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Article ; Online: Updated knowledge and a proposed nomenclature for nuclear receptors with two DNA binding domains (2DBD-NRs).

Wu, Wenjie / LoVerde, Philip T

2023 Volume 18, Issue 9, Page(s) e0286107

Abstract: Nuclear receptors (NRs) are important transcriptional modulators in metazoans. Typical NRs possess a conserved DNA binding domain (DBD) and a ligand binding domain (LBD). Since we discovered a type of novel NRs each of them has two DBDs and single LBD ( ... ...

Abstract	Nuclear receptors (NRs) are important transcriptional modulators in metazoans. Typical NRs possess a conserved DNA binding domain (DBD) and a ligand binding domain (LBD). Since we discovered a type of novel NRs each of them has two DBDs and single LBD (2DBD-NRs) more than decade ago, there has been very few studies about 2DBD-NRs. Recently, 2DBD-NRs have been only reported in Platyhelminths and Mollusca and are thought to be specific NRs to lophotrochozoan. In this study, we searched different databases and identified 2DBD-NRs in different animals from both protostomes and deuterostomes. Phylogenetic analysis shows that at least two ancient 2DBD-NR genes were present in the urbilaterian, a common ancestor of protostomes and deuterostomes. 2DBD-NRs underwent gene duplication and loss after the split of different animal phyla, most of them in a certain animal phylum are paralogues, rather than orthologues, like in other animal phyla. Amino acid sequence analysis shows that the conserved motifs in typical NRs are also present in 2DBD-NRs and they are gene specific. From our phylogenetic analysis of 2DBD-NRs and following the rule of Nomenclature System for the Nuclear Receptors, a nomenclature for 2DBD-NRs is proposed.
MeSH term(s)	Animals ; Phylogeny ; Databases, Factual ; Gene Duplication ; Receptors, Cytoplasmic and Nuclear/genetics ; DNA
Chemical Substances	Receptors, Cytoplasmic and Nuclear ; DNA (9007-49-2)
Language	English
Publishing date	2023-09-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0286107
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Article: Schistosomiasis.

LoVerde, Philip T

Advances in experimental medicine and biology

2019 Volume 1154, Page(s) 45–70

Abstract: Schistosomiasis is a major cause of morbidity in the world; it is second only to malaria as a major infectious disease. Globally, it is estimated that the disease affects over 250 million people in 78 countries of the world and is responsible for some ... ...

Abstract	Schistosomiasis is a major cause of morbidity in the world; it is second only to malaria as a major infectious disease. Globally, it is estimated that the disease affects over 250 million people in 78 countries of the world and is responsible for some 280,000 deaths each year. The three major schistosomes infecting humans are Schistosoma mansoni, S. japonicum, and S. haematobium. This chapter covers a wide range of aspects of schistosomiasis, including basic biology of the parasites, epidemiology, immunopathology, treatment, control, vaccines, and genomics/proteomics. In this chapter, the reader will understand the significant toll this disease takes in terms of mortality and morbidity. A description of the various life stages of schistosomes is presented, which will be informative for both those unfamiliar with the disease and experienced scientists. Clinical and public health aspects are addressed that cover acute and chronic disease, diagnosis, current treatment regimens and alternative drugs, and schistosomiasis control programs. A brief overview of genomics and proteomics is included that details recent advances in the field that will help scientists investigate the molecular biology of schistosomes. The reader will take away an appreciation for general aspects of schistosomiasis and research advances.
MeSH term(s)	Animals ; Humans ; Research/trends ; Schistosoma/physiology ; Schistosomiasis/drug therapy ; Schistosomiasis/parasitology ; Schistosomiasis/pathology ; Schistosomiasis/prevention & control
Language	English
Publishing date	2019-07-11
Publishing country	United States
Document type	Journal Article
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-030-18616-6_3
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Article ; Online: The effect of fs800 on female egg production in Schistosoma mansoni.

