scholarly journals The transcriptome of Balamuthia mandrillaris trophozoites for structure-guided drug design

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Isabelle Q. Phan ◽  
Christopher A. Rice ◽  
Justin Craig ◽  
Rooksana E. Noorai ◽  
Jacquelyn R. McDonald ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Target Genes ◽  
Direct Sequencing ◽  
Case Fatality ◽  
Skin Lesions ◽  
Free Living ◽  
Antiparasitic Activity ◽  
Balamuthia Mandrillaris ◽  
Granulomatous Amoebic Encephalitis ◽  
The Central Nervous System

AbstractBalamuthia mandrillaris, a pathogenic free-living amoeba, causes cutaneous skin lesions as well as granulomatous amoebic encephalitis, a ‘brain-eating’ disease. As with the other known pathogenic free-living amoebas (Naegleria fowleri and Acanthamoeba species), drug discovery efforts to combat Balamuthia infections of the central nervous system are sparse; few targets have been validated or characterized at the molecular level, and little is known about the biochemical pathways necessary for parasite survival. Current treatments of encephalitis due to B. mandrillaris lack efficacy, leading to case fatality rates above 90%. Using our recently published methodology to discover potential drugs against pathogenic amoebas, we screened a collection of 85 compounds with known antiparasitic activity and identified 59 compounds that impacted the growth of Balamuthia trophozoites at concentrations below 220 µM. Since there is no fully annotated genome or proteome of B. mandrillaris, we sequenced and assembled its transcriptome from a high-throughput RNA-sequencing (RNA-Seq) experiment and located the coding sequences of the genes potentially targeted by the growth inhibitors from our compound screens. We determined the sequence of 17 of these target genes and obtained expression clones for 15 that we validated by direct sequencing. These will be used in the future in combination with the identified hits in structure guided drug discovery campaigns to develop new approaches for the treatment of Balamuthia infections.

scholarly journals The transcriptome of Balamuthia mandrillaris trophozoites for structure-based drug design

2020 ◽  
Author(s):  
Isabelle Q. Phan ◽  
Christopher A. Rice ◽  
Justin Craig ◽  
Rooksana E. Noorai ◽  
Jacquelyn McDonald ◽  
...  
Keyword(s):  
Target Genes ◽  
Direct Sequencing ◽  
Skin Lesions ◽  
Rna Seq ◽  
Structure Based Drug Design ◽  
Antiparasitic Activity ◽  
Balamuthia Mandrillaris ◽  
Granulomatous Amoebic Encephalitis ◽  
Small Pool

AbstractBalamuthia mandrillaris, a pathogenic free-living amoeba (FLA), causes cutaneous skin lesions as well as the brain-eating disease: Balamuthia granulomatous amoebic encephalitis (GAE). These diseases, and diseases caused by other pathogenic FLA, Naegleria fowleri or Acanthamoeba species, are minimally studied from a drug discovery perspective; few targets have been validated or characterized at the molecular level, and little is known about the biochemical pathways necessary for parasite survival. Chemotherapies for CNS disease caused by B. mandrillaris require vast improvement. Current therapeutics are limited to a small number of drugs that were previously discovered in the last century through in vitro testing or identified after use in the small pool of surviving reports.Using our recently published methodology to identify potentially useful therapeutics, we screened a collection of 85 compounds that have previously been reported to have antiparasitic activity. We identified 59 compounds that impacted growth at concentrations below 220 μM. Since there is no fully annotated genome or proteome, we used RNA-Seq to reconstruct the transcriptome of B. mandrillaris and locate the coding sequences of the specific genes potentially targeted by the compounds identified to inhibit trophozoite growth. We determined the sequence of 17 of these target genes and obtained expression clones for 15 that we validated by direct sequencing.

scholarly journals Increasing Importance of Balamuthia mandrillaris

2008 ◽  
Vol 21 (3) ◽  
pp. 435-448 ◽  
Author(s):  
Abdul Matin ◽  
Ruqaiyyah Siddiqui ◽  
Samantha Jayasekera ◽  
Naveed Ahmed Khan
Keyword(s):  
Case Fatality Rate ◽  
Molecular Mechanisms ◽  
Case Fatality ◽  
Protozoan Parasite ◽  
Therapeutic Interventions ◽  
Fatality Rate ◽  
Balamuthia Mandrillaris ◽  
Preventative Measures ◽  
Granulomatous Amoebic Encephalitis ◽  
The Central Nervous System

SUMMARY Balamuthia mandrillaris is an emerging protozoan parasite, an agent of granulomatous amoebic encephalitis involving the central nervous system, with a case fatality rate of >98%. This review presents our current understanding of Balamuthia infections, their pathogenesis and pathophysiology, and molecular mechanisms associated with the disease, as well as virulence traits of Balamuthia that may be potential targets for therapeutic interventions and/or for the development of preventative measures.

