scholarly journals Antimalarial Activity of Human Group IIA Secreted Phospholipase A2 in Relation to Enzymatic Hydrolysis of Oxidized Lipoproteins

2019 ◽  
Vol 87 (11) ◽  
Author(s):  
Mélanie Dacheux ◽  
Véronique Sinou ◽  
Christine Payré ◽  
Louise Jeammet ◽  
Daniel Parzy ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Plasma Lipoproteins ◽  
Human Group ◽  
Nonesterified Fatty Acids ◽  
Content Type ◽  
Parasite Culture ◽  
Normal Plasma ◽  
Oxidized Lipoproteins ◽  
Healthy Donors ◽  
Hydrolysis Of

ABSTRACT The level of human group IIA secreted phospholipase A2 (hGIIA sPLA2) is increased in the plasma of malaria patients, but its role is unknown. In parasite culture with normal plasma, hGIIA is inactive against Plasmodium falciparum, contrasting with hGIIF, hGV, and hGX sPLA2s, which readily hydrolyze plasma lipoproteins, release nonesterified fatty acids (NEFAs), and inhibit parasite growth. Here, we revisited the anti-Plasmodium activity of hGIIA under conditions closer to those of malaria physiopathology where lipoproteins are oxidized. In parasite culture containing oxidized lipoproteins, hGIIA sPLA2 was inhibitory, with a 50% inhibitory concentration value of 150.0 ± 40.8 nM, in accordance with its capacity to release NEFAs from oxidized particles. With oxidized lipoproteins, hGIIF, hGV, and hGX sPLA2s were also more potent, by 4.6-, 2.1-, and 1.9-fold, respectively. Using specific immunoassays, we found that hGIIA sPLA2 is increased in plasma from 41 patients with malaria over levels for healthy donors (median [interquartile range], 1.6 [0.7 to 3.4] nM versus 0.0 [0.0 to 0.1] nM, respectively; P < 0.0001). Other sPLA2s were not detected. Malaria plasma, but not normal plasma, contains oxidized lipoproteins and was inhibitory to P. falciparum when spiked with hGIIA sPLA2. Injection of recombinant hGIIA into mice infected with P. chabaudi reduced the peak of parasitemia, and this was effective only when the level of plasma peroxidation was increased during infection. In conclusion, we propose that malaria-induced oxidation of lipoproteins converts these into a preferential substrate for hGIIA sPLA2, promoting its parasite-killing effect. This mechanism may contribute to host defense against P. falciparum in malaria where high levels of hGIIA are observed.

scholarly journals In VitroAnti-Plasmodium falciparum Properties of the Full Set of Human Secreted Phospholipases A2

2015 ◽  
Vol 83 (6) ◽  
pp. 2453-2465 ◽  
Author(s):  
Carole Guillaume ◽  
Christine Payré ◽  
Ikram Jemel ◽  
Louise Jeammet ◽  
Sofiane Bezzine ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Plasmodium Falciparum ◽  
Critical Role ◽  
Plasma Lipoproteins ◽  
Nonesterified Fatty Acids ◽  
Content Type ◽  
Phospholipases A2

