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ACS Omega Sep 2020The rising prevalence of multidrug-resistant hospital-acquired infections has increased the need for new antibacterial agents. In this study, a library of 1586...
The rising prevalence of multidrug-resistant hospital-acquired infections has increased the need for new antibacterial agents. In this study, a library of 1586 FDA-approved drugs was screened against , a representative of the complex. Three compounds were found to have previously undiscovered antibacterial properties against : antifungal Miconazole, anthelminthic Dichlorophen, and Bithionol. These three drugs were tested against a wide range of Gram-positive and Gram-negative bacteria and confirmed to have broad-spectrum antibacterial properties. Combinations of these three drugs were also tested against the same bacteria, and two novel combination therapies with synergistic effects were discovered. In the future, antibacterial properties of these three drugs and two combination therapies will be evaluated against pathogenic bacteria using an animal model.
PubMed: 32984715
DOI: 10.1021/acsomega.0c03211 -
The Journal of Biological Chemistry May 2020-Acyl-phosphatidylethanolamine phospholipase D (NAPE-PLD) (EC 3.1.4.4) catalyzes the final step in the biosynthesis of -acyl-ethanolamides. Reduced NAPE-PLD expression...
-Acyl-phosphatidylethanolamine phospholipase D (NAPE-PLD) (EC 3.1.4.4) catalyzes the final step in the biosynthesis of -acyl-ethanolamides. Reduced NAPE-PLD expression and activity may contribute to obesity and inflammation, but a lack of effective NAPE-PLD inhibitors has been a major obstacle to elucidating the role of NAPE-PLD and -acyl-ethanolamide biosynthesis in these processes. The endogenous bile acid lithocholic acid (LCA) inhibits NAPE-PLD activity (with an IC of 68 μm), but LCA is also a highly potent ligand for TGR5 (EC 0.52 μm). Recently, the first selective small-molecule inhibitor of NAPE-PLD, ARN19874, has been reported (having an IC of 34 μm). To identify more potent inhibitors of NAPE-PLD, here we used a quenched fluorescent NAPE analog, PED-A1, as a substrate for recombinant mouse Nape-pld to screen a panel of bile acids and a library of experimental compounds (the Spectrum Collection). Muricholic acids and several other bile acids inhibited Nape-pld with potency similar to that of LCA. We identified 14 potent Nape-pld inhibitors in the Spectrum Collection, with the two most potent (IC = ∼2 μm) being symmetrically substituted dichlorophenes, hexachlorophene and bithionol. Structure-activity relationship assays using additional substituted dichlorophenes identified key moieties needed for Nape-pld inhibition. Both hexachlorophene and bithionol exhibited significant selectivity for Nape-pld compared with nontarget lipase activities such as PLD or serum lipase. Both also effectively inhibited NAPE-PLD activity in cultured HEK293 cells. We conclude that symmetrically substituted dichlorophenes potently inhibit NAPE-PLD in cultured cells and have significant selectivity for NAPE-PLD other tissue-associated lipases.
Topics: Animals; Bacterial Proteins; Bithionol; Dichlorophen; Enzyme Inhibitors; HEK293 Cells; Hexachlorophene; Humans; Mice; Phospholipase D; Quinazolines; Streptomyces; Sulfonamides
PubMed: 32284327
DOI: 10.1074/jbc.RA120.013362 -
Environmental Health Perspectives Oct 2020Endocrine-disrupting chemicals can interfere with hormonal homeostasis and have adverse effects for both humans and the environment. Their identification is increasingly...
BACKGROUND
Endocrine-disrupting chemicals can interfere with hormonal homeostasis and have adverse effects for both humans and the environment. Their identification is increasingly difficult due to lack of adequate toxicological tests. This difficulty is particularly problematic for cosmetic ingredients, because testing is now banned completely in the European Union.
OBJECTIVES
The aim was to identify candidate preservatives as endocrine disruptors by methods and to confirm endocrine receptors' activities through nuclear receptors .
METHODS
We screened preservatives listed in Annex V in the European Union Regulation on cosmetic products to predict their binding to nuclear receptors using the Endocrine Disruptome and VirtualToxLab™ version 5.8 tools. Five candidate preservatives were further evaluated for androgen receptor (AR), estrogen receptor (), glucocorticoid receptor (GR), and thyroid receptor (TR) agonist and antagonist activities in cell-based luciferase reporter assays in AR-EcoScreen, , MDA-kb2, and GH3.TRE-Luc cell lines. Additionally, assays to test for false positives were used (nonspecific luciferase gene induction and luciferase inhibition).
RESULTS
Triclocarban had agonist activity on AR and at and antagonist activity on GR at and TR at . Triclosan showed antagonist effects on AR, , GR at and TR at , and bromochlorophene at (AR and TR) and at ( and GR). AR antagonist activity of chlorophene was observed [inhibitory concentration at 50% (IC) ], as for its substantial agonist at and TR antagonist activity at . Climbazole showed AR antagonist (), agonist at , and TR antagonist activity at .
