scholarly journals Characterization of the phototoxicity, chemigenetic profile, and mutational signatures of the chemotherapeutic CX-5461 in Caenorhabditis elegans

2019 ◽  
Author(s):  
Frank B. Ye ◽  
Akil Hamza ◽  
Tejomayee Singh ◽  
Stephane Flibotte ◽  
Philip Hieter ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Cancer Therapeutics ◽  
Copy Number Variations ◽  
Factors Affecting ◽  
C Elegans ◽  
Dna Damaging Agents ◽  
Wide Range ◽  
Anti Cancer ◽  
Exogenous Factors

ABSTRACTNew anti-cancer therapeutics require extensive in vivo characterization to identify endogenous and exogenous factors affecting efficacy, to measure toxicity and mutagenicity, and to determine genotypes resulting in therapeutic sensitivity or resistance. We used Caenorhabditis elegans as a platform with which to characterize properties of anti-cancer therapeutic agents in vivo. We generated a map of chemigenetic interactions between DNA damage response mutants and common DNA damaging agents. We used this map to investigate the properties of the new anti-cancer therapeutic CX-5461. We phenocopied the photoreactivity observed in CX-5461 clinical trials and found that CX-5461 generates reactive oxygen species when exposed to UVA radiation. We demonstrated that CX-5461 is a mutator, resulting in both large copy number variations and a high frequency of single nucleotide variations (SNVs). CX-5461-induced SNVs exhibited a distinct mutational signature. Consistent with the wide range of CX-5461-induced mutation types, we found that multiple repair pathways were needed for CX-5461 tolerance. Together, the data from C. elegans demonstrate that CX-5461 is a multimodal DNA damaging agent with strong similarity to ellipticines, a class of antineoplastic agents, and to anthracycline-based chemotherapeutics.

scholarly journals A Multimodal Genotoxic Anticancer Drug Characterized by Pharmacogenetic Analysis in Caenorhabditis elegans

Genetics ◽  
2020 ◽  
Vol 215 (3) ◽  
pp. 609-621
Author(s):  
Frank B. Ye ◽  
Akil Hamza ◽  
Tejomayee Singh ◽  
Stephane Flibotte ◽  
Philip Hieter ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Excision Repair ◽  
Copy Number Variations ◽  
Induced Mutations ◽  
End Joining ◽  
Factors Affecting ◽  
C Elegans ◽  
Homology Directed Repair ◽  
Dna Replication And Repair

New anticancer therapeutics require extensive in vivo characterization to identify endogenous and exogenous factors affecting efficacy, to measure toxicity and mutagenicity, and to determine genotypes that result in therapeutic sensitivity or resistance. We used Caenorhabditis elegans as a platform with which to characterize properties of the anticancer therapeutic CX-5461. To understand the processes that respond to CX-5461-induced damage, we generated pharmacogenetic profiles for a panel of C. elegans DNA replication and repair mutants with common DNA-damaging agents for comparison with the profile of CX-5461. We found that multiple repair pathways, including homology-directed repair, microhomology-mediated end joining, nucleotide excision repair, and translesion synthesis, were needed for CX-5461 tolerance. To determine the frequency and spectrum of CX-5461-induced mutations, we used a genetic balancer to capture CX-5461-induced mutations. We found that CX-5461 is mutagenic, resulting in both large copy number variations and a high frequency of single-nucleotide variations (SNVs), which are consistent with the pharmacogenetic profile for CX-5461. Whole-genome sequencing of CX-5461-exposed animals found that CX-5461-induced SNVs exhibited a distinct mutational signature. We also phenocopied the CX-5461 photoreactivity observed in clinical trials and demonstrated that CX-5461 generates reactive oxygen species when exposed to UVA radiation. Together, the data from C. elegans demonstrate that CX-5461 is a multimodal DNA-damaging anticancer agent.

scholarly journals ATM Induces Cell Death with Autophagy in Response to H2O2 Specifically in Caenorhabditis elegans Nondividing Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Takahito Moriwaki ◽  
Akira Yamasaki ◽  
Qiu-Mei Zhang-Akiyama
Keyword(s):  
Cell Death ◽  
Caenorhabditis Elegans ◽  
Somatic Cells ◽  
Dead Cell ◽  
C Elegans ◽  
Cell Staining ◽  
Dna Damaging Agents ◽  
Gfp Reporter ◽  
Wide Range ◽  
Reporter Assays