We have previously shown that secreted phospholipases A2(sPLA2s) from animal venoms inhibit thein vitrodevelopment ofPlasmodium falciparum, the agent of malaria. In addition, the inflammatory-type human group IIA (hGIIA) sPLA2circulates at high levels in the serum of malaria patients. However, the role of the different human sPLA2s in host defense againstP. falciparumhas not been investigated. We show here that 4 out of 10 human sPLA2s, namely, hGX, hGIIF, hGIII, and hGV, exhibit potentin vitroanti-Plasmodiumproperties with half-maximal inhibitory concentrations (IC50s) of 2.9 ± 2.4, 10.7 ± 2.1, 16.5 ± 9.7, and 94.2 ± 41.9 nM, respectively. Other human sPLA2s, including hGIIA, are inactive. The inhibition is dependent on sPLA2catalytic activity and primarily due to hydrolysis of plasma lipoproteins from the parasite culture. Accordingly, purified lipoproteins that have been prehydrolyzed by hGX, hGIIF, hGIII, and hGV are more toxic toP. falciparumthan native lipoproteins. However, the total enzymatic activities of human sPLA2s on purified lipoproteins or plasma did not reflect their inhibitory activities onP. falciparum. For instance, hGIIF is 9-fold more toxic than hGV but releases a lower quantity of nonesterified fatty acids (NEFAs). Lipidomic analyses of released NEFAs from lipoproteins demonstrate that sPLA2s with anti-Plasmodiumproperties are those that release polyunsaturated fatty acids (PUFAs), with hGIIF being the most selective enzyme. NEFAs purified from lipoproteins hydrolyzed by hGIIF were more potent at inhibitingP. falciparumthan those from hGV, and PUFA-enriched liposomes hydrolyzed by sPLA2s were highly toxic, demonstrating the critical role of PUFAs. The selectivity of sPLA2s toward low- and high-density (LDL and HDL, respectively) lipoproteins and their ability to directly attack parasitized erythrocytes further explain their anti-Plasmodiumactivity. Together, our findings indicate that 4 human sPLA2s are active againstP. falciparumin vitroand pave the way to future investigations on theirin vivocontribution in malaria pathophysiology.

scholarly journals Characterization of Glycoside Hydrolase Family 5 Proteins in Schizosaccharomyces pombe

2010 ◽  
Vol 9 (11) ◽  
pp. 1650-1660 ◽  
Author(s):  
Encarnación Dueñas-Santero ◽  
Ana Belén Martín-Cuadrado ◽  
Thierry Fontaine ◽  
Jean-Paul Latgé ◽  
Francisco del Rey ◽  
...  
Keyword(s):  
Cell Wall ◽  
Schizosaccharomyces Pombe ◽  
Protein Characterization ◽  
Wall Material ◽  
Glycoside Hydrolase Family ◽  
Content Type ◽  
Hydrolysis Of ◽  
Controlled Hydrolysis ◽  
Hydrolase Family

ABSTRACT In yeast, enzymes with β-glucanase activity are thought to be necessary in morphogenetic events that require controlled hydrolysis of the cell wall. Comparison of the sequence of the Saccharomyces cerevisiae exo-β(1,3)-glucanase Exg1 with the Schizosaccharomyces pombe genome allowed the identification of three genes that were named exg1 + (locus SPBC1105.05), exg2 + (SPAC12B10.11), and exg3 + (SPBC2D10.05). The three proteins have different localizations: Exg1 is secreted to the periplasmic space, Exg2 is a membrane protein, and Exg3 is a cytoplasmic protein. Characterization of the biochemical activity of the proteins indicated that Exg1 and Exg3 are active only against β(1,6)-glucans while no activity was detected for Exg2. Interestingly, Exg1 cleaves the glucans with an endohydrolytic mode of action. exg1 + showed periodic expression during the cell cycle, with a maximum coinciding with the septation process, and its expression was dependent on the transcription factor Sep1. The Exg1 protein localizes to the septum region in a pattern that was different from that of the endo-β(1,3)-glucanase Eng1. Overexpression of Exg2 resulted in an increase in cell wall material at the poles and in the septum, but the putative catalytic activity of the protein was not required for this effect.

scholarly journals Antimalarial Activity of the Myxobacterial Macrolide Chlorotonil A

2014 ◽  
Vol 58 (11) ◽  
pp. 6378-6384 ◽  
Author(s):  
Jana Held ◽  
Tamirat Gebru ◽  
Markus Kalesse ◽  
Rolf Jansen ◽  
Klaus Gerth ◽  
...  
Keyword(s):  
Screening Program ◽  
Antimalarial Activity ◽  
Stage Iv ◽  
Short Exposure ◽  
Parasite Development ◽  
Content Type ◽  
Highly Active ◽  
New Antibiotics ◽  
Further Development ◽  
Antimalarial Action

