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1
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Qin K, Wu L, Fu S, Que H, Shi B. Transcriptomic Analysis Reveals the Mechanisms of Cadmium Transport and Detoxification in Portuguese Oysters ( Crassostrea angulata). Animals (Basel) 2025; 15:1041. [PMID: 40218434 PMCID: PMC11988029 DOI: 10.3390/ani15071041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 03/23/2025] [Accepted: 04/01/2025] [Indexed: 04/14/2025] Open
Abstract
Oysters are a globally distributed aquatic economic shellfish with a remarkable ability to accumulate cadmium (Cd). The phenomenon of Cd content exceeding safety standards in oysters occurs frequently, posing a significant risk to food safety. In this study, Portuguese oysters (Crassostrea angulata) were exposed to 2 μg/L of Cd for 15 days. Individuals with significantly different Cd accumulation were selected for transcriptomic sequencing analysis. KEGG enrichment analysis revealed that the differentially expressed genes (DEGs) between high- and low-Cd-accumulation individuals, as well as those before and after Cd exposure, were primarily enriched in metabolic pathways (33.8%) and organismal systems (32.2%). ABC transporters, phagosomes, glutathione metabolism, and the biosynthesis of amino acids played crucial roles in Cd accumulation and detoxification processes. Metal cation transport-related genes, including zip1, copt5.1, and orct2, may be involved in the Cd transport process in Portuguese oysters, and their differential expression influences Cd accumulation in the soft tissues. Meanwhile, genes such as sod3, cyp4f22, and abca3 are likely to play significant roles in detoxification under Cd exposure. Additionally, alternative splicing analysis identified 13 potential genes associated with Cd response in Portuguese oysters, including cs2, gfpt1, and acox1.
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Affiliation(s)
| | | | | | - Huayong Que
- State Key Laboratory of Mariculture Breeding, Fisheries College, Jimei University, Xiamen 361005, China; (K.Q.); (L.W.); (S.F.)
| | - Bo Shi
- State Key Laboratory of Mariculture Breeding, Fisheries College, Jimei University, Xiamen 361005, China; (K.Q.); (L.W.); (S.F.)
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2
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Qiu C, Lu Y, Wu S, Guo W, Ni J, Song J, Liu Z, Chang X, Wang K, Sun P, Zhang Q, Yang S, Li K. Blocking Adipocyte YY1 Decouples Thermogenesis From Beneficial Metabolism by Promoting Spermidine Production. Diabetes 2025; 74:295-307. [PMID: 39621859 DOI: 10.2337/db24-0501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 11/25/2024] [Indexed: 02/22/2025]
Abstract
The accumulation of mitochondria in thermogenic adipose tissue (i.e., brown and beige fat) increases energy expenditure, which can aid in alleviating obesity and metabolic disorders. However, recent studies have shown that knocking out key proteins required to maintain mitochondrial function inhibits the energy expenditure in thermogenic fat, and yet the knockout (KO) mice are unexpectedly protected from developing obesity or metabolic disorders when fed a high-fat diet (HFD). In the current study, nonbiased sequencing-based screening revealed the importance of Yin Yang 1 (YY1) in the transcription of electron transport chain genes and the enhancement of mitochondrial function in thermogenic adipose tissue. Specifically, YY1 adipocyte-null (YAKO) mice showed lower energy expenditure and were intolerant to cold stress. Interestingly, YAKO mice showed alleviation of HFD-induced metabolic disorders, which can be attributed to a suppression of adipose tissue inflammation. Metabolomic analysis revealed that blocking YY1 directed glucose metabolism toward lactate, enhanced the uptake of glutamine, and promoted the production of anti-inflammatory spermidine. Conversely, blocking spermidine production in YAKO mice reversed their resistance to HFD-induced disorders. Thus, although blocking adipocyte YY1 impairs the thermogenesis, it promotes spermidine production, alleviates adipose tissue inflammation, and therefore leads to an uncoupling of adipose tissue energy expenditure from HFD-induced metabolic disorders. ARTICLE HIGHLIGHTS Chromatin open atlas profiling in white, beige, and brown adipocytes identified Yin Yang 1 (YY1) as a key transcription factor governing electron transport chain gene expression and mitochondrial function in thermogenic adipocytes. Knocking out adipocyte YY1 leads to impaired thermogenesis under cold stress while protecting the mice from diet-induced obesity and metabolic disorders. YY1-null adipocytes undergo metabolic reprogramming, with increased glutamine use and spermidine generation that combat adipose tissue inflammation and insulin resistance, resulting in an uncoupling of thermogenic capacity and metabolic benefits.
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Affiliation(s)
- Chen Qiu
- Department of Endocrinology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
- Key Laboratory of the Model Animal Research, Animal Core Facility of Nanjing Medical University, Nanjing, China
| | - Yu Lu
- Department of Endocrinology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China
| | - Suyang Wu
- Department of Science and Technology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Nanjing, China
| | - Wenli Guo
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Jiahao Ni
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Jiyuan Song
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Zichao Liu
- Department of Nutrition and Health, China Agricultural University, Beijing, China
| | - Xiaoai Chang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Kai Wang
- Endocrine and Metabolic Disease Medical Center, Drum Tower Hospital affiliated to Nanjing University Medical School, Nanjing, China
- Department of Medical Technology, Anhui Medical College, Hefei, Anhui, China
| | - Peng Sun
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Qian Zhang
- Department of Nutrition and Health, China Agricultural University, Beijing, China
| | - Shufang Yang
- Department of Endocrinology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China
- School of Medicine, Southeast University, Nanjing, China
| | - Kai Li
- Department of Endocrinology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
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3
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Filisola-Villaseñor JG, Arroyo-Sánchez BI, Navarro-González LJ, Morales-Ríos E, Olin-Sandoval V. Ornithine decarboxylase and its role in cancer. Arch Biochem Biophys 2025; 765:110321. [PMID: 39870288 DOI: 10.1016/j.abb.2025.110321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 01/03/2025] [Accepted: 01/24/2025] [Indexed: 01/29/2025]
Abstract
Cancer is among the leading causes of death worldwide. The effectiveness of conventional chemotherapy has some drawbacks, therefore, there is an urgency to develop novel strategies to fight this disease. Ornithine decarboxylase (ODC) is the most finely tuned enzyme of the polyamine (PA) biosynthesis pathway as it is regulated at different levels: transcriptional, translational, post-translational, and by feedback inhibition. In cancer, this enzyme is overexpressed due to its regulation by the protooncogene c-Myc, thus it has been proposed as a drug target against this disease. This review describes information regarding the biochemistry and regulation of the ODC at different levels and its role in cancer. Moreover, we discuss the molecules aiming on the inhibition of the ODC activity that have been tested as therapeutic options. ODC remains as a therapeutic opportunity that needs to be more explored.
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Affiliation(s)
| | - Beatriz Irene Arroyo-Sánchez
- Department of Biotechnology and Bioengineering, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico
| | - Luis Janiel Navarro-González
- Department of Biochemistry, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico
| | - Edgar Morales-Ríos
- Department of Biochemistry, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico.
| | - Viridiana Olin-Sandoval
- Department of Biotechnology and Bioengineering, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico.
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4
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Pochini L. Involvement of mammalian SoLute Carriers (SLC) in the traffic of polyamines. Front Mol Biosci 2024; 11:1452184. [PMID: 39130372 PMCID: PMC11310933 DOI: 10.3389/fmolb.2024.1452184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 07/10/2024] [Indexed: 08/13/2024] Open
Abstract
Polyamines interact with different molecular targets to regulate a vast range of cellular processes. A network of enzymes and transport systems is crucial for the maintenance of polyamine homeostasis. Indeed, polyamines after synthesis must be distributed to the various tissues and some intracellular organelles. Differently from the well characterized enzymes devoted to polyamine synthesis, the transport systems are not unequivocally identified or characterized. Besides some ATPases which have been identified as polyamine transporters, much less is known about solute carriers (SLC) involved in the transport of these compounds. Only two SLCs have been unequivocally identified as polyamine transporters: SLC18B1 (VPAT) and SLC22A4 (OCTN1). Transport studies have been performed with cells transfected with the cDNAs encoding the two and other SLCs or, in the case of OCTN1, also by in vitro assay using proteoliposomes harboring the recombinant human protein. According to the role proposed for OCTN1, polyamines have been associated with prolonged and quality of life. This review provides an update on the most recent findings concerning the polyamine transporters or the prediction of the putative ones.
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Affiliation(s)
- Lorena Pochini
- Laboratory of Biochemistry, Molecular Biotechnology and Molecular Biology, Department DiBEST (Biologia, Ecologia, Scienze Della Terra), University of Calabria, Rende, Italy
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council (CNR), Bari, Italy
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Zayas-Santiago A, Malpica-Nieves CJ, Ríos DS, Díaz-García A, Vázquez PN, Santiago JM, Rivera-Aponte DE, Veh RW, Méndez-González M, Eaton M, Skatchkov SN. Spermidine Synthase Localization in Retinal Layers: Early Age Changes. Int J Mol Sci 2024; 25:6458. [PMID: 38928162 PMCID: PMC11204015 DOI: 10.3390/ijms25126458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 06/06/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024] Open
Abstract
Polyamine (PA) spermidine (SPD) plays a crucial role in aging. Since SPD accumulates in glial cells, particularly in Müller retinal cells (MCs), the expression of the SPD-synthesizing enzyme spermidine synthase (SpdS) in Müller glia and age-dependent SpdS activity are not known. We used immunocytochemistry, Western blot (WB), and image analysis on rat retinae at postnatal days 3, 21, and 120. The anti-glutamine synthetase (GS) antibody was used to identify glial cells. In the neonatal retina (postnatal day 3 (P3)), SpdS was expressed in almost all progenitor cells in the neuroblast. However, by day 21 (P21), the SpdS label was pronouncedly expressed in multiple neurons, while GS labels were observed only in radial Müller glial cells. During early cell adulthood, at postnatal day 120 (P120), SpdS was observed solely in ganglion cells and a few other neurons. Western blot and semi-quantitative analyses of SpdS labeling showed a dramatic decrease in SpdS at P21 and P120 compared to P3. In conclusion, the redistribution of SpdS with aging indicates that SPD is first synthesized in all progenitor cells and then later in neurons, but not in glia. However, MCs take up and accumulate SPD, regardless of the age-associated decrease in SPD synthesis in neurons.
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Affiliation(s)
- Astrid Zayas-Santiago
- Department of Pathology and Laboratory Medicine, Universidad Central del Caribe, Bayamón, PR 00956, USA;
| | | | - David S. Ríos
- College of Science and Health Professions, Universidad Central de Bayamón, Bayamón, PR 00960, USA;
| | - Amanda Díaz-García
- Department of Biochemistry, Universidad Central del Caribe, Bayamón, PR 00956, USA; (A.D.-G.); (D.E.R.-A.); (M.E.)
| | - Paola N. Vázquez
- Department of Natural Sciences, University of Puerto Rico-Carolina, Carolina, PR 00984, USA; (P.N.V.); (J.M.S.)
| | - José M. Santiago
- Department of Natural Sciences, University of Puerto Rico-Carolina, Carolina, PR 00984, USA; (P.N.V.); (J.M.S.)
| | - David E. Rivera-Aponte
- Department of Biochemistry, Universidad Central del Caribe, Bayamón, PR 00956, USA; (A.D.-G.); (D.E.R.-A.); (M.E.)
| | - Rüdiger W. Veh
- Charité–Universitätsmedizin Berlin, Institut für Zell- und Neurobiologie, Centrum 2, Charitéplatz 1, D-10117 Berlin, Germany;
| | | | - Misty Eaton
- Department of Biochemistry, Universidad Central del Caribe, Bayamón, PR 00956, USA; (A.D.-G.); (D.E.R.-A.); (M.E.)
| | - Serguei N. Skatchkov
- Department of Biochemistry, Universidad Central del Caribe, Bayamón, PR 00956, USA; (A.D.-G.); (D.E.R.-A.); (M.E.)
- Department of Physiology, Universidad Central del Caribe, Bayamón, PR 00956, USA
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Vieira LS, Seguin RP, Xu L, Wang J. Interaction and Transport of Benzalkonium Chlorides by the Organic Cation and Multidrug and Toxin Extrusion Transporters. Drug Metab Dispos 2024; 52:312-321. [PMID: 38307853 PMCID: PMC10955720 DOI: 10.1124/dmd.123.001625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/28/2024] [Accepted: 01/29/2024] [Indexed: 02/04/2024] Open
Abstract
Humans are chronically exposed to benzalkonium chlorides (BACs) from environmental sources. The U.S. Food and Drug Administration (FDA) has recently called for additional BAC safety data, as these compounds are cytotoxic and have great potential for biochemical interactions. Biodistribution studies revealed that BACs extensively distribute to many tissues and accumulate at high levels, especially in the kidneys, but the underlying mechanisms are unclear. In this study, we characterized the interactions of BACs of varying alkyl chain length (C8 to C14) with the human organic cation transporters (hOCT1-3) and multidrug and toxin extrusion proteins (hMATE1/2K) with the goal to identify transporters that could be involved in BAC disposition. Using transporter-expressing cell lines, we showed that all BACs are inhibitors of hOCT1-3 and hMATE1/2K (IC50 ranging 0.83-25.8 μM). Further, the short-chain BACs (C8 and C10) were identified as substrates of these transporters. Interestingly, although BAC C8 displayed typical Michaelis-Menten kinetics, C10 demonstrated a more complex substrate-inhibition profile. Transwell studies with transfected Madin-Darby canine kidney cells revealed that intracellular accumulation of basally applied BAC C8 and C10 was substantially higher (8.2- and 3.7-fold, respectively) in hOCT2/hMATE1 double-transfected cells in comparison with vector-transfected cells, supporting a role of these transporters in mediating renal accumulation of these compounds in vivo. Together, our results suggest that BACs interact with hOCT1-3 and hMATE1/2K as both inhibitors and substrates and that these transporters may play important roles in tissue-specific accumulation and potential toxicity of short-chain BACs. Our findings have important implications for understanding human exposure and susceptibility to BACs due to environmental exposure. SIGNIFICANCE STATEMENT: Humans are systemically exposed to benzalkonium chlorides (BACs). These compounds broadly distribute through tissues, and their safety has been questioned by the FDA. Our results demonstrate that hOCT2 and hMATE1 contribute to the renal accumulation of BAC C8 and C10 and that hOCT1 and hOCT3 may be involved in the tissue distribution of these compounds. These findings can improve our understanding of BAC disposition and toxicology in humans, as their accumulation could lead to biochemical interactions and deleterious effects.