Introduction. Ataxia-telangiectasia-mutated (ATM) kinase is a master regulator of the DNA damage response and is directly activated by reactive oxygen species (ROSs) in addition to DNA double-stranded breaks. However, the physiological function of the response to ROSs is not understood. Purpose. In the present study, we investigated how ATM responds to ROSs in Caenorhabditis elegans (C. elegans). Materials and Methods. First, we measured sensitivities of larvae to DNA-damaging agents and ROSs. Next, we analyzed the drug sensitivities of fully matured adult worms, which consist of nondividing somatic cells. Dead cell staining with acridine orange was performed to visualize the dead cells. In addition, we performed GFP reporter assays of lgg-1, an autophagy-related gene, to determine the types of cell death. Results. atm-1(tm5027) larvae showed a wide range of sensitivities to both DNA-damaging agents and ROSs. In contrast, fully matured adult worms, which consist of nondividing somatic cells, showed sensitivity to DNA-damaging agent, NaHSO3, but they showed resistance to H2O2. Dead cell staining and GFP reporter assays of lgg-1 suggest that C. elegans ATM-1 induces the cell death with autophagy in intestinal cells in response to H2O2. Conclusion. We revealed that ATM induces cell death in response to H2O2.

scholarly journals Caenorhabditis elegans PIEZO Channel Coordinates Multiple Reproductive Tissues to Govern Ovulation

2019 ◽  
Author(s):  
Xiaofei Bai ◽  
Jeff Bouffard ◽  
Avery Lord ◽  
Katherine Brugman ◽  
Paul W. Sternberg ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Ion Channels ◽  
Calcium Signaling ◽  
Brood Size ◽  
Mechanical Stimuli ◽  
C Elegans ◽  
Reproductive Tissues ◽  
Physiological Processes ◽  
Wide Range

AbstractThe PIEZO proteins are involved in a wide range of developmental and physiological processes. Human PIEZO1 and PIEZO2 are newly identified excitatory mechano-sensitive proteins; they are non-selective ion channels that exhibit a preference for calcium in response to mechanical stimuli. To further understand the function of these proteins, we investigated the roles of pezo-1, the sole PIEZO ortholog in C. elegans. pezo-1 is expressed throughout development in C. elegans, with strong expression in reproductive tissues. A number of deletion alleles as well as a putative gain-of-function mutant caused severe defects in reproduction. A reduced brood size was observed in the strains depleted of PEZO-1. In vivo observations show that oocytes undergo a variety of transit defects as they enter and exit the spermatheca during ovulation. Post ovulation oocytes were frequently damaged during spermathecal contraction. Calcium signaling in the spermatheca is normal during ovulation in pezo-1 mutants, however, pezo-1 interacts genetically with known regulators of calcium signaling. Lastly, loss of PEZO-1 caused defective sperm navigation after being pushed out of the spermatheca during ovulation. Mating with males rescued these reproductive deficiencies in our pezo-1 mutants. These findings suggest that PEZO-1 may act in different reproductive tissues to promote proper ovulation and fertilization in C. elegans.

Ethnomedicinal uses, Phytochemistry and Pharmacological Aspects of the Genus Berberis Linn: A Comprehensive Review

2020 ◽  
Vol 23 ◽  
Author(s):  
Roohi Mohi-ud-din ◽  
Reyaz Hassan Mir ◽  
Prince Ahad Mir ◽  
Saeema Farooq ◽  
Syed Naiem Raza ◽  
...  
Keyword(s):  
Chemical Constituents ◽  
Pharmacological Activities ◽  
Traditional Use ◽  
Comprehensive Review ◽  
Wide Range ◽  
Anti Cancer ◽  
Comprehensive Survey ◽  
Ethnomedicinal Uses

Background: Genus Berberis (family Berberidaceae), which contains about 650 species and 17 genera worldwide, has been used in folklore and various traditional medicine systems. Berberis Linn. is the most established group among genera with around 450-500 species across the world. This comprehensive review will not only help researchers for further evaluation but also provide substantial information for future exploitation of species to develop novel herbal formulations. Objective: The present review is focussed to summarize and collect the updated review of information of Genus Berberis species reported to date regarding their ethnomedicinal information, chemical constituents, traditional/folklore use, and reported pharmacological activities on more than 40 species of Berberis. Conclusion: A comprehensive survey of the literature reveals that various species of the genus possess various phytoconstituents mainly alkaloids, flavonoid based compounds isolated from different parts of a plant with a wide range of pharmacological activities. So far, many pharmacological activities like anti-cancer, anti-hyperlipidemic, hepatoprotective, immunomodulatory, anti-inflammatory both in vitro & in vivo and clinical study of different extracts/isolated compounds of different species of Berberis have been reported, proving their importance as a medicinal plant and claiming their traditional use.

scholarly journals Caenorhabditis elegans as an in vivo Model to Assess Amphetamine Tolerance

