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Transport of Nutrients and Ions Relevant to Human Pathophysiology
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Transport of Nutrients and Ions Relevant to Human Pathophysiology

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 20 April 2025 | Viewed by 6828

Special Issue Editors

Prof. Dr. Lorena Pochini

E-Mail Website
Guest Editor
Department DiBEST (Biologia, Ecologia, Scienze della Terra), University of Calabria, Via P. Bucci 4c, 87036 Arcavacata di Rende, CS, Italy
Interests: membrane transporters; drug transport; drug interaction; proteoliposomes; recombinant protein production and purification; carnitine; glutamine; acetylcholine
Dr. Tiziano Mazza

E-Mail Website
Guest Editor
Department DiBEST, Unit of Biochemistry & Molecular Biotechnology, University of Calabria, Arcavacata di Rende, Italy
Interests: proteoliposome; membrane proteins; protein purification,; cryo-EM

Special Issue Information

Dear Colleagues,

Membrane transporters are essential players in cell metabolism since they sustain homeostasis-mediating nutrients and cofactor intestinal absorption, renal reabsorption, and distribution to various tissues. These processes are achieved by the concerted action of transporters belonging to four protein superfamilies: the solute carrier (SLC), the ATP-binding cassette (ABC), ATPases, and channels. SLCs make up the largest group of membrane transporters, which includes transporters for nutrients, cofactors (such as ions), and cofactor precursors (such as vitamins). The crucial role of transporters is definitively revealed by human diseases caused by various defects. Moreover, the altered expression of several transporters is a hallmark of cancer. Therefore, understanding the function and the regulation of nutrient transporters is mandatory for the knowledge and treatment of many diseases. Identification, functional, and structure–function relationship studies have been performed using different and complementary experimental tools from ex vivo and in vitro systems, as well as in silico methodologies. This Special Issue aims to cover recent, novel, and promising research achievements in the field of these transporters, stimulating future research on these important proteins. Original manuscripts and reviews dealing with specific and/or systematic aspects of nutrient and ion transportation, metabolism, and pathophysiology from outstanding experts on the topic are most welcome.

Prof. Dr. Lorena Pochini
Dr. Tiziano Mazza
Guest Editors

Manuscript Submission Information

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Keywords

  • membrane transporters
  • SLC
  • transport system
  • nutrient transport
  • ion transport
  • metabolism
  • human pathophysiology

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Published Papers (6 papers)