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Affiliation(s)
- Letícia Salvador Vieira
- Department of Pharmaceutics (L.S.V., J.W.), Department of Medicinal Chemistry (R.P.S., L.X.), and Department of Environmental and Occupational Health Sciences, School of Public Health (L.X.), University of Washington, Seattle, Washington
| | - Ryan P Seguin
- Department of Pharmaceutics (L.S.V., J.W.), Department of Medicinal Chemistry (R.P.S., L.X.), and Department of Environmental and Occupational Health Sciences, School of Public Health (L.X.), University of Washington, Seattle, Washington
| | - Libin Xu
- Department of Pharmaceutics (L.S.V., J.W.), Department of Medicinal Chemistry (R.P.S., L.X.), and Department of Environmental and Occupational Health Sciences, School of Public Health (L.X.), University of Washington, Seattle, Washington
| | - Joanne Wang
- Department of Pharmaceutics (L.S.V., J.W.), Department of Medicinal Chemistry (R.P.S., L.X.), and Department of Environmental and Occupational Health Sciences, School of Public Health (L.X.), University of Washington, Seattle, Washington
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7
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Sao Emani C, Reiling N. The efflux pumps Rv1877 and Rv0191 play differential roles in the protection of Mycobacterium tuberculosis against chemical stress. Front Microbiol 2024; 15:1359188. [PMID: 38516013 PMCID: PMC10956863 DOI: 10.3389/fmicb.2024.1359188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 02/12/2024] [Indexed: 03/23/2024] Open
Abstract
Background It was previously shown that GlnA3sc enabled Streptomyces coelicolor to survive in excess polyamines. However, subsequent studies revealed that Rv1878, the corresponding Mycobacterium tuberculosis (M.tb) ortholog, was not essential for the detoxification of spermine (Spm), in M.tb. On the other hand, the multi-drug efflux pump Rv1877 was previously shown to enable export of a wide range of compounds, while Rv0191 was shown to be more specific to chloramphenicol. Rationale Therefore, we first wanted to determine if detoxification of Spm by efflux can be achieved by any efflux pump, or if that was dependent upon the function of the pump. Next, since Rv1878 was found not to be essential for the detoxification of Spm, we sought to follow-up on the investigation of the physiological role of Rv1878 along with Rv1877 and Rv0191. Approach To evaluate the specificity of efflux pumps in the mycobacterial tolerance to Spm, we generated unmarked ∆rv1877 and ∆rv0191 M.tb mutants and evaluated their susceptibility to Spm. To follow up on the investigation of any other physiological roles they may have, we characterized them along with the ∆rv1878 M.tb mutant. Results The ∆rv1877 mutant was sensitive to Spm stress, while the ∆rv0191 mutant was not. On the other hand, the ∆rv1878 mutant grew better than the wild-type during iron starvation yet was sensitive to cell wall stress. The proteins Rv1877 and Rv1878 seemed to play physiological roles during hypoxia and acidic stress. Lastly, the ∆rv0191 mutant was the only mutant that was sensitive to oxidative stress. Conclusion The multidrug MFS-type efflux pump Rv1877 is required for Spm detoxification, as opposed to Rv0191 which seems to play a more specific role. Moreover, Rv1878 seems to play a role in the regulation of iron homeostasis and the reconstitution of the cell wall of M.tb. On the other hand, the sensitivity of the ∆rv0191 mutant to oxidative stress, suggests that Rv0191 may be responsible for the transport of low molecular weight thiols.
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Affiliation(s)
- Carine Sao Emani
- Microbial Interface Biology, Research Center Borstel, Leibniz Lung Center, Borstel, Germany
| | - Norbert Reiling
- Microbial Interface Biology, Research Center Borstel, Leibniz Lung Center, Borstel, Germany
- German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Borstel, Germany
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Ojomoko LO, Kryukova EV, Egorova NS, Salikhov AI, Epifanova LA, Denisova DA, Khomutov AR, Sukhov DA, Vassilevski AA, Khomutov MA, Tsetlin VI, Shelukhina IV. Inhibition of nicotinic acetylcholine receptors by oligoarginine peptides and polyamine-related compounds. Front Pharmacol 2023; 14:1327603. [PMID: 38169863 PMCID: PMC10758494 DOI: 10.3389/fphar.2023.1327603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 11/30/2023] [Indexed: 01/05/2024] Open
Abstract
Oligoarginine peptides, known mostly for their cell-penetrating properties, are also inhibitors of the nicotinic acetylcholine receptors (nAChRs). Since octa-arginine (R8) inhibits α9α10 nAChR and suppresses neuropathic pain, we checked if other polycationic compounds containing amino and/or guanidino groups could be effective and tested the activity of the disulfide-fixed "cyclo"R8, a series of biogenic polyamines (putrescine, spermidine, and spermine), C-methylated spermine analogs, agmatine and its analogs, as well as acylpolyamine argiotoxin-636 from spider venom. Their inhibitory potency on muscle-type, α7 and α9α10 nAChRs was determined using radioligand analysis, electrophysiology, and calcium imaging. "Cyclo"R8 showed similar activity to that of R8 against α9α10 nAChR (IC50 ≈ 60 nM). Biogenic polyamines as well as agmatine and its analogs displayed low activity on muscle-type Torpedo californica, as well as α7 and α9α10 nAChRs, which increased with chain length, the most active being spermine and its C-methylated derivatives having IC50 of about 30 μM against muscle-type T. californica nAChR. Argiotoxin-636, which contains a polyamine backbone and terminal guanidino group, also weakly inhibited T. californica nAChR (IC50 ≈ 15 μM), but it revealed high potency against rat α9α10 nAChR (IC50 ≈ 200 nM). We conclude that oligoarginines and similar polycationic compounds effectively inhibiting α9α10 nAChR may serve as a basis for the development of analgesics to reduce neuropathic pain.
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Affiliation(s)
- Lucy O. Ojomoko
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | - Elena V. Kryukova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | - Natalya S. Egorova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | - Arthur I. Salikhov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Lyubov A. Epifanova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | - Daria A. Denisova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | - Alex R. Khomutov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Dmitry A. Sukhov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | - Alexander A. Vassilevski
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
- Moscow Institute of Physics and Technology (State University), Moscow, Russia
| | - Maxim A. Khomutov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Victor I. Tsetlin
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | - Irina V. Shelukhina
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
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Jimenez Gutierrez GE, Borbolla Jiménez FV, Muñoz LG, Tapia Guerrero YS, Murillo Melo NM, Cristóbal-Luna JM, Leyva Garcia N, Cordero-Martínez J, Magaña JJ. The Molecular Role of Polyamines in Age-Related Diseases: An Update. Int J Mol Sci 2023; 24:16469. [PMID: 38003659 PMCID: PMC10671757 DOI: 10.3390/ijms242216469] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 11/09/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
Polyamines (Pas) are short molecules that exhibit two or three amine groups that are positively charged at a physiological pH. These small molecules are present in high concentrations in a wide variety of organisms and tissues, suggesting that they play an important role in cellular physiology. Polyamines include spermine, spermidine, and putrescine, which play important roles in age-related diseases that have not been completely elucidated. Aging is a natural process, defined as the time-related deterioration of the physiological functions; it is considered a risk factor for degenerative diseases such as cardiovascular, neurodegenerative, and musculoskeletal diseases; arthritis; and even cancer. In this review, we provide a new perspective on the participation of Pas in the cellular and molecular processes related to age-related diseases, focusing our attention on important degenerative diseases such as Alzheimerߣs disease, Parkinsonߣs disease, osteoarthritis, sarcopenia, and osteoporosis. This new perspective leads us to propose that Pas function as novel biomarkers for age-related diseases, with the main purpose of achieving new molecular alternatives for healthier aging.
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Affiliation(s)
- Guadalupe Elizabeth Jimenez Gutierrez
- Laboratorio de Medicina Genómica, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico; (G.E.J.G.); (F.V.B.J.); (L.G.M.); (Y.S.T.G.); (N.M.M.M.); (N.L.G.)
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City 04510, Mexico
| | - Fabiola V. Borbolla Jiménez
- Laboratorio de Medicina Genómica, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico; (G.E.J.G.); (F.V.B.J.); (L.G.M.); (Y.S.T.G.); (N.M.M.M.); (N.L.G.)
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City 04510, Mexico
| | - Luis G. Muñoz
- Laboratorio de Medicina Genómica, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico; (G.E.J.G.); (F.V.B.J.); (L.G.M.); (Y.S.T.G.); (N.M.M.M.); (N.L.G.)
| | - Yessica Sarai Tapia Guerrero
- Laboratorio de Medicina Genómica, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico; (G.E.J.G.); (F.V.B.J.); (L.G.M.); (Y.S.T.G.); (N.M.M.M.); (N.L.G.)
| | - Nadia Mireya Murillo Melo
- Laboratorio de Medicina Genómica, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico; (G.E.J.G.); (F.V.B.J.); (L.G.M.); (Y.S.T.G.); (N.M.M.M.); (N.L.G.)
| | - José Melesio Cristóbal-Luna
- Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional, Mexico City 07738, Mexico;
| | - Norberto Leyva Garcia
- Laboratorio de Medicina Genómica, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico; (G.E.J.G.); (F.V.B.J.); (L.G.M.); (Y.S.T.G.); (N.M.M.M.); (N.L.G.)
| | - Joaquín Cordero-Martínez
- Laboratorio de Bioquímica Farmacológica, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | - Jonathan J. Magaña
- Laboratorio de Medicina Genómica, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico; (G.E.J.G.); (F.V.B.J.); (L.G.M.); (Y.S.T.G.); (N.M.M.M.); (N.L.G.)
- Department of Bioengineering, Escuela de Ingeniería y Ciencias, Tecnologico de Monterrey, Campus Ciudad de México, Mexico City 14380, Mexico
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10
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Schweighofer N, Strasser M, Obermayer A, Trummer O, Sourij H, Sourij C, Obermayer-Pietsch B. Identification of Novel Intronic SNPs in Transporter Genes Associated with Metformin Side Effects. Genes (Basel) 2023; 14:1609. [PMID: 37628660 PMCID: PMC10454417 DOI: 10.3390/genes14081609] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 08/08/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Metformin is a widely used and effective medication in type 2 diabetes (T2DM) as well as in polycystic ovary syndrome (PCOS). Single nucleotide polymorphisms (SNPs) contribute to the occurrence of metformin side effects. The aim of the present study was to identify intronic genetic variants modifying the occurrence of metformin side effects and to replicate them in individuals with T2DM and in women with PCOS. We performed Next Generation Sequencing (Illumina Next Seq) of 115 SNPs in a discovery cohort of 120 metformin users and conducted a systematic literature review. Selected SNPs were analysed in two independent cohorts of individuals with either T2DM or PCOS, using 5'-3'exonucleaseassay. A total of 14 SNPs in the organic cation transporters (OCTs) showed associations with side effects in an unadjusted binary logistic regression model, with eight SNPs remaining significantly associated after appropriate adjustment in the discovery cohort. Five SNPs were confirmed in a combined analysis of both replication cohorts but showed different association patterns in subgroup analyses. In an unweighted polygenic risk score (PRS), the risk for metformin side effects increased with the number of risk alleles. Intronic SNPs in the OCT cluster contribute to the development of metformin side effects in individuals with T2DM and in women with PCOS and are therefore of interest for personalized therapy options.
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Affiliation(s)
- Natascha Schweighofer
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria; (N.S.); (M.S.); (A.O.); (H.S.); barbar (B.O.-P.)
- Center for Biomarker Research in Medicine, CBmed, 8010 Graz, Austria
| | - Moritz Strasser
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria; (N.S.); (M.S.); (A.O.); (H.S.); barbar (B.O.-P.)
- Department of Health Studies, Institute of Biomedical, FH Joanneum University of Applied Sciences, 8020 Graz, Austria
| | - Anna Obermayer
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria; (N.S.); (M.S.); (A.O.); (H.S.); barbar (B.O.-P.)
- Interdisciplinary Metabolic Medicine Trials Unit, Medical University of Graz, 8036 Graz, Austria
| | - Olivia Trummer
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria; (N.S.); (M.S.); (A.O.); (H.S.); barbar (B.O.-P.)
| | - Harald Sourij
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria; (N.S.); (M.S.); (A.O.); (H.S.); barbar (B.O.-P.)
- Interdisciplinary Metabolic Medicine Trials Unit, Medical University of Graz, 8036 Graz, Austria
| | - Caren Sourij
- Division of Cardiology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria;
| | - Barbara Obermayer-Pietsch
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria; (N.S.); (M.S.); (A.O.); (H.S.); barbar (B.O.-P.)
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11
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Benedikt J, Malpica-Nieves CJ, Rivera Y, Méndez-González M, Nichols CG, Veh RW, Eaton MJ, Skatchkov SN. The Polyamine Spermine Potentiates the Propagation of Negatively Charged Molecules through the Astrocytic Syncytium. Biomolecules 2022; 12:biom12121812. [PMID: 36551240 PMCID: PMC9775384 DOI: 10.3390/biom12121812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/16/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022] Open
Abstract
The interest in astrocytes, the silent brain cells that accumulate polyamines (PAs), is growing. PAs exert anti-inflammatory, antioxidant, antidepressant, neuroprotective, and other beneficial effects, including increasing longevity in vivo. Unlike neurons, astrocytes are extensively coupled to others via connexin (Cx) gap junctions (GJs). Although there are striking modulatory effects of PAs on neuronal receptors and channels, PA regulation of the astrocytic GJs is not well understood. We studied GJ-propagation using molecules of different (i) electrical charge, (ii) structure, and (iii) molecular weight. Loading single astrocytes with patch pipettes containing membrane-impermeable dyes, we observed that (i) even small molecules do not easily permeate astrocytic GJs, (ii) the ratio of the charge to weight of these molecules is the key determinant of GJ permeation, (iii) the PA spermine (SPM) induced the propagation of negatively charged molecules via GJs, (iv) while no effects were observed on propagation of macromolecules with net-zero charge. The GJ uncoupler carbenoxolone (CBX) blocked such propagation. Taken together, these findings indicate that SPM is essential for astrocytic GJ communication and selectively facilitates intracellular propagation via GJs for negatively charged molecules through glial syncytium.
