7,330 results match your criteria lethality induced


The Drosophila melanogaster PIF1 Helicase Promotes Survival During Replication Stress and Processive DNA Synthesis During Double-Strand Gap Repair.

Genetics 2019 Nov;213(3):835-847

Department of Biology, Tufts University, Medford, Massachusetts 02155.

PIF1 is a 5' to 3' DNA helicase that can unwind double-stranded DNA and disrupt nucleic acid-protein complexes. In Saccharomyces cerevisiae, Pif1 plays important roles in mitochondrial and nuclear genome maintenance, telomere length regulation, unwinding of G-quadruplex structures, and DNA synthesis during break-induced replication. Some, but not all, of these functions are shared with other eukaryotes. Read More

View Article and Full-Text PDF
November 2019

The Drosophila melanogaster PIF1 Helicase Promotes Survival During Replication Stress and Processive DNA Synthesis During Double-Strand Gap Repair.

Genetics 2019 Nov;213(3):835-847

Department of Biology, Tufts University, Medford, Massachusetts 02155.

PIF1 is a 5' to 3' DNA helicase that can unwind double-stranded DNA and disrupt nucleic acid-protein complexes. In Saccharomyces cerevisiae, Pif1 plays important roles in mitochondrial and nuclear genome maintenance, telomere length regulation, unwinding of G-quadruplex structures, and DNA synthesis during break-induced replication. Some, but not all, of these functions are shared with other eukaryotes. Read More

View Article and Full-Text PDF
November 2019

Disruption of entire locus leads to embryonic lethality by diminished gene expression and enhanced p53 pathway.

Elife 2021 May 5;10. Epub 2021 May 5.

Laboratory Animal Resource Center, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

In vivo function of CDK5 and Abl enzyme substrate 2 (Cables2), belonging to the Cables protein family, is unknown. Here, we found that targeted disruption of the entire locus () caused growth retardation and enhanced apoptosis at the gastrulation stage and then induced embryonic lethality in mice. Comparative transcriptome analysis revealed disruption of , 50% down-regulation of abutting on the locus, and up-regulation of p53-target genes in gastrulas. Read More

View Article and Full-Text PDF

TSL-1502, a glucuronide prodrug of a poly (ADP-ribose) polymerase (PARP) inhibitor, exhibits potent anti-tumor activity in preclinical models.

Am J Cancer Res 2021 15;11(4):1632-1645. Epub 2021 Apr 15.

Shanghai Institute of Materia Medica, Chinese Academy of Sciences 555 Zuchongzhi Road, Shanghai 201203, China.

Poly (ADP-ribose) polymerase (PARP) enzymes play an important role in the cellular response to DNA damage and the inhibition of PARP causes synthetic lethality in homologous recombination (HR)-deficient cancer. Multiple PARP inhibitors have been developed and have shown remarkable clinical benefits. However, treatment-related toxicities, especially the hematologic toxicities, are common and restrict the clinical applications of PARP inhibitors. Read More

View Article and Full-Text PDF

Synergistic action of the gut microbiota in environmental RNA interference in a leaf beetle.

Microbiome 2021 May 4;9(1):98. Epub 2021 May 4.

State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, 430062, China.

Background: RNA interference (RNAi) has emerged as an efficient tool to control insect pests. When insects ingest double-stranded RNAs (dsRNAs) targeted against essential genes, strong gene silencing and mortality can be induced. To exert their function, dsRNA molecules must pass through the insect's gut and enter epithelial cells and/or the hemolymph. Read More

View Article and Full-Text PDF

Catalase Protects Biofilm of against Daptomycin Activity.

Antibiotics (Basel) 2021 Apr 30;10(5). Epub 2021 Apr 30.

Costerton Biofilm Center, Department of Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.

Daptomycin is recommended for the treatment of infections due to its bactericidal activity. However, its mechanism of action is poorly understood. The involvement of reactive oxygen species (ROS) in the bactericidal activity of daptomycin has been proved against planktonic , but not against the biofilm of . Read More

View Article and Full-Text PDF

Synergistic effect of Chloroquine and Panobinostat in ovarian cancer through induction of DNA damage and inhibition of DNA repair.

Neoplasia 2021 Apr 27;23(5):515-528. Epub 2021 Apr 27.

Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain; Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain. Electronic address:

Ovarian cancer (OC) is the deadliest gynecologic malignancy, which is mainly due to late-stage diagnosis and chemotherapy resistance. Therefore, new and more effective treatments are urgently needed. The in vitro effects of Panobinostat (LBH), a histone deacetylase inhibitor that exerts pleiotropic antitumor effects but induces autophagy, in combination with Chloroquine (CQ), an autophagy inhibitor that avoid this cell survival mechanism, were evaluated in 4 OC cell lines. Read More

View Article and Full-Text PDF

Therapeutic Opportunities of Targeting Canonical and Noncanonical PcG/TrxG Functions in Acute Myeloid Leukemia.

Annu Rev Genomics Hum Genet 2021 Apr 30. Epub 2021 Apr 30.

Leukaemia and Stem Cell Biology Group, School of Cancer and Pharmaceutical Sciences, King's College London, London SE5 9NU, United Kingdom; email:

Transcriptional deregulation is a key driver of acute myeloid leukemia (AML), a heterogeneous blood cancer with poor survival rates. Polycomb group (PcG) and Trithorax group (TrxG) genes, originally identified in several decades ago as master regulators of cellular identity and epigenetic memory, not only are important in mammalian development but also play a key role in AML disease biology. In addition to their classical canonical antagonistic transcriptional functions, noncanonical synergistic and nontranscriptional functions of PcG and TrxG are emerging. Read More

View Article and Full-Text PDF

FEN1 Blockade for Platinum Chemo-Sensitization and Synthetic Lethality in Epithelial Ovarian Cancers.

Cancers (Basel) 2021 Apr 14;13(8). Epub 2021 Apr 14.

Translational Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham NG7 2RD, UK.

FEN1 plays critical roles in long patch base excision repair (LP-BER), Okazaki fragment maturation, and rescue of stalled replication forks. In a clinical cohort, FEN1 overexpression is associated with aggressive phenotype and poor progression-free survival after platinum chemotherapy. Pre-clinically, FEN1 is induced upon cisplatin treatment, and nuclear translocation of FEN1 is dependent on physical interaction with importin β. Read More

View Article and Full-Text PDF

Evaluation of Sex Differences in Murine Diabetic Ketoacidosis and Neutropenic Models of Invasive Mucormycosis.

J Fungi (Basel) 2021 Apr 18;7(4). Epub 2021 Apr 18.

The Division of Infectious Diseases, The Lundquist Institute for Biomedical Innovation at Harbor-University of California at Los Angeles (UCLA) Medical Center, Torrance, CA 90502, USA.

There is increased concern that the quality, generalizability and reproducibility of biomedical research can be influenced by the sex of animals used. We studied the differences between male and female mice in response to invasive pulmonary mucormycosis including susceptibility to infection, host immune reaction and responses to antifungal therapy. We used diabetic ketoacidotic (DKA) or neutropenic mice infected with either or . Read More

View Article and Full-Text PDF

Perampanel, a potent AMPA receptor antagonist, protects against tetramethylenedisulfotetramine-induced seizures and lethality in mice: comparison with diazepam.

Arch Toxicol 2021 Apr 29. Epub 2021 Apr 29.

Department of Neurology, School of Medicine, University of California, Davis, Sacramento, CA, 95817, USA.

Tetramethylenedisulfotetramine (TETS), a noncompetitive GABA receptor antagonist, is a potent, highly lethal convulsant that is considered to be a chemical threat agent. Here, we assessed the ability of the AMPA receptor antagonist perampanel to protect against TETS-induced seizures and lethality in mice when administered before or after treatment with the toxicant. For comparison, we conducted parallel testing with diazepam, which is a first-line treatment for chemically induced seizures in humans. Read More

View Article and Full-Text PDF

Protein kinase D1 variant associated with human epilepsy and peripheral nerve hypermyelination.

Clin Genet 2021 Apr 27. Epub 2021 Apr 27.

Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville.

We report the case of a patient with severe progressive epilepsy and peripheral neuropathy and a novel de novo inactivating variant (p.E79X) in Protein Kinase D1 (PKD1). Using CRISPR/Cas9, we engineered the homologous variant in mice and showed that in the homozygote mouse, it recapitulated the patient peripheral nerve hypermyelination pathology. Read More

View Article and Full-Text PDF

Methionine restriction breaks obligatory coupling of cell proliferation and death by an oncogene Src in .

