Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal

Oxidative Medicine and Cellular Longevity, Год журнала: 2014, Номер 2014, С. 1 - 31

Опубликована: Янв. 1, 2014

Lipid peroxidation can be described generally as a process under which oxidants such free radicals attack lipids containing carbon-carbon double bond(s), especially polyunsaturated fatty acids (PUFAs). Over the last four decades, an extensive body of literature regarding lipid has shown its important role in cell biology and human health. Since early 1970s, total published research articles on topic was 98 (1970–1974) been increasing at almost 135-fold, by up to 13165 4 years (2010–2013). New discoveries about involvement cellular physiology pathology, well control peroxidation, continue emerge every day. Given enormity this field, review focuses biochemical concepts production, metabolism, signaling mechanisms two main omega-6 products: malondialdehyde (MDA) and, particular, 4-hydroxy-2-nonenal (4-HNE), summarizing not only physiological protective function molecule stimulating gene expression survival, but also cytotoxic inhibiting promoting death. Finally, overviews vivo mammalian model systems used study process, common pathological processes linked MDA 4-HNE are shown.

Язык: Английский

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Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis

Journal of Innate Immunity, Год журнала: 2016, Номер 8(4), С. 330 - 349

Опубликована: Янв. 1, 2016

R-roscovitine (seliciclib, CYC202) is a cyclin-dependent kinase inhibitor currently in phase II clinical trials patients with cancer. Here, we describe its mouse metabolism and pharmacokinetics as well the identification of principal metabolites hepatic microsomes, plasma, urine. Following microsomal incubation at 10 microg/mL (28 micromol/L) for 60 minutes, 86.7% parent drug was metabolized 60% this loss due to formation one particular metabolite. This identified carboxylic acid resulting from oxidation hydroxymethyl group amino alcohol substituent C2 purine core present R-roscovitine. Identification confirmed by chemical synthesis comparison an authentic sample R-roscovitine-derived carboxylate metabolite (COOH-R-roscovitine). Other minor were C8-oxo-R-roscovitine N9-desisopropyl-R-roscovitine; these accounted 4.9% 2.6% parent, respectively. The same metabolic pattern observed vivo, 4.5-fold lower AUC(infinity) (38 micromol/L/h) than COOH-R-roscovitine (174 micromol/L/h). Excretion urine up 24 hours post-dosing average only 0.02% administered dose 50 mg/kg, whereas represented 65% 68% irrespective route administration (i.v., i.p., or p.o.). A partially deuterated derivative (R-roscovitine-d9) synthesized investigate if could be inhibited replacement metabolically labile protons deuterium. After minutes R-roscovitine-d9 liver COOH-R-roscovitine-d9 decreased approximately 24% compared production COOH-R-roscovitine. In addition, levels remaining 33% higher those However, several enhanced R-roscovitine-d9, suggesting that switching major carbinol pathway had occurred. Synthetic tested functional assays shown less active R-roscovitine, confirming reactions are deactivation pathways.

Язык: Английский

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The history and future of targeting cyclin-dependent kinases in cancer therapy

Nature Reviews Drug Discovery, Год журнала: 2015, Номер 14(2), С. 130 - 146

Опубликована: Янв. 30, 2015

Язык: Английский

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Cyclin-dependent kinases

Genome biology, Год журнала: 2014, Номер 15(6)

Опубликована: Июнь 30, 2014

Cyclin-dependent kinases (CDKs) are protein characterized by needing a separate subunit - cyclin that provides domains essential for enzymatic activity. CDKs play important roles in the control of cell division and modulate transcription response to several extra- intracellular cues. The evolutionary expansion CDK family mammals led into three cell-cycle-related subfamilies (Cdk1, Cdk4 Cdk5) five transcriptional (Cdk7, Cdk8, Cdk9, Cdk11 Cdk20). Unlike prototypical Cdc28 kinase budding yeast, most these bind one or few cyclins, consistent with functional specialization during evolution. This review summarizes how, although traditionally separated cell-cycle CDKs, activities frequently combined many members. Not surprisingly, deregulation this proteins is hallmark diseases, including cancer, drug-targeted inhibition specific members has generated very encouraging results clinical trials.