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Affiliation(s)
- Jan Benedikt
- Department of Physiology, Universidad Central del Caribe, Bayamón, PR 00956, USA
| | - Christian J. Malpica-Nieves
- Department of Biochemistry, Universidad Central del Caribe, Bayamón, PR 00956, USA
- Correspondence: (C.J.M.-N.); (S.N.S.); Tel.: +1-787-798-3001 (ext. 2057) (S.N.S.)
| | - Yomarie Rivera
- Department of Chiropractic, Universidad Central del Caribe, Bayamón, PR 00956, USA
| | | | - Colin G. Nichols
- Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Rüdiger W. Veh
- Institut für Zell- und Neurobiologie, Charité, 10115 Berlin, Germany
| | - Misty J. Eaton
- Department of Biochemistry, Universidad Central del Caribe, Bayamón, PR 00956, USA
| | - Serguei N. Skatchkov
- Department of Physiology, Universidad Central del Caribe, Bayamón, PR 00956, USA
- Department of Biochemistry, Universidad Central del Caribe, Bayamón, PR 00956, USA
- Correspondence: (C.J.M.-N.); (S.N.S.); Tel.: +1-787-798-3001 (ext. 2057) (S.N.S.)
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12
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Azfar M, van Veen S, Houdou M, Hamouda NN, Eggermont J, Vangheluwe P. P5B-ATPases in the mammalian polyamine transport system and their role in disease. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2022; 1869:119354. [PMID: 36064065 DOI: 10.1016/j.bbamcr.2022.119354] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/26/2022] [Accepted: 08/27/2022] [Indexed: 06/15/2023]
Abstract
Polyamines (PAs) are physiologically relevant molecules that are ubiquitous in all organisms. The vitality of PAs to the healthy functioning of a cell is due to their polycationic nature causing them to interact with a vast plethora of cellular players and partake in numerous cellular pathways. Naturally, the homeostasis of such essential molecules is tightly regulated in a strictly controlled interplay between intracellular synthesis and degradation, uptake from and secretion to the extracellular compartment, as well as intracellular trafficking. Not surprisingly, dysregulated PA homeostasis and signaling are implicated in multiple disorders, ranging from cancer to neurodegeneration; leading many to propose rectifying the PA balance as a potential therapeutic strategy. Despite being well characterized in bacteria, fungi and plants, the molecular identity and properties of the PA transporters in animals are poorly understood. This review brings together the current knowledge of the cellular function of the mammalian PA transport system (PTS). We will focus on the role of P5B-ATPases ATP13A2-5 which are PA transporters in the endosomal system that have emerged as key players in cellular PA uptake and organelle homeostasis. We will discuss recent breakthroughs on their biochemical and structural properties as well as their implications for disease and therapy.
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Affiliation(s)
- Mujahid Azfar
- Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, KU Leuven, B-3000 Leuven, Belgium
| | - Sarah van Veen
- Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, KU Leuven, B-3000 Leuven, Belgium
| | - Marine Houdou
- Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, KU Leuven, B-3000 Leuven, Belgium
| | - Norin Nabil Hamouda
- Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium
| | - Jan Eggermont
- Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium
| | - Peter Vangheluwe
- Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, KU Leuven, B-3000 Leuven, Belgium.
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13
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Grison S, Legendre A, Svilar L, Elie C, Kereselidze D, Gloaguen C, Lestaevel P, Martin JC, Souidi M. Multigenerational Exposure to Uranium Changes Sperm Metabolome in Rats. Int J Mol Sci 2022; 23:8349. [PMID: 35955476 PMCID: PMC9369047 DOI: 10.3390/ijms23158349] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/22/2022] [Accepted: 07/25/2022] [Indexed: 02/01/2023] Open
Abstract
Male infertility is a major public health issue that can be induced by a host of lifestyle risk factors such as environment, nutrition, smoking, stress, and endocrine disruptors. Regarding the human population exposed to uranium, it is necessary to explore these effects on male reproduction in multigenerational studies. The sensitivity of mass spectrometry (MS)-based methods has already proved to be extremely useful in metabolite identification in rats exposed to low doses of uranium, but also in human sperm. We applied this method to rat sperm over three generations (F0, F1 and F2) with multigenerational uranium exposure. Our results show a significant content of uranium in generation F0, and a reduction in the pregnancy rate only in generation F1. Based on principal component analysis (PCA), we observed discriminant profiles between generations. The partial least squares discriminant analysis (PLS-DA) of the 48 annotated variables confirmed that parental exposure of generation F0 (during both the preconceptional and prenatal periods) can have metabolic effects on spermatozoa for the next two generations. Metabolomics applied to epididymal spermatozoa is a novel approach to detecting the multigenerational effects of uranium in an experimental model, but could be also recommended to identify potential biomarkers evaluating the impact of uranium on sperm in exposed infertile men.
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Affiliation(s)
- Stéphane Grison
- Institut de Radioprotection et de Sûreté Nucléaire, PSE-SANTE, 92260 Fontenay-aux-Roses, France; (A.L.); (C.E.); (D.K.); (C.G.); (P.L.); (M.S.)
| | - Audrey Legendre
- Institut de Radioprotection et de Sûreté Nucléaire, PSE-SANTE, 92260 Fontenay-aux-Roses, France; (A.L.); (C.E.); (D.K.); (C.G.); (P.L.); (M.S.)
| | - Ljubica Svilar
- C2VN, CRIBIOM, Aix Marseille Université, 13007 Marseille, France;
| | - Christelle Elie
- Institut de Radioprotection et de Sûreté Nucléaire, PSE-SANTE, 92260 Fontenay-aux-Roses, France; (A.L.); (C.E.); (D.K.); (C.G.); (P.L.); (M.S.)
| | - Dimitri Kereselidze
- Institut de Radioprotection et de Sûreté Nucléaire, PSE-SANTE, 92260 Fontenay-aux-Roses, France; (A.L.); (C.E.); (D.K.); (C.G.); (P.L.); (M.S.)
| | - Céline Gloaguen
- Institut de Radioprotection et de Sûreté Nucléaire, PSE-SANTE, 92260 Fontenay-aux-Roses, France; (A.L.); (C.E.); (D.K.); (C.G.); (P.L.); (M.S.)
| | - Philippe Lestaevel
- Institut de Radioprotection et de Sûreté Nucléaire, PSE-SANTE, 92260 Fontenay-aux-Roses, France; (A.L.); (C.E.); (D.K.); (C.G.); (P.L.); (M.S.)
| | - Jean-Charles Martin
- C2VN, INRAE, INSERM, BIOMET, Aix Marseille Université, 13007 Marseille, France;
| | - Maâmar Souidi
- Institut de Radioprotection et de Sûreté Nucléaire, PSE-SANTE, 92260 Fontenay-aux-Roses, France; (A.L.); (C.E.); (D.K.); (C.G.); (P.L.); (M.S.)
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14
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Harbison RA, Pandey R, Considine M, Leone RD, Murray-Stewart T, Erbe R, Mandal R, Burns M, Casero RA, Seiwert T, Fakhry C, Pardoll D, Fertig E, Powell JD. Interrogation of T Cell-Enriched Tumors Reveals Prognostic and Immunotherapeutic Implications of Polyamine Metabolism. CANCER RESEARCH COMMUNICATIONS 2022; 2:639-652. [PMID: 36052016 PMCID: PMC9432485 DOI: 10.1158/2767-9764.crc-22-0061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 04/05/2022] [Accepted: 06/21/2022] [Indexed: 11/16/2022]
Abstract
Metabolic features of the tumor microenvironment (TME) antagonize anti-tumor immunity. We hypothesized that T cell infiltrated tumors with a known antigen should exhibit superior clinical outcomes, though some fare worse given unfavorable metabolic features leveraging T cell-infiltrated (Thi), human papillomavirus-related (HPV+) head and neck squamous cell carcinomas (HNSC) to test this hypothesis. Expression of 2,520 metabolic genes were analyzed among Thi HPV+ HNSCs stratified by high-risk molecular subtype. RNAseq data from The Cancer Genome Atlas (TCGA; 10 cancer types), single cell RNAseq data, and an immunotherapy-treated melanoma cohort were used to test the association between metabolic gene expression and clinical outcomes and contribution of tumor versus stromal cells to metabolic gene expression. Polyamine (PA) metabolism genes were overexpressed in high-risk, Thi HPV+ HNSCs. Genes involved in PA biosynthesis and transport were associated with T cell infiltration, recurrent or persistent cancer, overall survival status, primary site, molecular subtype, and MYC genomic alterations. PA biogenesis gene sets were associated with tumor intrinsic features while myeloid cells in HPV+ HNSCs were enriched in PA catabolism, regulatory, transport, putrescine, and spermidine gene set expression. PA gene set expression also correlated with IFNγ or cytotoxic T cell ssGSEA scores across TCGA tumor types. PA transport ssGSEA scores were associated with poor survival whereas putrescine ssGSEA scores portended better survival for several tumor types. Thi melanomas enriched in PA synthesis or combined gene set expression exhibited worse anti-PD-1 responses. These data address hurdles to anti-tumor immunity warranting further investigation of divergent polyamine metabolism in the TME.
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Affiliation(s)
- R. Alex Harbison
- Department of Otolaryngology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Rajeev Pandey
- Department of Otolaryngology Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Michael Considine
- Department of Otolaryngology Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Biomedical Engineering, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Robert D. Leone
- Department of Otolaryngology Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Tracy Murray-Stewart
- Department of Otolaryngology Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Rossin Erbe
- Department of Otolaryngology Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Otolaryngology Human Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Biomedical Engineering, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Raj Mandal
- Department of Otolaryngology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Mark Burns
- Aminex Therapeutics, Kirkland, Washington
| | - Robert A. Casero
- Department of Otolaryngology Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Tanguy Seiwert
- Department of Otolaryngology Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Carole Fakhry
- Department of Otolaryngology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Drew Pardoll
- Department of Otolaryngology Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Elana Fertig
- Department of Otolaryngology Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Biomedical Engineering, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jonathan D. Powell
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland
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15
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Gould GG, Barba-Escobedo PA, Horton RE, Daws LC. High Affinity Decynium-22 Binding to Brain Membrane Homogenates and Reduced Dorsal Camouflaging after Acute Exposure to it in Zebrafish. Front Pharmacol 2022; 13:841423. [PMID: 35754508 PMCID: PMC9218599 DOI: 10.3389/fphar.2022.841423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/29/2022] [Indexed: 11/13/2022] Open
Abstract
Organic cation transporters (OCTs) are expressed in the mammalian brain, kidney, liver, placenta, and intestines, where they facilitate the transport of cations and other substrates between extracellular fluids and cells. Despite increasing reliance on ectothermic vertebrates as alternative toxicology models, properties of their OCT homologs transporting many drugs and toxins remain poorly characterized. Recently, in zebrafish (Danio rerio), two proteins with functional similarities to human OCTs were shown to be highly expressed in the liver, kidney, eye, and brain. This study is the first to characterize in vivo uptake to the brain and the high-affinity brain membrane binding of the mammalian OCT blocker 1-1'-diethyl-2,2'cyanine iodide (decynium-22 or D-22) in zebrafish. Membrane saturation binding of [3H] D-22 in pooled zebrafish whole brain versus mouse hippocampal homogenates revealed a high-affinity binding site with a KD of 5 ± 2.5 nM and Bmax of 1974 ± 410 fmol/mg protein in the zebrafish brain, and a KD of 3.3 ± 2.3 and Bmax of 704 ± 182 fmol/mg protein in mouse hippocampus. The binding of [3H] D-22 to brain membrane homogenates was partially blocked by the neurotoxic cation 1-methyl-4-phenylpyridinium (MPP+), a known OCT substrate. To determine if D-22 bath exposures reach the brain, zebrafish were exposed to 25 nM [3H] D-22 for 10 min, and 736 ± 68 ng/g wet weight [3H] D-22 was bound. Acute behavioral effects of D-22 in zebrafish were characterized in two anxiety-relevant tests. In the first cohort of zebrafish, 12.5, 25, or 50 mg/L D-22 had no effect on their height in the dive tank or entries and time spent in white arms of a light/dark plus maze. By contrast, 25 mg/L buspirone increased zebrafish dive tank top-dwelling (p < 0.05), an anticipated anxiolytic effect. However, a second cohort of zebrafish treated with 50 mg/L D-22 made more white arm entries, and females spent more time in white than controls. Based on these findings, it appears that D-22 bath treatments reach the zebrafish brain and have partial anxiolytic properties, reducing anti-predator dorsal camouflaging, without increasing vertical exploration. High-affinity binding of [3H] D-22 in zebrafish brain and mouse brain was similar, with nanomolar affinity, possibly at conserved OCT site(s).
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Affiliation(s)
- Georgianna G Gould
- Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.,Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Priscilla A Barba-Escobedo
- Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.,Department of Endodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Rebecca E Horton
- Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.,Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Lynette C Daws
- Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.,Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.,Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
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16
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Rieck J, Skatchkov SN, Derst C, Eaton MJ, Veh RW. Unique Chemistry, Intake, and Metabolism of Polyamines in the Central Nervous System (CNS) and Its Body. Biomolecules 2022; 12:biom12040501. [PMID: 35454090 PMCID: PMC9025450 DOI: 10.3390/biom12040501] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 03/16/2022] [Accepted: 03/17/2022] [Indexed: 02/04/2023] Open
Abstract
Polyamines (PAs) are small, versatile molecules with two or more nitrogen-containing positively charged groups and provide widespread biological functions. Most of these aspects are well known and covered by quite a number of excellent surveys. Here, the present review includes novel aspects and questions: (1) It summarizes the role of most natural and some important synthetic PAs. (2) It depicts PA uptake from nutrition and bacterial production in the intestinal system following loss of PAs via defecation. (3) It highlights the discrepancy between the high concentrations of PAs in the gut lumen and their low concentration in the blood plasma and cerebrospinal fluid, while concentrations in cellular cytoplasm are much higher. (4) The present review provides a novel and complete scheme for the biosynthesis of Pas, including glycine, glutamate, proline and others as PA precursors, and provides a hypothesis that the agmatine pathway may rescue putrescine production when ODC knockout seems to be lethal (solving the apparent contradiction in the literature). (5) It summarizes novel data on PA transport in brain glial cells explaining why these cells but not neurons preferentially accumulate PAs. (6) Finally, it provides a novel and complete scheme for PA interconversion, including hypusine, putreanine, and GABA (unique gliotransmitter) as end-products. Altogether, this review can serve as an updated contribution to understanding the PA mystery.