Alwan, Sevan N / LoVerde, Philip T

Molecular and biochemical parasitology

2021 Volume 245, Page(s) 111412

Abstract: During schistosomiasis, the paired Schistosoma mansoni female produces about 300 eggs each day. These eggs are responsible for the clinical picture and the transmission of the disease. During female development and egg production, fs800 is expressed only ...

Abstract	During schistosomiasis, the paired Schistosoma mansoni female produces about 300 eggs each day. These eggs are responsible for the clinical picture and the transmission of the disease. During female development and egg production, fs800 is expressed only in female vitelline cells. Blast search of fs800 did not show similarities with any published sequences by NCBI. We hypothesize that the product of this gene plays a role in S. mansoni egg production. By using RNA interference to knockdown fs800 and quantitative PCR to measure the gene expression in the female schistosomes, we were able to demonstrate that fs800 product is crucial for viable egg production, it has no effect on worm health or male-female pairing. Our data suggest fs800 inhibition as a potential target to prevent transmission and pathology of schistosomiasis.
MeSH term(s)	Animals ; Female ; Gene Expression ; Male ; Schistosoma mansoni/genetics ; Schistosomiasis ; Schistosomiasis mansoni
Language	English
Publishing date	2021-09-04
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	756166-0
ISSN	1872-9428 ; 0166-6851
ISSN (online)	1872-9428
ISSN	0166-6851
DOI	10.1016/j.molbiopara.2021.111412
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Article ; Online: Identification and evolution of nuclear receptors in Platyhelminths.

Wu, Wenjie / LoVerde, Philip T

PloS one

2021 Volume 16, Issue 8, Page(s) e0250750

Abstract: Since the first complete set of Platyhelminth nuclear receptors (NRs) from Schistosoma mansoni were identified a decade ago, more flatworm genome data is available to identify their NR complement and to analyze the evolutionary relationship of ... ...

Abstract	Since the first complete set of Platyhelminth nuclear receptors (NRs) from Schistosoma mansoni were identified a decade ago, more flatworm genome data is available to identify their NR complement and to analyze the evolutionary relationship of Platyhelminth NRs. NRs are important transcriptional modulators that regulate development, differentiation and reproduction of animals. In this study, NRs are identified in genome databases of thirty-three species including in all Platyhelminth classes (Rhabditophora, Monogenea, Cestoda and Trematoda). Phylogenetic analysis shows that NRs in Platyhelminths follow two different evolutionary lineages: 1) NRs in a free-living freshwater flatworm (Schmidtea mediterranea) and all parasitic flatworms share the same evolutionary lineage with extensive gene loss. 2) NRs in a free-living intertidal zone flatworm (Macrostomum lignano) follow a different evolutionary lineage with a feature of multiple gene duplication and gene divergence. The DNA binding domain (DBD) is the most conserved region in NRs which contains two C4-type zinc finger motifs. A novel zinc finger motif is identified in parasitic flatworm NRs: the second zinc finger of parasitic Platyhelminth HR96b possesses a CHC2 motif which is not found in NRs of all other animals studied to date. In this study, novel NRs (members of NR subfamily 3 and 6) are identified in flatworms, this result demonstrates that members of all six classical NR subfamilies are present in the Platyhelminth phylum. NR gene duplication, loss and divergence in Platyhelminths are analyzed along with the evolutionary relationship of Platyhelminth NRs.
MeSH term(s)	Animals ; Evolution, Molecular ; Gene Duplication ; Phylogeny ; Platyhelminths/genetics ; Receptors, Cytoplasmic and Nuclear/genetics ; Zinc Fingers
Chemical Substances	Receptors, Cytoplasmic and Nuclear
Language	English
Publishing date	2021-08-13
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0250750
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Article ; Online: Identification and evolution of nuclear receptors in Platyhelminths.

