scholarly journals High-resolution AP-SMALDI MSI as a tool for drug imaging in Schistosoma mansoni

2021 ◽  
Author(s):  
Annika S. Mokosch ◽  
Stefanie Gerbig ◽  
Christoph G. Grevelding ◽  
Simone Haeberlein ◽  
Bernhard Spengler
Keyword(s):  
Schistosoma Mansoni ◽  
Egg Production ◽  
Drug Repurposing ◽  
Cancer Drug ◽  
Ionization Mass ◽  
Parasitic Flatworm ◽  
Paired Female ◽  
First Time ◽  
Organ Tropism

AbstractSchistosoma mansoni is a parasitic flatworm causing schistosomiasis, an infectious disease affecting several hundred million people worldwide. Schistosomes live dioeciously, and upon pairing with the male, the female starts massive egg production, which causes pathology. Praziquantel (PZQ) is the only drug used, but it has an inherent risk of resistance development. Therefore, alternatives are needed. In the context of drug repurposing, the cancer drug imatinib was tested, showing high efficacy against S. mansoni in vitro. Besides the gonads, imatinib mainly affected the integrity of the intestine in males and females. In this study, we investigated the potential uptake and distribution of imatinib in adult schistosomes including its distribution kinetics. To this end, we applied for the first time atmospheric-pressure scanning microprobe matrix-assisted laser desorption/ionization mass spectrometry imaging (AP-SMALDI MSI) for drug imaging in paired S. mansoni. Our results indicate that imatinib was present in the esophagus and intestine of the male as early as 20 min after in vitro exposure, suggesting an oral uptake route. After one hour, the drug was also found inside the paired female. The detection of the main metabolite, N-desmethyl imatinib, indicated metabolization of the drug. Additionally, a marker signal for the female ovary was successfully applied to facilitate further conclusions regarding organ tropism of imatinib. Our results demonstrate that AP-SMALDI MSI is a useful method to study the uptake, tissue distribution, and metabolization of imatinib in S. mansoni. The results suggest using AP-SMALDI MSI also for investigating other antiparasitic compounds and their metabolites in schistosomes and other parasites. Graphical abstract

scholarly journals In vitro effects of artesunate on the survival of worm pairs and egg production of Schistosoma mansoni

2009 ◽  
Vol 83 (1) ◽  
pp. 7-11 ◽  
Author(s):  
Y. Mitsui ◽  
M. Miura ◽  
Y. Aoki
Keyword(s):  
Schistosoma Mansoni ◽  
Adult Worm ◽  
Survival Time ◽  
Egg Production ◽  
Inhibitory Effect ◽  
Male And Female ◽  
Paired Male ◽  
In Vitro Effects ◽  
Paired Female

AbstractThe effect of artesunate (ART) on the survival time of adult worm pairs of Schistosoma mansoni and on their egg output during in vitro culture was assessed. ART significantly decreased the survival time of both paired male and female worms at concentrations of 5, 10, 20 and 40 mg l− 1 during in vitro cultivation. An inhibitory effect of ART on the daily egg output of paired female worms during in vitro cultivation was also observed.

scholarly journals In Vitro and In Vivo Studies of Spironolactone as an Antischistosomal Drug Capable of Clinical Repurposing

2018 ◽  
Vol 63 (3) ◽  
Author(s):  
Rafael A. Guerra ◽  
Marcos P. Silva ◽  
Tais C. Silva ◽  
Maria C. Salvadori ◽  
Fernanda S. Teixeira ◽  
...  
Keyword(s):  
Egg Production ◽  
Oral Treatment ◽  
Drug Repurposing ◽  
In Vivo Studies ◽  
Content Type ◽  
Low Concentrations ◽  
Parasitic Flatworm ◽  
And Control

ABSTRACT Schistosomiasis is a parasitic flatworm disease that infects over 200 million people worldwide, especially in poor communities. Treatment and control of the disease rely on just one drug, praziquantel. Since funding for drug development for poverty-associated diseases is very limited, drug repurposing is a promising strategy. In this study, from a screening of 13 marketed diuretics, we identified that spironolactone, a potassium-sparing diuretic, had potent antischistosomal effects on Schistosoma mansoni in vitro and in vivo in a murine model of schistosomiasis. In vitro, spironolactone at low concentrations (<10 µM) is able to alter worm motor activity and the morphology of adult schistosomes, leading to parasitic death. In vivo, oral treatment with spironolactone at a single dose (400 mg/kg) or daily for five consecutive days (100 mg/kg/day) in mice harboring either patent or prepatent infections significantly reduced worm burden, egg production, and hepato- and splenomegaly (P < 0.05 to P < 0.001). Taken together, with the safety profile of spironolactone, supported by its potential to affect schistosomes, these results indicate that spironolactone could be a potential treatment for schistosomiasis and make it promising for repurposing.