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Affiliation(s)
- Julian Rieck
- Institut für Zell- und Neurobiologie, Centrum 2, Charité—Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany;
| | - Serguei N. Skatchkov
- Department of Physiology, Universidad Central del Caribe, Bayamón, PR 00956, USA
- Department of Biochemistry, Universidad Central del Caribe, Bayamón, PR 00956, USA;
- Correspondence: (S.N.S.); (R.W.V.)
| | - Christian Derst
- Institut für Integrative Neuroanatomie, Centrum 2, Charité—Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany;
| | - Misty J. Eaton
- Department of Biochemistry, Universidad Central del Caribe, Bayamón, PR 00956, USA;
| | - Rüdiger W. Veh
- Institut für Zell- und Neurobiologie, Centrum 2, Charité—Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany;
- Correspondence: (S.N.S.); (R.W.V.)
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17
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Polyamine Immunometabolism: Central Regulators of Inflammation, Cancer and Autoimmunity. Cells 2022; 11:cells11050896. [PMID: 35269518 PMCID: PMC8909056 DOI: 10.3390/cells11050896] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 03/01/2022] [Accepted: 03/03/2022] [Indexed: 02/06/2023] Open
Abstract
Polyamines are ubiquitous, amine-rich molecules with diverse processes in biology. Recent work has highlighted that polyamines exert profound roles on the mammalian immune system, particularly inflammation and cancer. The mechanisms by which they control immunity are still being described. In the context of inflammation and autoimmunity, polyamine levels inversely correlate to autoimmune phenotypes, with lower polyamine levels associated with higher inflammatory responses. Conversely, in the context of cancer, polyamines and polyamine biosynthetic genes positively correlate with the severity of malignancy. Blockade of polyamine metabolism in cancer results in reduced tumor growth, and the effects appear to be mediated by an increase in T-cell infiltration and a pro-inflammatory phenotype of macrophages. These studies suggest that polyamine depletion leads to inflammation and that polyamine enrichment potentiates myeloid cell immune suppression. Indeed, combinatorial treatment with polyamine blockade and immunotherapy has shown efficacy in pre-clinical models of cancer. Considering the efficacy of immunotherapies is linked to autoimmune sequelae in humans, termed immune-adverse related events (iAREs), this suggests that polyamine levels may govern the inflammatory response to immunotherapies. This review proposes that polyamine metabolism acts to balance autoimmune inflammation and anti-tumor immunity and that polyamine levels can be used to monitor immune responses and responsiveness to immunotherapy.
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18
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Li R, Wu X, Zhu Z, Lv Y, Zheng Y, Lu H, Zhou K, Wu D, Zeng W, Dong W, Zhang T. Polyamines protect boar sperm from oxidative stress in vitro. J Anim Sci 2022; 100:6542920. [PMID: 35247050 PMCID: PMC9030141 DOI: 10.1093/jas/skac069] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 03/03/2022] [Indexed: 11/13/2022] Open
Abstract
Sperm are susceptible to excessive reactive oxygen species (ROS). Spermine and spermidine are secreted in large amounts by the prostate and potent natural free radical scavengers and protect cells against redox disorder. Thus, we used boar sperm as a model to study the polyamines uptake and elucidate whether polyamines protected sperm from ROS stress. Seven mature and fertile Duroc boars (aged 15 to 30 mo) were used in this study. In experiment 1, spermine and spermidine (3.6 ± 0.3 and 3.3 ± 0.2 mmol/L, respectively) were abundant in seminal plasma, and the content of polyamine decreased (P < 0.05) after preservation at 17 °C for 7 d or incubation at 37 °C for 6 h. In experiment 2, using labeling of spermine or spermidine by conjugation with fluorescein isothiocyanate and ultra-high-performance liquid chromatography, we found that the accumulation of spermine or spermidine in sperm was inhibited by quinidine and dl-tetrahydropalmatine (THP, organic cation transporters [OCT] inhibitors, P < 0.05), but not mildronate and l-carnitine (organic cation/carnitine transporter [OCTN] inhibitors, P > 0.05). In experiment 3, the addition of spermine or spermidine (0.5 mmol/L) in the extender resulted in higher motility, plasma membrane and acrosome integrity, and lower ROS level after preservation in vitro at 17 °C for 7 d (P < 0.05). In experiment 4, in the condition of oxidative stress (treatment with H2O2 at 37 °C for 2 h), the addition of spermine (1 mmol/L) or spermidine (0.5 mmol/L) in extender increased activities of glutathione peroxidase, glutathione reductase, and glutathione S-transferase; reduced glutathione and oxidized glutathione ratio (P < 0.05); and alleviate oxidative stress-induced lipid peroxidation, DNA damage, mitochondrial membrane potential (ΔΨm) decline, adenosine triphosphate depletion, and intracellular calcium concentration ([Ca2+]i) overload (P < 0.05), thereby improving boar sperm motility, the integrity of plasma membrane and acrosome (P < 0.05) in vitro. These data suggest that spermine and spermidine alleviate oxidative stress via the antioxidant capacity, thereby improving the efficacy of boar semen preservation.
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Affiliation(s)
- Rongnan Li
- Key Laboratory for Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A & F University, Yangling, Shaanxi 712100, China
| | - Xiaodong Wu
- Key Laboratory for Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A & F University, Yangling, Shaanxi 712100, China
| | - Zhendong Zhu
- Key Laboratory for Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A & F University, Yangling, Shaanxi 712100, China
| | - Yinghua Lv
- College of Chemistry and Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Yi Zheng
- Key Laboratory for Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A & F University, Yangling, Shaanxi 712100, China
| | - Hongzhao Lu
- School of Biological Science and Engineering, Shaanxi University of Technology, Hanzhong, Shaanxi 723001, China
| | - Kaifeng Zhou
- Shandong Provincial Animal Husbandry General Station, Jinan, Shandong 250000, China
| | - De Wu
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education of China, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan 611100, China
| | - Wenxian Zeng
- Key Laboratory for Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A & F University, Yangling, Shaanxi 712100, China,Corresponding author:
| | - Wuzi Dong
- Key Laboratory for Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A & F University, Yangling, Shaanxi 712100, China
| | - Tao Zhang
- School of Biological Science and Engineering, Shaanxi University of Technology, Hanzhong, Shaanxi 723001, China
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MPP +-Induced Changes in Cellular Impedance as a Measure for Organic Cation Transporter (SLC22A1-3) Activity and Inhibition. Int J Mol Sci 2022; 23:ijms23031203. [PMID: 35163125 PMCID: PMC8835585 DOI: 10.3390/ijms23031203] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/13/2022] [Accepted: 01/19/2022] [Indexed: 02/04/2023] Open
Abstract
The organic cation transporters OCT1-3 (SLC22A1-3) facilitate the transport of cationic endo- and xenobiotics and are important mediators of drug distribution and elimination. Their polyspecific nature makes OCTs highly susceptible to drug-drug interactions (DDIs). Currently, screening of OCT inhibitors depends on uptake assays that require labeled substrates to detect transport activity. However, these uptake assays have several limitations. Hence, there is a need to develop novel assays to study OCT activity in a physiological relevant environment without the need to label the substrate. Here, a label-free impedance-based transport assay is established that detects OCT-mediated transport activity and inhibition utilizing the neurotoxin MPP+. Uptake of MPP+ by OCTs induced concentration-dependent changes in cellular impedance that were inhibited by decynium-22, corticosterone, and Tyrosine Kinase inhibitors. OCT-mediated MPP+ transport activity and inhibition were quantified on both OCT1-3 overexpressing cells and HeLa cells endogenously expressing OCT3. Moreover, the method presented here is a valuable tool to identify novel inhibitors and potential DDI partners for MPP+ transporting solute carrier proteins (SLCs) in general.
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20
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Bernstein HG, Keilhoff G, Laube G, Dobrowolny H, Steiner J. Polyamines and polyamine-metabolizing enzymes in schizophrenia: Current knowledge and concepts of therapy. World J Psychiatry 2021; 11:1177-1190. [PMID: 35070769 PMCID: PMC8717027 DOI: 10.5498/wjp.v11.i12.1177] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/30/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Polyamines play preeminent roles in a variety of cellular functions in the central nervous system and other organs. A large body of evidence suggests that the polyamine pathway is prominently involved in the etiology and pathology of schizophrenia. Alterations in the expression and activity of polyamine metabolizing enzymes, as well as changes in the levels of the individual polyamines, their precursors and derivatives, have been measured in schizophrenia and animal models of the disease. Additionally, neuroleptic treatment has been shown to influence polyamine concentrations in brain and blood of individuals with schizophrenia. Thus, the polyamine system may appear to be a promising target for neuropharmacological treatment of schizophrenia. However, for a number of practical reasons there is currently only limited hope for a polyamine-based schizophrenia therapy.
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Affiliation(s)
- Hans-Gert Bernstein
- Department of Psychiatry, University of Magdeburg, Magdeburg D-39116, Saxony-Anhalt, Germany
| | - Gerburg Keilhoff
- Institute of Biochemistry and Cell Biology, University of Magdeburg, Magdeburg D-39116, Saxony-Anhalt, Germany
| | - Gregor Laube
- Department of Anatomy, Charite, Berlin D-10117, Germany
| | - Henrik Dobrowolny
- Department of Psychiatry, University of Magdeburg, Magdeburg D-39116, Saxony-Anhalt, Germany
| | - Johann Steiner
- Department of Psychiatry, University of Magdeburg, Magdeburg D-39116, Saxony-Anhalt, Germany
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21
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Banerjee B, Khrystoforova I, Polis B, Zvi IB, Karasik D. Acute hypoxia elevates arginase 2 and induces polyamine stress response in zebrafish via evolutionarily conserved mechanism. Cell Mol Life Sci 2021; 79:41. [PMID: 34913090 PMCID: PMC11072480 DOI: 10.1007/s00018-021-04043-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 11/01/2021] [Accepted: 11/14/2021] [Indexed: 10/19/2022]
Abstract
Living organisms repeatedly encounter stressful events and apply various strategies to survive. Polyamines are omnipresent bioactive molecules with multiple functions. Their transient synthesis, inducible by numerous stressful stimuli, is termed the polyamine stress response. Animals developed evolutionarily conserved strategies to cope with stresses. The urea cycle is an ancient attribute that deals with ammonia excess in terrestrial species. Remarkably, most fish retain the urea cycle genes fully expressed during the early stages of development and silenced in adult animals. Environmental challenges instigate urea synthesis in fish despite substantial energetic costs, which poses the question of the urea cycle's evolutionary significance. Arginase plays a critical role in oxidative stress-dependent reactions being the final urea cycle enzyme. Its unique subcellular localization, high inducibility, and several regulation levels provide a supreme ability to control the polyamine synthesis rate. Notably, oxidative stress instigates the arginase-1 activity in mammals. Arginase is also dysregulated in aging organisms' brain and muscle tissues, indicating its role in the pathogenesis of age-associated diseases. We designed a study to investigate the levels of the urea cycle and polyamine synthesis-related enzymes in a fish model of acute hypoxia. We evidence synchronized elevation of arginase-2 and ornithine decarboxylase following oxidative stress in adult fish and aging animals signifying the specific function of arginase-2 in fish. Moreover, we demonstrate oxidative stress-associated polyamine synthesis' induction and urea cycle' arrest in adult fish. The subcellular arginase localization found in the fish seems to correspond to its possible evolutionary roles.
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Affiliation(s)
| | | | - Baruh Polis
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
| | - Inbar Ben Zvi
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - David Karasik
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
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22
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Interaction Profiles of Central Nervous System Active Drugs at Human Organic Cation Transporters 1-3 and Human Plasma Membrane Monoamine Transporter. Int J Mol Sci 2021; 22:ijms222312995. [PMID: 34884800 PMCID: PMC8657792 DOI: 10.3390/ijms222312995] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/26/2021] [Accepted: 11/28/2021] [Indexed: 12/31/2022] Open
Abstract
Many psychoactive compounds have been shown to primarily interact with high-affinity and low-capacity solute carrier 6 (SLC6) monoamine transporters for norepinephrine (NET; norepinephrine transporter), dopamine (DAT; dopamine transporter) and serotonin (SERT; serotonin transporter). Previous studies indicate an overlap between the inhibitory capacities of substances at SLC6 and SLC22 human organic cation transporters (SLC22A1-3; hOCT1-3) and the human plasma membrane monoamine transporter (SLC29A4; hPMAT), which can be classified as high-capacity, low-affinity monoamine transporters. However, interactions between central nervous system active substances, the OCTs, and the functionally-related PMAT have largely been understudied. Herein, we report data from 17 psychoactive substances interacting with the SLC6 monoamine transporters, concerning their potential to interact with the human OCT isoforms and hPMAT by utilizing radiotracer-based in vitro uptake inhibition assays at stably expressing human embryonic kidney 293 cells (HEK293) cells. Many compounds inhibit substrate uptake by hOCT1 and hOCT2 in the low micromolar range, whereas only a few substances interact with hOCT3 and hPMAT. Interestingly, methylphenidate and ketamine selectively interact with hOCT1 or hOCT2, respectively. Additionally, 3,4-methylenedioxymethamphetamine (MDMA) is a potent inhibitor of hOCT1 and 2 and hPMAT. Enantiospecific differences of R- and S-α-pyrrolidinovalerophenone (R- and S-α-PVP) and R- and S-citalopram and the effects of aromatic substituents are explored. Our results highlight the significance of investigating drug interactions with hOCTs and hPMAT, due to their role in regulating monoamine concentrations and xenobiotic clearance.
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23
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Koepp TN, Tokaj A, Nedvetsky PI, Conchon Costa AC, Snieder B, Schröter R, Ciarimboli G. Properties of Transport Mediated by the Human Organic Cation Transporter 2 Studied in a Polarized Three-Dimensional Epithelial Cell Culture Model. Int J Mol Sci 2021; 22:ijms22179658. [PMID: 34502566 PMCID: PMC8432172 DOI: 10.3390/ijms22179658] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/01/2021] [Accepted: 09/01/2021] [Indexed: 02/06/2023] Open
Abstract
The renal secretory clearance for organic cations (neurotransmitters, metabolism products and drugs) is mediated by transporters specifically expressed in the basolateral and apical plasma membrane domains of proximal tubule cells. Here, human organic cation transporter 2 (hOCT2) is the main transporter for organic cations in the basolateral membrane domain. In this study, we stably expressed hOCT2 in Madin-Darby Canine Kidney (MDCK) cells and cultivated these cells in the presence of an extracellular matrix to obtain three-dimensional (3D) structures (cysts). The transport properties of hOCT2 expressed in MDCK cysts were compared with those measured using human embryonic kidney cells (HEK293) stably transfected with hOCT2 (hOCT2-HEK cells). In the MDCK cysts, hOCT2 was expressed in the basolateral membrane domain and showed a significant uptake of the fluorescent organic cation 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP+) with an affinity (Km) of 3.6 ± 1.2 µM, similar to what was measured in the hOCT2-HEK cells (Km = 3.1 ± 0.2 µM). ASP+ uptake was inhibited by tetraethylammonium (TEA+), tetrapentylammonium (TPA+), metformin and baricitinib both in the hOCT2-HEK cells and the hOCT2- MDCK cysts, even though the apparent affinities of TEA+ and baricitinib were dependent on the expression system. Then, hOCT2 was subjected to the same rapid regulation by inhibition of p56lck tyrosine kinase or calmodulin in the hOCT2-HEK cells and hOCT2- MDCK cysts. However, inhibition of casein kinase II regulated only activity of hOCT2 expressed in MDCK cysts and not in HEK cells. Taken together, these results suggest that the 3D cell culture model is a suitable tool for the functional analysis of hOCT2 transport properties, depending on cell polarization.