DISCUSSION
These data support the concerns of regulatory authorities about the endocrine-disrupting potential of preservatives. These data also define the need to further determine their effects on the endocrine system and the need to reassess the risks they pose to human health and the environment. https://doi.org/10.1289/EHP6596.
Topics: Androgen Receptor Antagonists; Carbanilides; Cell Line; Computer Simulation; Dichlorophen; Endocrine Disruptors; Genes, Reporter; Humans; Imidazoles; Receptors, Androgen; Receptors, Estrogen; Receptors, Glucocorticoid; Triclosan
PubMed: 33064576
DOI: 10.1289/EHP6596 -
Brazilian Journal of Microbiology :... Dec 2020With the high-frequency use or abuse of antifungal drugs, the crisis of drug-resistant fungi continues to increase worldwide; in particular, the infection of...
With the high-frequency use or abuse of antifungal drugs, the crisis of drug-resistant fungi continues to increase worldwide; in particular, the infection of drug-resistant Candida albicans brings the great challenge to the clinical treatment. Therefore, to decelerate the spread of this resistance, it is extremely urgent to facilitate the new antifungal targets with novel drugs. Phosphopantetheinyl transferases PPTases (Ppt2 in Candida albicans) had been identified in bacterium and fungi and mammals, effects as a vital enzyme in the metabolism of organisms in C. albicans. Ppt2 transfers the phosphopantetheinyl group of coenzyme A to the acyl carrier protein Acp1 in mitochondria for the synthesis of lipoic acid that is essential for fungal respiration, so making Ppt2 an ideal target for antifungal drugs. In this study, 110 FDA-approved drugs were utilized to investigate the Ppt2 inhibition against drug-resistant Candida albicans by the improved fluorescence polarization experiments, which have enough druggability and structural variety under the novel strategy of drug repurposing. Thereinto, eight agents revealed the favourable Ppt2 inhibitory activities. Further, broth microdilution assay of incubating C. albicans with these eight drugs showed that pterostilbene, procyanidine, dichlorophen and tea polyphenol had the superior MIC values. In summary, these findings provide more valuable insight into the treatment of drug-resistant C. albicans.
Topics: Antifungal Agents; Candida albicans; Drug Repositioning; Drug Resistance, Fungal; Enzyme Inhibitors; Fungal Proteins; Microbial Sensitivity Tests; Transferases (Other Substituted Phosphate Groups)
PubMed: 32557281
DOI: 10.1007/s42770-020-00318-w -
Journal of Neurophysiology Nov 2008Previous studies have demonstrated that locally administered cannabinoids attenuate allodynia and hyperalgesia through activation of peripheral cannabinoid receptors...
Previous studies have demonstrated that locally administered cannabinoids attenuate allodynia and hyperalgesia through activation of peripheral cannabinoid receptors (CB(1) and CB(2)). However, it is currently unknown if cannabinoids alter the response properties of nociceptors. In the present study, correlative behavioral and in vivo electrophysiological studies were conducted to determine if peripheral administration of the cannabinoid receptor agonists arachidonyl-2'-chloroethylamide (ACEA) or (R)-(+)-methanandamide (methAEA) could attenuate mechanical allodynia and hyperalgesia, and decrease mechanically evoked responses of Adelta nociceptors. Twenty-four hours after intraplantar injection of complete Freund's adjuvant (CFA), rats exhibited allodynia (decrease in paw withdrawal threshold) and hyperalgesia (increase in paw withdrawal frequency), which were attenuated by both ACEA and methAEA. The antinociceptive effects of these cannabinoids were blocked by co-administration with the CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophen yl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) but not with the CB(2) receptor antagonist 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-y l](4-methoxyphenyl)methanone (AM630). ACEA and methAEA did not produce antinociception under control, non-inflamed conditions 24 h after intraplantar injection of saline. In parallel studies, recordings were made from cutaneous Adelta nociceptors from inflamed or control, non-inflamed skin. Both ACEA and methAEA decreased responses evoked by mechanical stimulation of Adelta nociceptors from inflamed skin but not from non-inflamed skin, and this decrease was blocked by administration of the CB(1) receptor antagonist AM251. These results suggest that attenuation of mechanically evoked responses of Adelta nociceptors contributes to the behavioral antinociception produced by activation of peripheral CB(1) receptors during inflammation.
Topics: Action Potentials; Analysis of Variance; Animals; Arachidonic Acids; Cannabinoids; Dose-Response Relationship, Drug; Drug Interactions; Freund's Adjuvant; Inflammation; Male; Nerve Fibers, Myelinated; Neural Conduction; Nociceptors; Pain Measurement; Pain Threshold; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Reaction Time; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Skin
PubMed: 18784270
DOI: 10.1152/jn.90809.2008 -
Biosensors Feb 2021Chlorophene is an important antimicrobial agent present in disinfectant products which has been related to health and environmental effects, and its detection has been...
