halogenated
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A Novel Support Vector Machine-Based One-Day, Single-Dose Prediction Model of Genotoxic Hepatocarcinogenicity in Rats bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-20 Min Gi, Shugo Suzuki, Masayuki Kanki, Masanao Yokohira, Tetsuya Tsukamoto, Masaki Fujioka, Arpamas Vachiraarunwong, Guiyu Qiu, Runjie Guo, Hideki Wanibuchi
The development of a rapid and accurate model for determining the genotoxicity and carcinogenicity of chemicals is crucial for effective cancer risk assessment, and it also contributes to cancer prevention. This study aims to develop a one-day, single-dose model for identifying genotoxic hepatocarcinogens (GHCs) in rats. Microarray gene expression data from the livers of rats administered a single
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Chemical genetics in C. elegans identifies anticancer mycotoxins chaetocin and chetomin as potent inducers of a nuclear metal homeostasis response bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-20 Elijah Abraham, A. M. Gihan K. Athapaththu, Kalina R. Atanasova, Qi-Yin Chen, Taylor J. Corcoran, Juan Piloto, Cheng-Wei Wu, Ranjala Ratnayake, Hendrik Luesch, Keith P. Choe
C. elegans numr-1/2 (nuclear-localized metal-responsive) is an identical gene pair encoding a nuclear protein previously shown to be activated by cadmium and disruption of the integrator RNA metabolism complex. We took a chemical genetic approach to further characterize regulation of this novel metal response by screening 41,716 compounds and extracts for numr-1p::GFP activation. The most potent activator
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Qualitative and Quantitative Concentration-Response Modelling of Gene Co-expression Networks to Unlock Hepatotoxic Mechanisms for Next Generation Chemical Safety Assessment bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-19 Steven J Kunnen, Emma Arnesdotter, Christian Tobias Willenbockel, Mathieu Vinken, Bob van de Water
Next generation risk assessment of chemicals revolves around the use of mechanistic information without animal experimentation. In this regard, toxicogenomics has proven to be a useful tool to elucidate the underlying mechanisms of adverse effects of xenobiotics. In the present study, two widely used human in vitro hepatocyte culture systems, namely primary human hepatocytes (PHH) and human hepatoma
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Jianpi Jiedu Recipe inhibits proliferation through reactive oxygen species-induced incomplete autophagy and reduces PD-L1 expression in colon cancer bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-19 Lingling Cheng, Liangfeng Xu, Hua Yuan, Qihao Zhao, Wei Yue, Shuang Ma, Xiaojing Wu, Dandan Gu, Yurong Sun, Haifeng Shi, Jianlin Xu
Abstract: Background: Jianpi Jiedu Recipe has been used to treat digestive tract tumors in China since ancient times, and its reliability has been proven by clinical research. Currently, the specific biological mechanism of JPJDR in treating tumors is unclear. Methodology: CCK-8 assay was used to detect cell viability. Clone formation assay and EdU assay were used to detect cell proliferation potential
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Taurine/chenodeoxycholic acid ratio as a circulating biomarker of insidious vitamin B12 deficiency in humans bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-19 Madhu Baghel, Sting L. Shi, Himani Patel, Vidya Velagapudi, Abdullah M. Ali, Vijay K. Yadav
Deficiency of vitamin B12 (B12), an essential water-soluble vitamin, leads to irreversible neurological damage, osteoporosis, cardiovascular diseases, and anemia. Clinical tests to detect B12 deficiency lack specificity and sensitivity. B12 deficiency is thus insidious because progressive decline in organ functions may go unnoticed until the damage is advanced or irreversible. Here, using targeted
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Dual Targeting of STING and PI3Kγ Eliminates Regulatory B Cells to Overcome STING Resistance for Pancreatic Cancer Immunotherapy bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-18 Chengyi LI, Shuai Mao, Hongyi Zhao, Miao He, Meilin Wang, Zhongwei Liu, Hanning Wen, Zhixin Yu, Bo Wen, Mahamadou Djibo, Jinsong Tao, Yingzi Bu, Wei Gao, Duxin Sun
The immune suppression in tumors and lymph nodes of pancreatic ductal adenocarcinoma (PDAC), regulated by suppressive myeloid cells and regulatory B (Breg) cells, hinders the effectiveness of immunotherapy. Although STING agonists activate myeloid cells to overcome immune suppression, it expands Breg cells, conferring STING resistance in PDAC. We discovered that blocking PI3Kγ during STING activation
