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      Diethylcarbamazine elicits Ca 2+ signals through TRP-2 channels that are potentiated by emodepside in Brugia malayi muscles

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          ABSTRACT

          Filarial nematode infections are a major health concern in several countries. Lymphatic filariasis is caused by Wuchereria bancrofti and Brugia spp. affecting over 120 million people. Heavy infections can lead to elephantiasis, which has serious effects on individuals’ lives. Although current anthelmintics are effective at killing microfilariae in the bloodstream, they have little to no effect against adult parasites found in the lymphatic system. The anthelmintic diethylcarbamazine is one of the central pillars of lymphatic filariasis control. Recent studies have reported that diethylcarbamazine can open transient receptor potential (TRP) channels in the muscles of adult female Brugia malayi, leading to contraction and paralysis. Diethylcarbamazine has synergistic effects in combination with emodepside on Brugia, inhibiting motility: emodepside is an anthelmintic that has effects on filarial nematodes and is under trial for the treatment of river blindness. Here, we have studied the effects of diethylcarbamazine on single Brugia muscle cells by measuring the change in Ca 2+ fluorescence in the muscle using Ca 2+-imaging techniques. Diethylcarbamazine interacts with the transient receptor potential channel, C classification (TRPC) ortholog receptor TRP-2 to promote Ca 2+ entry into the Brugia muscle cells, which can activate Slopoke (SLO-1) Ca 2+-activated K + channels, the putative target of emodepside. A combination of diethylcarbamazine and emodepside leads to a bigger Ca 2+ signal than when either compound is applied alone. Our study shows that diethylcarbamazine targets TRP channels to promote Ca 2+ entry that is increased by emodepside activation of SLO-1 K + channels.

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          A new mathematical model for relative quantification in real-time RT-PCR.

          M. Pfaffl (2001)
          Use of the real-time polymerase chain reaction (PCR) to amplify cDNA products reverse transcribed from mRNA is on the way to becoming a routine tool in molecular biology to study low abundance gene expression. Real-time PCR is easy to perform, provides the necessary accuracy and produces reliable as well as rapid quantification results. But accurate quantification of nucleic acids requires a reproducible methodology and an adequate mathematical model for data analysis. This study enters into the particular topics of the relative quantification in real-time RT-PCR of a target gene transcript in comparison to a reference gene transcript. Therefore, a new mathematical model is presented. The relative expression ratio is calculated only from the real-time PCR efficiencies and the crossing point deviation of an unknown sample versus a control. This model needs no calibration curve. Control levels were included in the model to standardise each reaction run with respect to RNA integrity, sample loading and inter-PCR variations. High accuracy and reproducibility (<2.5% variation) were reached in LightCycler PCR using the established mathematical model.
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            2-aminoethoxydiphenyl borate (2-APB) is a reliable blocker of store-operated Ca2+ entry but an inconsistent inhibitor of InsP3-induced Ca2+ release.

            Since its introduction to Ca2+ signaling in 1997, 2-aminoethoxydiphenyl borate (2-APB) has been used in many studies to probe for the involvement of inositol 1,4,5-trisphosphate receptors in the generation of Ca2+ signals. Due to reports of some nonspecific actions of 2-APB, and the fact that its principal antagonistic effect is on Ca2+ entry rather than Ca2+ release, this compound may not have the utility first suggested. However, 2-APB has thrown up some interesting results, particularly with respect to store-operated Ca2+ entry in nonexcitable cells. These data indicate that although it must be used with caution, 2-APB can be useful in probing certain aspects of Ca2+ signaling.
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              Mode of action of benzimidazoles.

              Benzimidazoles represent the only class of truly broad-spectrum anthelmintics, however, they also show activity against fungi and mammalian cells. This raises the question as to why benzimidazoles can selectively kill helminths and yet exhibit little or no mammalian toxicity. In this paper, Ernest Lacey examines this example of selectivity of drug action to the ubiquitous target of these drugs, the structural protein, tubulin.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review and editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review and editing
                Role: InvestigationRole: MethodologyRole: SoftwareRole: SupervisionRole: VisualizationRole: Writing – review and editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review and editing
                Role: Editor
                Journal
                Antimicrob Agents Chemother
                Antimicrob Agents Chemother
                aac
                Antimicrobial Agents and Chemotherapy
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                0066-4804
                1098-6596
                October 2023
                20 September 2023
                20 September 2023
                : 67
                : 10
                : e00419-23
                Affiliations
                [1 ] Department of Biomedical Sciences, Iowa State University; , Ames, Iowa, USA
                The Children's Hospital of Philadelphia; , Philadelphia, Pennsylvania, USA
                Author notes
                Address correspondence to Richard J. Martin, rjmartin@ 123456iastate.edu

                The authors declare no conflict of interest.

                Author information
                https://orcid.org/0000-0002-1056-5334
                https://orcid.org/0000-0003-2422-1847
                Article
                00419-23 aac.00419-23
                10.1128/aac.00419-23
                10583680
                37728916
                afe71b15-d261-494f-a32b-18869eaa8d0e
                Copyright © 2023 Williams et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 10 April 2023
                : 03 July 2023
                Page count
                supplementary-material: 3, authors: 4, Figures: 7, References: 40, Pages: 16, Words: 7583
                Funding
                Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID);
                Award ID: R01AI047194
                Award Recipient :
                Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID);
                Award ID: R01AI155413
                Award Recipient :
                Funded by: E. A. Benbrook Foundataion for Pathology and Parasitology;
                Award ID: Direct
                Award Recipient :
                Categories
                Mechanisms of Action: Physiological Effects
                antimicrobial-chemotherapy, Antimicrobial Chemotherapy
                Custom metadata
                October 2023

                Infectious disease & Microbiology
                diethylcarbamazine,emodepside,brugia malayi,calcium signaling,fluo-4,muscle,trp,trp-2,lymphatic filariasis,anthelmintic

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