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Molecules (Basel, Switzerland) Jun 2022, the causative agent for human African trypanosomiasis, is an emerging ergosterol-dependent parasite that produces chokepoint enzymes, sterol methyltransferases (SMT),...
, the causative agent for human African trypanosomiasis, is an emerging ergosterol-dependent parasite that produces chokepoint enzymes, sterol methyltransferases (SMT), not synthesized in their animal hosts that can regulate cell viability. Here, we report the lethal effects of two recently described natural product antimetabolites that disrupt sterol methylation and growth, cholesta-5,7,22,24-tetraenol (CHT) and ergosta-5,7,22,24(28)-tetraenol (ERGT) that can equally target . We found that CHT/ERGT inhibited cell growth in vitro, yielding EC values in the low nanomolar range with washout experiments showing cidal activity against the bloodstream form, consistent with their predicted mode of suicide inhibition on SMT activity and ergosterol production. Antimetabolite treatment generated altered cell morphology and death rapidly within hours. Notably, in vivo ERGT/CHT protected mice infected with , doubling their survival time following daily treatment for 8-10 days at 50 mg/kg or 100 mg/kg. The current study demonstrates a new class of lead antibiotics, in the form of common fungal sterols, for antitrypanosomal drug development.
Topics: Animals; Antimetabolites; Ergosterol; Humans; Mice; Steroids; Sterols; Trypanosoma brucei brucei; Trypanosomiasis, African
PubMed: 35807334
DOI: 10.3390/molecules27134088 -
Medicine Oct 2022The additive effects of ezetimibe, evolocumab or alirocumab on lipid level, plaque volume, and plaque composition using intravascular ultrasound (IVUS) remain unclear. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The additive effects of ezetimibe, evolocumab or alirocumab on lipid level, plaque volume, and plaque composition using intravascular ultrasound (IVUS) remain unclear.
METHODS
According to the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement, we performed a systematic review and meta-analysis of trials assessing the effects of ezetimibe, evolocumab, and alirocumab on coronary atherosclerosis using IVUS. The primary outcome was change in total atheroma volume (TAV), and the secondary outcomes were changes and differences in plaque composition and lipid content.
RESULTS
Data were collected from 9 trials, involving 917 patients who received ezetimibe, evolocumab or alirocumab in addition to a statin and 919 patients who received statins alone. The pooled estimate demonstrated a significant reduction in TAV with the addition of ezetimibe and favorable effects of evolocumab and alirocumab on TAV. Subgroup analysis also supported favorable effects of evolocumab and alirocumab on TAV, according to baseline TAV, gender, type 2 diabetes mellitus, and prior stain use. Addition of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to statin therapy resulted in significant reductions in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG), but not in high-density lipoprotein cholesterol (HDL-C). The pooled estimate also showed significant favorable effects of ezetimibe on LDL-C, TC, and TG, but an insignificant effect on HDL-C. Patients who received ezetimibe showed similar changes in the necrotic core, fibro-fatty plaque, fibrous plaque, and dense calcification compared with patients not treated with ezetimibe.
CONCLUSIONS
The addition of ezetimibe to statin therapy may further reduce plaque and lipid burdens but may not modify plaque composition. Although current evidence supports a similar impact from the addition of PCSK9 inhibitors to statin therapy, more evidence is needed to confirm such an effect.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; PCSK9 Inhibitors; Plaque, Atherosclerotic; Proprotein Convertase 9; Subtilisins; Triglycerides; Ultrasonography, Interventional
PubMed: 36254013
DOI: 10.1097/MD.0000000000031199 -
Biochemical Pharmacology Sep 2023Nucleoside-based drugs, recognized as purine or pyrimidine analogs, have been potent therapeutic agents since their introduction in 1950, deployed widely in the... (Review)
Review
Nucleoside-based drugs, recognized as purine or pyrimidine analogs, have been potent therapeutic agents since their introduction in 1950, deployed widely in the treatment of diverse diseases such as cancers, myelodysplastic syndromes, multiple sclerosis, and viral infections. These antimetabolites establish complex interactions with cellular molecular constituents, primarily via activation of phosphorylation cascades leading to consequential interactions with nucleic acids. However, the therapeutic efficacy of these agents is frequently compromised by the development of drug resistance, a continually emerging challenge in their clinical application. This comprehensive review explores the mechanisms of resistance to nucleoside-based drugs, encompassing a wide spectrum of phenomena from alterations in membrane transporters and activating kinases to changes in drug elimination strategies and DNA damage repair mechanisms. The critical analysis in this review underlines complex interactions of drug and cell and also guides towards novel therapeutic strategies to counteract resistance. The development of targeted therapies, novel nucleoside analogs, and synergistic drug combinations are promising approaches to restore tumor sensitivity and improve patient outcomes.