Structure-Reactivity Relationships on Substrates and Inhibitors of the Lysine Deacylase Sirtuin 2 from Schistosoma Mansoni (SmSirt2)

2019 ◽  
Author(s):  
Daria Monaldi ◽  
Dante Rotili ◽  
Julien Lancelot ◽  
Martin Marek ◽  
Nathalie Wössner ◽  
...  
Keyword(s):  
Schistosoma Mansoni ◽  
Human Cancer ◽  
Egg Laying ◽  
Human Cancer Cells ◽  
Parasite Survival ◽  
Survival And Reproduction ◽  
Emergence Of Resistance ◽  
First Time ◽  
Parasitic Life Cycle

The only drug for treatment of Schistosomiasis is Praziquantel, and the possible emergence of resistance makes research on novel therapeutic agents necessary. Targeting of Schistosoma mansoni epigenetic enzymes, which regulate the parasitic life cycle, emerged as promising approach. Due to the strong effects of human Sirtuin inhibitors on parasite survival and reproduction, Schistosoma sirtuins were postulated as therapeutic targets. In vitro testing of synthetic substrates of S. mansoni Sirtuin 2 (SmSirt2) and kinetic experiments on a myristoylated peptide demonstrated lysine long chain deacylation as an intrinsic SmSirt2 activity for the first time. Focused in vitro screening of the GSK Kinetobox library and structure-activity relationships (SAR) of identified hits, led to the first SmSirt2 inhibitors with activity in the low micromolar range. Several SmSirt2 inhibitors showed potency against both larval schistosomes (viability) and adult worms (pairing, egg laying) in culture without general toxicity to human cancer cells.<br>

scholarly journals Lanostane Triterpenes from Gloeophyllum odoratum and Their Anti-Influenza Effects

Planta Medica ◽  
2018 ◽  
Vol 85 (03) ◽  
pp. 195-202 ◽  
Author(s):  
Ulrike Grienke ◽  
Julia Zwirchmayr ◽  
Ursula Peintner ◽  
Ernst Urban ◽  
Martin Zehl ◽  
...  
Keyword(s):  
Fruit Body ◽  
Ionization Mass ◽  
Body Extract ◽  
H1n1 Strain ◽  
Ic50 Values ◽  
H3n2 Influenza ◽  
Work Up ◽  
First Time ◽  
H3n2 Influenza Virus

AbstractIn an in vitro screening for anti-influenza agents from European polypores, the fruit body extract of Gloeophyllum odoratum dose-dependently inhibited the cytopathic effect of the H3N2 influenza virus A/Hong Kong/68 (HK/68) in Madin Darby canine kidney cells with a 50% inhibitory concentration (IC50) of 15 µg/mL, a noncytotoxic concentration. After a chromatographic work-up, eight lanostane triterpenes (1–8) were isolated and their structures were elucidated based on high-resolution electrospray ionization mass spectrometry analyses, and one- and two-dimensional nuclear magnetic resonance experiments. Constituents 1 (gloeophyllin K) and 2 (gloeophyllin L) are reported here for the first time, and compounds 5, 7, and 8 have not been described for the investigated fungal material so far. The highest activity was determined for trametenolic acid B (3) against HK/68 and the 2009 pandemic H1N1 strain A/Jena/8178/09 with IC50 values of 14 and 11 µM, respectively. In a plaque reduction assay, this compound was able to bind to cell-free viruses and to neutralize their infectivity.

scholarly journals Cytotoxic Pentacyclic Triterpenoids from Combretum oliviforme

2010 ◽  
Vol 5 (7) ◽  
pp. 1934578X1000500
Author(s):  
Xiao-Peng Wu ◽  
Chang-Ri Han ◽  
Guang-Ying Chen ◽  
Yuan Yuan ◽  
Jian-Ying Xie
Keyword(s):  
Cytotoxic Activity ◽  
Cancer Cell Line ◽  
Lung Cancer Cell Line ◽  
Human Lung Cancer ◽  
Ionization Mass ◽  
Human Gastric Cancer ◽  
Pentacyclic Triterpenoids ◽  
Acetyl Group ◽  
First Time

