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Cell Reports Mar 2020Ferroptosis is a type of regulated cell death driven by the iron-dependent accumulation of oxidized polyunsaturated fatty acid-containing phospholipids. There is no...
Ferroptosis is a type of regulated cell death driven by the iron-dependent accumulation of oxidized polyunsaturated fatty acid-containing phospholipids. There is no reliable way to selectively stain ferroptotic cells in tissue sections to characterize the extent of ferroptosis in animal models or patient samples. We address this gap by immunizing mice with membranes from lymphoma cells treated with the ferroptosis inducer piperazine erastin and screening ∼4,750 of the resulting monoclonal antibodies generated for their ability to selectively detect cells undergoing ferroptosis. We find that one antibody, 3F3 ferroptotic membrane antibody (3F3-FMA), is effective as a selective ferroptosis-staining reagent. The antigen of 3F3-FMA is identified as the human transferrin receptor 1 protein (TfR1). We validate this finding with several additional anti-TfR1 antibodies and compare them to other potential ferroptosis-detecting reagents. We find that anti-TfR1 and anti-malondialdehyde adduct antibodies are effective at staining ferroptotic tumor cells in multiple cell culture and tissue contexts.
Topics: Animals; Antibodies, Monoclonal; Antigens; Biomarkers; Cell Line; Cell Line, Tumor; Cell Membrane; Ferroptosis; Golgi Apparatus; Humans; Injections; Mice; Piperazine; Piperazines; Receptors, Transferrin; Xenograft Model Antitumor Assays
PubMed: 32160546
DOI: 10.1016/j.celrep.2020.02.049 -
Nucleic Acids Research Jul 2021Because undesirable pharmacokinetics and toxicity of candidate compounds are the main reasons for the failure of drug development, it has been widely recognized that...
Because undesirable pharmacokinetics and toxicity of candidate compounds are the main reasons for the failure of drug development, it has been widely recognized that absorption, distribution, metabolism, excretion and toxicity (ADMET) should be evaluated as early as possible. In silico ADMET evaluation models have been developed as an additional tool to assist medicinal chemists in the design and optimization of leads. Here, we announced the release of ADMETlab 2.0, a completely redesigned version of the widely used AMDETlab web server for the predictions of pharmacokinetics and toxicity properties of chemicals, of which the supported ADMET-related endpoints are approximately twice the number of the endpoints in the previous version, including 17 physicochemical properties, 13 medicinal chemistry properties, 23 ADME properties, 27 toxicity endpoints and 8 toxicophore rules (751 substructures). A multi-task graph attention framework was employed to develop the robust and accurate models in ADMETlab 2.0. The batch computation module was provided in response to numerous requests from users, and the representation of the results was further optimized. The ADMETlab 2.0 server is freely available, without registration, at https://admetmesh.scbdd.com/.
Topics: Drug-Related Side Effects and Adverse Reactions; Internet; Pharmaceutical Preparations; Pharmacokinetics; Phthalazines; Piperazines; Software
PubMed: 33893803
DOI: 10.1093/nar/gkab255 -
Cancer Discovery Feb 2022Cyclin-dependent kinases 4 and 6 (CDK4/6) represent a major therapeutic vulnerability for breast cancer. The kinases are clinically targeted via ATP competitive...
Cyclin-dependent kinases 4 and 6 (CDK4/6) represent a major therapeutic vulnerability for breast cancer. The kinases are clinically targeted via ATP competitive inhibitors (CDK4/6i); however, drug resistance commonly emerges over time. To understand CDK4/6i resistance, we surveyed over 1,300 breast cancers and identified several genetic alterations (e.g., , , or loss) converging on upregulation of CDK6. Mechanistically, we demonstrate CDK6 causes resistance by inducing and binding CDK inhibitor INK4 proteins (e.g., p18). binding and kinase assays together with physical modeling reveal that the p18-cyclin D-CDK6 complex occludes CDK4/6i binding while only weakly suppressing ATP binding. Suppression of INK4 expression or its binding to CDK6 restores CDK4/6i sensitivity. To overcome this constraint, we developed bifunctional degraders conjugating palbociclib with E3 ligands. Two resulting lead compounds potently degraded CDK4/6, leading to substantial antitumor effects , demonstrating the promising therapeutic potential for retargeting CDK4/6 despite CDK4/6i resistance. SIGNIFICANCE: CDK4/6 kinase activation represents a common mechanism by which oncogenic signaling induces proliferation and is potentially targetable by ATP competitive inhibitors. We identify a CDK6-INK4 complex that is resilient to current-generation inhibitors and develop a new strategy for more effective inhibition of CDK4/6 kinases..
Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor Proteins; Drug Resistance, Neoplasm; Female; Humans; Piperazines; Protein Kinase Inhibitors; Pyridines; Tumor Suppressor Proteins
PubMed: 34544752
DOI: 10.1158/2159-8290.CD-20-1726 -
Nature Communications Aug 2022In humans, lipid nanoparticles (LNPs) have safely delivered therapeutic RNA to hepatocytes after systemic administration and to antigen-presenting cells after...
In humans, lipid nanoparticles (LNPs) have safely delivered therapeutic RNA to hepatocytes after systemic administration and to antigen-presenting cells after intramuscular injection. However, systemic RNA delivery to non-hepatocytes remains challenging, especially without targeting ligands such as antibodies, peptides, or aptamers. Here we report that piperazine-containing ionizable lipids (Pi-Lipids) preferentially deliver mRNA to immune cells in vivo without targeting ligands. After synthesizing and characterizing Pi-Lipids, we use high-throughput DNA barcoding to quantify how 65 chemically distinct LNPs functionally delivered mRNA (i.e., mRNA translated into functional, gene-editing protein) in 14 cell types directly in vivo. By analyzing the relationships between lipid structure and cellular targeting, we identify lipid traits that increase delivery in vivo. In addition, we characterize Pi-A10, an LNP that preferentially delivers mRNA to the liver and splenic immune cells at the clinically relevant dose of 0.3 mg/kg. These data demonstrate that high-throughput in vivo studies can identify nanoparticles with natural non-hepatocyte tropism and support the hypothesis that lipids with bioactive small-molecule motifs can deliver mRNA in vivo.
Topics: Humans; Lipids; Liposomes; Nanoparticles; Piperazine; RNA, Messenger; RNA, Small Interfering
PubMed: 35970837
DOI: 10.1038/s41467-022-32281-5 -
Cell Research Jul 2022
Topics: Cell Line, Tumor; Ferroptosis; Piperazines
PubMed: 35352032
DOI: 10.1038/s41422-022-00642-w -
Science (New York, N.Y.) Apr 2020The success of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (PARPi) to treat cancer relates to their ability to trap PARP-1 at the site of a DNA break. Although...
The success of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (PARPi) to treat cancer relates to their ability to trap PARP-1 at the site of a DNA break. Although different forms of PARPi all target the catalytic center of the enzyme, they have variable abilities to trap PARP-1. We found that several structurally distinct PARPi drive PARP-1 allostery to promote release from a DNA break. Other inhibitors drive allostery to retain PARP-1 on a DNA break. Further, we generated a new PARPi compound, converting an allosteric pro-release compound to a pro-retention compound and increasing its ability to kill cancer cells. These developments are pertinent to clinical applications where PARP-1 trapping is either desirable or undesirable.
Topics: Allosteric Regulation; Benzimidazoles; Cell Line, Tumor; DNA Breaks; DNA Damage; Humans; Isoindoles; Neoplasms; Piperazines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Protein Domains
PubMed: 32241924
DOI: 10.1126/science.aax6367 -
British Journal of Clinical Pharmacology Jan 2016Olaparib is used to treat BReast CAncer susceptibility protein (BRCA)-associated, platinum-sensitive ovarian cancer. Olaparib inhibits poly(ADP-ribose) polymerase,...
Olaparib is used to treat BReast CAncer susceptibility protein (BRCA)-associated, platinum-sensitive ovarian cancer. Olaparib inhibits poly(ADP-ribose) polymerase, thereby blocking the repair of single-strand DNA breaks. This results in synthetic lethality in BRCA-associated cancer cells, which have a dysfunction of another DNA repair pathway - homologous recombination.
Topics: Antineoplastic Agents; DNA Repair; Humans; Neoplasms; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 26344419
DOI: 10.1111/bcp.12761 -
Journal of Affective Disorders May 2023Patients with major depressive disorder (MDD) often experience comorbid anxiety symptoms. Vortioxetine has demonstrated efficacy in treating anxiety symptoms in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients with major depressive disorder (MDD) often experience comorbid anxiety symptoms. Vortioxetine has demonstrated efficacy in treating anxiety symptoms in patients with MDD; however, efficacy and tolerability have not been assessed across the entire approved dosage range.