Wenjie Wu / Philip T LoVerde

PLoS ONE, Vol 16, Iss 8, p e

2021 Volume 0250750

Abstract	Since the first complete set of Platyhelminth nuclear receptors (NRs) from Schistosoma mansoni were identified a decade ago, more flatworm genome data is available to identify their NR complement and to analyze the evolutionary relationship of Platyhelminth NRs. NRs are important transcriptional modulators that regulate development, differentiation and reproduction of animals. In this study, NRs are identified in genome databases of thirty-three species including in all Platyhelminth classes (Rhabditophora, Monogenea, Cestoda and Trematoda). Phylogenetic analysis shows that NRs in Platyhelminths follow two different evolutionary lineages: 1) NRs in a free-living freshwater flatworm (Schmidtea mediterranea) and all parasitic flatworms share the same evolutionary lineage with extensive gene loss. 2) NRs in a free-living intertidal zone flatworm (Macrostomum lignano) follow a different evolutionary lineage with a feature of multiple gene duplication and gene divergence. The DNA binding domain (DBD) is the most conserved region in NRs which contains two C4-type zinc finger motifs. A novel zinc finger motif is identified in parasitic flatworm NRs: the second zinc finger of parasitic Platyhelminth HR96b possesses a CHC2 motif which is not found in NRs of all other animals studied to date. In this study, novel NRs (members of NR subfamily 3 and 6) are identified in flatworms, this result demonstrates that members of all six classical NR subfamilies are present in the Platyhelminth phylum. NR gene duplication, loss and divergence in Platyhelminths are analyzed along with the evolutionary relationship of Platyhelminth NRs.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Addressing the oxamniquine in vitro-in vivo paradox to facilitate a new generation of anti-schistosome treatments.

Toth, Katalin / Alwan, Sevan / Khan, Susan / McHardy, Stanton F / LoVerde, Philip T / Cameron, Michael D

International journal for parasitology. Drugs and drug resistance

2023 Volume 21, Page(s) 65–73

Abstract: The antischistosomal drug oxamniquine, OXA, requires activation by a sulfotransferase within the parasitic worm to enable killing. Examination of the pharmacokinetic/pharmacodynamic (PK/PD) relationship for OXA identified an in vitro-in vivo paradox with ...

Abstract	The antischistosomal drug oxamniquine, OXA, requires activation by a sulfotransferase within the parasitic worm to enable killing. Examination of the pharmacokinetic/pharmacodynamic (PK/PD) relationship for OXA identified an in vitro-in vivo paradox with the maximal clinical plasma concentrations five-to ten-times lower than the efficacious concentration for in vitro schistosomal killing. The parasite resides in the vasculature between the intestine and the liver, and modeling the PK data to determine portal concentrations fits with in vitro studies and explains the required human dose. In silico models were used to predict murine dosing to recapitulate human conditions for OXA portal concentration and time course. Follow-up PK studies verified in mice that a 50-100 mg/kg oral gavage dose of OXA formulated in acetate buffer recapitulates the 20-40 mg/kg dose common in patients. OXA was rapidly cleared through a combination of metabolism and excretion into bile. OXA absorbance and tissue distribution were similar in wild-type and P-gp efflux transporter knockout mice. The incorporation of in vitro efficacy data and portal concentration was demonstrated for an improved OXA-inspired analog that has been shown to kill S. mansoni, S. haematobium, and S. japonicum, whereas OXA is only effective against S. mansoni. Second-generation OXA analogs should optimize both in vitro killing and physiochemical properties to achieve high portal concentration via rapid oral absorption, facilitated by favorable solubility, permeability, and minimal intestinal metabolism.
MeSH term(s)	Humans ; Mice ; Animals ; Oxamniquine/pharmacology ; Schistosoma ; Schistosomicides/pharmacology ; Schistosoma mansoni
Chemical Substances	Oxamniquine (0O977R722D) ; Schistosomicides
Language	English
Publishing date	2023-01-30
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2751132-7
ISSN	2211-3207 ; 2211-3207
ISSN (online)	2211-3207
ISSN	2211-3207
DOI	10.1016/j.ijpddr.2023.01.003
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Article ; Online: Oxamniquine derivatives overcome Praziquantel treatment limitations for Schistosomiasis.