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Named Entity Recognition of Pharmacokinetic parameters in the scientific literature bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-14 Ferran Gonzalez Hernandez, Quang Nguyen, Victoria C Smith, Jose Antonio Cordero, Maria Rosa Ballester, Marius Duran, Albert Sole, Palang Chotsiri, Thanaporn Wattanakul, Gill Mundin, Watjana Lilaonitkul, Joseph F. Standing, Frank Kloprogge
The development of accurate predictions for a new drug's absorption, distribution, metabolism, and excretion profiles in the early stages of drug development is crucial due to high candidate failure rates. The absence of comprehensive, standardised, and updated pharmacokinetic (PK) repositories limits pre-clinical predictions and often requires searching through the scientific literature for PK parameter
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Hyperactivity Induced By Vapor Inhalation of Nicotine in Male and Female Rats bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-14 Mehrak Javadi-Paydar, Tony M Kerr, Michael A Taffe
Rationale: Preclinical models of electronic nicotine delivery system (ENDS; "e-cigarette") use have been rare, so there is an urgent need to develop experimental approaches to evaluate their effects. Objective: To contrast the impact of inhaled nicotine across sex. Methods: Male and female Wistar rats were exposed to vapor from a propylene glycol vehicle (PG), nicotine (NIC; 1-30 mg/mL in PG), or were
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Skin Sensitisation Case Study: Comparison of Defined Approaches including OECD 497 Guidance bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-14 Barry Hardy, Pascal Ankli, Shaheena Parween, Béatrice Lopez, Pierre Daligaux, Tomaz Mohoric, Thomas Darde, Christophe Chesné, Nathan Stockman, Csaba Boglari, Amanda Poon
Characterising known and new chemical compounds for skin sensitisation provides a basis for the development of safer products where ingredients are exposed to skin. By including new approaches, such as tiered testing strategies and integrated data analysis, it is possible to develop next generation products adhering to emerging regulations, scientific evidence and animal welfare principles. To ensure
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Discovery of a novel inhibitor of macropinocytosis with antiviral activity bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-13 Bartlomiej Porebski, Wanda Christ, Alba Corman, Martin Haraldsson, Myriam Barz, Louise Lidemalm, Maria Haggblad, Juliana Illmain, Shane Wright, Matilde Murga, Jan Schlegel, Erdinc Sezgin, Gira Bhabha, Volker M Lauschke, Miguel Lafarga, Jonas Klingstrom, Daniela Huhn, Oscar Fernandez-Capetillo
Several viruses hijack various forms of endocytosis in order to infect host cells. Here, we report the discovery of a new molecule with antiviral properties that we named virapinib, which limits viral entry by macropinocytosis. The identification of virapinib derives from a chemical screen using High-Throughput Microscopy, where we identified new chemical entities capable of preventing infection with
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Activating SRC/MAPK signaling via 5-HT1A receptor contributes to the effect of vilazodone on improving thrombocytopenia bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-13 Ling Zhou, Chengyang Ni, Ruixue Liao, Xiaoqin Tang, Taian Yi, Mei Ran, Miao Huang, Rui Liao, Xiaogang Zhou, Dalian Qin, Long Wang, Feihong Huang, Xiang Xie, Ying Wan, Jiesi Luo, Yiwei Wang, Jianming Wu
Thrombocytopenia caused by long-term radiotherapy and chemotherapy exists in cancer treatment. Previous research demonstrates that 5-Hydroxtrayptamine (5-HT) and its receptors induces the formation of megakaryocytes (MKs) and platelets. However, the relationships between 5-HT1A receptor (5-HTR1A) and MKs is unclear so far. We screened and investigated the mechanism of vilazodone as a 5-HTR1A partial
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Cell circuits underlying nanomaterial specific respiratory toxicology bioRxiv. Pharmacol. Toxicol. Pub Date : 2024-02-12 Carola Voss, Lianyong Han, Meshal Ansari, Maximilian Strunz, Verena Haefner, Carol Ballester-Lopez, Ilias Angelidis, Christoph H Mayr, Trine Berthing, Thomas Conlon, Qiongliang Liu, Hongyu Ren, Qiaoxia Zhou, Otmar Schmid, Ali Oender Yildirim, Markus Rehberg, Ulla Vogel, Janine Gothe-Schniering, Fabian J Theis, Herbert B Schiller, Tobias Stoeger
Nanomaterials emerged as boundless resource of innovation, but their shape and biopersistence related to respiratory toxicology raise longstanding concerns. The development of predictive safety tests for inhaled nanomaterials, however, is hampered by limited understanding of cell type-specific responses. To advance this knowledge, we used single-cell RNA-sequencing to longitudinally analyze cellular