-
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 -
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 -
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 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 -
Monaldi Archives For Chest Disease =... Sep 2021Ranolazine derives from piperazine and has been approved as a drug for the therapy of chronic stable angina. It acts by selectively inhibiting the late sodium inward... (Review)
Review
Ranolazine derives from piperazine and has been approved as a drug for the therapy of chronic stable angina. It acts by selectively inhibiting the late sodium inward current. Moreover, ranolazine has other metabolic features which makes it effective in other diseases as well as coronary artery ones. In this paper I make an updated review of all possible therapeutic roles of ranolazine: through cardiology and beyond.
Topics: Acetanilides; Heart; Humans; Piperazines; Ranolazine
PubMed: 34498453
DOI: 10.4081/monaldi.2021.1806 -
Acta Pharmaceutica (Zagreb, Croatia) Dec 2020Piperazine derivatives are a group of compounds with a psychostimulant effect. They are an alternative to illegal drugs. They are being searched for recreational use due... (Review)
Review
Piperazine derivatives are a group of compounds with a psychostimulant effect. They are an alternative to illegal drugs. They are being searched for recreational use due to their psychoactive and hallucinogenic effects. The high popularity of these compounds can be noticed all over the world due to easy purchase, lack of legal regulations and incorrect assessment of the safety of use. The recreational use of piperazine derivatives can often result in chronic and acute health problems and additionally with unpredictable remote effects. It is also common to take mixtures of psychoactive compounds. This hinders the correct diagnosis and treatment of patients with poisoning. The presented work is an illustration of the wide problem of piperazine derivatives abuse. The health effects and the possibility of identifying these compounds in preparations and biological material are described.
Topics: Animals; Designer Drugs; Humans; Illicit Drugs; Piperazines; Psychotropic Drugs; Substance-Related Disorders
PubMed: 32412428
DOI: 10.2478/acph-2020-0035 -
Chembiochem : a European Journal of... Dec 2022Epipolythiodioxopiperazines (ETPs) are fungal secondary metabolites that share a 2,5-diketopiperazine scaffold built from two amino acids and bridged by a sulfide... (Review)
Review
Epipolythiodioxopiperazines (ETPs) are fungal secondary metabolites that share a 2,5-diketopiperazine scaffold built from two amino acids and bridged by a sulfide moiety. Modifications of the core and the amino acid side chains, for example by methylations, acetylations, hydroxylations, prenylations, halogenations, cyclizations, and truncations create the structural diversity of ETPs and contribute to their biological activity. However, the key feature responsible for the bioactivities of ETPs is their sulfide moiety. Over the last years, combinations of genome mining, reverse genetics, metabolomics, biochemistry, and structural biology deciphered principles of ETP production. Sulfurization via glutathione and uncovering of the thiols followed by either oxidation or methylation crystallized as fundamental steps that impact expression of the biosynthesis cluster, toxicity and secretion of the metabolite as well as self-tolerance of the producer. This article showcases structure and activity of prototype ETPs such as gliotoxin and discusses the current knowledge on the biosynthesis routes of these exceptional natural products.
Topics: Biological Products; Gliotoxin; Multigene Family; Sulfides; Piperazines
PubMed: 35997236
DOI: 10.1002/cbic.202200341 -
Bioorganic Chemistry Sep 2020The UDP-2,3-diacylglucosamine pyrophosphate hydrolase LpxH is essential in lipid A biosynthesis and has emerged as a promising target for the development of novel...
The UDP-2,3-diacylglucosamine pyrophosphate hydrolase LpxH is essential in lipid A biosynthesis and has emerged as a promising target for the development of novel antibiotics against multidrug-resistant Gram-negative pathogens. Recently, we reported the crystal structure of Klebsiella pneumoniae LpxH in complex with 1 (AZ1), a sulfonyl piperazine LpxH inhibitor. The analysis of the LpxH-AZ1 co-crystal structure and ligand dynamics led to the design of 2 (JH-LPH-28) and 3 (JH-LPH-33) with enhanced LpxH inhibition. In order to harness our recent findings, we prepared and evaluated a series of sulfonyl piperazine analogs with modifications in the phenyl and N-acetyl groups of 3. Herein, we describe the synthesis and structure-activity relationship of sulfonyl piperazine LpxH inhibitors. We also report the structural analysis of an extended N-acyl chain analog 27b (JH-LPH-41) in complex with K. pneumoniae LpxH, revealing that 27b reaches an untapped polar pocket near the di-manganese cluster in the active site of K. pneumoniae LpxH. We expect that our findings will provide designing principles for new LpxH inhibitors and establish important frameworks for the future development of antibiotics against multidrug-resistant Gram-negative pathogens.