Alwan, Sevan N / Taylor, Alexander B / Rhodes, Jayce / Tidwell, Michael / McHardy, Stanton F / LoVerde, Philip T

PLoS pathogens

2023 Volume 19, Issue 7, Page(s) e1011018

Abstract: Human schistosomiasis is a neglected tropical disease caused by Schistosoma mansoni, S. haematobium, and S. japonicum. Praziquantel (PZQ) is the method of choice for treatment. Due to constant selection pressure, there is an urgent need for new therapies ...

Abstract	Human schistosomiasis is a neglected tropical disease caused by Schistosoma mansoni, S. haematobium, and S. japonicum. Praziquantel (PZQ) is the method of choice for treatment. Due to constant selection pressure, there is an urgent need for new therapies for schistosomiasis. Previous treatment of S. mansoni included the use of oxamniquine (OXA), a drug that is activated by a schistosome sulfotransferase (SULT). Guided by data from X-ray crystallography and Schistosoma killing assays more than 350 OXA derivatives were designed, synthesized, and tested. We were able to identify CIDD-0150610 and CIDD-0150303 as potent derivatives in vitro that kill (100%) of all three Schistosoma species at a final concentration of 71.5 μM. We evaluated the efficacy of the best OXA derivates in an in vivo model after treatment with a single dose of 100 mg/kg by oral gavage. The highest rate of worm burden reduction was achieved by CIDD -150303 (81.8%) against S. mansoni, CIDD-0149830 (80.2%) against S. haematobium and CIDD-066790 (86.7%) against S. japonicum. We have also evaluated the ability of the derivatives to kill immature stages since PZQ does not kill immature schistosomes. CIDD-0150303 demonstrated (100%) killing for all life stages at a final concentration of 143 μM in vitro and effective reduction in worm burden in vivo against S. mansoni. To understand how OXA derivatives fit in the SULT binding pocket, X-ray crystal structures of CIDD-0150303 and CIDD-0150610 demonstrate that the SULT active site will accommodate further modifications to our most active compounds as we fine tune them to increase favorable pharmacokinetic properties. Treatment with a single dose of 100 mg/kg by oral gavage with co-dose of PZQ + CIDD-0150303 reduced the worm burden of PZQ resistant parasites in an animal model by 90.8%. Therefore, we conclude that CIDD-0150303, CIDD-0149830 and CIDD-066790 are novel drugs that overcome some of PZQ limitations, and CIDD-0150303 can be used with PZQ in combination therapy.
MeSH term(s)	Animals ; Humans ; Praziquantel/pharmacology ; Praziquantel/chemistry ; Oxamniquine/pharmacology ; Schistosomiasis/drug therapy ; Schistosomiasis/parasitology ; Schistosoma mansoni ; Combined Modality Therapy ; Neglected Diseases/drug therapy ; Schistosomiasis mansoni/drug therapy ; Schistosomiasis mansoni/parasitology ; Anthelmintics
Chemical Substances	Praziquantel (6490C9U457) ; Oxamniquine (0O977R722D) ; Anthelmintics
Language	English
Publishing date	2023-07-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011018
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Article ; Online: Corrigendum to "Rational approach to drug discovery for human schistosomiasis" [Int. J. Parasitol. Drugs Drug Resist. 16 (2021) 140-147].