Topics: Humans; Nucleosides; Antineoplastic Agents; Neoplasms; Drug Resistance; Membrane Transport Proteins; Antimetabolites
PubMed: 37567317
DOI: 10.1016/j.bcp.2023.115741 -
World Journal of Gastroenterology Nov 2018Glutathione (GSH) is a tripeptide that constitutes one of the main intracellular reducing compounds. The normal content of GSH in the intestine is essential to optimize... (Review)
Review
Glutathione (GSH) is a tripeptide that constitutes one of the main intracellular reducing compounds. The normal content of GSH in the intestine is essential to optimize the intestinal Ca absorption. The use of GSH depleting drugs such as DL-buthionine-S,R-sulfoximine, menadione or vitamin K, sodium deoxycholate or diets enriched in fructose, which induce several features of the metabolic syndrome, produce inhibition of the intestinal Ca absorption. The GSH depleting drugs switch the redox state towards an oxidant condition provoking oxidative/nitrosative stress and inflammation, which lead to apoptosis and/or autophagy of the enterocytes. Either the transcellular Ca transport or the paracellular Ca route are altered by GSH depleting drugs. The gene and/or protein expression of transporters involved in the transcellular Ca pathway are decreased. The flavonoids quercetin and naringin highly abrogate the inhibition of intestinal Ca absorption, not only by restoration of the GSH levels in the intestine but also by their anti-apoptotic properties. Ursodeoxycholic acid, melatonin and glutamine also block the inhibition of Ca transport caused by GSH depleting drugs. The use of any of these antioxidants to ameliorate the intestinal Ca absorption under oxidant conditions associated with different pathologies in humans requires more investigation with regards to the safety, pharmacokinetics and pharmacodynamics of them.
Topics: Antimetabolites; Antioxidants; Calcium; Glutathione; Humans; Intestinal Absorption; Intestinal Mucosa; Oxidants
PubMed: 30510373
DOI: 10.3748/wjg.v24.i44.4979 -
Journal of Biological Rhythms Apr 2023The circadian timing system controls absorption, distribution, metabolism, and elimination processes of drug pharmacokinetics over a 24-h period. Exposure of target...
The circadian timing system controls absorption, distribution, metabolism, and elimination processes of drug pharmacokinetics over a 24-h period. Exposure of target tissues to the active form of the drug and cytotoxicity display variations depending on the chronopharmacokinetics. For anticancer drugs with narrow therapeutic ranges and dose-limiting side effects, it is particularly important to know the temporal changes in pharmacokinetics. A previous study indicated that pharmacokinetic profile of capecitabine was different depending on dosing time in rat. However, it is not known how such difference is attributed with respect to diurnal rhythm. Therefore, in this study, we evaluated capecitabine-metabolizing enzymes in a diurnal rhythm-dependent manner. To this end, C57BL/6J male mice were orally treated with 500 mg/kg capecitabine at ZT1, ZT7, ZT13, or ZT19. We then determined pharmacokinetics of capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine (5'DFCR), 5'-deoxy-5-fluorouridine (5'DFUR), 5-fluorouracil (5-FU), in plasma and liver. Results revealed that plasma and AUC (area under the plasma concentration-time curve from 0 to 6 h) values of capecitabine, 5'DFUR, and 5-FU were higher during the rest phase (ZT1 and ZT7) than the activity phase (ZT13 and ZT19) ( < 0.05). Similarly, and AUC values of 5'DFUR and 5-FU in liver were higher during the rest phase than activity phase ( < 0.05), while there was no significant difference in liver concentrations of capecitabine and 5'DFCR. We determined the level of the enzymes responsible for the conversion of capecitabine and its metabolites at each ZT. Results indicated the levels of carboxylesterase 1 and 2, cytidine deaminase, uridine phosphorylase 2, and dihydropyrimidine dehydrogenase ( < 0.05) are being rhythmically regulated and, in turn, attributed different pharmacokinetics profiles of capecitabine and its metabolism. This study highlights the importance of capecitabine administration time to increase the efficacy with minimum adverse effects.