ABSTRACTMyxobacteria are Gram-negative soil-dwelling bacteria belonging to the phylumProteobacteria. They are a rich source of promising compounds for clinical application, such as epothilones for cancer therapy and several new antibiotics. In the course of a bioactivity screening program of secondary metabolites produced bySorangium cellulosumstrains, the macrolide chlorotonil A was found to exhibit promising antimalarial activity. Subsequently, we evaluated chlorotonil A againstPlasmodium falciparumlaboratory strains and clinical isolates from Gabon. Chlorotonil A was highly active, with a 50% inhibitory concentration between 4 and 32 nM; additionally, no correlations between the activities of chlorotonil A and artesunate (rho, 0.208) or chloroquine (rho, −0.046) were observed.Per ostreatment ofPlasmodium berghei-infected mice with four doses of as little as 36 mg of chlorotonil A per kg of body weight led to the suppression of parasitemia with no obvious signs of toxicity. Chlorotonil A acts against all stages of intraerythrocytic parasite development, including ring-stage parasites and stage IV to V gametocytes, and it requires only a very short exposure to the parasite to exert its antimalarial action. Conclusively, chlorotonil A has an exceptional and unprecedented profile of action and represents an urgently required novel antimalarial chemical scaffold. Therefore, we propose it as a lead structure for further development as an antimalarial chemotherapeutic.

scholarly journals Draft Genome Sequence of Microbacterium esteraromaticum MM1, a Bacterium That Hydrolyzes the Organophosphorus Pesticide Fenamiphos, Isolated from Golf Course Soil

2018 ◽  
Vol 7 (4) ◽  
Author(s):  
Logeshwaran Panneerselvan ◽  
Kannan Krishnan ◽  
Suresh R. Subashchandrabose ◽  
Ravi Naidu ◽  
Mallavarapu Megharaj
Keyword(s):  
Polycyclic Aromatic Hydrocarbon ◽  
Genome Sequence ◽  
Draft Genome ◽  
Organophosphorus Pesticide ◽  
South Australia ◽  
Draft Genome Sequence ◽  
Golf Course ◽  
Content Type ◽  
Polycyclic Aromatic ◽  
Hydrolysis Of

In this study, we report the first draft genome sequence of Microbacterium esteraromaticum MM1, isolated from golf course soil in South Australia. The genome possesses genes for the hydrolysis of organophosphorus (OP) pesticides and polycyclic aromatic hydrocarbon (PAH) degradation.

Corrosion inhibition of N80 steel in 10% HCl + 8% HBF4solution

2019 ◽  
Vol 66 (1) ◽  
pp. 1-10
Author(s):  
Juan Du ◽  
Yuning He ◽  
Pingli Liu ◽  
Yigang Liu ◽  
Xianghai Meng ◽  
...  
Keyword(s):  
Corrosion Inhibition ◽  
Design Methodology ◽  
X Ray Diffraction ◽  
Corrosion Morphology ◽  
Content Type ◽  
X Ray ◽  
N80 Steel ◽  
Corrosion Reaction ◽  
Hydrolysis Of ◽  
Scanning Electron

PurposeThis paper aims to analyze the corrosion and corrosion inhibition of N80 in 10 per cent HCl + 8 per cent fluoroboric acid (HBF4) solution for acidizing operation.Design/methodology/approachThe corrosion rate, kinetic parameters (Ea, A) and thermodynamic parameters (ΔH, ΔS) of N80 steel in fresh acid and spent acid, 10 per cent HCl + 8 per cent HBF4, 10 per cent HCl and 8 per cent HBF4solutions were calculated through immersion tests. The corrosion and inhibition properties were studied through X-ray diffraction and electrochemical measurements. The corrosion morphology of the corrosion product was examined by scanning electron microscopy (SEM).FindingsThe results demonstrated that the spent acid was the main cause of acidification corrosion, and the HBF4would cause serious corrosion to N80 steel. The results showed that the N80 steel was more seriously corroded in the spent acid than in fresh acid, and the hydrolysis of HBF4accelerates the dissolution process of N80 steel anode to control the corrosion reaction. The results showed that the acidification will definitely cause serious corrosion to the oil tube; therefore, necessary anti-corrosion measures must be taken in the acidification process.Originality/valueThe results showed that acidizing the formation with 10 per cent HCl + 8 per cent HBF4will definitely cause serious corrosion to the oil tube, especially when the spent acid flows back. Therefore, necessary anti-corrosion measures must be taken in the acidification process, especially in the spent acid flowback stage.

