scholarly journals Modulation of the PGE2-Mediated Pathway in the Eclosion Blocking Effect of Flumethrin and Terpenoid Subfraction Isolated from Artemesia nilagirica in Rhipicephalus annulatus

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 4905
Author(s):  
Panicker Devyani Ramachandran ◽  
Mahesh Doddadasarahalli Muniyappa ◽  
Sreelekha Kanapadinchareveetil ◽  
Suresh Narayanan Nair ◽  
Karapparambu Gopalan Ajithkumar ◽  
...  
Keyword(s):  
Drug Targets ◽  
Tick Control ◽  
Blocking Effect ◽  
Egg Laying ◽  
Prostaglandin E ◽  
Ovarian Maturation ◽  
Prostaglandin E Synthase ◽  
Significant Difference ◽  
Key Enzyme ◽  
Rhipicephalus Annulatus

Prostaglandins are a group of important cell-signaling molecules involved in the regulation of ovarian maturation, oocyte development, egg laying and associated behaviors in invertebrates. However, the presence of prostaglandin E2 (PGE2), the key enzymes for PGE2 biosynthesis and its interference by drugs were not investigated previously in the ovary of ticks. The present study was undertaken to assess the modulation of the PGE2-mediated pathway in the eclosion blocking effect of flumethrin and terpenoid subfraction isolated from Artemisia nilagirica in Rhipicephalus annulatus ticks. The acaricidal activities and chemical profiling of the terpenoid subfraction were performed. The localization of the cyclooxygenase1 (COX1) and prostaglandin E synthase (PGES) enzymes and the quantification of PGE2 in the ovaries of the ticks treated with methanol (control), flumethrin and terpenoid subfraction were also undertaken. In addition, the vitellogenin concentration in hemolymph was also assayed. Both flumethrin and the terpenoid subfraction of A. nilagirica elicited a concentration-dependent inhibition of fecundity and blocking of hatching of the eggs. The COX1 could not be detected in the ovaries of treated and control ticks, while there was no significant difference observed in the concentration of vitellogenin (Vg) in them. The presence of PGES in the oocytes of control ticks was confirmed while the immunoreactivities against PGES were absent in the vitellogenic oocytes of ticks treated with flumethrin and terpenoid subfraction. The levels of PGE2 were below the detection limit in the ovaries of the flumethrin-treated ticks, while it was significantly lower in the ovaries of the terpenoid subfraction-treated ticks. Hence, the prostaglandin E synthase and PGE2 were identified as very important mediators for the signaling pathway for ovarian maturation and oviposition in ticks. In addition, the key enzyme for prostaglandin biosynthesis, PGES and the receptors for PGE2 can be exploited as potential drug targets for tick control. The detection of PGES by immunohistochemistry and quantification of PGE2 by LC-MSMS can be employed as valuable tools for screening newer compounds for their eclosion blocking acaricidal effects.

scholarly journals First Report of Cattle Tick Rhipicephalus (Boophilus) annulatus in Egypt Resistant to Ivermectin

Insects ◽  
2019 ◽  
Vol 10 (11) ◽  
pp. 404 ◽  
Author(s):  
Saeed El-Ashram ◽  
Shawky M. Aboelhadid ◽  
Asmaa A. Kamel ◽  
Lilian N. Mahrous ◽  
Magdy M. Fahmy
Keyword(s):  
Immersion Test ◽  
Tick Control ◽  
Cattle Tick ◽  
First Report ◽  
Significant Difference ◽  
History Of ◽  
Rhipicephalus Annulatus ◽  
Almost All ◽  
Lower Slope ◽  
Egg Fertility