Topics: Male; Mice; Rats; Animals; Capecitabine; Antimetabolites, Antineoplastic; Circadian Rhythm; Mice, Inbred C57BL; Fluorouracil
PubMed: 36762608
DOI: 10.1177/07487304221148779 -
IUBMB Life Mar 2017Glycolytic inhibitors are of interest therapeutically as they are effective against cancers that display increased glycolytic rate and mitochondrial defects.... (Review)
Review
Glycolytic inhibitors are of interest therapeutically as they are effective against cancers that display increased glycolytic rate and mitochondrial defects. 2-Deoxyglucose (2-DG) is one such glycolytic inhibitor and was identified to be a competitive inhibitor of glucose. Studies from past few decades have shown that the mechanism of action of 2-DG is complex involving several metabolic and signaling pathways. Budding yeast Saccharomyces cerevisiae and fission yeast Schizosaccharomyces pombe are two important models for studying metabolism, cell cycle and cell signaling. These two unicellular eukaryotes are Crabtree positive yeasts exhibiting a metabolism similar to that of cancer cells. Effects of 2-DG in yeast is of interest owing to these similarities and hence yeasts have emerged as ideal model organisms to study the mode of action and resistance to 2-DG. In this review, we summarize the studies on biological effect and resistance to 2-DG in budding and fission yeasts and give an insight into its possible mechanism of action as models for understanding cancer metabolism and drugs affecting cancer progression. © 2017 IUBMB Life, 69(3):137-147, 2017.
Topics: Animals; Antimetabolites, Antineoplastic; Cell Line, Tumor; Deoxyglucose; Drug Screening Assays, Antitumor; Energy Metabolism; Humans; Neoplasms; Schizosaccharomyces
PubMed: 28093891
DOI: 10.1002/iub.1599 -
American Journal of Hematology Jan 2016Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders with an inherent tendency for leukemic transformation. Diagnosis is currently... (Review)
Review
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders with an inherent tendency for leukemic transformation. Diagnosis is currently based on the presence of peripheral blood cytopenias, peripheral blood and bone marrow dysplasia/blasts, and clonal cytogenetic abnormalities. With the advent of next generation sequencing, recurrent somatic mutations in genes involved in epigenetic regulation (TET2, ASXL1, EZH2, DNMT3A, IDH1/2), RNA splicing (SF3B1, SRSF2, U2AF1, ZRSR2), DNA damage response (TP53), transcriptional regulation (RUNX1, BCOR, ETV6) and signal transduction (CBL, NRAS, JAK2) have been identified in MDS. Conventional prognostication is by the revised International prognostic scoring system (IPSS-R) with additional adverse prognosis conferred by presence of ASXL1, EZH2, or TP53 mutations. Currently Food and Drug administration (FDA)-approved drugs for the treatment of MDS are not curative and their effect on survival is limited; they include the hypomethylating agents (HMA) azacitidine and decitabine and lenalidomide for MDS with isolated del(5q). To date, allogeneic stem cell transplant (ASCT) remains the only treatment option for possible cure. Given the current lack of drugs with convincing evidence of favorable effect on survival, we consider ASCT as the treatment of choice for most patients with symptomatic disease, and especially for those with high-risk disease. For nontransplant candidates, participation in clinical trials is preferred over conventional therapy. There is not one right way of treatment for patients who are not candidates for either ASCT or clinical trials and palliative drugs of choice depend on the clinical problem, such as symptomatic anemia (ESAs, danazol, HMA), thrombocytopenia (HMA), or neutropenia (myeloid growth factors). Conversely, there is no controlled evidence to support the use of iron chelating agents in MDS. Going forward, we believe it is time to incorporate mutation information in clinically derived prognostic models in MDS and encourage development of novel drugs with disease-modifying activity.
