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Results 941 through 960 out of 1135

in category pharmacology and toxicology


941: Membrane-tethered peptides derived from intracellular loops 2 and 3 of the urotensin II receptor act as allosteric biased ligands

Hassan Nassour, Tuan Anh Hoang et al.

126 downloads (posted 24 Nov 2020)

Over the last decade, the urotensinergic system has garnered significant attention as a promising new target for the treatment of various cardiovascular diseases and also cancer. Significant investment toward the development of clinically relevant UT ligands for therapeutic intervention has been made but have met little to no success to date. The UT system, which has yet to be effectively targeted, therefore remains to be therapeutically exploited. The discovery of allosteric sites that allow modulation of receptor activity will increase the searchable chemical space against a disease-relevant target. Pepducins and other lipidated peptides have been used as both mechanistic probes and potential therapeutics. Therefore, pepducins derived from the human urotensin II receptor might represent unique tools to generate signaling bias and study UT signaling networks. Two hUT-derived pepducins, derived from the second and the third intracellular loop of UT, respectively, have been synthesized and pharmacologically characterized. Our results demonstrated that hUT-Pep2 and [Trp1, Leu2]hUT-Pep3 acted as biased ago-allosteric modulators, triggered ERK1/2 phosphorylation and to a lesser extent, IP1 production, stimulated cell proliferation yet were devoid of contractile activity. Interestingly, both hUT-derived pepducins were able to modulate hUII- and URP-mediated contraction albeit to different extents. These new derivatives represent unique tools to reveal the intricacies of hUT signaling and also a novel avenue to design allosteric ligands selectively targeting UT signaling that could prove to be useful for the treatment of hUT-associated diseases.


942: Embryonic exposure to cannabidiol disrupts active neural circuits, an effect increased by Δ-9-tetrahydrocannabinol and involving CB1R and CB2R in zebrafish

Richard Kanyo, Md. Ruhul Amin et al.

126 downloads (posted 05 Jan 2021)

Considering the wide spread use of cannabis as a recreational and medicinal drug, a knowledge gap exists regarding biological mechanisms and health implication. In the light of legislative changes, delayed effects of cannabis upon brief exposure during embryonic development are of high interest as early pregnancies often go undetected. We hypothesized that brief early cannabinoid exposure impacts neural activity by affecting embryonic brain development through cannabinoid-1 (CB1R) and -2 (CB2R). Zebrafish larvae were ex...


943: Prophylactic efficacy of riluzole against anxiety- and depressive-like behaviors in two rodent stress models

Corey Fee, Keith A Misquitta et al.

125 downloads (posted 07 Aug 2020)

Background: Chronic stress-related illnesses, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), share symptomatology, including anxiety, anhedonia, and helplessness. Across disorders, neurotoxic dysregulated glutamate (Glu) signaling may underlie symptom emergence. Current first-line antidepressant drugs (ADs), which do not directly target Glu signaling, fail to provide adequate benefit for many patients and are associated with high relapse rates. Riluzole modulates glutamatergic neurotr...


944: Sodium Diethyldithiocarbamate antiparasitic activity against different Trypanosoma cruzi strains: Insights of its biological activity

Johny Wysllas de Freitas Oliveira, Taffarel Melo Torres et al.

125 downloads (posted 06 Jul 2020)

Background . Chagas disease is caused by the protozoan Trypanosoma cruzi , a neglected tropical disease that affects thousands of people, mainly in Latin America. The drugs currently used in therapy are toxic and have therapeutic limitations during treatment. In addition, the genetic diversity of T. cruzi represents an important variable and challenge with regard to the pathogenesis of the infection, the epidemiological profile of the cases, and the therapeutic control of the infection. Sodium diethyldithiocarbamate (DE...


945: Deep Learning for Virtual Screening: Five Reasons to Use ROC Cost Functions

Vladimir Golkov, Alexander Becker et al.

125 downloads (posted 26 Jun 2020)

Computer-aided drug discovery is an essential component of modern drug development. Therein, deep learning has become an important tool for rapid screening of billions of molecules in silico for potential hits containing desired chemical features. Despite its importance, substantial challenges persist in training these models, such as severe class imbalance, high decision thresholds, and lack of ground truth labels in some datasets. In this work we argue in favor of directly optimizing the receiver operating characteris...


946: Evaluation of Neuropharmacological Effects of Different Chemical Extracts of Flemingia Stricta (Roxb.) Leaves.

Md. Shahrear Biozid, Mohammad Nazmul Alam et al.