Elife 2021 04 27;10. Epub 2021 Apr 27.

RIKEN CPR, Kobe, Japan.

Oncogenes often promote cell death as well as proliferation. How oncogenes drive these diametrically opposed phenomena remains to be solved. A key question is whether cell death occurs as a response to aberrant proliferation signals or through a proliferation-independent mechanism. Read More

View Article and Full-Text PDF

PBRM1 Deficiency Confers Synthetic Lethality to DNA Repair Inhibitors in Cancer.

Cancer Res 2021 Apr 22. Epub 2021 Apr 22.

ATIP-Avenir group, Inserm Unit U981, Gustave Roussy, Villejuif, France.

Inactivation of (), a specific subunit of the PBAF chromatin remodeling complex, occurs frequently in cancer, including 40% of clear cell renal cell carcinomas (ccRCC). To identify novel therapeutic approaches to targeting PBRM1-defective cancers, we used a series of orthogonal functional genomic screens that identified PARP and ATR inhibitors as being synthetic lethal with deficiency. The PBRM1/PARP inhibitor synthetic lethality was recapitulated using several clinical PARP inhibitors in a series of model systems and in a xenograft model of ccRCC. Read More

View Article and Full-Text PDF

Cytotoxicity, Anti-diabetic, and hepato-protective potential of Ajuga bracteosa-conjugated silver nanoparticles in Balb/c mice.

Curr Pharm Biotechnol 2021 Apr 20. Epub 2021 Apr 20.

Department of Chemistry, University of Azad Jammu and Kashmir, Muzaffarabad, 13100, Pakistan.

Background: Ajuga bracteosa is a traditional herb used against various diseases.

Objective: Current research aimed to investigate the anti-diabetic and hepato-protective effect of green synthesized silver nanoparticles (ABAgNPs) using Ajuga bracteosa aqueous extract (ABaqu).

Methods: In vitro anti-diabetic and cytotoxic effects were carried out via α- glucosidase inhibition, brine shrimp lethality, and protein kinase inhibition assays. Read More

View Article and Full-Text PDF

Hierarchical cell-type-specific functions of caspase-11 in LPS shock and antibacterial host defense.

Cell Rep 2021 Apr;35(3):109012

Department of Immunology, UConn Health School of Medicine, 263 Farmington Ave., Farmington, CT 06030, USA. Electronic address:

Caspase-11 sensing of intracellular lipopolysaccharide (LPS) plays critical roles during infections and sepsis. However, the key cell types that sense intracellular LPS and their contributions to the host responses at the organismal level are not completely clear. Here, we show that macrophage/monocyte-specific caspase-11 plays a dominant role in mediating the pathological manifestations of endotoxemia, including gasdermin D (GSDMD) activation, interleukin (IL)-1β, IL-18, and damage-associated molecular pattern (DAMP) release, tissue damage, and death. Read More

View Article and Full-Text PDF

FANCM regulates repair pathway choice at stalled replication forks.

Mol Cell 2021 Apr 16. Epub 2021 Apr 16.

Department of Medicine, Division of Hematology-Oncology and Cancer Research Institute, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA 02215, USA. Electronic address:

Repair pathway "choice" at stalled mammalian replication forks is an important determinant of genome stability; however, the underlying mechanisms are poorly understood. FANCM encodes a multi-domain scaffolding and motor protein that interacts with several distinct repair protein complexes at stalled forks. Here, we use defined mutations engineered within endogenous Fancm in mouse embryonic stem cells to study how Fancm regulates stalled fork repair. Read More

View Article and Full-Text PDF

Cytoplasmic condensation induced by membrane damage is associated with antibiotic lethality.

Nat Commun 2021 04 19;12(1):2321. Epub 2021 Apr 19.

Institute for Medical Engineering & Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

Bactericidal antibiotics kill bacteria by perturbing various cellular targets and processes. Disruption of the primary antibiotic-binding partner induces a cascade of molecular events, leading to overproduction of reactive metabolic by-products. It remains unclear, however, how these molecular events contribute to bacterial cell death. Read More

View Article and Full-Text PDF

A multi-herb-combined remedy to overcome hyper-inflammatory response by reprogramming transcription factor profile and shaping monocyte subsets.