METHODS
The efficacy and tolerability of vortioxetine 5-20 mg/day were assessed in patients with MDD and high levels of anxiety symptoms (Hamilton Anxiety Rating Scale [HAM-A] total score ≥ 20) using pooled data from four randomized, fixed-dose, placebo-controlled studies (n = 842). Data from a randomized, double-blind study of vortioxetine 10-20 mg/day versus agomelatine 25-50 mg/day in patients with an inadequate response to prior therapy (n = 299) were analyzed separately. Mean changes from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS), HAM-A, and Sheehan Disability Scale (SDS) total scores were analyzed by vortioxetine dosage.
RESULTS
The pooled analysis of fixed-dose studies demonstrated a clear dose-response relationship for vortioxetine 5-20 mg/day for improvements in MADRS, HAM-A, and SDS total scores. Vortioxetine 20 mg/day demonstrated significant effects versus placebo from week 4 onwards. In the post-hoc analysis of the active-controlled study in patients with an inadequate response to prior therapy, vortioxetine 10-20 mg/day was superior to agomelatine across all outcome measures from week 4 onwards. Up-titration of vortioxetine to 20 mg/day was not associated with an increase in adverse events.
LIMITATIONS
Short-term trials.
CONCLUSIONS
Vortioxetine is efficacious and well tolerated in patients with MDD and high levels of anxiety symptoms, including those with an inadequate response to prior therapy. The greatest therapeutic benefits were observed with vortioxetine 20 mg/day.
TRIAL REGISTRATION
NCT01140906, NCT01153009, NCT01163266, NCT01255787, NCT01488071.
Topics: Humans; Vortioxetine; Depressive Disorder, Major; Piperazines; Treatment Outcome; Sulfides; Anxiety; Double-Blind Method; Acetamides
PubMed: 36708956
DOI: 10.1016/j.jad.2023.01.074 -
Journal of Medicine and Life Apr 2022Cytokine response to () infection was measured after starting treatments with piperazine. This study aims to determine the impact of cytokine production after infection...
Cytokine response to () infection was measured after starting treatments with piperazine. This study aims to determine the impact of cytokine production after infection with before and after treatment with piperazine. Blood and stool samples of 50 patients with infection and 28 healthy individuals (control) were collected. In this study, IFNγ, IL-5, IL-12, and IL-13 in serum (using ELISA-based methods) were measured. Stool samples were examined using the Kato-Katz technique to detect parasites. Blood and stool samples were analyzed 14 days after starting piperazine treatment for infection. The medium concentration of IFNγ, IL-5, IL-12, and IL-13 in the serum samples with infection is higher than that of the control group. IFNγ, IL-5, IL-12, and IL-13 levels were significantly higher in the infected individuals (10.5±7.4 pg/ml, 14.6±5.1 pg/ml, 8.5±3.2 pg/ml and 13.6±7.5 pg/ml respectively) than the control group (4.7±2.4 pg/ml, 7.8±4.06 pg/ml, 6.3±3.4 pg/ml and 3.5±2.7 pg/ml respectively). Also, piperazine treatment can significantly reduce cytokines levels (IFN-γ: P=0.043, IL-5: P=0.02, and IL-12, p=0.001). This study shows that piperazine treatment can reduce cytokines profiles in patients with infection.
Topics: Ancylostomiasis; Cytokines; Humans; Interleukin-12; Interleukin-13; Interleukin-5; Piperazines
PubMed: 35646178
DOI: 10.25122/jml-2021-0383 -
Marine Drugs Nov 2019The spread of studies on biodiversity in different environmental contexts is particularly fruitful for natural product discovery, with the finding of novel secondary... (Review)
Review
The spread of studies on biodiversity in different environmental contexts is particularly fruitful for natural product discovery, with the finding of novel secondary metabolites and structural models, which are sometimes specific to certain organisms. Within the large class of the epipolythiodioxopiperazines, which are typical of fungi, thiosilvatins represent a homogeneous family that, so far, has been reported in low frequency in both marine and terrestrial contexts. However, recent observations indicate that these compounds have been possibly neglected in the metabolomic characterization of fungi, particularly from marine sources. Aspects concerning occurrence, bioactivities, structural, and biosynthetic properties of thiosilvatins are reviewed in this paper.
Topics: Biodiversity; Biological Products; Fungi; Oceans and Seas; Piperazines
PubMed: 31779089
DOI: 10.3390/md17120664