125 downloads (posted 11 Apr 2020)

Background: Traditional preparation of the leaf of Flemingia stricta (Fabaceae) Roxb., a medicinal plant of the Indian subcontinent, has been used for treatment of different diseases as herbal preparation. Our purpose was to analyze Neuropharmacological effects of different chemical extracts of Flemingia stricta Roxb. as particular form of behavioral inhibition that occurs in response to novel environmental events. Methods: In present study, the anxiogenic activity of crude extracts of Flemingia stricta leaves was deter...


947: Natural variation in Caenorhabditis elegans responses to the anthelmintic emodepside

Janneke Wit, Briana C. Rodriguez et al.

124 downloads (posted 06 Jan 2021)

Treatment of parasitic nematode infections depends primarily on the use of anthelmintics. However, this drug arsenal is limited, and resistance against most anthelmintics is widespread. Emodepside is a new anthelmintic drug effective against gastrointestinal and filarial nematodes. Nematodes that are resistant to other anthelmintic drug classes are susceptible to emodepside, indicating that the emodepside mode of action is distinct from previous anthelmintics. The laboratory-adapted Caenorhabditis elegans strain N2 is s...


948: Annexin a2 as a target protein for chlorogenic acid in human lung cancer A549 cells

Lei Wang, Hongwu Du et al.

124 downloads (posted 12 Jun 2020)

Chlorogenic acid, an important active component of coffee with anti-tumor activities, has been found for many years. However, the lack of understanding about its target proteins greatly limits the exploration of its anti-tumor molecular mechanism and clinical application. Here, in vitro and animal experiments showed that chlorogenic acid had a significant inhibitory effect on the proliferation of A549 cells. Using the spontaneous fluorescence characteristic of chlorogenic acid to screen the target proteins cleverly to a...


949: Gastrointestinal absorption of pimozide is enhanced by inhibition of P-glycoprotein

Hiroki Morishita, Kozue Okawa et al.

124 downloads (posted 16 Apr 2020)

Following the death due to cardiac arrest of a patient taking pimozide, sertraline and aripiprazole antipsychotic/antidepressant combination therapy, a role of drug-drug interaction was suggested. Here, we investigated P-glycoprotein (P-gp)-mediated interaction among the three drugs using in vitro methods. Sertraline or aripiprazole significantly increased the permeability of pimozide in Caco-2 cell monolayers. ATPase assay indicated that pimozide is a P-gp substrate, and might act as a P-gp inhibitor at higher concentr...


950: Discovery of isoplumbagin as a novel NQO1 substrate and anti-cancer quinone

Yen-Chi Tsao, Yu-Jung Chang et al.

124 downloads (posted 30 Apr 2020)

Isoplumbagin (5-hydroxy-3-methyl-1,4-naphthoquinone), a naturally occurring quinone from Lawsonia inermis and Plumbago europaea, that has been reported to have anti-inflammatory and anti-microbial activity. Inflammation has long been implicated in cancer progression. In this study, we examined the anti-cancer effect of chemically-synthesized isoplumbagin. Our results revealed that isoplumbagin treatment suppressed cell viability and invasion of highly invasive oral squamous cell carcinoma (OSCC) OC3-IV2 cells, glioblast...


951: Identification of compounds producing non-visual photosensation via TrpA1 in zebrafish

Darya Cheng, Matthew N McCarroll et al.

123 downloads (posted 10 Jun 2020)

TrpA1 receptors sense chemical irritants. But, they do not normally respond to light. Previous studies have identified compounds that confer photosensitivity onto vertebrate TrpA1. However, the pharmacology of TrpA1-mediated non-visual photosensation remains poorly understood. To identify novel compounds that affect this process, we screened a large chemical library for compounds that increased light-elicited motor activity in larval zebrafish. We found structurally diverse hit compounds that were photoreactive and prod...


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

Samar El Kholy, John P. Giesy et al.

123 downloads (posted 16 Jul 2020)

Nanoparticles of cadmium oxide (CdO NPs) are among the most common industrial metal oxide nanoparticles. Early adulthood (F0) fruit flies (D. melanogaster) were exposed for 7 days to a sub lethal concentration (0.03 mg CdO NPs/ml, which was 20% of the LC50), spiked into food media to test for long term-effects over time and beyond their direct exposure on key life history traits. Effects on survival, developmental time, eclosion rate, fecundity and negative geotaxis performance were assessed. Potential effects on ultras...


953: Cellular feedback to organotelluranes displays modulation of antioxidant proteins gene expression

Felipe S. Pessoto, César H. Yokomizo et al.

122 downloads (posted 06 Jan 2021)

Organotelluranes, RT3 and RT4, are thiol reagents that induce mitochondrial transition pore (MTP) opening in the manner sensitive and insensitive to cyclosporin A. Although RT3 and RT4 promote glutathione depletion, paradoxically, they are also efficient antioxidant for membrane lipids. These antagonistic effects of these compounds elicited the challenging question of how the gene expression of antioxidant enzymes would respond to treatment with these compounds. The influence of RT3 and RT4 on the expression of antioxid...