2021 ◽  
pp. 1-9
Author(s):  
Dayana Torres Valladares ◽  
Sirisha Kudumala ◽  
Murad Hossain ◽  
Lucia Carvelli
Keyword(s):  
Caenorhabditis Elegans ◽  
Molecular Mechanisms ◽  
Drugs Of Abuse ◽  
Genetic Model ◽  
In Vivo Model ◽  
C Elegans ◽  
Hyperactivity Disorder ◽  
In Vitro Data

Amphetamine is a potent psychostimulant also used to treat attention deficit/hyperactivity disorder and narcolepsy. In vivo and in vitro data have demonstrated that amphetamine increases the amount of extra synaptic dopamine by both inhibiting reuptake and promoting efflux of dopamine through the dopamine transporter. Previous studies have shown that chronic use of amphetamine causes tolerance to the drug. Thus, since the molecular mechanisms underlying tolerance to amphetamine are still unknown, an animal model to identify the neurochemical mechanisms associated with drug tolerance is greatly needed. Here we took advantage of a unique behavior caused by amphetamine in <i>Caenorhabditis elegans</i> to investigate whether this simple, but powerful, genetic model develops tolerance following repeated exposure to amphetamine. We found that at least 3 treatments with 0.5 mM amphetamine were necessary to see a reduction in the amphetamine-induced behavior and, thus, to promote tolerance. Moreover, we found that, after intervals of 60/90 minutes between treatments, animals were more likely to exhibit tolerance than animals that underwent 10-minute intervals between treatments. Taken together, our results show that <i>C. elegans</i> is a suitable system to study tolerance to drugs of abuse such as amphetamines.

scholarly journals Surface-Initiated Atom Transfer Polymerized Anionic Corona on Gold Nanoparticles for Anti-Cancer Therapy

Pharmaceutics ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 261
Author(s):  
Wei Mao ◽  
Sol Lee ◽  
Ji Un Shin ◽  
Hyuk Sang Yoo
Keyword(s):  
Gold Nanoparticles ◽  
Transfection Efficiency ◽  
Cancer Therapeutics ◽  
Atom Transfer ◽  
Layer By Layer ◽  
Dependent Manner ◽  
Metallic Particles ◽  
Anti Cancer

Surface initiated atom transfer radical polymerization (SI-ATRP) documented a simple but efficient technique to grow a dense polymer layer on any surface. Gold nanoparticles (AuNPs) give a broad surface to immobilize sulfhyryl group-containing initiators for SI-ATRP; in addition, AuNPs are the major nanoparticulate carriers for delivery of anti-cancer therapeutics, since they are biocompatible and bioinert. In this work, AuNPs with a disulfide initiator were polymerized with sulfoethyl methacrylate by SI-ATRP to decorate the particles with anionic corona, and branched polyethyeleneimine (PEI) and siRNA were sequentially layered onto the anionic corona of AuNP by electrostatic interaction. The in vitro anti-cancer effect confirmed that AuNP with anionic corona showed higher degrees of apoptosis as well as suppression of the oncogene expression in a siRNA dose-dependent manner. The in vivo study of tumor-bearing nude mice revealed that mice treated with c-Myc siRNA-incorporated AuNPs showed dramatically decreased tumor size in comparison to those with free siRNA for 4 weeks. Furthermore, histological examination and gene expression study revealed that the decorated AuNP significantly suppressed c-Myc expression. Thus, we envision that the layer-by-layer assembly on the anionic brushes can be potentially used to incorporate nucleic acids onto metallic particles with high transfection efficiency.

scholarly journals Designer Oncolytic Adenovirus: Coming of Age

Cancers ◽  
2018 ◽  
Vol 10 (6) ◽  
pp. 201 ◽  
Author(s):  
Alexander Baker ◽  
Carmen Aguirre-Hernández ◽  
Gunnel Halldén ◽  
Alan Parker
Keyword(s):  
Checkpoint Inhibitors ◽  
Coming Of Age ◽  
Oncolytic Adenovirus ◽  
Detailed Knowledge ◽  
Immunomodulatory Agents ◽  
Double Stranded Dna ◽  
Wide Range ◽  
Anti Cancer ◽  
Targeting Ability

The licensing of talimogene laherparepvec (T-Vec) represented a landmark moment for oncolytic virotherapy, since it provided unequivocal evidence for the long-touted potential of genetically modified replicating viruses as anti-cancer agents. Whilst T-Vec is promising as a locally delivered virotherapy, especially in combination with immune-checkpoint inhibitors, the quest continues for a virus capable of specific tumour cell killing via systemic administration. One candidate is oncolytic adenovirus (Ad); it’s double stranded DNA genome is easily manipulated and a wide range of strategies and technologies have been employed to empower the vector with improved pharmacokinetics and tumour targeting ability. As well characterised clinical and experimental agents, we have detailed knowledge of adenoviruses’ mechanisms of pathogenicity, supported by detailed virological studies and in vivo interactions. In this review we highlight the strides made in the engineering of bespoke adenoviral vectors to specifically infect, replicate within, and destroy tumour cells. We discuss how mutations in genes regulating adenoviral replication after cell entry can be used to restrict replication to the tumour, and summarise how detailed knowledge of viral capsid interactions enable rational modification to eliminate native tropisms, and simultaneously promote active uptake by cancerous tissues. We argue that these designer-viruses, exploiting the viruses natural mechanisms and regulated at every level of replication, represent the ideal platforms for local overexpression of therapeutic transgenes such as immunomodulatory agents. Where T-Vec has paved the way, Ad-based vectors now follow. The era of designer oncolytic virotherapies looks decidedly as though it will soon become a reality.