Topics: Antinematodal Agents; Enzyme Inhibitors; Humans; Piperazine; Structure-Activity Relationship
PubMed: 32663666
DOI: 10.1016/j.bioorg.2020.104055 -
Emergencias : Revista de La Sociedad... Jun 2022To detect the presence of unsuspected and/or undeclared cathinone and piperazine-type designer drugs in methamphetamine (METH) and amphetamine users treated in emergency... (Observational Study)
Observational Study
OBJECTIVES
To detect the presence of unsuspected and/or undeclared cathinone and piperazine-type designer drugs in methamphetamine (METH) and amphetamine users treated in emergency departments, and to compare clinical and toxicologic profiles.
MATERIAL AND METHODS
Retrospective observational study of emergency department patients treated for confirmed acute intoxication by recreational drugs (METH and amphetamines) between March 2019 and December 2020. We ordered high-performance liquid chromatography with tandem mass spectrometry to detect cathinones (methylone, fluoromethcathinone, mexedrone, fluoromethamphetamine, mephedrone, methylenedioxypyrovalerone) and synthetic piperazines (meta-chlorophenylpiperazine and trifluoromethylphenylpiperazine). Demographic, clinical, and toxicologic variables were analyzed with SPSS software (version 23).
RESULTS
Thirty-nine patients were included: 24 (61.5%) had used METH and 15 (38.5%) an amphetamine. Synthetic cathinones were detected in samples from 11 patients (28.2%), 10 (90.9%) in the METH group and 1 (9.1%) in the amphetamine group (P = .028). The METH users had taken mephedrone (8 patients) or methylone (2 patients); the amphetamine user had taken mephedrone. None of the patients had declared use of a cathinone; nor was use suspected. The mean (SD) number of substances involved was higher among users of cathinones (3.5 [1.13] vs 2.5 [1.40] in those who took no cathinones; P = .036). Among the cathinone users, 90.9% were men, 90.9% had used METH, and 45.5% had practiced chemsex. HIV positivity was significantly associated with cathinone use (in 45.5% vs 10.7% of those not using cathinones; P = .028). All 5 of the patients who had taken cathinones and also practiced chemsex were HIV positive. Significantly more patients who had taken cathinones presented with anxiety (72.7% vs 21.43%; P = .007). No differences in clinical management were found.
CONCLUSION
Detection of METH in intoxicated patients should raise suspicion of probable use of a synthetic cathinone. Patients in whom new psychoactive substances are detected should be kept under observation, and clinical protocols should include referring them to addiction treatment centers.
Topics: Alkaloids; Amphetamine; Emergency Service, Hospital; Female; Humans; Male; Methamphetamine; Piperazine; Piperazines
PubMed: 35736521
DOI: No ID Found -
Alzheimer's Research & Therapy Oct 2022PPARγ agonists have been proven to be neuroprotective in vitro and in vivo models of Alzheimer's disease (AD). In the present study, we identified ligustrazine...
PPARγ agonists have been proven to be neuroprotective in vitro and in vivo models of Alzheimer's disease (AD). In the present study, we identified ligustrazine piperazine derivative (LPD) as a novel PPARγ agonist, which was detected by a dual-luciferase reporter assay system. LPD treatment dose-dependently reduced Aβ40 and Aβ42 levels in PC12 cells stably transfected with APP695swe and PSEN1dE9. Intragastric administration of LPD for 3 months dose-dependently reversed cognitive deficits in APP/PS1 mice. LPD treatment substantially decreased hippocampal Aβ plaques in APP/PS1 mice and decreased the levels of Aβ40 and Aβ42 in vivo and in vitro. Moreover, LPD treatment induced mitophagy in vivo and in vitro and increased brain F-FDG uptake in APP/PS1 mice. LPD treatment significantly increased OCR, ATP production, maximal respiration, spare respiratory capacity, and basal respiration in APP/PS1 cells. Mechanistically, LPD treatment upregulated PPARγ, PINK1, and the phosphorylation of Parkin (Ser65) and increased the LC3-II/LC3-I ratio but decreased SQSTM1/p62 in vivo and in vitro. Importantly, all these protective effects mediated by LPD were abolished by cotreatment with the selective PPARγ antagonist GW9662. In summary, LPD could increase brain glucose metabolism and ameliorate cognitive deficits through PPARγ-dependent enhancement of mitophagy in APP/PS1 mice.
Topics: Adenosine Triphosphate; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cognition; Disease Models, Animal; Fluorodeoxyglucose F18; Glucose; Luciferases; Mice; Mice, Transgenic; Mitophagy; PPAR gamma; Piperazine; Presenilin-1; Protein Kinases; Pyrazines; Rats; Sequestosome-1 Protein; Ubiquitin-Protein Ligases
PubMed: 36217155
DOI: 10.1186/s13195-022-01092-7