954: The kallikrein-kinin system is falling into pieces: bradykinin fragments are biological active peptides

Igor Maciel Souza-Silva, Cristiane Amorim de Paula et al.

122 downloads (posted 14 Sep 2020)

Background and purpose Bradykinin [BK-(1-9)] is an endogenous peptide involved in many physiological and pathological processes, such as cardiovascular homeostasis and inflammation. The central dogma of the kallikrein-kinin system is that BK-(1-9) fragments are biologically inactive. In this manuscript, we proposed to test whether these fragments were indeed inactive. Experimental Approach Nitric oxide (NO) was quantified in human, mouse and rat cells loaded with DAF-FM after stimulation with BK-(1-9), BK-(1-7), BK-(1-...


955: Methylation-directed Acetylation of Histone H3 Regulates Developmental Sensitivity to Histone Deacetylase Inhibition

Li-Yao Huang, Duen-Wei Hsu et al.

122 downloads (posted 24 Jul 2020)

Background: Treatment of cells with hydroxamate-based lysine deacetylase inhibitors (KDACis) such as Trichostatin A (TSA) can induce biological effects such as differentiation or apoptosis of cancer cells, and a number of related compounds have been approved for clinical use. TSA treatment induces rapid initial acetylation of histone 3 (H3) proteins which are already modified by tri-methylation on lysine 4 (H3K4me3) while acetylation of bulk histones, lacking this mark, is delayed. Sgf29, a subunit of the SAGA acetyltra...


956: Epigenetic compound screening uncovers small molecules for re-activation of latent HIV-1

Ariane Zutz, Lin Chen et al.

122 downloads (posted 24 Aug 2020)

During infection with the human immunodeficiency virus type 1 (HIV-1), latent reservoirs are established, which circumvent full eradication of the virus by antiretroviral therapy (ART) and are the source for viral rebound after cessation of therapy. As these reservoirs are phenotypically undistinguishable from infected cells, current strategies aim to reactivate these reservoirs, followed by pharmaceutical and immunological destruction of the cells. Here, we employed a simple and convenient cell-based reporter system, w...


957: Combination of ipratropium bromide and salbutamol in children and adolescents with asthma: a meta-analysis

Hongzhen Xu, Lin Tong et al.

122 downloads (posted 31 Jul 2020)

Background A combination of ipratropium bromide (IB) and salbutamol is commonly used to treat asthma in children and adolescents; however, there has been a lack of consistency in its usage in clinical practice. Objective To evaluate the efficacy and safety of IB + salbutamol in the treatment of asthma in children and adolescents. Methods The MEDLINE, Embase, and Cochrane Library as well as other Chinese biomedical databases (including China Biological Medicine Database, Chinese National Knowledge Infrastructure, Chongqi...


958: Chronic Developmental Lead Exposure increases μ-Opiate Receptor Levels in the Adolescent Rat Brain

Damaris Albores-Garcia, Jennifer L McGlothan et al.

121 downloads (posted 20 Apr 2020)

Opioid use and abuse has reached epidemic proportion in the United States resulting in a significant number of deaths due to overdose. While environmental factors are implicated in opioid addiction, less is known about the role of exposure to environmental pollutants on the brain opioid system. Human and preclinical studies have suggested an association between childhood lead (Pb2+) intoxication and proclivity to substance abuse and delinquent behavior. Opioid receptors are involved in the biological effects of opioids ...


959: Cardiac toxicity predictions: Safety pharmacologists correlate with the CiPA model

Hitesh B. Mistry, Jaimit Parikh

121 downloads (posted 12 Jun 2020)

There has been a lot of interest and publicity regarding the use of a complex biophysical model within drug development for predicting the TdeP risk of new compounds. Throughout the development of the complex model numerous groups have shown that a simple linear mechanistic model explains the predictive behaviour of complex mechanistic models. That is the input-output relationship is almost linear even when complex kinetic assays are used. We hypothesized that given this linear relationship that scientist would be able ...


960: Human ES and iPS Cells Display Less Drug Resistance Than Differentiated Cells, and Naïve-State Induction Further Decreases Drug Resistance

Yulia Panina, Junko Yamane et al.

121 downloads (posted 17 Aug 2020)

Pluripotent stem cells (PSCs) possess unique characteristics that distinguish them from other cell types. Human embryonic stem (ES) cells are recently gaining attention as a powerful tool for human toxicity assessment without the use of experimental animals, and an embryonic stem cell test (EST) was introduced for this purpose. However, human PSCs have not been thoroughly investigated in terms of drug resistance or compared with other cell types or cell states, such as naive state, to date. Aiming to close this gap in r...