Tick control is mainly dependent on the application of acaricides, but resistance has developed to almost all classes of acaricides, including macrolactones. Therefore, we aimed to investigate ivermectin resistance among tick populations in middle Egypt. The larval immersion test was conducted using a commercial formulation of ivermectin (1%). Different concentrations of the immersion solution (0.0000625% (625 × 10−7%), 0.000125% (125 × 10−6%), 0.0005% (5 × 10−4%), 0.001% (1 × 10−3%), 0.0025% (2.5 × 10−3%), 0.005% (5 × 10−3), and 0.01% (1 × 10−2%)) were prepared by diluting a commercial ivermectin (1%) with distilled water containing 1% (v/v) ethanol and 2% (v/v) TritonX-100. Field populations of Rhipicephalus annulatus were collected from five different localities in Beni-Suef province, Egypt. Adult engorged female ticks were collected and assessed for oviposition and egg fertility. Eggs were collected, and hatched larvae were then used in the experiment. Application of acaricides was conducted on 10-day-old larvae. There was a significant difference in the LC50 (50% lethal concentration) among the examined localities on the log dose-response plot, where, the LC50 of tick populations from two localities (Emin elaros and Aldiabia) was higher than the other localities (Alhalabia, Alkom, and Beshnna). Besides, tick populations from Emin elaros and Aldiabia showed higher LC90 values with lower slope values compared to those from Alhalabia, Alkom, and Beshnna. According to these values (LC50, LC90, and slope values), as well as a history of acaricide failure to ticks in these areas, R. annulatus developed resistance to ivermectin. This study documents the first report of field populations of R. annulatus resistant to ivermectin in Egypt.

In silico Defining the Repeat-containing Proteins in the Acinetobacter baumannii Proteome, a Great Reservoir of Templates for Synthetic Biology

2019 ◽  
Vol 13 (2) ◽  
pp. 149-158
Author(s):  
Mohammad Reza Rahbar ◽  
Mahboubeh Zarei ◽  
Navid Nezafat ◽  
Manica Negahdaripour ◽  
Younes Ghasemi
Keyword(s):  
Acinetobacter Baumannii ◽  
Drug Targets ◽  
Closely Related Species ◽  
Great Ability ◽  
Repeat Proteins ◽  
Significant Difference ◽  
Biological Determinants ◽  
Tandem Repeat Proteins ◽  
Diagnostic Approaches ◽  
Novel Therapeutic

Background: Acinetobacter baumannii is an important nosocomial pathogen with great ability to resist antibiotics. Tandem repeat proteins, abundant in prokaryotic proteomes, attract attention due to their role in virulence and various biological processes. Defining repeat- containing proteins may pave the way to find novel therapeutic targets as well as vaccine candidate and give pieces of evidence of mechanisms of evolution and adaptation of organisms to various environmental conditions. Objective: In the present study, we employed bioinformatics tools to define repeatcontaining proteins within A. baumannii proteome for emphasizing the existence of natural sources for synthesizing novel therapeutic and diagnosis material. Results: We defined various kinds of repeat modules in a number of proteins and compared the abundance of these proteins in some closely related species. No significant difference was observed in the count of repeat-containing proteins in different species. But the existence of some important virulence factors is mentionable in our screening. Conclusion: Repeat containing proteins are important biological determinants of A. baumannii and are well worth researching for finding drug targets and vaccine candidates. These proteins can be served as a template for designing and synthesizing peptides for therapeutic and diagnostic approaches.

scholarly journals SAT0315 INHIBITION OF MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 (MPGES-1) BY GS-248 REDUCES PROSTAGLANDIN E2 BIOSYNTHESIS WHILE INCREASING PROSTACYCLIN IN HUMAN SUBJECTS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1103.2-1103
Author(s):  
C. Edenius ◽  
G. Ekström ◽  
J. Kolmert ◽  
R. Morgenstern ◽  
P. Stenberg ◽  
...  
Keyword(s):  
Whole Blood ◽  
Vascular Tone ◽  
Ex Vivo ◽  
Prostaglandin E ◽  
Maximum Plasma ◽  
Prostaglandin E Synthase ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Oral Doses ◽  
Microsomal Prostaglandin E Synthase