Four pentacyclic triterpenoids were obtained from the leaves of Combretum oliviforme Chao, 3β–hydroxyolean–12–en–28–oic acid (1), 23– O–[α-L-(4′-acetylrhamnopyranosyl)]–imberbic acid (2), 23–acetoxy–3β–acetylimberbic acid–29–methyl ester (3), and 23– O–[α-L-rhamnopyranosyl]-1,3β-diacetylimberbic acid (4). Hydrolysis of 2 and 4 gave 23–hydroxyimberbic acid (5). The structures were elucidated by NMR, electrospray ionization mass spectrometry (ESIMS) and comparison with literature data. Compounds 1, 2, 3 and 4 were isolated from C. oliviforme Chao leaves for the first time and 3 for the first time from any natural source. All compounds were tested in vitro for their activity against human lung cancer cell line SPC-A-1, human erythroleukaemic line K562 and human gastric cancer SGC-7901 cells. Compounds 1, 3, 4 and 5 had cytotoxic activity for the three cell lines with IC50 0.69-69.68 μM. These results suggest that the presence of acetyl group in the triterpene aglycone structure plays an essential role for cytotoxic activity.

scholarly journals Oviposition by Schistosoma mansoni during in vitro cultivation

1996 ◽  
Vol 38 (6) ◽  
pp. 423-426 ◽  
Author(s):  
Leo Roberto Barth ◽  
Ana Paula Morais Fernandes ◽  
Vanderlei Rodrigues
Keyword(s):  
Schistosoma Mansoni ◽  
Egg Production ◽  
Culture Medium ◽  
Parasite Development ◽  
In Vitro Cultivation ◽  
Progressive Reduction ◽  
Maximum Period ◽  
Medium Time ◽  
Kinetics Of

Observation of Schistosoma mansoni oviposition during in vitro culture of adult worms for a maximum period of 10 days showed three well distinct phases in the kinetics of oviposition: an initial phase with low egg production, a period of maximum oviposition and finally a progressive reduction in the number of eggs during the late phases of culture. The kinetics of oviposition and the number of eggs laid by the parasites are influenced by the number of worm pairs per amount of RPMI 1640 medium, time of parasite development in the vertebrate host and type of serum utilized in the culture medium.

scholarly journals EGFR and PI3K Pathway Activities Might Guide Drug Repurposing in HPV-Negative Head and Neck Cancers

2021 ◽  
Vol 11 ◽  
Author(s):  
Andreas Mock ◽  
Michaela Plath ◽  
Julius Moratin ◽  
Maria Johanna Tapken ◽  
Dirk Jäger ◽  
...  
Keyword(s):  
Head And Neck ◽  
Hdac Inhibitors ◽  
Drug Repurposing ◽  
B Cell Lymphoma ◽  
Pi3k Pathway ◽  
Genetic Alterations ◽  
The Cancer Genome Atlas ◽  
Cancer Drug ◽  
Oncogenic Signaling

While genetic alterations in Epidermal growth factor receptor (EGFR) and PI3K are common in head and neck squamous cell carcinomas (HNSCC), their impact on oncogenic signaling and cancer drug sensitivities remains elusive. To determine their consequences on the transcriptional network, pathway activities of EGFR, PI3K, and 12 additional oncogenic pathways were inferred in 498 HNSCC samples of The Cancer Genome Atlas using PROGENy. More than half of HPV-negative HNSCC showed a pathway activation in EGFR or PI3K. An amplification in EGFR and a mutation in PI3KCA resulted in a significantly higher activity of the respective pathway (p = 0.017 and p = 0.007). Interestingly, both pathway activations could only be explained by genetic alterations in less than 25% of cases indicating additional molecular events involved in the downstream signaling. Suitable in vitro pathway models could be identified in a published drug screen of 45 HPV-negative HNSCC cell lines. An active EGFR pathway was predictive for the response to the PI3K inhibitor buparlisib (p = 6.36E-03) and an inactive EGFR and PI3K pathway was associated with efficacy of the B-cell lymphoma (BCL) inhibitor navitoclax (p = 9.26E-03). In addition, an inactive PI3K pathway correlated with a response to multiple Histone deacetylase inhibitor (HDAC) inhibitors. These findings require validation in preclinical models and clinical studies.