Chlorophene is an important antimicrobial agent present in disinfectant products which has been related to health and environmental effects, and its detection has been limited to chromatographic techniques. Thus, there is a lack of research that attempts to develop new analytical tools, such as biosensors, that address the detection of this emerging pollutant. Therefore, a new biosensor for the direct detection of chlorophene in real water is presented, based on surface plasmon resonance (SPR) and using a laccase enzyme as a recognition element. The biosensor chip was obtained by covalent immobilization of the laccase on a gold-coated surface through carbodiimide esters. The analytical parameters accomplished resulted in a limit of detection and quantification of 0.33 mg/L and 1.10 mg/L, respectively, fulfilling the concentrations that have already been detected in environmental samples. During the natural river's measurements, no significant matrix effects were observed, obtaining a recovery percentage of 109.21% ± 7.08, which suggested that the method was suitable for the fast and straightforward analysis of this contaminant. Finally, the SPR measurements were validated with an HPLC method, which demonstrated no significant difference in terms of precision and accuracy, leading to the conclusion that the biosensor reflects its potential as an alternative analytical tool for the monitoring of chlorophene in aquatic environments.
Topics: Anti-Infective Agents; Biosensing Techniques; Carbodiimides; Dichlorophen; Gold; Limit of Detection; Surface Plasmon Resonance
PubMed: 33572259
DOI: 10.3390/bios11020043 -
ACS Omega Sep 2020Of the numerous infectious diseases afflicting humans, anthrax disease, caused by , poses a major threat in its virulence and lack of effective treatment. The currently...
Of the numerous infectious diseases afflicting humans, anthrax disease, caused by , poses a major threat in its virulence and lack of effective treatment. The currently lacking standards of care, as well as the lengthy drug approval process, demonstrate the pressing demand for treatment for infections. The present study screened 1586 clinically approved drugs in an attempt to identify repurposable compounds against , a relative strain that shares many physical and genetic characteristics with . Our study yielded five drugs that successfully inhibited growth: dichlorophen, oxiconazole, suloctidil, bithionol, and hexestrol. These drugs exhibited varying levels of efficacy in broad-spectrum experiments against several Gram-positive and Gram-negative bacterial strains, with hexestrol showing the greatest inhibition across all tested strains. Through tests for the efficacy of each drug on , bithionol was the single most potent compound on both solid and liquid media and exhibited even greater eradication of in combination with suloctidil on solid agar. This multifaceted study of approved drugs demonstrates the potential to repurpose these drugs as treatments for anthrax disease in a time-efficient manner to address a global health need.
PubMed: 32905429
DOI: 10.1021/acsomega.0c03207 -
British Journal of Pharmacology Jan 2009The cardiovascular effects of cannabinoids can be influenced by anaesthesia and can differ in chronic hypertension, but the extent to which they are influenced by acute...
BACKGROUND AND PURPOSE
The cardiovascular effects of cannabinoids can be influenced by anaesthesia and can differ in chronic hypertension, but the extent to which they are influenced by acute hypertension in conscious animals has not been determined.
EXPERIMENTAL APPROACH
We examined cardiovascular responses to intravenous administration of anandamide and the synthetic cannabinoid, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55212-2), in conscious male Wistar rats made acutely hypertensive by infusion of angiotensin II (AII) and arginine vasopressin (AVP). Rats were chronically instrumented for measurement of arterial blood pressure and vascular conductances in the renal, mesenteric and hindquarters beds.
KEY RESULTS
Anandamide dose-dependently decreased the mean arterial blood pressure of rats made hypertensive by AII-AVP infusion, but not normotensive rats. Interestingly, acute hypertension also revealed a hypotensive response to WIN55212-2, which caused hypertension in normotensive animals. The enhanced depressor effects of the cannabinoids in acute hypertension were associated with increased vasodilatation in hindquarters, renal and mesenteric vascular beds. Treatment with URB597, which inhibits anandamide degradation by fatty acid amide hydrolase, potentiated the depressor and mesenteric vasodilator responses to anandamide. Furthermore, haemodynamic responses to WIN55212-2, but not to anandamide, were attenuated by the CB(1) receptor antagonist, AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophen yl)-4-methyl-1H-pyrazole-3-carboxamide].
CONCLUSIONS AND IMPLICATIONS
These results broadly support the literature showing that the cardiovascular effects of cannabinoids can be exaggerated in hypertension, but highlight the involvement of non-CB(1) receptor-mediated mechanisms in the actions of anandamide.