Pharmacol Res 2021 Apr 17;169:105617. Epub 2021 Apr 17.

Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Dongcheng District, Beijing 100700, China. Electronic address:

Traditional Chinese multi-herb-combined prescriptions usually show better performance than a single agent since a group of effective compounds interfere multiple disease-relevant targets simultaneously. Huang-Lian-Jie-Du decoction is a remedy made of four herbs that are widely used to treat oral ulcers, gingivitis, and periodontitis. However, the active ingredients and underlying mechanisms are not clear. Read More

View Article and Full-Text PDF

Heliconia rostrata rhizomes mitigate chemical-induced liver injury by debilitating oxidative stress in HepG2 cells and rats.

J Ethnopharmacol 2021 Apr 20;275:114113. Epub 2021 Apr 20.

Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences, Siksha O Anusnadhan Deemed to Be University, Kalinga Nagar, Bhubaneswar, Odisha, 751003, India. Electronic address:

Ethnopharmacological Relevance: Heliconia rostrata Ruiz and Pav. belongs to the family Heliconiaceae. Plant was traditionally used to cure jaundice, intestinal pain, diabetes and hypertension. Read More

View Article and Full-Text PDF

Inhibition of SARS-CoV-2 main protease: a repurposing study that targets the dimer interface of the protein.

J Biomol Struct Dyn 2021 Apr 13:1-16. Epub 2021 Apr 13.

Regenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey.

Coronavirus disease-2019 (COVID-19) was firstly reported in Wuhan, China, towards the end of 2019, and emerged as a pandemic. The spread and lethality rates of the COVID-19 have ignited studies that focus on the development of therapeutics for either treatment or prophylaxis purposes. In parallel, drug repurposing studies have also come into prominence. Read More

View Article and Full-Text PDF

A derivative of vitamin B applied several days after exposure reduces lethality of severely irradiated mice.

Sci Rep 2021 Apr 12;11(1):7922. Epub 2021 Apr 12.

Department of Radiobiology and Radiation Protection, Military Institute of Hygiene and Epidemiology, 4 Kozielska St., 01-163, Warsaw, Poland.

Most, if not all, of the hitherto tested substances exert more or less pronounced pro-survival effects when applied before or immediately after the exposure to high doses of ionizing radiation. In the present study we demonstrate for the first time that 1-methyl nicotinamide (MNA), a derivative of vitamin B, significantly (1.6 to 1. Read More

View Article and Full-Text PDF

The Candidate Photoperiod Gene Promotes Growth and Flowering in .

Front Plant Sci 2021 26;12:634091. Epub 2021 Mar 26.

The Flowering Lab, School of Biological Sciences, University of Auckland, Auckland, New Zealand.

Flowering time influences the yield and productivity of legume crops. is a reference temperate legume that, like the winter annual , shows accelerated flowering in response to vernalization (extended cold) and long-day (LD) photoperiods (VLD). However, unlike , appears to lack functional homologs of core flowering time regulators () and () which act upstream of the mobile florigen FLOWERING LOCUS T (FT). Read More

View Article and Full-Text PDF

Enhanced cytarabine-induced killing in OGG1-deficient acute myeloid leukemia cells.

Proc Natl Acad Sci U S A 2021 Mar;118(11)

Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239;

Human clinical trials suggest that inhibition of enzymes in the DNA base excision repair (BER) pathway, such as PARP1 and APE1, can be useful in anticancer strategies when combined with certain DNA-damaging agents or tumor-specific genetic deficiencies. There is also evidence suggesting that inhibition of the BER enzyme 8-oxoguanine DNA glycosylase-1 (OGG1), which initiates repair of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy-dG), could be useful in treating certain cancers. Specifically, in acute myeloid leukemia (AML), both the RUNX1-RUNX1T1 fusion and the CBFB-MYH11 subtypes have lower levels of expression, which correlate with increased therapeutic-induced cell cytotoxicity and good prognosis for improved, relapse-free survival compared with other AML patients. Read More

View Article and Full-Text PDF

MicroRNA-29 is an essential regulator of brain maturation through regulation of CH methylation.