scholarly journals Collinsella vaginalis sp. nov. strain Marseille-P2666T, a new member of the Collinsella genus isolated from the genital tract of a patient suffering from bacterial vaginosis

2019 ◽  
Vol 69 (4) ◽  
pp. 949-956 ◽  
Author(s):  
Awa Diop ◽  
Khoudia Diop ◽  
Enora Tomei ◽  
Nicholas Armstrong ◽  
Florence Bretelle ◽  
...  
Keyword(s):  
Bacterial Vaginosis ◽  
Type Strain ◽  
Sequence Similarity ◽  
Strictly Anaerobic ◽  
16S Rrna Sequence ◽  
Content Type ◽  
Link Type ◽  
Vaginal Sample ◽  
Bacterium Strain ◽  
Hydrolysis Of

A strictly anaerobic, Gram-stain-positive, non motile and non-spore-forming rod-shaped bacterium, strain Marseille-P2666T, was isolated using the culturomics approach from a vaginal sample of a French patient suffering from bacterial vaginosis. Cells were saccharolytic and were negative for catalase, oxidase, urease, nitrate reduction, indole production, hydrolysis of aesculin and gelatin. Strain Marseille-P2666T exhibited 97.04 % 16S rRNA sequence similarity to Collinsella tanakaei type strain YIT 12063T, the phylogenetically closest species with standing in nomenclature. The major fatty acids were C18:1ω9 (38 %), C16 : 0 (24 %) and C18 : 0 (19 %). The G+C content of the genome sequence of strain Marseille-P2666T is 64.6 mol%. On the basis of its phenotypic, phylogenetic and genomic features, strain Marseille-P2666T (=CSUR 2666T=DSM103342T) was classified as type strain of a novel species within the genus Collinsella for which the name Collinsella vaginalis sp. nov. is proposed.

scholarly journals Increased Hydrolysis of Oximino-β-Lactams by CMY-107, a Tyr199Cys Mutant Form of CMY-2 Produced by Escherichia coli

2015 ◽  
Vol 59 (12) ◽  
pp. 7894-7898 ◽  
Author(s):  
S. D. Kotsakis ◽  
V. Miriagou ◽  
E. E. Vetouli ◽  
E. Bozavoutoglou ◽  
E. Lebessi ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Clinical Strain ◽  
Mutant Form ◽  
Content Type ◽  
Hydrolysis Of

ABSTRACTThe cephalosporinase CMY-107, a Tyr199Cys mutant form of CMY-2 encoded by an IncI self-transferable plasmid carried by anEscherichia coliclinical strain, was characterized. The enzyme hydrolyzed oximino-cephalosporins and aztreonam more efficiently than CMY-2 did.

scholarly journals In VitroandIn VivoActivity of Solithromycin (CEM-101) against Plasmodium Species

2011 ◽  
Vol 56 (2) ◽  
pp. 703-707 ◽  
Author(s):  
Sergio Wittlin ◽  
Eric Ekland ◽  
J Carl Craft ◽  
Julie Lotharius ◽  
Ian Bathurst ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Antimalarial Activity ◽  
Plasmodium Species ◽  
Parasite Clearance ◽  
Response To Treatment ◽  
Cross Resistance ◽  
Asexual Blood Stage ◽  
Content Type

