New methods in synthesis of acetylcholinesterase reactivators and evaluation of their potency to reactivate cyclosarin-inhibited AChE

2006 ◽  
Vol 60 (1) ◽  
Author(s):  
K. Musílek ◽  
L. Lipka ◽  
V. Račáková ◽  
K. Kuča ◽  
D. Jun ◽  
...  
Keyword(s):  
Nerve Agent ◽  
Structural Factors ◽  
New Methods ◽  
Pyridinium Ring ◽  
Acetylcholinesterase Reactivators

AbstractNine potential AChE reactivators were synthesized using modification of currently known synthetic pathways. Their potency to reactivate AChE inhibited by cyclosarin nerve agent was tested in vitro. According to the previous results, 1,4-bis(2-hydroxyiminomethylpyridinium)butane dibromide seems to be the most potent AChE reactivator. The reactivation potency of these compounds depends on structural factors such as presence of quaternary nitrogens, length of the linking chain between both pyridinium rings, and position of the oxime moiety at the pyridinium ring.

scholarly journals Evaluation of Potency of Known Oximes (Pralidoxime, Trimedoxime, HI-6, Methoxime, Obidoxime) to in vitro Reactivate Acetylcholinesterase Inhibited by Pesticides (Chlorpyrifos and Methylchlorpyrifos and Nerve Agent (Russian VX)

2007 ◽  
Vol 50 (3) ◽  
pp. 203-206 ◽  
Author(s):  
Kamil Musílek ◽  
Kamil Kuča ◽  
Daniel Jun
Keyword(s):  
Organophosphorus Pesticides ◽  
Nerve Agents ◽  
Nerve Agent ◽  
Hi 6 ◽  
Acetylcholinesterase Reactivators

Nerve agents and pesticides belong to the group of organophosphates. They are able to inhibit irreversibly the enzyme acetylcholinesterase (AChE). Acetylcholinesterase reactivators were designed for the treatment of nerve agent intoxications. Their potency to reactivate pesticide-inhibited AChE was many times evaluated. In this study, five commonly used AChE reactivators (pralidoxime, methoxime, HI-6, obidoxime, trimedoxime) for the reactivation of AChE inhibited by two pesticides (chlorpyrifos and methylchlorpyrifos) were used. Russian VX (nerve agent) as a member of nerve agents’ family was taken for comparison. Obtained results show that oximes developed against nerve agent intoxication are less effective for intoxication with organophosphorus pesticides. Especially, methylchlorpyrifos-inhibited AChE was found to be poorly reactivated by the compounds used.

scholarly journals Design, synthesis, in silico studies and in vitro evaluation of isatin-pyridine oximes hybrids as novel acetylcholinesterase reactivators

2021 ◽  
Vol 36 (1) ◽  
pp. 1370-1377
Author(s):  
Daniel A. S. Kitagawa ◽  
Rafael B. Rodrigues ◽  
Thiago N. Silva ◽  
Wellington V. dos Santos ◽  
Vinicius C. V. da Rocha ◽  
...  
Keyword(s):  
In Silico ◽  
Design Synthesis ◽  
In Vitro Evaluation ◽  
In Silico Studies ◽  
Acetylcholinesterase Reactivators

An aniline-substituted bile salt analog protects both mice and hamsters from multiple Clostridioides difficile strains

2021 ◽  
Author(s):  
Jacqueline R. Phan ◽  
Dung M. Do ◽  
Minh Chau Truong ◽  
Connie Ngo ◽  
Julian H. Phan ◽  
...  
Keyword(s):  
Bile Salt ◽  
Spore Germination ◽  
Dependent Manner ◽  
Germination Inhibitors ◽  
New Methods ◽  
Clostridioides Difficile ◽  
Antibiotic Associated Diarrhea ◽  
Careful Screening ◽  
Strain Dependent