Cell Rep 2021 Apr;35(1):108946

Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA; Neurobiology Curriculum, University of North Carolina, Chapel Hill, NC, USA; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC, USA; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA. Electronic address:

Although embryonic brain development and neurodegeneration have received considerable attention, the events that govern postnatal brain maturation are less understood. Here, we identify the miR-29 family to be strikingly induced during the late stages of brain maturation. Brain maturation is associated with a transient, postnatal period of de novo non-CG (CH) DNA methylation mediated by DNMT3A. Read More

View Article and Full-Text PDF

Targeting nucleotide metabolism enhances the efficacy of anthracyclines and anti-metabolites in triple-negative breast cancer.

NPJ Breast Cancer 2021 Apr 6;7(1):38. Epub 2021 Apr 6.

Medicine, Dentistry and Biomedical Sciences: Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK.

Triple-negative breast cancer (TNBC) remains the most lethal breast cancer subtype with poor response rates to the current chemotherapies and a lack of additional effective treatment options. We have identified deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) as a critical gatekeeper that protects tumour DNA from the genotoxic misincorporation of uracil during treatment with standard chemotherapeutic agents commonly used in the FEC regimen. dUTPase catalyses the hydrolytic dephosphorylation of deoxyuridine triphosphate (dUTP) to deoxyuridine monophosphate (dUMP), providing dUMP for thymidylate synthase as part of the thymidylate biosynthesis pathway and maintaining low intracellular dUTP concentrations. Read More

View Article and Full-Text PDF

Chromatin Regulator SRG3 Overexpression Protects against LPS/D-GalN-Induced Sepsis by Increasing IL10-Producing Macrophages and Decreasing IFNγ-Producing NK Cells in the Liver.

Int J Mol Sci 2021 Mar 16;22(6). Epub 2021 Mar 16.

Department of Integrative Bioscience and Biotechnology, Institute of Anticancer Medicine Development, Sejong University, Seoul 05006, Korea.

We previously showed that ubiquitous overexpression of the chromatin remodeling factor SWItch3-related gene (SRG3) promotes M2 macrophage differentiation, resulting in anti-inflammatory responses in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Since hepatic macrophages are responsible for sepsis-induced liver injury, we investigated herein the capacity of transgenic SRG3 overexpression (SRG3 mice) to modulate sepsis in mice exposed to lipopolysaccharide (LPS) plus d-galactosamine (d-GalN). Our results demonstrated that ubiquitous SRG3 overexpression significantly protects mice from LPS/d-GalN-induced lethality mediated by hepatic M1 macrophages. Read More

View Article and Full-Text PDF

Preclinical Verification of the Efficacy and Safety of Aqueous Plasma for Ovarian Cancer Therapy.

Cancers (Basel) 2021 Mar 7;13(5). Epub 2021 Mar 7.

Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya 466-8550, Japan.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The major cause of EOC's lethality is that intraperitoneal recurrence occurs with high frequency due to occult metastasis. We had demonstrated that plasma-activated medium (PAM) exerts a metastasis-inhibitory effect on ovarian cancer in vitro and in vivo. Read More

View Article and Full-Text PDF

Tumor Hypoxia Drives Genomic Instability.

Front Cell Dev Biol 2021 16;9:626229. Epub 2021 Mar 16.

Centre for Genomics and Personalised Health, Queensland University of Technology (QUT), Brisbane, QLD, Australia.

Cancer is a leading cause of death worldwide. As a common characteristic of cancer, hypoxia is associated with poor prognosis due to enhanced tumor malignancy and therapeutic resistance. The enhanced tumor aggressiveness stems at least partially from hypoxia-induced genomic instability. Read More

View Article and Full-Text PDF

L-Se-methylselenocysteine sensitizes lung carcinoma to chemotherapy.

Cell Prolif 2021 May 1;54(5):e13038. Epub 2021 Apr 1.

State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Objectives: Organic Selenium (Se) compounds such as L-Se-methylselenocysteine (L-SeMC/SeMC) have been employed as a class of anti-oxidant to protect normal tissues and organs from chemotherapy-induced systemic toxicity. However, their comprehensive effects on cancer cell proliferation and tumour progression remain elusive.

Materials And Methods: CCK-8 assays were conducted to determine the viabilities of cancer cells after exposure to SeMC, chemotherapeutics or combined treatment. Read More

View Article and Full-Text PDF