LoVerde, Philip T / Alwan, Sevan N / Taylor, Alexander B / Rhodes, Jayce / Chevalier, Frédéric D / Anderson, Timothy Jc / McHardy, Stanton F

International journal for parasitology. Drugs and drug resistance

2022 Volume 18, Page(s) 103

Language	English
Publishing date	2022-01-19
Publishing country	Netherlands
Document type	Published Erratum
ZDB-ID	2751132-7
ISSN	2211-3207 ; 2211-3207
ISSN (online)	2211-3207
ISSN	2211-3207
DOI	10.1016/j.ijpddr.2022.01.003
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Article: The effect of fs800 on female egg production in Schistosoma mansoni

Alwan, Sevan N. / LoVerde, Philip T.

Molecular and biochemical parasitology. 2021 Sept., v. 245

2021

Abstract	During schistosomiasis, the paired Schistosoma mansoni female produces about 300 eggs each day. These eggs are responsible for the clinical picture and the transmission of the disease. During female development and egg production, fs800 is expressed only in female vitelline cells. Blast search of fs800 did not show similarities with any published sequences by NCBI. We hypothesize that the product of this gene plays a role in S. mansoni egg production. By using RNA interference to knockdown fs800 and quantitative PCR to measure the gene expression in the female schistosomes, we were able to demonstrate that fs800 product is crucial for viable egg production, it has no effect on worm health or male-female pairing. Our data suggest fs800 inhibition as a potential target to prevent transmission and pathology of schistosomiasis.
Keywords	RNA interference ; Schistosoma mansoni ; egg production ; females ; gene expression ; genes ; parasitology ; quantitative polymerase chain reaction ; schistosomiasis
Language	English
Dates of publication	2021-09
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	756166-0
ISSN	1872-9428 ; 0166-6851
ISSN (online)	1872-9428
ISSN	0166-6851
DOI	10.1016/j.molbiopara.2021.111412
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Nuclear hormone receptors in parasitic Platyhelminths.

Wu, Wenjie / LoVerde, Philip T

Molecular and biochemical parasitology

2019 Volume 233, Page(s) 111218

Abstract: Nuclear receptors (NRs) belong to a large protein superfamily which includes intracellular receptors for secreted hydrophobic signal molecules, such as steroid hormones and thyroid hormones. They regulate development and reproduction in metazoans by ... ...

Abstract	Nuclear receptors (NRs) belong to a large protein superfamily which includes intracellular receptors for secreted hydrophobic signal molecules, such as steroid hormones and thyroid hormones. They regulate development and reproduction in metazoans by binding to the promoter region of their target gene to activate or repress mRNA synthesis. Isolation and characterization of NRs in the parasitic trematode Schistosoma mansoni identified two homologues of mammalian thyroid receptor (TR). This was the first known protostome exhibiting TR homologues. Three novel NRs each possess a novel set of two DNA binding domains (DBD) in tandem with a ligand binding domain (LBD) (2DBD-NRs) isolated in Schistosoma mansoni revealed a novel NR modular structure: A/B-DBD-DBD-hinge-LBD. Full length cDNA of several NRs have been isolated and studied in the parasitic trematodes S. mansoni, S. japonicum and in the cestode Echinococcus multilocularis. The genome of the blood flukes S. mansoni, S. japonicum and S. haematobium, the liver fluke Clonorchis sinensis and the cestode Echinococcus multilocularis have been sequenced. Study of the NR complement in parasitic Platyhelminths will help us to understand the role of NRs in regulation of their development and understand the evolution of NR in animals.
MeSH term(s)	Animals ; Clonorchis sinensis/metabolism ; Echinococcus multilocularis/metabolism ; Evolution, Molecular ; Helminth Proteins/genetics ; Phylogeny ; Platyhelminths/metabolism ; Receptors, Cytoplasmic and Nuclear/chemistry ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/metabolism ; Schistosoma/metabolism ; Schistosoma mansoni/metabolism
Chemical Substances	Helminth Proteins ; Receptors, Cytoplasmic and Nuclear
Language	English
Publishing date	2019-08-27
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	756166-0
ISSN	1872-9428 ; 0166-6851
ISSN (online)	1872-9428
ISSN	0166-6851
DOI	10.1016/j.molbiopara.2019.111218
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