Topics: Antimetabolites, Antineoplastic; Azacitidine; Decitabine; Disease-Free Survival; Humans; Myelodysplastic Syndromes; Stem Cell Transplantation
PubMed: 26769228
DOI: 10.1002/ajh.24253 -
Protein Science : a Publication of the... Feb 2016The AbgT family of transporters was thought to contribute to bacterial folate biosynthesis by importing the catabolite p-aminobenzoyl-glutamate for producing this... (Review)
Review
The AbgT family of transporters was thought to contribute to bacterial folate biosynthesis by importing the catabolite p-aminobenzoyl-glutamate for producing this essential vitamin. Approximately 13,000 putative transporters of the family have been identified. However, before our work, no structural information was available and even functional data were minimal for this family of membrane proteins. To elucidate the structure and function of the AbgT family of transporters, we recently determined the X-ray structures of the full-length Alcanivorax borkumensis YdaH and Neisseria gonorrhoeae MtrF membrane proteins. The structures reveal that these two transporters assemble as dimers with architectures distinct from all other families of transporters. Both YdaH and MtrF are bowl-shaped dimers with a solvent-filled basin extending from the cytoplasm halfway across the membrane bilayer. The protomers of YdaH and MtrF contain nine transmembrane helices and two hairpins. These structures directly suggest a plausible pathway for substrate transport. A combination of the crystal structure, genetic analysis and substrate accumulation assay indicates that both YdaH and MtrF behave as exporters, capable of removing the folate metabolite p-aminobenzoic acid from bacterial cells. Further experimental data based on drug susceptibility and radioactive transport assay suggest that both YdaH and MtrF participate as antibiotic efflux pumps, importantly mediating bacterial resistance to sulfonamide antimetabolite drugs. It is possible that many of these AbgT-family transporters act as exporters, thereby conferring bacterial resistance to sulfonamides. The AbgT-family transporters may be important targets for the rational design of novel antibiotics to combat bacterial infections.
Topics: Amino Acid Sequence; Anti-Bacterial Agents; Antimetabolites; Bacteria; Bacterial Proteins; Biological Transport; Crystallography, X-Ray; Folic Acid; Gene Expression Regulation, Bacterial; Membrane Transport Proteins; Models, Molecular; Molecular Sequence Data; Protein Conformation; Sequence Alignment
PubMed: 26443496
DOI: 10.1002/pro.2820 -
Cleveland Clinic Journal of Medicine Feb 2020Familial hypercholesterolemia is an autosomal dominant disorder that affects the metabolism of low-density lipo-protein cholesterol (LDL-C) through mutations in the gene... (Review)
Review
Familial hypercholesterolemia is an autosomal dominant disorder that affects the metabolism of low-density lipo-protein cholesterol (LDL-C) through mutations in the gene for LDL receptor (), and less commonly in those for apolipoprotein B (), proprotein convertase subtili-sin-kexin type 9 (), and others. Patients with these mutations have elevated plasma levels of LDL-C and, as a result, an increased risk of atherosclerotic cardiovascular disease beginning in childhood, leading to significant risk of illness and death.
Topics: Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Genetic Testing; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemia Type II; Medical History Taking; PCSK9 Inhibitors; Practice Guidelines as Topic; Receptors, LDL; Risk Assessment
PubMed: 32015064
DOI: 10.3949/ccjm.87a.19021 -
Molecules (Basel, Switzerland) Jul 2020We review developments in fluorine chemistry contributing to the more precise use of fluorinated pyrimidines (FPs) to treat cancer. 5-Fluorouracil (5-FU) is the most... (Review)
Review
We review developments in fluorine chemistry contributing to the more precise use of fluorinated pyrimidines (FPs) to treat cancer. 5-Fluorouracil (5-FU) is the most widely used FP and is used to treat > 2 million cancer patients each year. We review methods for 5-FU synthesis, including the incorporation of radioactive and stable isotopes to study 5-FU metabolism and biodistribution. We also review methods for preparing RNA and DNA substituted with FPs for biophysical and mechanistic studies. New insights into how FPs perturb nucleic acid structure and dynamics has resulted from both computational and experimental studies, and we summarize recent results. Beyond the well-established role for inhibiting thymidylate synthase (TS) by the 5-FU metabolite 5-fluoro-2'-deoxyuridine-5'--monophosphate (FdUMP), recent studies have implicated new roles for RNA modifying enzymes that are inhibited by 5-FU substitution including tRNA methyltransferase 2 homolog A (TRMT2A) and pseudouridylate synthase in 5-FU cytotoxicity. Furthermore, enzymes not previously implicated in FP activity, including DNA topoisomerase 1 (Top1), were established as mediating FP anti-tumor activity. We review recent literature summarizing the mechanisms by which 5-FU inhibits RNA- and DNA-modifying enzymes and describe the use of polymeric FPs that may enable the more precise use of FPs for cancer treatment in the era of personalized medicine.
Topics: Antimetabolites, Antineoplastic; Chemical Phenomena; DNA; Drug Development; Fluorine Compounds; Fluorouracil; Humans; Precision Medicine; Pyrimidines; RNA; Structure-Activity Relationship; Thymidylate Synthase
PubMed: 32751071
DOI: 10.3390/molecules25153438