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24
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Mohamed Sofian Z, Harun N, Mahat MM, Nor Hashim NA, Jones SA. Investigating how amine structure influences drug-amine ion-pair formation and uptake via the polyamine transporter in A549 lung cells. Eur J Pharm Biopharm 2021; 168:53-61. [PMID: 34455038 DOI: 10.1016/j.ejpb.2021.08.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 08/09/2021] [Accepted: 08/16/2021] [Indexed: 11/24/2022]
Abstract
Transiently associating amines with therapeutic agents through the formation of ion-pairs has been established both in vitro and in vivo as an effective means to systemically direct drug delivery to the lung via the polyamine transport system (PTS). However, there remains a need to better understand the structural traits required for effective PTS uptake of drug ion-pairs. This study aimed to use a structurally related series of amine counterions to investigate how they influenced the stability of theophylline ion-pairs and their active uptake in A549 cells. Using ethylamine (mono-amine), ethylenediamine (di-amine), spermidine (tri-amine) and spermine (tetra-amine) as counterions the ion-pair affinity was shown to increase as the number of protonated amine groups in the counterion structure increased. The mono and diamines generated a single hydrogen bond and the weakest ion-pair affinities (pKFTIR: 1.32 ± 0.04 and 1.43 ± 0.02) whereas the polyamines produced two hydrogen bonds and thus the strongest ion-pair affinities (pKFTIR: 1.93 ± 0.05 and 1.96 ± 0.04). In A549 cells depleted of endogenous polyamines using α-difluoromethylornithine (DFMO), the spermine-theophylline uptake was significantly increased (p < 0.05) compared to non-amine depleted cells and this evidenced the active PTS sequestering of the ion-pair. The mono-amine and di-amine failed to enhance theophylline uptake in these A549 cells, but the tri-amine and tetra-amine both almost doubled the theophylline uptake into the cells when compared to the uptake of free drug. As the data indicated that polyamines with at least 3 amines were required to form ion-pairs that could enhance A549 cell uptake, it suggested that at least two amines were required to physically stabilise the ion-pair and one to interact with the PTS.
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Affiliation(s)
- Zarif Mohamed Sofian
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Universiti Malaya, 50603 Kuala Lumpur, Malaysia; Insitute of Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
| | - Norsyifa Harun
- Centre for Drug Research, Universiti Sains Malaysia, 11800 Minden, Pulau Pinang, Malaysia
| | - Mohd Muzamir Mahat
- Faculty of Applied Sciences, Universiti Teknologi MARA, 40000 Shah Alam, Selangor, Malaysia
| | - Nikman Adli Nor Hashim
- Centre for Drug Research in Systems Biology, Structural Bioinformatics and Human Digital Imaging (CRYSTAL), Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Stuart A Jones
- Insitute of Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK
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25
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Uptake of Biotinylated Spermine in Astrocytes: Effect of Cx43 siRNA, HIV-Tat Protein and Polyamine Transport Inhibitor on Polyamine Uptake. Biomolecules 2021; 11:biom11081187. [PMID: 34439853 PMCID: PMC8391674 DOI: 10.3390/biom11081187] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/06/2021] [Accepted: 08/08/2021] [Indexed: 12/14/2022] Open
Abstract
Polyamines (PAs) are polycationic biomolecules containing multiple amino groups. Patients with HIV-associated neurocognitive disorder (HAND) have high concentrations of the polyamine N-acetylated spermine in their brain and cerebral spinal fluid (CSF) and have increased PA release from astrocytes. These effects are due to the exposure to HIV-Tat. In healthy adult brain, PAs are accumulated but not synthesized in astrocytes, suggesting that PAs must enter astrocytes to be N-acetylated and released. Therefore, we tested if Cx43 hemichannels (Cx43-HCs) are pathways for PA flux in control and HIV-Tat-treated astrocytes. We used biotinylated spermine (b-SPM) to examine polyamine uptake. We found that control astrocytes and those treated with siRNA-Cx43 took up b-SPM, similarly suggesting that PA uptake is via a transporter/channel other than Cx43-HCs. Surprisingly, astrocytes pretreated with both HIV-Tat and siRNA-Cx43 showed increased accumulation of b-SPM. Using a novel polyamine transport inhibitor (PTI), trimer 44NMe, we blocked b-SPM uptake, showing that PA uptake is via a PTI-sensitive transport mechanism such as organic cation transporter. Our data suggest that Cx43 HCs are not a major pathway for b-SPM uptake in the condition of normal extracellular calcium concentration but may be involved in the release of PAs to the extracellular space during viral infection.
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26
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Sagar NA, Tarafdar S, Agarwal S, Tarafdar A, Sharma S. Polyamines: Functions, Metabolism, and Role in Human Disease Management. Med Sci (Basel) 2021; 9:44. [PMID: 34207607 PMCID: PMC8293435 DOI: 10.3390/medsci9020044] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/05/2021] [Accepted: 06/07/2021] [Indexed: 12/11/2022] Open
Abstract
Putrescine, spermine, and spermidine are the important polyamines (PAs), found in all living organisms. PAs are formed by the decarboxylation of amino acids, and they facilitate cell growth and development via different cellular responses. PAs are the integrated part of the cellular and genetic metabolism and help in transcription, translation, signaling, and post-translational modifications. At the cellular level, PA concentration may influence the condition of various diseases in the body. For instance, a high PA level is detrimental to patients suffering from aging, cognitive impairment, and cancer. The levels of PAs decline with age in humans, which is associated with different health disorders. On the other hand, PAs reduce the risk of many cardiovascular diseases and increase longevity, when taken in an optimum quantity. Therefore, a controlled diet is an easy way to maintain the level of PAs in the body. Based on the nutritional intake of PAs, healthy cell functioning can be maintained. Moreover, several diseases can also be controlled to a higher extend via maintaining the metabolism of PAs. The present review discusses the types, important functions, and metabolism of PAs in humans. It also highlights the nutritional role of PAs in the prevention of various diseases.
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Affiliation(s)
- Narashans Alok Sagar
- Department of Agriculture and Environmental Sciences, National Institute of Food Technology Entrepreneurship and Management, Kundli, Sonepat 131028, Haryana, India
- Food Microbiology Lab, Division of Livestock Products Technology, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, Uttar Pradesh, India
| | - Swarnava Tarafdar
- Department of Radiodiagnosis and Imaging, All India Institute of Medical Science, Rishikesh 249203, Uttarakhand, India;
| | - Surbhi Agarwal
- Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India;
| | - Ayon Tarafdar
- Livestock Production and Management Section, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, Uttar Pradesh, India;
| | - Sunil Sharma
- Department of Agriculture and Environmental Sciences, National Institute of Food Technology Entrepreneurship and Management, Kundli, Sonepat 131028, Haryana, India
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27
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Maier J, Rauter L, Rudin D, Niello M, Holy M, Schmid D, Wilson J, Blough BE, Gannon BM, Murnane KS, Sitte HH. α-PPP and its derivatives are selective partial releasers at the human norepinephrine transporter: A pharmacological characterization of interactions between pyrrolidinopropiophenones and high and low affinity monoamine transporters. Neuropharmacology 2021; 190:108570. [PMID: 33864800 DOI: 10.1016/j.neuropharm.2021.108570] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 03/31/2021] [Accepted: 04/12/2021] [Indexed: 12/31/2022]
Abstract
While classical cathinones, such as methcathinone, have been shown to be monoamine releasing agents at human monoamine transporters, the subgroup of α-pyrrolidinophenones has thus far solely been characterized as monoamine transporter reuptake inhibitors. Herein, we report data from previously undescribed α-pyrrolidinopropiophenone (α-PPP) derivatives and compare them with the pharmacologically well-researched α-PVP (α-pyrrolidinovalerophenone). Radiotracer-based in vitro uptake inhibition assays in HEK293 cells show that the investigated α-PPP derivatives inhibit the human high-affinity transporters of dopamine (hDAT) and norepinephrine (hNET) in the low micromolar range, with α-PVP being ten times more potent. Similar to α-PVP, no relevant pharmacological activity was found at the human serotonin transporter (hSERT). Unexpectedly, radiotracer-based in vitro release assays reveal α-PPP, MDPPP and 3Br-PPP, but not α-PVP, to be partial releasing agents at hNET (EC50 values in the low micromolar range). Furthermore, uptake inhibition assays at low-affinity monoamine transporters, i.e., the human organic cation transporters (hOCT) 1-3 and human plasma membrane monoamine transporter (hPMAT), bring to light that all compounds inhibit hOCT1 and 2 (IC50 values in the low micromolar range) while less potently interacting with hPMAT and hOCT3. In conclusion, this study describes (i) three new hybrid compounds that efficaciously block hDAT while being partial releasers at hNET, and (ii) highlights the interactions of α-PPP-derivatives with low-affinity monoamine transporters, giving impetus to further studies investigating the interaction of drugs of abuse with OCT1-3 and PMAT.
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Affiliation(s)
- Julian Maier
- Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Währingerstraße 13A, 1090, Vienna, Austria
| | - Laurin Rauter
- Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Währingerstraße 13A, 1090, Vienna, Austria
| | - Deborah Rudin
- Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Währingerstraße 13A, 1090, Vienna, Austria
| | - Marco Niello
- Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Währingerstraße 13A, 1090, Vienna, Austria
| | - Marion Holy
- Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Währingerstraße 13A, 1090, Vienna, Austria
| | - Diethart Schmid
- Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Physiology, Währingerstraße 13A, 1090, Vienna, Austria
| | - Joseph Wilson
- Research Triangle Institute, Center for Drug Discovery, Research Triangle Park, NC, USA
| | - Bruce E Blough
- Research Triangle Institute, Center for Drug Discovery, Research Triangle Park, NC, USA
| | - Brenda M Gannon
- Mercer University College of Pharmacy, Mercer University Health Sciences Center, Department of Pharmaceutical Sciences, Atlanta, GA, USA; Louisiana State University Health Sciences Center, Shreveport, Department of Pharmacology Toxicology & Neuroscience and Louisiana Addiction Research Center, Shreveport, LA, USA
| | - Kevin S Murnane
- Mercer University College of Pharmacy, Mercer University Health Sciences Center, Department of Pharmaceutical Sciences, Atlanta, GA, USA; Louisiana State University Health Sciences Center, Shreveport, Department of Pharmacology Toxicology & Neuroscience and Louisiana Addiction Research Center, Shreveport, LA, USA
| | - Harald H Sitte
- Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Währingerstraße 13A, 1090, Vienna, Austria; AddRess Centre for Addiction Research and Science, Medical University of Vienna, Währingerstraße 13A, 1090, Vienna, Austria.
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28
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Maier J, Niello M, Rudin D, Daws LC, Sitte HH. The Interaction of Organic Cation Transporters 1-3 and PMAT with Psychoactive Substances. Handb Exp Pharmacol 2021; 266:199-214. [PMID: 33993413 DOI: 10.1007/164_2021_469] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Organic cation transporters 1-3 (OCT1-3, SLC22A1-3) and the plasma membrane monoamine transporter (PMAT, SLC29A4) play a major role in maintaining monoaminergic equilibrium in the central nervous system. With many psychoactive substances interacting with OCT1-3 and PMAT, a growing literature focuses on characterizing their properties via in vitro and in vivo studies. In vitro studies mainly aim at characterizing compounds as inhibitors or substrates of murine, rat, and human isoforms. The preponderance of studies has put emphasis on phenylalkylamine derivatives, but ketamine and opioids have also been investigated. Studies employing in vivo (knockout) models mostly concentrate on the interaction of psychoactive substances and OCT3, with an emphasis on stress and addiction, pharmacokinetics, and sensitization to psychoactive drugs. The results highlight the importance of OCT3 in the mechanism of action of psychoactive compounds. Concerning in vivo studies, a veritable research gap concerning OCT1, 2, and PMAT exists. This review provides an overview and summary of research conducted in this field of research.
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Affiliation(s)
- Julian Maier
- Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Marco Niello
- Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Deborah Rudin
- Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Lynette C Daws
- Department of Cellular and Integrative Physiology, University of Texas Health, San Antonio, TX, USA
- Department of Pharmacology, University of Texas Health, San Antonio, TX, USA
| | - Harald H Sitte
- Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria.
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Substrates and Inhibitors of Organic Cation Transporters (OCTs) and Plasma Membrane Monoamine Transporter (PMAT) and Therapeutic Implications. Handb Exp Pharmacol 2021; 266:119-167. [PMID: 34495395 DOI: 10.1007/164_2021_516] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The gene products of the SLC22A gene family (hOCT1, hOCT2, and hOCT3) and of the SLC29A4 gene (hPMAT or hENT4) are all polyspecific organic cation transporters. Human OCTs (including hPMAT) are expressed in peripheral tissues such as small intestine, liver, and kidney involved in the pharmacokinetics of drugs. In the human brain, all four transporters are expressed at the blood-brain barrier (BBB), hOCT2 is additionally expressed in neurons, and hOCT3 and hPMAT in glia. More than 40% of the presently used drugs are organic cations. This chapter lists and discusses all known drugs acting as substrates or inhibitors of these four organic cation transporters, independently of whether the transporter is expressed in the central nervous system (CNS) or in peripheral tissues. Of interest is their involvement in drug absorption, distribution, and excretion as well as potential OCT-associated drug-drug interactions (DDIs), with a focus on drugs that act in the CNS.