Balamuthia mandrillaris: A Rare Free-Living Amoeba

2015 ◽  
Vol 2 (1) ◽  
Author(s):  
Jessica Chan ◽  
Mirella Mircescu ◽  
Pratik Shah ◽  
Andrew Liguori ◽  
Aaron Shmookler
Keyword(s):  
Free Living ◽  
Balamuthia Mandrillaris ◽  
Free Living Amoeba

Brain-eating Amoebae Infection: Challenges and Opportunities in Chemotherapy

2019 ◽  
Vol 19 (12) ◽  
pp. 980-987 ◽  
Author(s):  
Mohammad Ridwane Mungroo ◽  
Ayaz Anwar ◽  
Naveed Ahmed Khan ◽  
Ruqaiyyah Siddiqui
Keyword(s):  
Mortality Rate ◽  
Free Living ◽  
Outdoor Activities ◽  
The Past ◽  
Free Living Amoeba ◽  
Challenges And Opportunities ◽  
Life Threatening ◽  
The Central Nervous System ◽  
Living Nature ◽  
Treatment And Diagnosis

Pathogenic free-living amoeba are known to cause a devastating infection of the central nervous system and are often referred to as “brain-eating amoebae”. The mortality rate of more than 90% and free-living nature of these amoebae is a cause for concern. It is distressing that the mortality rate has remained the same over the past few decades, highlighting the lack of interest by the pharmaceutical industry. With the threat of global warming and increased outdoor activities of public, there is a need for renewed interest in identifying potential anti-amoebic compounds for successful prognosis. Here, we discuss the available chemotherapeutic options and opportunities for potential strategies in the treatment and diagnosis of these life-threatening infections.

scholarly journals Precision Medicine in Neurodegenerative Diseases: Some Promising Tips Coming from the microRNAs’ World

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 75 ◽  
Author(s):  
Nicoletta Nuzziello ◽  
Loredana Ciaccia ◽  
Maria Liguori
Keyword(s):  
Neurodegenerative Diseases ◽  
Precision Medicine ◽  
Target Genes ◽  
Drug Disposition ◽  
Therapeutic Potential ◽  
Response To Treatment ◽  
Therapeutic Effects ◽  
Exciting Potential ◽  
The Central Nervous System ◽  
Effective Use

Novel insights in the development of a precision medicine approach for treating the neurodegenerative diseases (NDDs) are provided by emerging advances in the field of pharmacoepigenomics. In this context, microRNAs (miRNAs) have been extensively studied because of their implication in several disorders related to the central nervous system, as well as for their potential role as biomarkers of diagnosis, prognosis, and response to treatment. Recent studies in the field of neurodegeneration reported evidence that drug response and efficacy can be modulated by miRNA-mediated mechanisms. In fact, miRNAs seem to regulate the expression of pharmacology target genes, while approved (conventional and non-conventional) therapies can restore altered miRNAs observed in NDDs. The knowledge of miRNA pharmacoepigenomics may offers new clues to develop more effective treatments by providing novel insights into interindividual variability in drug disposition and response. Recently, the therapeutic potential of miRNAs is gaining increasing attention, and miRNA-based drugs (for cancer) have been under observation in clinical trials. However, the effective use of miRNAs as therapeutic target still needs to be investigated. Here, we report a brief review of representative studies in which miRNAs related to therapeutic effects have been investigated in NDDs, providing exciting potential prospects of miRNAs in pharmacoepigenomics and translational medicine.

Comparative analyses of different genetic markers for the detection of Acanthamoeba spp. isolates

2014 ◽  
Vol 59 (3) ◽  
Author(s):  
Monika Derda ◽  
Agnieszka Wojtkowiak-Giera ◽  
Edward Hadaś
Keyword(s):  
Genetic Markers ◽  
Tap Water ◽  
Correct Diagnosis ◽  
Specific Marker ◽  
Pcr Assay ◽  
Free Living ◽  
Detection And Identification ◽  
Granulomatous Amoebic Encephalitis ◽  
Free Living Amoeba ◽  
Treatment Of Infection

AbstractAcanthamoeba are widespread free-living amoebae which may cause granulomatous amoebic encephalitis (GAE), keratitis, skin ulcerations and disseminated tissue infection. An important diagnostic and prognostic factor for the treatment of infection is a quick and correct diagnosis of amoebae strains. The aim of our study was to develop a rapid method for detection and identification of pathogenic Acanthamoeba spp. strains from diagnostic material collected from water. In this study we analysed five amplification-based genetic markers (Aca 16S, Ac6/210, GP, JDP, Nelson) used for identification of pathogenic Acanthamoeba spp. strains isolated in water sources in Poland, Iceland and Sweden. Our results demonstrated the presence of pathogenic Acanthamoeba strains in tap water. PCR assay appeared to be a more rapid and sensitive method to detect the presence of amoebae than the limited conventional techniques. Based on our observations, we can confirm that the use of four out of five genetic markers (Aca 16S, Ac 6/210, JDP, GP, Nelson) may be helpful in identification of Acanthamoeba spp. strains, but only one Aca 16S primer pair is a highly specific marker that distinguishes between pathogenic strains of Acanthamoeba and other free-living amoeba families.

scholarly journals Regulation of Cholesterol Homeostasis by the Liver X Receptors in the Central Nervous System

