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Histone deacetylase enzymes as potential drug targets of Neglected Tropical Diseases caused by cestodes.

ABSTRACT: Cestode parasites cause neglected diseases, such as echinococcosis and cysticercosis, which represent a significant problem in human and animal health. Benzimidazoles and praziquantel are the only available drugs for chemotherapy and it is therefore important to identify new alternative drugs against cestode parasites. Histone deacetylases (HDACs) are validated drug targets for the treatment of cancer and other diseases, including neglected diseases. However, knowledge of HDACs in cestodes is very scarce. In this work, we investigated cestode HDACs as potential drug targets to develop new therapies against neglected diseases caused by cestodes. Here we showed the full repertoire of HDAC coding genes in several members of the class Cestoda. Between 6 and 7 zinc-dependent HDAC coding genes were identified in the genomes of species from Echinococcus, Taenia, Mesocestoides and Hymenolepis genera. We classified them as Class I and II HDACs and analyzed their transcriptional expression levels throughout developmental stages of Echinococcus spp. We confirmed for the first time the complete HDAC8 nucleotide sequences from Echinococcus canadensis G7 and Mesocestoides corti. Homology models for these proteins showed particular structural features which differentiate them from HDAC8 from Homo sapiens. Furthermore, we showed that Trichostatin A (TSA), a pan-HDAC inhibitor, decreases the viability of M. corti, alters its tegument and morphology and produces an increment of the total amount of acetylated proteins, including acetylated histone H4. These results suggest that HDAC from cestodes are functional and might play important roles on survival and development. The particular structural features observed in cestode HDAC8 proteins suggest that these enzymes could be selectively targeted. This report provides the basis for further studies on cestode HDAC enzymes and for discovery of new HDAC inhibitors for the treatment of neglected diseases caused by cestode parasites.

SUBMITTER: Vaca HR

PROVIDER: S-EPMC6426703 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Histone deacetylase enzymes as potential drug targets of Neglected Tropical Diseases caused by cestodes.

Vaca Hugo R HR Celentano Ana M AM Macchiaroli Natalia N Kamenetzky Laura L Camicia Federico F Rosenzvit Mara C MC

International journal for parasitology. Drugs and drug resistance 20190223

Cestode parasites cause neglected diseases, such as echinococcosis and cysticercosis, which represent a significant problem in human and animal health. Benzimidazoles and praziquantel are the only available drugs for chemotherapy and it is therefore important to identify new alternative drugs against cestode parasites. Histone deacetylases (HDACs) are validated drug targets for the treatment of cancer and other diseases, including neglected diseases. However, knowledge of HDACs in cestodes is ve ...[more]

PMID: 30897528

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Project description:BackgroundSubcutaneous (deep) mycoses are a chronic infectious disease of the skin and underlying structures endemic in tropical countries. The disease has serious medical and socioeconomic consequences for patients, communities and health services in endemic areas. The inclusion of mycetoma and other subcutaneous mycoses in the list of Neglected Tropical Diseases by WHO highlights the need to assess the burden of these diseases and establish control programs where necessary. In Ethiopia no strategies can be devised because of a lack of epidemiologic information. To address this evidence gap, we performed a national rapid assessment of the geographic distribution of subcutaneous mycoses.MethodologyWe conducted a rapid retrospective assessment using hospital records to identify all suspected and confirmed cases of subcutaneous mycoses in 13 referral hospitals across the country between 2015 and 2022. In each hospital the logbooks were reviewed for diagnoses of subcutaneous mycosess, as diagnosed per routine practice. Descriptive analysis was done.ResultFrom 13 hospitals we extracted 143 cases of subcutaneous mycoses, registered from July 2018 to September 2022. 118 (82.5%) patients were diagnosed as mycetoma, 21 (14.7%) as chromoblastomycosis and the remaining 4 (2.8%) as sporotrichosis. The mean age of patients was 35.8 years (SD = 14.5). 101 (70.6%) patients were male and 96 (67.1%) patients were farmers. 64 (44.8%) cases were from the Tigray regional state. 56 (65.9%) patients had information on diagnostic microscopic evaluation: for mycetoma histopathologic evaluation and fine needle aspiration cytology had a higher positivity rate while for chromoblastomycosis potassium hydroxide (KOH) staining had a better yield. The main clinical presentations were nodules, sinuses and infiltrative plaques on the skin. Radiologic findings of bone involvement was present in some.ConclusionsMycetoma and other subcutaneous mycoses are endemic in Ethiopia, with cases reported from almost all regions with the highest cases numbers reported from the northern part of the country. A routine program and systems should be developed to identify and document the burden of subcutaneous fungal infections in the country. Diagnosis and treatment guidelines should be developed.

Project description:BackgroundThe World Health Organization's (WHO) Neglected Tropical Disease (NTD) Road Map for 2021-2030 was recently endorsed by all member states at the World Health Assembly in November 2020. Although only 3 of the 20 NTDs are endemic in Canada (i.e., echinococcosis, rabies, and scabies), the Canadian research community has contributed to advancing the knowledge base of all 20 NTDs. Previous research comprehensively detailed Canadian research on 11 NTDs between 1950 and 2010 using a network analysis approach. The specific objective of the present analysis was to update the publication record over the last decade (2010-2019) to include all 20 NTDs.Materials and methodsA bibliometric analysis was conducted in Scopus and Web of Science databases (for English or French articles published between January 1, 2010 and December 31, 2019) using appropriate search terms for each of the 20 NTDs and where at least 1 of the authors had a Canadian institution address. A 21st search was added to include publications including multiple NTDs or a discussion of NTDs in general. Following assessment of inclusion and exclusion criteria, 2 reviewers independently screened all abstracts, with discordant observations rereviewed to arrive at an agreement. Duplicates were removed.ResultsA total of 1,790 publications were retrieved (1,738 with a disease-specific NTD focus and 52 with a general NTD focus, resulting in 1,659 unique publications), giving an average of over 160 articles per year. Over 80% were classified as full-length research articles. The top 3 journals in terms of frequency were PLOS Neglected Tropical Diseases, PLOS ONE, and the American Journal of Tropical Medicine and Hygiene. Authors' institutions were from all Canadian provinces. While all 20 NTDs were addressed in these publications, the 5 most commonly studied were leishmaniasis, dengue fever and chikungunya, Chagas disease, soil-transmitted helminthiases, and rabies.ConclusionsCanadian researchers across the country have contributed to the evidence base of all 20 NTDs, publishing an average of over 160 publications per year between 2010 and 2019. As WHO NTD Road Map 2021-2030 rolls out globally, the Canadian research community, in collaboration with its partners and in solidarity with people living in vulnerable circumstances in endemic regions worldwide, is well positioned to meet future research challenges so that the goal of eliminating the disease burden attributable to NTDs can be achieved.

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Histone deacetylase enzymes as potential drug targets of Neglected Tropical Diseases caused by cestodes.

Publications

Histone deacetylase enzymes as potential drug targets of Neglected Tropical Diseases caused by cestodes.

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