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Milunović MNM, Palamarciuc O, Sirbu A, Shova S, Dumitrescu D, Dvoranová D, Rapta P, Petrasheuskaya TV, Enyedy EA, Spengler G, Ilic M, Sitte HH, Lubec G, Arion VB. Insight into the Anticancer Activity of Copper(II) 5-Methylenetrimethylammonium-Thiosemicarbazonates and Their Interaction with Organic Cation Transporters. Biomolecules 2020; 10:E1213. [PMID: 32825480 PMCID: PMC7565988 DOI: 10.3390/biom10091213] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 08/13/2020] [Accepted: 08/14/2020] [Indexed: 02/07/2023] Open
Abstract
A series of four water-soluble salicylaldehyde thiosemicarbazones with a positively charged trimethylammonium moiety ([H2LR]Cl, R = H, Me, Et, Ph) and four copper(II) complexes [Cu(HLR)Cl]Cl (1-4) were synthesised with the aim to study (i) their antiproliferative activity in cancer cells and, (ii) for the first time for thiosemicarbazones, the interaction with membrane transport proteins, specifically organic cation transporters OCT1-3. The compounds were comprehensively characterised by analytical, spectroscopic and X-ray diffraction methods. The highest cytotoxic effect was observed in the neuroblastoma cell line SH-5YSY after 24 h exposure and follows the rank order: 3 > 2 > 4 > cisplatin > 1 >>[H2LR]Cl. The copper(II) complexes showed marked interaction with OCT1-3, comparable to that of well-known OCT inhibitors (decynium 22, prazosin and corticosterone) in the cell-based radiotracer uptake assays. The work paves the way for the development of more potent and selective anticancer drugs and/or OCT inhibitors.
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Affiliation(s)
- Miljan N. M. Milunović
- Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria
| | - Oleg Palamarciuc
- Department of Chemistry, Moldova State University, A. Mateevici Street 60, MD-2009 Chisinau, Moldova; (O.P.); (A.S.)
| | - Angela Sirbu
- Department of Chemistry, Moldova State University, A. Mateevici Street 60, MD-2009 Chisinau, Moldova; (O.P.); (A.S.)
| | - Sergiu Shova
- Petru Poni Institute of Macromolecular Chemistry, Laboratory of Inorganic Polymers, Aleea Grigore Ghica Voda, Nr. 41A, 700487 Iasi, Romania;
| | - Dan Dumitrescu
- Elettra—Sincrotrone Trieste S.C.p.A, Strada Statale 14—km 163,5 in AREA Science Park, 34149 Basovizza, Trieste, Italy;
| | - Dana Dvoranová
- Institute of Physical Chemistry and Chemical Physics, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, SK-81237 Bratislava, Slovakia; (D.D.); (P.R.)
| | - Peter Rapta
- Institute of Physical Chemistry and Chemical Physics, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, SK-81237 Bratislava, Slovakia; (D.D.); (P.R.)
| | - Tatsiana V. Petrasheuskaya
- Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary; (T.V.P.); (E.A.E.)
- MTA-SZTE Lendület Functional Metal Complexes Research Group, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary;
| | - Eva A. Enyedy
- Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary; (T.V.P.); (E.A.E.)
- MTA-SZTE Lendület Functional Metal Complexes Research Group, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary;
| | - Gabriella Spengler
- MTA-SZTE Lendület Functional Metal Complexes Research Group, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary;
- Department of Medical Microbiology and Immunobiology, University of Szeged, Dóm tér 10, H-6720 Szeged, Hungary
| | - Marija Ilic
- Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, A-1090 Vienna, Austria;
- Institute of Pharmacology, Centre for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
- Neuroproteomics, Paracelsus Private Medical University, 5020 Salzburg, Austria;
| | - Harald H. Sitte
- Institute of Pharmacology, Centre for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
| | - Gert Lubec
- Neuroproteomics, Paracelsus Private Medical University, 5020 Salzburg, Austria;
| | - Vladimir B. Arion
- Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria
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Malpica-Nieves CJ, Rivera-Aponte DE, Tejeda-Bayron FA, Mayor AM, Phanstiel O, Veh RW, Eaton MJ, Skatchkov SN. The involvement of polyamine uptake and synthesis pathways in the proliferation of neonatal astrocytes. Amino Acids 2020; 52:1169-1180. [PMID: 32816168 PMCID: PMC7908810 DOI: 10.1007/s00726-020-02881-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 08/10/2020] [Indexed: 12/18/2022]
Abstract
Polyamines (PAs), such as spermidine (SPD) and spermine (SPM), are essential to promote cell growth, survival, proliferation, and longevity. In the adult central nervous system (CNS), SPD and SPM are accumulated predominantly in healthy adult glial cells where PA synthesis is not present. To date, the accumulation and biosynthesis of PAs in developing astrocytes are not well understood. The purpose of the present study was to determine the contribution of uptake and/or synthesis of PAs using proliferation of neonatal astrocytes as an endpoint. We inhibited synthesis of PAs using α-difluoromethylornithine (DFMO; an inhibitor of the PA biosynthetic enzyme ornithine decarboxylase (ODC)) and inhibited uptake of PAs using trimer44NMe (PTI; a novel polyamine transport inhibitor). DFMO, but not PTI alone, blocked proliferation, suggesting that PA biosynthesis was present. Furthermore, exogenous administration of SPD rescued cell proliferation when PA synthesis was blocked by DFMO. When both synthesis and uptake of PAs were inhibited (DFMO + PTI), exogenous SPD no longer supported proliferation. These data indicate that neonatal astrocytes synthesize sufficient quantities of PAs de novo to support cell proliferation, but are also able to import exogenous PAs. This suggests that the PA uptake mechanism is present in both neonates as well as in adults and can support cell proliferation in neonatal astrocytes when ODC is blocked.
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Affiliation(s)
- Christian J Malpica-Nieves
- Department of Biochemistry, School of Medicine, Universidad Central del Caribe, P.O. Box 60327, Bayamón, PR, 00960-6032, USA
| | - David E Rivera-Aponte
- Department of Biochemistry, School of Medicine, Universidad Central del Caribe, P.O. Box 60327, Bayamón, PR, 00960-6032, USA
| | - Flavia A Tejeda-Bayron
- Department of Biochemistry, School of Medicine, Universidad Central del Caribe, P.O. Box 60327, Bayamón, PR, 00960-6032, USA
| | - Angel M Mayor
- Department of Internal Medicine, Universidad Central del Caribe, Bayamón, PR, 00956, USA
| | - Otto Phanstiel
- Department of Medical Education, University of Central Florida, Orlando, FL, 32816, USA
| | - Rüdiger W Veh
- Institut für Zell- Und Neurobiologie, Charité, 10117, Berlin, Germany
| | - Misty J Eaton
- Department of Biochemistry, School of Medicine, Universidad Central del Caribe, P.O. Box 60327, Bayamón, PR, 00960-6032, USA
| | - Serguei N Skatchkov
- Department of Biochemistry, School of Medicine, Universidad Central del Caribe, P.O. Box 60327, Bayamón, PR, 00960-6032, USA.
- Department of Physiology, School of Medicine, Universidad Central del Caribe, P.O. Box 60327, Bayamón, PR, 00960-6032, USA.
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32
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Liu J, Qu C, Han C, Chen MM, An LJ, Zou W. Potassium channels and their role in glioma: A mini review. Mol Membr Biol 2020; 35:76-85. [PMID: 32067536 DOI: 10.1080/09687688.2020.1729428] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
K+ channels regulate a multitude of biological processes and play important roles in a variety of diseases by controlling potassium flow across cell membranes. They are widely expressed in the central and peripheral nervous system. As a malignant tumor derived from nerve epithelium, glioma has the characteristics of high incidence, high recurrence rate, high mortality rate, and low cure rate. Since glioma cells show invasive growth, current surgical methods cannot completely remove tumors. Adjuvant chemotherapy is still needed after surgery. Because the blood-brain barrier and other factors lead to a lower effective concentration of chemotherapeutic drugs in the tumor, the recurrence rate of residual lesions is extremely high. Therefore, new therapeutic methods are needed. Numerous studies have shown that different K+ channel subtypes are differentially expressed in glioma cells and are involved in the regulation of the cell cycle of glioma cells to arrest them at different stages of the cell cycle. Increasing evidence suggests that K+ channels express in glioma cells and regulate glioma cell behaviors such as cell cycle, proliferation and apoptosis. This review article aims to summarize the current knowledge on the function of K+ channels in glioma, suggests K+ channels participating in the development of glioma.
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Affiliation(s)
- Jia Liu
- School of Life Science and Biotechnology, Faculty of Chemical, Environmental and Biological Science, Technology, Dalian University of Technology, Dalian, China.,College of Life Science, Liaoning Normal University, Dalian, China
| | - Chao Qu
- College of Life Science, Liaoning Normal University, Dalian, China
| | - Chao Han
- Regenerative Medicine Center, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Meng-Meng Chen
- Company of Qingdao Re-Store Life Sciences, Qingdao, China
| | - Li-Jia An
- School of Life Science and Biotechnology, Faculty of Chemical, Environmental and Biological Science, Technology, Dalian University of Technology, Dalian, China
| | - Wei Zou
- College of Life Science, Liaoning Normal University, Dalian, China.,Company of Qingdao Re-Store Life Sciences, Qingdao, China
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33
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Schweighofer N, Genser B, Maerz W, Kleber ME, Trummer O, Pieber TR, Obermayer-Pietsch B. Intronic Variants in OCT1 are Associated with All-Cause and Cardiovascular Mortality in Metformin Users with Type 2 Diabetes. Diabetes Metab Syndr Obes 2020; 13:2069-2080. [PMID: 32606866 PMCID: PMC7308180 DOI: 10.2147/dmso.s235663] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 05/01/2020] [Indexed: 12/16/2022] Open
Abstract
PURPOSE Organic cation transporters (Octs) use cations like endogenous compounds, toxins, and drugs, such as metformin, as substrates. Therefore, these proteins determine the pharmacokinetics and -dynamics of metformin and thus its efficacy. Of note, metformin is today the most commonly used pharmaceutical in the treatment of type 2 diabetes (T2DM) with nevertheless a great variability in clinical response, which attributes to genetic variances. The aim of this study was to determine the influence of intronic OCT1 SNPs on prevalence of all-cause and cardiovascular death. PATIENTS AND METHODS Genotypes of 27 intronic SNPs in OCT1 were investigated in the LURIC study, a prospective cohort of 3316 participants scheduled for coronary angiography. We investigated whether these variants were associated with all-cause and cardiovascular death in 73 individuals with T2DM under metformin therapy, in individuals without diabetes, individuals with T2DM and individuals with T2DM without metformin therapy. RESULTS In a multivariate Cox regression analysis adjusted for classical cardiovascular risk factors, 4 intronic OCT1 SNPs were significantly associated with all-cause and cardiovascular mortality in individuals with T2DM on metformin therapy. CONCLUSION According to their OCT1 genotype, some individuals with T2DM on metformin therapy might be prone to an increased risk of cardiovascular death.
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Affiliation(s)
- Natascha Schweighofer
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University Graz, Graz, Austria
- CBmed GmbH, Center for Biomarker Research in Medicine, Graz, Austria
| | - Bernd Genser
- BG Stats Consulting, Vienna, Austria
- Institute of Public Health, Social and Preventive Medicine, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany
| | - Winfried Maerz
- Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- SynLaboratory Academy, SynLaboratory Holding Deutschland GmbH, Mannheim and Augsburg, Germany
| | - Marcus E Kleber
- Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Olivia Trummer
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University Graz, Graz, Austria
| | - Thomas R Pieber
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University Graz, Graz, Austria
- CBmed GmbH, Center for Biomarker Research in Medicine, Graz, Austria
| | - Barbara Obermayer-Pietsch
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University Graz, Graz, Austria
- CBmed GmbH, Center for Biomarker Research in Medicine, Graz, Austria
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34
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Chow LWC, Wong KL, Shiao LR, Wu KC, Leung YM. Polyamine stimulation perturbs intracellular Ca2+ homeostasis and decreases viability of breast cancer BT474 cells. ACTA ACUST UNITED AC 2020; 75:65-73. [PMID: 32092040 DOI: 10.1515/znc-2019-0119] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Accepted: 01/21/2020] [Indexed: 11/15/2022]
Abstract
Intracellular polyamines such as spermine and spermidine are essential to cell growth in normal and especially in cancer cells. However, whether extracellular polyamines affect cancer cell survival is unknown. We therefore examined the actions of extracellular polyamines on breast cancer BT474 cells. Our data showed that spermine, spermidine, and putrescine decreased cell viability by apoptosis. These polyamines also elicited Ca2+ signals, but the latter were unlikely triggered via Ca2+-sensing receptor (CaSR) as BT474 cells have been demonstrated previously to lack CaSR expression. Spermine-elicited Ca2+ response composed of both Ca2+ release and Ca2+ influx. Spermine caused a complete discharge of the cyclopiazonic acid (CPA)-sensitive Ca2+ pool and, expectedly, endoplasmic reticulum (ER) stress. The Ca2+ influx pore opened by spermine was Mn2+-impermeable, distinct from the CPA-triggered store-operated Ca2+ channel, which was Mn2+-permeable. Spermine cytotoxic effects were not due to oxidative stress, as spermine did not trigger reactive oxygen species formation. Our results therefore suggest that spermine acted on a putative polyamine receptor in BT474 cells, causing cytotoxicity by Ca2+ overload, Ca2+ store depletion, and ER stress.