2002 ◽  
Vol 16 (6) ◽  
pp. 1378-1385 ◽  
Author(s):  
Karl D. Whitney ◽  
Michael A. Watson ◽  
Jon L. Collins ◽  
William G. Benson ◽  
Tammy M. Stone ◽  
...  
Keyword(s):  
Gene Expression ◽  
Central Nervous System ◽  
Nervous System ◽  
Cholesterol Efflux ◽  
Target Genes ◽  
Cholesterol Homeostasis ◽  
Neuronal Cultures ◽  
Primary Neuronal Cultures ◽  
The Central Nervous System ◽  
Lxr Agonists

Abstract The nuclear oxysterol receptors liver X receptor-α [LXRα (NR1H3)] and LXRβ (NR1H2) coordinately regulate genes involved in cholesterol homeostasis. Although both LXR subtypes are expressed in the brain, their roles in this tissue remain largely unexplored. In this report, we show that LXR agonists have marked effects on gene expression in murine brain tissue both in vitro and in vivo. In primary astrocyte cultures, LXR agonists regulated several established LXR target genes, including ATP binding cassette transporter A1, and enhanced cholesterol efflux. In contrast, little or no effect on gene expression or cholesterol efflux was detected in primary neuronal cultures. Treatment of mice with a selective LXR agonist resulted in the induction of several LXR target genes related to cholesterol homeostasis in the cerebellum and hippocampus. These data provide the first evidence that the LXRs regulate cholesterol homeostasis in the central nervous system. Because dysregulation of cholesterol balance is implicated in central nervous system diseases such as Alzheimer’s and Niemann-Pick disease, pharmacological manipulation of the LXRs may prove beneficial in the treatment of these disorders.

Experimental modeling and clinical technology of photodynamic therapy

2020 ◽  
pp. 72-80
Author(s):  
Daria Aleksandrovna Krapivnitskaya ◽  
Kseniya Vyacheslavovna Kuznetsova ◽  
Igor Valentinovich Barskov ◽  
Vladimir Germanovich Taktarov ◽  
Vladimir Yurievich Pereverzev
Keyword(s):  
Central Nervous System ◽  
Photodynamic Therapy ◽  
Large Scale ◽  
Clinical Medicine ◽  
Practical Importance ◽  
Skin Lesions ◽  
Clinical Aspects ◽  
Regenerative Processes ◽  
Ischemic Tissue ◽  
The Central Nervous System

In recent years, the amount of large-scale experimental and clinical studies has increased considerably leading to the development of techniques and their widespread use both in their field and serving as a basis for the combination of even paradoxically incompatible areas of experimental and clinical medicine. The authors consider one of the main objectives of this work to identify a stable correlation between experimental pathomorphological study in ischemic tissue lesion and a therapeutic effect in dermatology in various pathological processes since the fundamental method in both cases is represented by a photochemical effect on the central nervous system and skin. These studies are not only of theoretical value but also of great practical importance both for neurological (search for medicines used to stimulate regenerative processes in ischemic pathology) and dermatological clinical aspects (ablation method of photodynamic therapy for various skin lesions).

Blastomycosis

2020 ◽  
Vol 41 (01) ◽  
pp. 031-041 ◽  
Author(s):  
Ilan S. Schwartz ◽  
Carol A. Kauffman
Keyword(s):  
North America ◽  
Amphotericin B ◽  
Skin Lesions ◽  
Primary Therapy ◽  
Temperature Dependent ◽  
Dimorphic Fungi ◽  
Disseminated Infection ◽  
The Central Nervous System ◽  
Yeast Phase ◽  
Tentative Diagnosis

AbstractBlastomycosis is a serious fungal disease of humans and other mammals caused by environmentally acquired infection with geographically restricted, thermally dimorphic fungi belonging to the genus Blastomyces. The genetic and geographic diversity of these pathogens is greater than previously appreciated. In addition to Blastomyces dermatitidis and the cryptic species Blastomyces gilchristii, which cause blastomycosis in mid-western and various eastern areas of North America, atypical blastomycosis is occasionally caused by Blastomyces helicus in western parts of North America and Blastomyces percursus in Africa. Blastomycosis is acquired by inhalation of the conidia that are produced in the mold phase; in the lungs, temperature-dependent transformation occurs to the yeast phase. In this form, the organism is phagocytized by macrophages and can spread hematogenously to various organs causing disseminated infection. Pulmonary disease is most common and varies from mild, self-limited infection to severe, potentially fatal adult respiratory distress syndrome. Disseminated infection is manifested primarily by skin lesions, but many other organs can be involved. Diagnosis is established by growth of the organism in culture; however, a tentative diagnosis can be made quickly by histopathological identification of the classic yeast form in tissues or by finding Blastomyces antigen in urine or serum. Blastomycosis is treated initially with amphotericin B when the disease is severe, involves the central nervous system, or the host is immunosuppressed. Itraconazole is recommended for primary therapy in mild-to-moderate infection and for step-down therapy after initial amphotericin B treatment. Voriconazole and posaconazole can be used for patients in whom itraconazole is not tolerated.

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