ABSTRACTWith the emergence ofPlasmodium falciparuminfections exhibiting increased parasite clearance times in response to treatment with artemisinin-based combination therapies, the need for new therapeutic agents is urgent. Solithromycin, a potent new fluoroketolide currently in development, has been shown to be an effective, broad-spectrum antimicrobial agent. Malarial parasites possess an unusual organelle, termed the apicoplast, which carries a cryptic genome of prokaryotic origin that encodes its own translation and transcription machinery. Given the similarity of apicoplast and bacterial ribosomes, we have examined solithromycin for antimalarial activity. Other antibiotics known to target the apicoplast, such as the macrolide azithromycin, demonstrate a delayed-death effect, whereby treated asexual blood-stage parasites die in the second generation of drug exposure. Solithromycin demonstrated potentin vitroactivity against the NF54 strain ofP. falciparum, as well as against two multidrug-resistant strains, Dd2 and 7G8. The dramatic increase in potency observed after two generations of exposure suggests that it targets the apicoplast. Solithromycin also retained potency against azithromycin-resistant parasites derived from Dd2 and 7G8, although these lines did demonstrate a degree of cross-resistance. In anin vivomodel ofP. bergheiinfection in mice, solithromycin demonstrated a 100% cure rate when administered as a dosage regimen of four doses of 100 mg/kg of body weight, the same dose required for artesunate or chloroquine to achieve 100% cure rates in this rodent malaria model. These promisingin vitroandin vivodata support further investigations into the development of solithromycin as an antimalarial agent.

scholarly journals Prospective Clinical Trial Assessing Species-Specific Efficacy of Artemether-Lumefantrine for the Treatment of Plasmodium malariae , Plasmodium ovale , and Mixed Plasmodium Malaria in Gabon

2018 ◽  
Vol 62 (3) ◽  
Author(s):  
Mirjam Groger ◽  
Luzia Veletzky ◽  
Albert Lalremruata ◽  
Chiara Cattaneo ◽  
Johannes Mischlinger ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Antimalarial Activity ◽  
Study Drug ◽  
Plasmodium Malariae ◽  
Fixed Dose ◽  
Plasmodium Ovale ◽  
Content Type ◽  
Primary Endpoints ◽  
Dose Combination ◽  
Species Specific

ABSTRACT Treatment recommendations for Plasmodium malariae and Plasmodium ovale malaria are largely based on anecdotal evidence. The aim of this prospective study, conducted in Gabon, was to systematically assess the efficacy and safety of artemether-lumefantrine for the treatment of patients with uncomplicated P. malariae or P. ovale species monoinfections or mixed Plasmodium infections. Patients with microscopically confirmed P. malariae , P. ovale , or mixed-species malaria with at least one of these two Plasmodium species were treated with an oral, fixed-dose combination of artemether-lumefantrine for 3 consecutive days. The primary endpoints were per-protocol PCR-corrected adequate clinical and parasitological response (ACPR) on days 28 and 42. Tolerability and safety were recorded throughout the follow-up period. Seventy-two participants (42 male and 30 female) were enrolled; 62.5% of them had PCR-corrected mixed Plasmodium infections. Per protocol, PCR-corrected ACPR rates were 96.6% (95% confidence interval [CI], 91.9 to 100) on day 28 and 94.2% (95% CI, 87.7 to 100) on day 42. Considering Plasmodium species independently from their coinfecting species, day 42 ACPR rates were 95.5% (95% CI, 89.0 to 100) for P. falciparum , 100% (exact CI, 84.6 to 100) for P. malariae , 100% (exact CI, 76.8 to 100) for P. ovale curtisi , and 90.9% (95% CI, 70.7 to 100) for P. ovale wallikeri . Study drug-related adverse events were generally mild or moderate. In conclusion, this clinical trial demonstrated satisfying antimalarial activity of artemether-lumefantrine against P. ovale wallikeri , P. ovale curtisi , P. malariae , and mixed Plasmodium infections, with per-protocol efficacies of 90% to 100% and without evident tolerability or safety concerns. (This trial was registered in the clinical study database ClinicalTrials.gov under the identifier NCT02528279.)

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