scholarly journals Antioxidant and Hepatoprotective Activity of Phenyl Glycosides Isolated From Heliciopsis lobata

2020 ◽  
Vol 15 (8) ◽  
pp. 1934578X2094625
Author(s):  
Bui Van Trung ◽  
Do Thi Thao ◽  
Duong Hong Anh ◽  
Phan Van Kiem ◽  
Pham Hung Viet
Keyword(s):  
Barbituric Acid ◽  
Multiple Bond ◽  
Radical Scavenging ◽  
Hepatoprotective Activity ◽  
Ionization Mass ◽  
Chemical Structures ◽  
Heteronuclear Single Quantum Correlation ◽  
First Time ◽  
C Nmr

A new macrocyclic glycoside named helilobatoside A (1) and 5 known phenyl glycosides as 3,5-dimethoxy-4-hydroxyphenyl-1- O-β-d-glucopyranoside (2), tachioside (3), isotachioside (4), 1-(4-hydroxy-3-methoxyphenyl)-1-propanone-3- O-β-d-glucopyranoside (5), and 1-(4-hydroxy-3,5-dimethoxyphenyl)-1-propanone-3- O-β-d-glucopyranoside (6), were isolated from the wood of Heliciopsis lobata (Merr.) Sleumer. Their chemical structures were elucidated using a combination of high-resolution electrospray ionization mass spectrometry, 1-dimensional (1D) and 2D nuclear magnetic resonance (NMR) spectral data as well as by comparison with data in the previous literature. This is the first time the 13C NMR data of compounds 5 and 6 were reported and also were assigned by heteronuclear single quantum correlation and heteronuclear multiple bond correlation spectra. Compounds 2-6 were first isolated from Heliciopsis genus. The isolated compounds were evaluated for their antioxidant and hepatoprotective activities in vitro. Compound 2 showed potential as an antioxidant in a 2,2-diphenyl-1-picryl-hydrazyl-hydrate assay (half-maximal inhibitory concentration [IC50] = 6.07 ± 0.17 µg/mL) and in thio-barbituric acid reactive substances assay (IC50 = 89.55 ± 8.26 µg/mL). This compound could also reduce the toxic effects of carbon tetrachloride on HepG2 survival and significantly protect the viability of cells up to 52.25 ± 4.36% at the 100 µg/mL treatment ( P < 0.05). Thus, with obtained results, the hepatoprotective activity of compound 2 could be related to radical scavenging and limited the lipid peroxidative activities.

scholarly journals Chemical Investigation of the Indonesian Tunicate Polycarpa aurata and Evaluation of the Effects Against Schistosoma mansoni of the Novel Alkaloids Polyaurines A and B

Marine Drugs ◽  
2019 ◽  
Vol 17 (5) ◽  
pp. 278 ◽  
Author(s):  
Marcello Casertano ◽  
Concetta Imperatore ◽  
Paolo Luciano ◽  
Anna Aiello ◽  
Masteria Yunovilsa Putra ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Schistosoma Mansoni ◽  
Mammalian Cells ◽  
Egg Production ◽  
2D Nmr ◽  
Chemical Investigation ◽  
Computational Studies ◽  
The Novel ◽  
Thiadiazole Ring

A deep study of the metabolic content of the tunicate Polycarpa aurata, collected from Indonesian coast, afforded the isolation of two novel alkaloids, polyaurines A (1) and B (2), along with two new p-substituted benzoyl derivatives (3 and 4) and four known compounds (5–8). The structural elucidation of the new secondary metabolites was assigned by 1D, 2D NMR, and HRESIMS techniques. Computational studies resulted a useful tool to unambiguously determine in polyaurine B the presence of rarely found 1,2,4-thiadiazole ring. The effects of polyaurines A and B on mammalian cells growth and on the viability of different blood-dwelling Schistosoma mansoni (phylum: Platyhelminthes) stages, as well as egg production, were evaluated. Both compounds resulted not cytotoxic; interestingly some of the eggs produced by polyaurine A-treated adult pairs in vitro are smaller, deformed, and/or fragmented; therefore, polyaurine A could represent an interesting bioactive natural molecule to be further investigated.

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