Clostridioides difficile infection (CDI) is the major identifiable cause of antibiotic-associated diarrhea. The emergence of hypervirulent C. difficile strains has led to increases in both hospital- and community-acquired CDI. Furthermore, CDI relapse from hypervirulent strains can reach up to 25%. Thus, standard treatments are rendered less effective, making new methods of prevention and treatment more critical. Previously, the bile salt analog CamSA was shown to inhibit spore germination in vitro and protect mice and hamsters from C. difficile strain 630. Here, we show that CamSA was less active at preventing spore germination of other C. difficile ribotypes, including the hypervirulent strain R20291. Strain-specific in vitro germination activity of CamSA correlated with its ability to prevent CDI in mice. Additional bile salt analogs were screened for in vitro germination inhibition activity against strain R20291, and the most active compounds were tested against other strains. An aniline-substituted bile salt analog, (CaPA), was found to be a better anti-germinant than CamSA against eight different C. difficile strains. In addition, CaPA was capable of reducing, delaying, or preventing murine CDI signs in all strains tested. CaPA-treated mice showed no obvious toxicity and showed minor effects on their gut microbiome. CaPA’s efficacy was further confirmed by its ability to prevent CDI in hamsters infected with strain 630. These data suggest that C. difficile spores respond to germination inhibitors in a strain-dependent manner. However, careful screening can identify anti-germinants with broad CDI prophylaxis activity.

scholarly journals Prohormone convertases 1/3 and 2 together orchestrate the site-specific cleavages of progastrin to release gastrin-34 and gastrin-17

2008 ◽  
Vol 415 (1) ◽  
pp. 35-43 ◽  
Author(s):  
Jens F. Rehfeld ◽  
Xiaorong Zhu ◽  
Christina Norrbom ◽  
Jens R. Bundgaard ◽  
Anders H. Johnsen ◽  
...  
Keyword(s):  
Structural Factors ◽  
Cleavage Sites ◽  
Wild Type ◽  
Prohormone Convertases ◽  
Site Specific ◽  
G Cells ◽  
Processing Site ◽  
Vitro Effect

Cellular synthesis of peptide hormones requires PCs (prohormone convertases) for the endoproteolysis of prohormones. Antral G-cells synthesize the most gastrin and express PC1/3, 2 and 5/6 in the rat and human. But the cleavage sites in progastrin for each PC have not been determined. Therefore, in the present study, we measured the concentrations of progastrin, processing intermediates and α-amidated gastrins in antral extracts from PC1/3-null mice and compared the results with those in mice lacking PC2 and wild-type controls. The expression of PCs was examined by immunocytochemistry and in situ hybridization of mouse G-cells. Finally, the in vitro effect of recombinant PC5/6 on progastrin and progastrin fragments containing the relevant dibasic cleavage sites was also examined. The results showed that mouse G-cells express PC1/3, 2 and 5/6. The concentration of progastrin in PC1/3-null mice was elevated 3-fold. Chromatography showed that cleavage of the Arg36Arg37 and Arg73Arg74 sites were grossly decreased. Accordingly, the concentrations of progastrin products were markedly reduced, α-amidated gastrins (-34 and -17) being 25% of normal. Lack of PC1/3 was without effect on the third dibasic site (Lys53Lys54), which is the only processing site for PC2. Recombinant PC5/6 did not cleave any of the dibasic processing sites in progastrin and fragments containing the relevant dibasic processing sites. The complementary cleavages of PC1/3 and 2, however, suffice to explain most of the normal endoproteolysis of progastrin. Moreover, the results show that PCs react differently to the same dibasic sequences, suggesting that additional structural factors modulate the substrate specificity.

scholarly journals Production and Application of Multicistronic Constructs for Various Human Disease Therapies

Pharmaceutics ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 580 ◽  
Author(s):  
Alisa A. Shaimardanova ◽  
Kristina V. Kitaeva ◽  
Ilmira I. Abdrakhmanova ◽  
Vladislav M. Chernov ◽  
Catrin S. Rutland ◽  
...  
Keyword(s):  
Human Diseases ◽  
Cellular Biology ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
New Methods ◽  
In Vivo Experiments ◽  
Mutant Genes ◽  
Methods Of Treatment