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Affiliation(s)
- Louis W C Chow
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China.,UNIMED Medical Institute, 8/F Club Lusitano, 16 Ice House Street, Hong Kong, China.,Organisation for Oncology and Translational Research, Unit A, 9/F, CNT Commercial Building, 302 Queen's Road Central, Hong Kong, China
| | - Kar-Lok Wong
- Department of Anesthesiology, China Medical University Hospital, Taichung, Taiwan
| | - Lian-Ru Shiao
- Department of Physiology, China Medical University, Taichung 40402, Taiwan
| | - King-Chuen Wu
- Department of Anesthesiology, Chang Gung Memorial Hospital, No. 6, Sec. West, Jiapu Rd., Puzi City, Chiayi County 61363, Taiwan.,Chang Gung University of Science and Technology, No. 2, Sec. West, Jiapu Rd., Puzi City, Chiayi County 61363, Taiwan
| | - Yuk-Man Leung
- Department of Physiology, China Medical University, Taichung 40402, Taiwan, Phone: +886-04-2205336 ext. 2185
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35
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Gamble LD, Purgato S, Murray J, Xiao L, Yu DMT, Hanssen KM, Giorgi FM, Carter DR, Gifford AJ, Valli E, Milazzo G, Kamili A, Mayoh C, Liu B, Eden G, Sarraf S, Allan S, Di Giacomo S, Flemming CL, Russell AJ, Cheung BB, Oberthuer A, London WB, Fischer M, Trahair TN, Fletcher JI, Marshall GM, Ziegler DS, Hogarty MD, Burns MR, Perini G, Norris MD, Haber M. Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma. Sci Transl Med 2020; 11:11/477/eaau1099. [PMID: 30700572 DOI: 10.1126/scitranslmed.aau1099] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 01/08/2019] [Indexed: 12/18/2022]
Abstract
Amplification of the MYCN oncogene is associated with an aggressive phenotype and poor outcome in childhood neuroblastoma. Polyamines are highly regulated essential cations that are frequently elevated in cancer cells, and the rate-limiting enzyme in polyamine synthesis, ornithine decarboxylase 1 (ODC1), is a direct transcriptional target of MYCN. Treatment of neuroblastoma cells with the ODC1 inhibitor difluoromethylornithine (DFMO), although a promising therapeutic strategy, is only partially effective at impeding neuroblastoma cell growth due to activation of compensatory mechanisms resulting in increased polyamine uptake from the surrounding microenvironment. In this study, we identified solute carrier family 3 member 2 (SLC3A2) as the key transporter involved in polyamine uptake in neuroblastoma. Knockdown of SLC3A2 in neuroblastoma cells reduced the uptake of the radiolabeled polyamine spermidine, and DFMO treatment increased SLC3A2 protein. In addition, MYCN directly increased polyamine synthesis and promoted neuroblastoma cell proliferation by regulating SLC3A2 and other regulatory components of the polyamine pathway. Inhibiting polyamine uptake with the small-molecule drug AMXT 1501, in combination with DFMO, prevented or delayed tumor development in neuroblastoma-prone mice and extended survival in rodent models of established tumors. Our findings suggest that combining AMXT 1501 and DFMO with standard chemotherapy might be an effective strategy for treating neuroblastoma.
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Affiliation(s)
- Laura D Gamble
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia
| | - Stefania Purgato
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy
| | - Jayne Murray
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia
| | - Lin Xiao
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia
| | - Denise M T Yu
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.,School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia
| | - Kimberley M Hanssen
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.,School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia
| | - Federico M Giorgi
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy
| | - Daniel R Carter
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.,School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia.,School of Biomedical Engineering, University of Technology, Sydney, NSW 2007, Australia
| | - Andrew J Gifford
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.,School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia.,Department of Anatomical Pathology (SEALS), Prince of Wales Hospital, Randwick, NSW 2031, Australia
| | - Emanuele Valli
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.,School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia
| | - Giorgio Milazzo
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy
| | - Alvin Kamili
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.,School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia
| | - Chelsea Mayoh
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.,School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia
| | - Bing Liu
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia
| | - Georgina Eden
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia
| | - Sara Sarraf
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia
| | - Sophie Allan
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia
| | - Simone Di Giacomo
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy
| | - Claudia L Flemming
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia
| | - Amanda J Russell
- Cancer Research Program, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Belamy B Cheung
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.,School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia
| | - Andre Oberthuer
- Children's Hospital, Department of Pediatric Oncology and Hematology, University of Cologne, Kerpener Strasse 62, D-50924 Cologne, Germany
| | - Wendy B London
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02215, USA
| | - Matthias Fischer
- Children's Hospital, Department of Pediatric Oncology and Hematology, University of Cologne, Kerpener Strasse 62, D-50924 Cologne, Germany
| | - Toby N Trahair
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.,School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia.,Kids Cancer Centre, Sydney Children's Hospital, High Street, Randwick, NSW 2031, Australia
| | - Jamie I Fletcher
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.,School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia
| | - Glenn M Marshall
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.,School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia.,Kids Cancer Centre, Sydney Children's Hospital, High Street, Randwick, NSW 2031, Australia
| | - David S Ziegler
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.,School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia.,Kids Cancer Centre, Sydney Children's Hospital, High Street, Randwick, NSW 2031, Australia
| | - Michael D Hogarty
- Division of Oncology, Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-4318, USA
| | - Mark R Burns
- Aminex Therapeutics, Aminex Therapeutics Inc., Kirkland, WA 98034, USA
| | - Giovanni Perini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy
| | - Murray D Norris
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia.,University of New South Wales Centre for Childhood Cancer Research, Sydney, NSW 2052, Australia
| | - Michelle Haber
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia. .,School of Women's & Children's Health, UNSW Australia, Randwick, NSW 2052, Australia
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Transporters in the Mammary Gland-Contribution to Presence of Nutrients and Drugs into Milk. Nutrients 2019; 11:nu11102372. [PMID: 31590349 PMCID: PMC6836069 DOI: 10.3390/nu11102372] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 09/19/2019] [Accepted: 09/25/2019] [Indexed: 02/07/2023] Open
Abstract
A large number of nutrients and bioactive ingredients found in milk play an important role in the nourishment of breast-fed infants and dairy consumers. Some of these ingredients include physiologically relevant compounds such as vitamins, peptides, neuroactive compounds and hormones. Conversely, milk may contain substances-drugs, pesticides, carcinogens, environmental pollutants-which have undesirable effects on health. The transfer of these compounds into milk is unavoidably linked to the function of transport proteins. Expression of transporters belonging to the ATP-binding cassette (ABC-) and Solute Carrier (SLC-) superfamilies varies with the lactation stages of the mammary gland. In particular, Organic Anion Transporting Polypeptides 1A2 (OATP1A2) and 2B1 (OATP2B1), Organic Cation Transporter 1 (OCT1), Novel Organic Cation Transporter 1 (OCTN1), Concentrative Nucleoside Transporters 1, 2 and 3 (CNT1, CNT2 and CNT3), Peptide Transporter 2 (PEPT2), Sodium-dependent Vitamin C Transporter 2 (SVCT2), Multidrug Resistance-associated Protein 5 (ABCC5) and Breast Cancer Resistance Protein (ABCG2) are highly induced during lactation. This review will focus on these transporters overexpressed during lactation and their role in the transfer of products into the milk, including both beneficial and harmful compounds. Furthermore, additional factors, such as regulation, polymorphisms or drug-drug interactions will be described.
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37
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Nazifi SMR, Sadeghi-aliabadi H, Fassihi A, Aliomrani M, Saghaie L. Synthesis and antiproliferative evaluation of some iron chelators as polyamine transporter targeting agents. CAN J CHEM 2019. [DOI: 10.1139/cjc-2019-0036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
A series of kojic acid derivatives based on monoamines, diamines, and triamines have been synthesized in good yield and purity. A spermidine (spd) rescue experiment was applied against MCF-7 cells to evaluate the polyamine transporter selectivity, and in vitro antiproliferative effects were determined against Hela and DU-145 cell lines. Overall, 5b showed the best selectivity for the polyamine transporter and antiproliferative effects. Therefore, the in-silico metabolism profile and ADMET properties of the title compounds were calculated by the PreADMET server. Additionally, physicochemical properties of ligands were predicted by using the Molinspiration online property calculation server.
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Affiliation(s)
- Seyed Mohamad Reza Nazifi
- Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, 81746-73461 Isfahan, Iran
| | - Hojjat Sadeghi-aliabadi
- Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, 81746-73461 Isfahan, Iran
| | - Afshin Fassihi
- Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, 81746-73461 Isfahan, Iran
| | - Mehdi Aliomrani
- Department of Toxicology and Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences and Health Services, Isfahan, Iran
| | - Lotfollah Saghaie
- Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, 81746-73461 Isfahan, Iran
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38
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Ramos-Molina B, Queipo-Ortuño MI, Lambertos A, Tinahones FJ, Peñafiel R. Dietary and Gut Microbiota Polyamines in Obesity- and Age-Related Diseases. Front Nutr 2019; 6:24. [PMID: 30923709 PMCID: PMC6426781 DOI: 10.3389/fnut.2019.00024] [Citation(s) in RCA: 129] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 02/20/2019] [Indexed: 12/14/2022] Open
Abstract
The polyamines putrescine, spermidine, and spermine are widely distributed polycationic compounds essential for cellular functions. Intracellular polyamine pools are tightly regulated by a complex regulatory mechanism involving de novo biosynthesis, catabolism, and transport across the plasma membrane. In mammals, both the production of polyamines and their uptake from the extracellular space are controlled by a set of proteins named antizymes and antizyme inhibitors. Dysregulation of polyamine levels has been implicated in a variety of human pathologies, especially cancer. Additionally, decreases in the intracellular and circulating polyamine levels during aging have been reported. The differences in the polyamine content existing among tissues are mainly due to the endogenous polyamine metabolism. In addition, a part of the tissue polyamines has its origin in the diet or their production by the intestinal microbiome. Emerging evidence has suggested that exogenous polyamines (either orally administrated or synthetized by the gut microbiota) are able to induce longevity in mice, and that spermidine supplementation exerts cardioprotective effects in animal models. Furthermore, the administration of either spermidine or spermine has been shown to be effective for improving glucose homeostasis and insulin sensitivity and reducing adiposity and hepatic fat accumulation in diet-induced obesity mouse models. The exogenous addition of agmatine, a cationic molecule produced through arginine decarboxylation by bacteria and plants, also exerts significant effects on glucose metabolism in obese models, as well as cardioprotective effects. In this review, we will discuss some aspects of polyamine metabolism and transport, how diet can affect circulating and local polyamine levels, and how the modulation of either polyamine intake or polyamine production by gut microbiota can be used for potential therapeutic purposes.
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Affiliation(s)
- Bruno Ramos-Molina
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research of Malaga, University and Malaga, Malaga, Spain.,CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Institute of Health Carlos III (ISCIII), Madrid, Spain
| | - Maria Isabel Queipo-Ortuño
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Institute of Health Carlos III (ISCIII), Madrid, Spain.,Department of Medical Oncology, Virgen de la Victoria University Hospital, Institute of Biomedical Research of Malaga, University and Malaga, Malaga, Spain
| | - Ana Lambertos
- Department of Biochemistry and Molecular Biology B and Immunology, Faculty of Medicine, University of Murcia, Murcia, Spain.,Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
| | - Francisco J Tinahones
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research of Malaga, University and Malaga, Malaga, Spain.,CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Institute of Health Carlos III (ISCIII), Madrid, Spain
| | - Rafael Peñafiel
- Department of Biochemistry and Molecular Biology B and Immunology, Faculty of Medicine, University of Murcia, Murcia, Spain.,Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
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Nirzhor SSR, Khan RI, Neelotpol S. The Biology of Glial Cells and Their Complex Roles in Alzheimer's Disease: New Opportunities in Therapy. Biomolecules 2018; 8:biom8030093. [PMID: 30201881 PMCID: PMC6164719 DOI: 10.3390/biom8030093] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 08/28/2018] [Accepted: 09/06/2018] [Indexed: 01/01/2023] Open
Abstract
Even though Alzheimer's disease (AD) is of significant interest to the scientific community, its pathogenesis is very complicated and not well-understood. A great deal of progress has been made in AD research recently and with the advent of these new insights more therapeutic benefits may be identified that could help patients around the world. Much of the research in AD thus far has been very neuron-oriented; however, recent studies suggest that glial cells, i.e., microglia, astrocytes, oligodendrocytes, and oligodendrocyte progenitor cells (NG2 glia), are linked to the pathogenesis of AD and may offer several potential therapeutic targets against AD. In addition to a number of other functions, glial cells are responsible for maintaining homeostasis (i.e., concentration of ions, neurotransmitters, etc.) within the central nervous system (CNS) and are crucial to the structural integrity of neurons. This review explores the: (i) role of glial cells in AD pathogenesis; (ii) complex functionalities of the components involved; and (iii) potential therapeutic targets that could eventually lead to a better quality of life for AD patients.
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Zhang J, Sun H, Salvi R, Ding D. Paraquat initially damages cochlear support cells leading to anoikis-like hair cell death. Hear Res 2018; 364:129-141. [PMID: 29563067 PMCID: PMC5984146 DOI: 10.1016/j.heares.2018.03.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 02/20/2018] [Accepted: 03/09/2018] [Indexed: 12/11/2022]
Abstract
Paraquat (PQ), one of the most widely used herbicides, is extremely dangerous because it generates the highly toxic superoxide radical. When paraquat was applied to cochlear organotypic cultures, it not only damaged the outer hair cells (OHCs) and inner hair cells (IHCs), but also caused dislocation of the hair cell rows. We hypothesized that the dislocation arose from damage to the support cells (SCs) that anchors hair cells within the epithelium. To test this hypothesis, rat postnatal cochlear cultures were treated with PQ. Shortly after PQ treatment, the rows of OHCs separated from one another and migrated radially away from IHCs suggesting loss of cell-cell adhesion that hold the hair cells in proper alignment. Hair cells dislocation was associated with extensive loss of SCs in the organ of Corti, loss of tympanic border cells (TBCs) beneath the basilar membrane, the early appearance of superoxide staining and caspase-8 labeling in SCs below the OHCs and disintegration of E-cadherin and β-catenin in the organ of Corti. Damage to the TBCs and SCs occurred prior to loss of OHC or IHC loss suggesting a form of detachment-induced apoptosis referred to as anoikis.
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Affiliation(s)
- Jianhui Zhang
- Department of Otorhinolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, China; Center for Hearing and Deafness, University at Buffalo, Buffalo, NY, 14214, USA
| | - Hong Sun
- Department of Otorhinolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, China; Center for Hearing and Deafness, University at Buffalo, Buffalo, NY, 14214, USA
| | - Richard Salvi
- Department of Otorhinolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, China; Center for Hearing and Deafness, University at Buffalo, Buffalo, NY, 14214, USA; Department of Audiology and Speech-Language Pathology, Asia University, Taichung, Taiwan, ROC
| | - Dalian Ding
- Department of Otorhinolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, China; Center for Hearing and Deafness, University at Buffalo, Buffalo, NY, 14214, USA.