Topics: Acute Disease; Amidohydrolases; Animals; Arachidonic Acids; Benzamides; Benzoxazines; Blood Pressure; Cannabinoids; Carbamates; Consciousness; Endocannabinoids; Hindlimb; Hypertension; Infusions, Intravenous; Injections, Intravenous; Male; Morpholines; Naphthalenes; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Renal Circulation; Splanchnic Circulation; Vascular Resistance; Vasodilation
PubMed: 19133994
DOI: 10.1111/j.1476-5381.2008.00034.x -
British Journal of Pharmacology Apr 2016High-throughput screening of compound libraries using genetically encoded fluorescent biosensors has identified several second-generation. low MW inhibitors of the...
BACKGROUND AND PURPOSE
High-throughput screening of compound libraries using genetically encoded fluorescent biosensors has identified several second-generation. low MW inhibitors of the calcium-activated chloride channel anoctamin 1 (CaCC/Ano1). Here we have (i) examined the effects of these Ano1 inhibitors on gastric and intestinal pacemaker activity; (ii) compared the effects of these inhibitors with those of the more classical CaCC inhibitor, 5-nitro-2-(3-phenylpropylalanine) benzoate (NPPB); (ii) examined the mode of action of these compounds on the waveform of pacemaker activity; and (iii) compared differences in the sensitivity between gastric and intestinal pacemaker activity to the Ano1 inhibitors.
EXPERIMENTAL APPROACH
Using intracellular microelectrode recordings of gastric and intestinal muscle preparations from C57BL/6 mice, the dose-dependent effects of Ano1 inhibitors were examined on spontaneous electrical slow waves.
KEY RESULTS
The efficacy of second-generation Ano1 inhibitors on gastric and intestinal pacemaker activity differed significantly. Antral slow waves were more sensitive to these inhibitors than intestinal slow waves. CaCCinh -A01 and benzbromarone were the most potent at inhibiting slow waves in both muscle preparations and more potent than NPPB. Dichlorophene and hexachlorophene were equally potent at inhibiting slow waves. Surprisingly, slow waves were relatively insensitive to T16Ainh -A01 in both preparations.
CONCLUSIONS AND IMPLICATIONS
We have identified several second-generation Ano1 inhibitors, blocking gastric and intestinal pacemaker activity. Different sensitivities to Ano1 inhibitors between stomach and intestine suggest the possibility of different splice variants in these two organs or the involvement of other conductances in the generation and propagation of pacemaker activity in these tissues.
Topics: Animals; Anoctamin-1; Benzbromarone; Chloride Channels; Dichlorophen; Dose-Response Relationship, Drug; Gastrointestinal Tract; Hexachlorophene; High-Throughput Screening Assays; Mice; Mice, Inbred C57BL; Structure-Activity Relationship; Thiophenes
PubMed: 26774021
DOI: 10.1111/bph.13431 -
BMC Oral Health May 2011The aim of this study was to compare the reaction of rat connective tissue to two root-end filling materials: white Mineral Trioxide Aggregate (WMTA) and Diaket. (Comparative Study)
Comparative Study
BACKGROUND
The aim of this study was to compare the reaction of rat connective tissue to two root-end filling materials: white Mineral Trioxide Aggregate (WMTA) and Diaket.
METHODS
Each of the materials was placed in dentine tubes and implanted subcutaneously in the dorsal connective tissue of 21 Wistar albino rats. Tissue biopsies were collected 7, 30, and 60 days after the implantation procedure. The specimens were processed and stained with hematoxylin and eosin and examined microscopically. After determining inflammatory cell numbers in sections from each specimen, inflammatory reaction scores were defined as follows: 0; no or few inflammatory cells (no reaction), 1; less than 25 cells (mild reaction), 2; 25 to 125 cells, (moderate reaction), and 3; 125 or more cells (severe reaction). Statistical analysis was performed using the Kruskal-Wallis and Mann-Whitney tests.
RESULTS
There were statistically significant differences in the median inflammatory cell numbers throughout the three test periods, with the most severe degree of inflammation observed at the one-week period. Few cases of necrosis were observed with WMTA. Diaket exhibited the most severe degree of inflammation and necrosis. After 30 days, both materials provoked moderate inflammatory reaction. The eight-week period showed the least severe degree of inflammation in all groups.
CONCLUSIONS
It was concluded that WMTA exhibits a more favourable tissue response compared with Diaket which induced more severe inflammatory reaction than WMTA and the control.
Topics: Aluminum Compounds; Animals; Bismuth; Calcium Compounds; Connective Tissue; Dentin; Drug Combinations; Humans; Inflammation; Male; Oxides; Polyvinyls; Rats; Rats, Wistar; Root Canal Filling Materials; Silicates; Statistics, Nonparametric; Time Factors; Zinc Oxide
PubMed: 21569463
DOI: 10.1186/1472-6831-11-17