Transfer and tissue-specific accumulation of components in embryos of Caenorhabditis elegans and dolichura: in vivo analysis with a low-cost signal

Development ◽  
1992 ◽  
Vol 114 (2) ◽  
pp. 317-330 ◽  
Author(s):  
O. Bossinger ◽  
E. Schierenberg
Keyword(s):  
Caenorhabditis Elegans ◽  
Low Cost ◽  
Free Living ◽  
Tissue Specific ◽  
C Elegans ◽  
Specific Accumulation ◽  
In Vivo Analysis

The pattern of autofluorescence in the two free-living namatodes Rhabditis dolichura and Caenorhabditis compared. In C. elegans, during later embryogenesis cells develop a typical bluish autofluorescence as illumination, while in Rh. dolichura a strong already present in the unfertilized egg. Using a new,

scholarly journals Edible Flowers of Tagetes erecta L. as Functional Ingredients: Phenolic Composition, Antioxidant and Protective Effects on Caenorhabditis elegans

Nutrients ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 2002 ◽  
Author(s):  
Cristina Moliner ◽  
Lillian Barros ◽  
Maria Dias ◽  
Víctor López ◽  
Elisa Langa ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
In Vivo Model ◽  
Tagetes Erecta ◽  
Protective Effects ◽  
Phenolic Composition ◽  
C Elegans ◽  
Amyloid Toxicity ◽  
Phenolic Profiles ◽  
Tagetes Erecta L

Tagetes erecta L. has long been consumed for culinary and medicinal purposes in different countries. The aim of this study was to explore the potential benefits from two cultivars of T. erecta related to its polyphenolic profile as well as antioxidant and anti-aging properties. The phenolic composition was analyzed by LC-DAD-ESI/MSn. Folin-Ciocalteu, DPPH·, and FRAP assays were performed in order to evaluate reducing antiradical properties. The neuroprotective potential was evaluated using the enzymes acetylcholinesterase and monoamine oxidase. Caenorhabditis elegans was used as an in vivo model to assess extract toxicity, antioxidant activity, delayed aging, and reduced β-amyloid toxicity. Both extracts showed similar phenolic profiles and bioactivities. The main polyphenols found were laricitin and its glycosides. No acute toxicity was detected for extracts in the C. elegans model. T. erecta flower extracts showed promising antioxidant and neuroprotective properties in the different tested models. Hence, these results may add some information supporting the possibilities of using these plants as functional foods and/or as nutraceutical ingredients.

scholarly journals Identification of gmhA, a Yersinia pestis Gene Required for Flea Blockage, by Using a Caenorhabditis elegans Biofilm System

2005 ◽  
Vol 73 (11) ◽  
pp. 7236-7242 ◽  
Author(s):  
Creg Darby ◽  
Sandya L. Ananth ◽  
Li Tan ◽  
B. Joseph Hinnebusch
Keyword(s):  
Caenorhabditis Elegans ◽  
Yersinia Pestis ◽  
Biofilm Formation ◽  
Yersinia Pseudotuberculosis ◽  
C Elegans ◽  
Transposon Insertion ◽  
Insertion Mutants ◽  
Random Screening

ABSTRACT Yersinia pestis, the cause of bubonic plague, blocks feeding by its vector, the flea. Recent evidence indicates that blockage is mediated by an in vivo biofilm. Y. pestis and the closely related Yersinia pseudotuberculosis also make biofilms on the cuticle of the nematode Caenorhabditis elegans, which block this laboratory animal's feeding. Random screening of Y. pseudotuberculosis transposon insertion mutants with a C. elegans biofilm assay identified gmhA as a gene required for normal biofilms. gmhA encodes phosphoheptose isomerase, an enzyme required for synthesis of heptose, a conserved component of lipopolysaccharide and lipooligosaccharide. A Y. pestis gmhA mutant was constructed and was severely defective for C. elegans biofilm formation and for flea blockage but only moderately defective in an in vitro biofilm assay. These results validate use of the C. elegans biofilm system to identify genes and pathways involved in Y. pestis flea blockage.

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