Язык: Английский

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The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

International Journal of Molecular Sciences, Год журнала: 2020, Номер 21(6), С. 1960 - 1960

Опубликована: Март 13, 2020

Cyclin-dependent kinases (CDKs) are serine/threonine whose catalytic activities regulated by interactions with cyclins and CDK inhibitors (CKIs). CDKs key regulatory enzymes involved in cell proliferation through regulating cell-cycle checkpoints transcriptional events response to extracellular intracellular signals. Not surprisingly, the dysregulation of is a hallmark cancers, inhibition specific members considered an attractive target cancer therapy. In breast (BC), dual CDK4/6 inhibitors, palbociclib, ribociclib, abemaciclib, combined other agents, were approved Food Drug Administration (FDA) recently for treatment hormone receptor positive (HR+) advanced or metastatic (A/MBC), as well sub-types cancer. Furthermore, ongoing studies identified more selective promising clinical targets. this review, we focus on roles driving progression, checkpoints, regulation, highlight dysregulated activation BC. We also discuss most relevant currently BC trials, special emphasis used estrogen receptor-positive (ER+)/human epidermal growth factor 2-negative (HER2−) M/ABC patients, emerging precise therapeutic strategies, such combination therapies microRNA (miRNA)

Язык: Английский

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Evaluation of the use of therapeutic peptides for cancer treatment

Journal of Biomedical Science, Год журнала: 2017, Номер 24(1)

Опубликована: Март 21, 2017

Cancer along with cardiovascular disease are the main causes of death in industrialised countries around World. Conventional cancer treatments losing their therapeutic uses due to drug resistance, lack tumour selectivity and solubility as such there is a need develop new agents. Therapeutic peptides promising novel approach treat many diseases including cancer. They have several advantages over proteins or antibodies: they (a) easy synthesise, (b) high target specificity (c) low toxicity. do some significant drawbacks related stability short half-life. In this review, strategies used overcome peptide limitations enhance effect will be compared. The use cell permeable that interfere inhibit protein-protein interactions also evaluated.

Язык: Английский

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Single-cell multiomic analysis identifies regulatory programs in mixed-phenotype acute leukemia

Nature Biotechnology, Год журнала: 2019, Номер 37(12), С. 1458 - 1465

Опубликована: Дек. 1, 2019

Язык: Английский

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Cyclin-dependent protein serine/threonine kinase inhibitors as anticancer drugs

Pharmacological Research, Год журнала: 2018, Номер 139, С. 471 - 488

Опубликована: Ноя. 30, 2018

Язык: Английский

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CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought

Cancer Cell, Год журнала: 2018, Номер 34(1), С. 9 - 20

Опубликована: Май 3, 2018

Язык: Английский

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Targeting Cyclin-Dependent Kinases in Human Cancers: From Small Molecules to Peptide Inhibitors

Cancers, Год журнала: 2015, Номер 7(1), С. 179 - 237

Опубликована: Янв. 23, 2015

Cyclin-dependent kinases (CDK/Cyclins) form a family of heterodimeric that play central roles in regulation cell cycle progression, transcription and other major biological processes including neuronal differentiation metabolism. Constitutive or deregulated hyperactivity these due to amplification, overexpression mutation cyclins CDK, contributes proliferation cancer cells, aberrant activity has been reported wide variety human cancers. These therefore constitute biomarkers attractive pharmacological targets for development anticancer therapeutics. The structural features several have elucidated their molecular mechanisms characterized depth, providing clues drugs inhibitors disrupt function. However, like most kinases, they challenging class therapeutic highly conserved ATP-binding pocket. Notwithstanding, classes discovered from natural sources, small molecule derivatives synthesized through rational, structure-guided approaches identified high throughput screens. larger part target ATP pockets, but growing number peptides targeting protein/protein interfaces are being proposed, compounds allosteric sites reported.

Язык: Английский

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