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Research

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12 pages, 965 KiB  
Article
The ABCG2 Transporter Affects Plasma Levels, Tissue Distribution and Milk Secretion of Lumichrome, a Natural Derivative of Riboflavin
by Alicia Millán-García, Laura Álvarez-Fernández, Esther Blanco-Paniagua, Ana I. Álvarez and Gracia Merino
Int. J. Mol. Sci. 2024, 25(18), 9884; https://doi.org/10.3390/ijms25189884 - 13 Sep 2024
Viewed by 715
Abstract
The ABCG2 membrane transporter affects bioavailability and milk secretion of xenobiotics and natural compounds, including vitamins such as riboflavin. We aimed to characterize the in vitro and in vivo interaction of ABCG2 with lumichrome, the main photodegradation product of riboflavin, which has proven [...] Read more.
The ABCG2 membrane transporter affects bioavailability and milk secretion of xenobiotics and natural compounds, including vitamins such as riboflavin. We aimed to characterize the in vitro and in vivo interaction of ABCG2 with lumichrome, the main photodegradation product of riboflavin, which has proven in vitro anti-cancer activity and a therapeutical role in antibacterial photodynamic therapy as an efficient photosensitizer. Using MDCK-II polarized cells overexpressing murine Abcg2 and human ABCG2 we found that lumichrome was efficiently transported by both variants. After lumichrome administration to wild-type and Abcg2-/- mice, plasma AUC20–120 min was 1.8-fold higher in Abcg2-/- mice compared with wild-type mice. The liver and testis from Abcg2-/- mice showed significantly higher lumichrome levels compared with wild-type, whereas lumichrome accumulation in small intestine content of wild-type mice was 2.7-fold higher than in Abcg2-/- counterparts. Finally, a 4.1-fold-higher lumichrome accumulation in milk of wild-type versus Abcg2-/- mice was found. Globally, our results show that ABCG2 plays a crucial role in plasma levels, tissue distribution and milk secretion of lumichrome potentially conditioning its biological activity. Full article
(This article belongs to the Special Issue Transport of Nutrients and Ions Relevant to Human Pathophysiology)
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13 pages, 1689 KiB  
Article
The Influence of Retinol Ointment on Rabbit Skin (Oryctolagus cuniculus) Ion Transport—An In Vitro Study
by Klaudia Dłubała, Sandra Wasiek, Patrycja Pilarska, Karolina Szewczyk-Golec, Celestyna Mila-Kierzenkowska, Krzysztof Z. Łączkowski, Marta Sobiesiak, Marcin Gackowski, Bartosz Tylkowski and Iga Hołyńska-Iwan
Int. J. Mol. Sci. 2024, 25(17), 9670; https://doi.org/10.3390/ijms25179670 - 6 Sep 2024
Viewed by 560
Abstract
Retinoids are known to improve the condition of the skin. Transepithelial transport of sodium and chloride ions is important for proper skin function. So far, the effect of applying vitamin A preparations to the skin on ion transport has not been evaluated. In [...] Read more.
Retinoids are known to improve the condition of the skin. Transepithelial transport of sodium and chloride ions is important for proper skin function. So far, the effect of applying vitamin A preparations to the skin on ion transport has not been evaluated. In the study, electrophysiological parameters, including transepithelial electric potential (PD) and transepithelial resistance (R), of rabbit skin specimens after 24 h exposure to retinol ointment (800 mass units/g) were measured in a modified Ussing chamber. The R of the fragments incubated with retinol was significantly different than that of the control skin samples incubated in iso-osmotic Ringer solution. For the controls, the PD values were negative, whereas the retinol-treated specimens revealed positive PD values. Mechanical–chemical stimulation with the use of inhibitors of the transport of sodium (amiloride) or chloride (bumetanide) ions revealed specific changes in the maximal and minimal PD values measured for the retinol-treated samples. Retinol was shown to slightly modify the transport pathways of sodium and chloride ions. In particular, an intensification of the chloride ion secretion from keratinocytes was observed. The proposed action may contribute to deep hydration and increase skin tightness, limiting the action of other substances on its surface. Full article
(This article belongs to the Special Issue Transport of Nutrients and Ions Relevant to Human Pathophysiology)
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16 pages, 1686 KiB  
Article
Modulating the Activity of the Human Organic Cation Transporter 2 Emerges as a Potential Strategy to Mitigate Unwanted Toxicities Associated with Cisplatin Chemotherapy
by Anna Hucke, Marta Kantauskaite, Tim N. Köpp, Christoph A. Wehe, Uwe Karst, Pavel I. Nedvetsky and Giuliano Ciarimboli
Int. J. Mol. Sci. 2024, 25(5), 2922; https://doi.org/10.3390/ijms25052922 - 2 Mar 2024
Viewed by 1136
Abstract
Cisplatin (CDDP) stands out as an effective chemotherapeutic agent; however, its application is linked to the development of significant adverse effects, notably nephro- and ototoxicity. The human organic cation transporter 2 (hOCT2), found in abundance in the basolateral membrane domain of renal proximal [...] Read more.