The development of multicistronic vectors has opened up new opportunities to address the fundamental issues of molecular and cellular biology related to the need for the simultaneous delivery and joint expression of several genes. To date, the examples of the successful use of multicistronic vectors have been described for the development of new methods of treatment of various human diseases, including cardiovascular, oncological, metabolic, autoimmune, and neurodegenerative disorders. The safety and effectiveness of the joint delivery of therapeutic genes in multicistronic vectors based on the internal ribosome entry site (IRES) and self-cleaving 2A peptides have been shown in both in vitro and in vivo experiments as well as in clinical trials. Co-expression of several genes in one vector has also been used to create animal models of various inherited diseases which are caused by mutations in several genes. Multicistronic vectors provide expression of all mutant genes, which allows the most complete mimicking disease pathogenesis. This review comprehensively discusses multicistronic vectors based on IRES nucleotide sequence and self-cleaving 2A peptides, including its features and possible application for the treatment and modeling of various human diseases.

scholarly journals A simple mathematical model of skin diffusion of nerve agent VX in vitro

2020 ◽  
pp. 100137
Author(s):  
John Jenner ◽  
Christopher H. Dalton ◽  
Stuart J. Graham
Keyword(s):  
Mathematical Model ◽  
Nerve Agent ◽  
Simple Mathematical Model

scholarly journals Structural Basis of Resistant Starch (RS) in Bread: Natural and Commercial Alternatives

Foods ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 267 ◽  
Author(s):  
Laura Roman ◽  
Mario M. Martinez
Keyword(s):  
Health Outcomes ◽  
Resistant Starch ◽  
In Vitro Digestion ◽  
Postprandial Blood Glucose ◽  
Structural Basis ◽  
Structural Factors ◽  
Bread Making ◽  
Positive Health ◽  
Definition Of

Bread is categorized as having a high amount of rapidly digested starch that may result in a rapid increase in postprandial blood glucose and, therefore, poor health outcomes. This is mostly the result of the complete gelatinization that starch undergoes during baking. The inclusion of resistant starch (RS) ingredients in bread formulas is gaining prominence, especially with the current positive health outcomes attributed to RS and the apparition of novel RS ingredients in the market. However, many RS ingredients contain RS structures that do not resist baking and, therefore, are not suitable to result in a meaningful RS increase in the final product. In this review, the structural factors for the resistance to digestion and hydrothermal processing of RS ingredients are reviewed, and the definition of each RS subtype is expanded to account for novel non-digestible structures recently reported. Moreover, the current in vitro digestion methods used to measure RS content are critically discussed with a view of highlighting the importance of having a harmonized method to determine the optimum RS type and inclusion levels for bread-making.

scholarly journals Agrobiological Interactions of Essential Oils of Two Menthol Mints: Mentha piperita and Mentha arvensis

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 59 ◽  
Author(s):  
Danuta Kalemba ◽  
Agnieszka Synowiec
Keyword(s):  
Biological Activities ◽  
Review Article ◽  
Mentha Piperita ◽  
Agricultural Pest ◽  
Mentha Arvensis ◽  
Botanical Pesticides ◽  
New Methods ◽  
In Situ Experiments

This review article discusses the active constituents and potential of two menthol mint oils, Mentha piperita (MPEO) and Mentha arvensis (MAEO), as natural sources for botanical pesticides. The biological activities of these menthol mint oils, which can be useful in agriculture, have been broadly researched, especially toward phytotoxic microorganisms. To a lesser extent, the insecticidal and herbicidal activities of mint EOs have also been studied. It is apparent that the prospect of using menthol mint oils in agriculture is increasing in popularity. A number of investigations showed that the in vitro efficacy of MPEO and MAEO, as well as that of their main constituent, menthol, is pronounced. The results of in vitro research are useful for choosing EOs for further investigations. However, it is clear that in situ experiments are crucial and should be more extensively developed. At the same time, known techniques are to be applied to this area and new methods should be worked out, aiming at the improvement of EOs’ pesticidal efficacy and cost-effectiveness, for future implementation in agricultural pest control.

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