Background:Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes the formation prostaglandin (PG) E2from cyclooxygenase derived PGH2(1, 2). Inhibition of mPGES-1 leads to reduction of pro-inflammatory PGE2, while in vessels there is a concomitant increase of vasoprotective prostacyclin (PGI2) via shunting of PGH2(3,4). Apart from relieving symptoms in experimental animal models of inflammation, inhibitors of mPGES-1 cause relaxation of human medium sized arteries(4)and resistance arteries(5). The prostaglandin profile following mPGES-1 inhibition, explains the anti-inflammatory effects and also opens for the possibility of treating inflammatory diseases with concomitant vasculopathies. GS-248 is a potent and selective inhibitor of mPGES-1 exhibiting sub-nanomolar IC50in human whole bloodex vivo.Objectives:To evaluate safety, tolerability, pharmacokinetics and pharmacodynamics of GS-248.Methods:Healthy males and females (age 18–73 years) were included in the study. Six cohorts were administrated single oral doses of 1-300mg GS-248 (n=36) or placebo (n=12), three cohorts were administered once daily doses of 20-180mg GS-248 (n=18) or placebo (n=12) over ten days. In addition, 8 subjects were treated in a separate cohort with 200mg celecoxib bid for ten days. Blood samples were drawn for measurement of GS-248 exposure and production of PGE2after LPS incubationex vivo. The content of PGE2and PGI2metabolites was measured in urine. All analyses were performed by LC-MS/MS.Results:GS-248 was safe and well tolerated at all tested dose levels. Maximum plasma concentration was achieved 1 - 2.5 hours after dosing, and half-life was about 10 hours. Induced PGE2formationex vivo,catalyzed by mPGES-1, was completely inhibited for 24 hours after a single low dose (40mg) of GS-248. In urine, GS-248 dose-dependently reduced the excretion of PGE2metabolite by more than 50% whereas the excretion of PGI2metabolite increased more than twice the baseline levels. In the celecoxib cohort urinary metabolites of both PGE2and PGI2were reduced with approx 50%.Conclusion:GS-248 at investigated oral doses was safe and well tolerated. There was a sustained inhibition of LPS induced PGE2formation in whole blood. In urine, there was a metabolite shift showing reduced PGE2and increased PGI2, while celecoxib reduced both PGE2and PGI2metabolites. This suggests that selective inhibition of mPGES-1 results in systemic shunting of PGH2to PGI2formation, leading to anti-inflammatory and vasodilatory effects, while preventing platelet activation. The results warrant further evaluation of GS-248 in inflammatory conditions with vasculopathies such as Digital Ulcers and Raynaud’s Phenomenon in Systemic Sclerosis.References:[1]Korotkova M, Jakobsson PJ. Persisting eicosanoid pathways in rheumatic diseases. Nat Rev Rheumatol. 2014;10:229-41[2]Bergqvist F, Morgenstern R, Jakobsson PJ. A review on mPGES-1 inhibitors: From preclinical studies to clinical applications. Prostaglandins Other Lipid Mediat. 2019;147:106383[3]Kirkby NS, et al. Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis. Cardiovasc Res. 2020[4]Ozen G, et al. Inhibition of microsomal PGE synthase-1 reduces human vascular tone by increasing PGI2: a safer alternative to COX-2 inhibition. Br J Pharmacol. 2017;174:4087-98[5]Larsson K, et al. Biological characterization of new inhibitors of microsomal PGE synthase-1 in preclinical models of inflammation and vascular tone. Br J Pharmacol. 2019;176:4625-38Disclosure of Interests:Charlotte Edenius Shareholder of: Gesynta Pharma, Consultant of: Gesynta Pharma,, Gunilla Ekström Shareholder of: Gesynta Pharma, Consultant of: Gesynta Pharma,, Johan Kolmert Consultant of: Gesynta Pharma,, Ralf Morgenstern Shareholder of: Gesynta Pharma, Employee of: Gesynta Pharma, Patric Stenberg Shareholder of: Gesynta Pharma, Employee of: Gesynta Pharma, Per-Johan Jakobsson Shareholder of: Gesynta Pharma, Grant/research support from: Gesynta Pharma, AstraZeneca,, Göran Tornling Shareholder of: Gesynta Pharma, Vicore Pharma,, Consultant of: Gesynta Pharma, Vicore Pharma, AnaMar

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