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41
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Genetic Heterogeneity of SLC22 Family of Transporters in Drug Disposition. J Pers Med 2018; 8:jpm8020014. [PMID: 29659532 PMCID: PMC6023491 DOI: 10.3390/jpm8020014] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 04/04/2018] [Accepted: 04/10/2018] [Indexed: 12/14/2022] Open
Abstract
An important aspect of modern medicine is its orientation to achieve more personalized pharmacological treatments. In this context, transporters involved in drug disposition have gained well-justified attention. Owing to its broad spectrum of substrate specificity, including endogenous compounds and xenobiotics, and its strategical expression in organs accounting for drug disposition, such as intestine, liver and kidney, the SLC22 family of transporters plays an important role in physiology, pharmacology and toxicology. Among these carriers are plasma membrane transporters for organic cations (OCTs) and anions (OATs) with a marked overlap in substrate specificity. These two major clades of SLC22 proteins share a similar membrane topology but differ in their degree of genetic variability. Members of the OCT subfamily are highly polymorphic, whereas OATs have a lower number of genetic variants. Regarding drug disposition, changes in the activity of these variants affect intestinal absorption and target tissue uptake, but more frequently they modify plasma levels due to enhanced or reduced clearance by the liver and secretion by the kidney. The consequences of these changes in transport-associated function markedly affect the effectiveness and toxicity of the treatment in patients carrying the mutation. In solid tumors, changes in the expression of these transporters and the existence of genetic variants substantially determine the response to anticancer drugs. Moreover, chemoresistance usually evolves in response to pharmacological and radiological treatment. Future personalized medicine will require monitoring these changes in a dynamic way to adapt the treatment to the weaknesses shown by each tumor at each stage in each patient.
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Benaouda F, Jones SA, Chana J, Dal Corno BM, Barlow DJ, Hider RC, Page CP, Forbes B. Ion-Pairing with Spermine Targets Theophylline To the Lungs via the Polyamine Transport System. Mol Pharm 2018; 15:861-870. [DOI: 10.1021/acs.molpharmaceut.7b00715] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Faiza Benaouda
- Institute of Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom
| | - Stuart A. Jones
- Institute of Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom
| | - Jasminder Chana
- Institute of Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom
| | - Benedetta M. Dal Corno
- Institute of Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom
| | - David J. Barlow
- Institute of Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom
| | - Robert C. Hider
- Institute of Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom
| | - Clive P. Page
- Institute of Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom
- Sackler Institute of Pulmonary Pharmacology, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom
| | - Ben Forbes
- Institute of Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom
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Brown PMGE, McGuire H, Bowie D. Stargazin and cornichon-3 relieve polyamine block of AMPA receptors by enhancing blocker permeation. J Gen Physiol 2017; 150:67-82. [PMID: 29222130 PMCID: PMC5749116 DOI: 10.1085/jgp.201711895] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 10/06/2017] [Accepted: 11/06/2017] [Indexed: 01/12/2023] Open
Abstract
Polyamine block of AMPA-type ionotropic glutamate receptors is attenuated by auxiliary proteins stargazin and cornichon-3. Brown et al. show that relief from block is due to enhanced blocker permeation and present a modified model of permeant channel block to account for their experimental findings. Most ligand- and voltage-gated ion channels assemble as signaling complexes consisting of pore-forming and auxiliary subunits. In the mammalian brain, AMPA-type ionotropic glutamate receptors (AMPARs) coassemble with several families of auxiliary subunits that regulate channel gating as well as ion channel block and permeation. Previous work has shown that auxiliary proteins stargazin (or γ2) and cornichon-3 (CNIH-3) attenuate the cytoplasmic polyamine channel block of AMPARs, although the underlying mechanism has yet to be established. Here, we show that γ2 and CNIH-3 relieve channel block by enhancing the rate of blocker permeation. Surprisingly, the relative permeability of the polyamine spermine (Spm) through the pore of the AMPAR-γ2 or -CNIH-3 complexes is considerably more than AMPARs expressed alone. Spm permeability is comparable to that of Na+ for the GluA2-γ2 complex and four times greater than Na+ with GluA2 + CNIH-3. A modified model of permeant channel block fully accounts for both the voltage- and time-dependent nature of Spm block. Estimates of block rate constants reveal that auxiliary subunits do not attenuate block by shifting the location of the block site within the membrane electric field, and they do not affect the blocker’s ability to reach it. Instead, γ2 and CNIH-3 relieve channel block by facilitating the blocker’s exit rates from the open channel. From a physiological perspective, the relief of channel block exerted by γ2 and CNIH-3 ensures that there is unfettered signaling by AMPARs at glutamatergic synapses. Moreover, the pronounced ability of AMPARs to transport polyamines may have an unexpected role in regulating cellular polyamine levels.
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Affiliation(s)
- Patricia M G E Brown
- Integrated Program in Neurosciences, McGill University, Montréal, Québec, Canada.,Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Hugo McGuire
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Derek Bowie
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
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Lenis YY, Elmetwally MA, Tang W, Satterfield C, Dunlap K, Wu G, Bazer FW. Functional roles of agmatinase during the peri-implantation period of pregnancy in sheep. Amino Acids 2017; 50:293-308. [PMID: 29196820 DOI: 10.1007/s00726-017-2515-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 11/21/2017] [Indexed: 01/15/2023]
Abstract
This study investigated the effect of agmatine (Agm) in proliferation of ovine trophecdoderm cells (oTr1) as well as the importance of the arginine decarboxylase (ADC) and agmatinase (AGMAT) alternative pathway for synthesis of polyamines in ovine conceptuses during the peri-implantation period of pregnancy. Morpholino antisense oligonucleotides (MAOs) were used to inhibit translation of mRNAs for ODC1 alone, AGMAT alone, and their combination. Rambouillet ewes (N = 50) were assigned randomly to the following treatments on Day 8 of pregnancy: MAO control (n = 10); MAO-ODC1 (n = 8); MAO-ADC (n = 6); MAO-ODC1:MAO-ADC (n = 9); or MAO-ODC1:MAO-AGMAT (n = 9). Ewes were ovario-hysterectomized on Day 16 of pregnancy to obtain uterine flushings, uterine endometrium, and conceptus tissues. Inhibition of translation of both ODC1 and AGMAT resulted in 22% of ewes having morphologically and functionally normal (elongated and healthy) conceptuses designated MAO-ODC1:MAO-AGMAT (A). But, 78% of the MAO-ODC1:MAO-AGMAT ewes had morphologically and functionally abnormal (not elongated and fragmented) conceptuses designated MAO-ODC1:MAO-AGMAT (B). The pregnancy rate was less (22%; P < 0.05) for MAO-ODC1:MAO-AGMAT ewes than for MAO-control (80%), MAO-ODC1 (75%), MAO-ADC (84%), and MAO-ODC1:MAO-ADC (44%) ewes. Moreover, inhibition of translational of both ODC1 and AGMAT mRNAs increased expression of ADC, SLC22A1, SLC22A2, and SLC22A3 mRNAs, as well as abundances of agmatine, putrescine, spermindine, and spermine in conceptus tissue. However, MAO-ODC1:AGMAT(B) ewes had greater abundances of agmatine, putrescine, and spermidine and reduced amounts of spermine in uterine flushes. Thus, in vivo knockdown of translation of ODC1 and AGMAT mRNAs increased expression of genes for the synthesis and transport of polyamines in ovine conceptuses during the peri-implantation period of pregnancy.
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Affiliation(s)
- Yasser Y Lenis
- Department of Animal Science, Texas A&M University, College Station, TX, 77843-2471, USA.,Center for Animal Biotechnology and Genomics, Texas A&M University, College Station, TX, 77843, USA.,Centauro Research Group, School of Veterinary Medicine, Faculty of Agrarian Science, Universidad de Antioquia, Calle 70 No. 52-21, Medellín, Colombia.,Faculty of Agricultural Sciences, UDCA, Calle 222 No. 55-37, Bogota, Colombia
| | - Mohammed A Elmetwally
- Department of Animal Science, Texas A&M University, College Station, TX, 77843-2471, USA.,Center for Animal Biotechnology and Genomics, Texas A&M University, College Station, TX, 77843, USA.,Faculty of Veterinary Medicine, Department of Theriogenology, Mansoura University, Mansoura, 35516, Egypt
| | - Wanjin Tang
- Department of Animal Science, Texas A&M University, College Station, TX, 77843-2471, USA.,Center for Animal Biotechnology and Genomics, Texas A&M University, College Station, TX, 77843, USA
| | - Carey Satterfield
- Department of Animal Science, Texas A&M University, College Station, TX, 77843-2471, USA
| | - Kathrin Dunlap
- Department of Animal Science, Texas A&M University, College Station, TX, 77843-2471, USA
| | - Guoyao Wu
- Department of Animal Science, Texas A&M University, College Station, TX, 77843-2471, USA.,Center for Animal Biotechnology and Genomics, Texas A&M University, College Station, TX, 77843, USA
| | - Fuller W Bazer
- Department of Animal Science, Texas A&M University, College Station, TX, 77843-2471, USA. .,Center for Animal Biotechnology and Genomics, Texas A&M University, College Station, TX, 77843, USA.
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Izumi Y, Kondo N, Takahashi R, Akaike A, Kume T. Reduction of Immunoreactivity Against the C-Terminal Region of the Intracellular α-Synuclein by Exogenous α-Synuclein Aggregates: Possibility of Conformational Changes. JOURNAL OF PARKINSONS DISEASE 2017; 6:569-79. [PMID: 27314756 DOI: 10.3233/jpd-160835] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND The formation of intracellular aggregates containing α-synuclein (α-syn) is a main pathological feature of Parkinson disease. The propagation of α-syn aggregation via cell-to-cell transmission has been implicated in the progression of Parkinson disease. OBJECTIVE Our aim is to clarify the molecular mechanisms underlying the formation of intracellular aggregation by extracellular α-syn. METHODS We investigated the effects of exogenous α-syn aggregates on intracellular α-syn immunoreactivity in α-syn-overexpressing SH-SY5Y cells using two antibodies to distinct epitopes of α-syn. To obtain α-syn aggregates, α-syn solution was aged with continuous agitation. RESULTS Immunoreactivity against the acidic C-terminal domain of the intracellular α-syn was reduced by exposure to agedα-syn, whereas that against the hydrophobic non-amyloid component region was not changed. The reduction in immunoreactivity was not suppressed by protease inhibitors but was mimicked by neutralization of the negative charges on the C-terminal of the intracellular α-syn induced by spermine or extracellular acidification. CONCLUSIONS These results suggest that the reduction in immunoreactivity is attributed not to proteolytic cleavage but to a conformational change at the C-terminus of the intracellular α-syn. The conformational change at the C-terminus of the intracellular α-syn might be involved in an initial step of fibril formation by exogenous α-syn aggregates.
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Affiliation(s)
- Yasuhiko Izumi
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
| | - Naoto Kondo
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
| | - Ryosuke Takahashi
- Department of Neurology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Akinori Akaike
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.,Department of Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Japan
| | - Toshiaki Kume
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
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46
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Agmatine: multifunctional arginine metabolite and magic bullet in clinical neuroscience? Biochem J 2017; 474:2619-2640. [DOI: 10.1042/bcj20170007] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 05/23/2017] [Accepted: 05/25/2017] [Indexed: 12/12/2022]
Abstract
Agmatine, the decarboxylation product of arginine, was largely neglected as an important player in mammalian metabolism until the mid-1990s, when it was re-discovered as an endogenous ligand of imidazoline and α2-adrenergic receptors. Since then, a wide variety of agmatine-mediated effects have been observed, and consequently agmatine has moved from a wallflower existence into the limelight of clinical neuroscience research. Despite this quantum jump in scientific interest, the understanding of the anabolism and catabolism of this amine is still vague. The purification and biochemical characterization of natural mammalian arginine decarboxylase and agmatinase still are open issues. Nevertheless, the agmatinergic system is currently one of the most promising candidates in order to pharmacologically interfere with some major diseases of the central nervous system, which are summarized in the present review. Particularly with respect to major depression, agmatine, its derivatives, and metabolizing enzymes show great promise for the development of an improved treatment of this common disease.
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Akanuma SI, Shimada H, Kubo Y, Hosoya KI. Involvement of Carrier-Mediated Transport at the Blood–Cerebrospinal Fluid Barrier in Spermine Clearance from Rat Brain. Biol Pharm Bull 2017; 40:1599-1603. [DOI: 10.1248/bpb.b17-00394] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Shin-ichi Akanuma
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
| | - Hirokazu Shimada
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
| | - Yoshiyuki Kubo
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
| | - Ken-ichi Hosoya
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
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Wagner DJ, Hu T, Wang J. Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics. Pharmacol Res 2016; 111:237-246. [PMID: 27317943 DOI: 10.1016/j.phrs.2016.06.002] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 06/02/2016] [Indexed: 01/11/2023]
Abstract
Most drugs are intended to act on molecular targets residing within a specific tissue or cell type. Therefore, the drug concentration within the target tissue or cells is most relevant to its pharmacological effect. Increasing evidences suggest that drug transporters not only play a significant role in governing systemic drug levels, but are also an important gate keeper for intra-tissue and intracellular drug concentrations. This review focuses on polyspecific organic cation transporters, which include the organic cation transporters 1-3 (OCT1-3), the multidrug and toxin extrusion proteins 1-2 (MATE1-2) and the plasma membrane monoamine transporter (PMAT). Following an overview of the tissue distribution, transport mechanisms, and functional characteristics of these transporters, we highlight the studies demonstrating the ability of locally expressed OCTs to impact intracellular drug concentrations and directly influence their pharmacological and toxicological activities. Specifically, OCT1-mediated metformin access to its site of action in the liver is impacted by genetic polymorphisms and chemical inhibition of OCT1. The impact of renal OCT2 and MATE1/2-K in cisplatin intrarenal accumulation and nephrotoxicity is reviewed. New data demonstrating the role of OCT3 in salivary drug accumulation and secretion is discussed. Whenever possible, the pharmacodynamic response and toxicological effects is presented and discussed in light of intra-tissue and intracellular drug exposure. Current challenges, knowledge gaps, and future research directions are discussed. Understanding the impact of transporters on intra-tissue and intracellular drug concentrations has important implications for rational-based optimization of drug efficacy and safety.
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Affiliation(s)
- David J Wagner
- Department of Pharmaceutics, University of Washington, Seattle, WA, United States.
| | - Tao Hu
- Department of Pharmaceutics, University of Washington, Seattle, WA, United States.
| | - Joanne Wang
- Department of Pharmaceutics, University of Washington, Seattle, WA, United States.
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Skatchkov SN, Antonov SM, Eaton MJ. Glia and glial polyamines. Role in brain function in health and disease. BIOCHEMISTRY MOSCOW SUPPLEMENT SERIES A-MEMBRANE AND CELL BIOLOGY 2016. [DOI: 10.1134/s1990747816010116] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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50
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Hyrsova L, Smutny T, Trejtnar F, Pavek P. Expression of organic cation transporter 1 (OCT1): unique patterns of indirect regulation by nuclear receptors and hepatospecific gene regulation. Drug Metab Rev 2016; 48:139-58. [DOI: 10.1080/03602532.2016.1188936] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Lucie Hyrsova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
| | - Tomas Smutny
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
| | - Frantisek Trejtnar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
| | - Petr Pavek
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
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