Cisplatin (CDDP) stands out as an effective chemotherapeutic agent; however, its application is linked to the development of significant adverse effects, notably nephro- and ototoxicity. The human organic cation transporter 2 (hOCT2), found in abundance in the basolateral membrane domain of renal proximal tubules and the Corti organ, plays a crucial role in the initiation of nephro- and ototoxicity associated with CDDP by facilitating its uptake in kidney and ear cells. Given its limited presence in cancer cells, hOCT2 emerges as a potential druggable target for mitigating unwanted toxicities associated with CDDP. Potential strategies for mitigating CDDP toxicities include competing with the uptake of CDDP by hOCT2 or inhibiting hOCT2 activity through rapid regulation mediated by specific signaling pathways. This study investigated the interaction between the already approved cationic drugs disopyramide, imipramine, and orphenadrine with hOCT2 that is stably expressed in human embryonic kidney cells. Regarding disopyramide, its influence on CDDP cellular transport by hOCT2 was further characterized through inductively coupled plasma isotope dilution mass spectrometry. Additionally, its potential protective effects against cellular toxicity induced by CDDP were assessed using a cytotoxicity test. Given that hOCT2 is typically expressed in the basolateral membrane of polarized cells, with specific regulatory mechanisms, this work studied the regulation of hOCT2 that is stably expressed in Madin–Darby Canine Kidney (MDCK) cells. These cells were cultured in a matrix to induce the formation of cysts, exposing hOCT2 in the basolateral plasma membrane domain, which was freely accessible to experimental solutions. The study specifically tested the regulation of ASP+ uptake by hOCT2 in MDCK cysts through the inhibition of casein kinase II (CKII), calmodulin, or p56lck tyrosine kinase. Furthermore, the impact of this manipulation on the cellular toxicity induced by CDDP was examined using a cytotoxicity test. All three drugs—disopyramide, imipramine, and orphenadrine—demonstrated inhibition of ASP+ uptake, with IC50 values in the micromolar (µM) range. Notably, disopyramide produced a significant reduction in the CDDP cellular toxicity and platinum cellular accumulation when co-incubated with CDDP. The activity of hOCT2 in MDCK cysts experienced a significant down-regulation under inhibition of CKII, calmodulin, or p56lck tyrosine kinase. Interestingly, only the inhibition of p56lck tyrosine kinase demonstrated the capability to protect the cells against CDDP toxicity. In conclusion, certain interventions targeting hOCT2 have demonstrated the ability to reduce CDDP cytotoxicity, at least in vitro. Further investigations in in vivo systems are warranted to ascertain their potential applicability as co-treatments for mitigating undesired toxicities associated with CDDP in patients. Full article
(This article belongs to the Special Issue Transport of Nutrients and Ions Relevant to Human Pathophysiology)
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14 pages, 1804 KiB  
Article
The Use of an Antioxidant Enables Accurate Evaluation of the Interaction of Curcumin on Organic Anion-Transporting Polypeptides 4C1 by Preventing Auto-Oxidation
by Toshihiro Sato, Ayaka Yagi, Minami Yamauchi, Masaki Kumondai, Yu Sato, Masafumi Kikuchi, Masamitsu Maekawa, Hiroaki Yamaguchi, Takaaki Abe and Nariyasu Mano
Int. J. Mol. Sci. 2024, 25(2), 991; https://doi.org/10.3390/ijms25020991 - 12 Jan 2024
Viewed by 1320
Abstract
Flavonoids have garnered attention because of their beneficial bioactivities. However, some flavonoids reportedly interact with drugs via transporters and may induce adverse drug reactions. This study investigated the effects of food ingredients on organic anion-transporting polypeptide (OATP) 4C1, which handles uremic toxins and [...] Read more.
Flavonoids have garnered attention because of their beneficial bioactivities. However, some flavonoids reportedly interact with drugs via transporters and may induce adverse drug reactions. This study investigated the effects of food ingredients on organic anion-transporting polypeptide (OATP) 4C1, which handles uremic toxins and some drugs, to understand the safety profile of food ingredients in renal drug excretion. Twenty-eight food ingredients, including flavonoids, were screened. We used ascorbic acid (AA) to prevent curcumin oxidative degradation in our method. Twelve compounds, including apigenin, daidzein, fisetin, genistein, isorhamnetin, kaempferol, luteolin, morin, quercetin, curcumin, resveratrol, and ellagic acid, altered OATP4C1-mediated transport. Kaempferol and curcumin strongly inhibited OATP4C1, and the Ki values of kaempferol (AA(−)), curcumin (AA(−)), and curcumin (AA(+)) were 25.1, 52.2, and 23.5 µM, respectively. The kinetic analysis revealed that these compounds affected OATP4C1 transport in a competitive manner. Antioxidant supplementation was determined to benefit transporter interaction studies investigating the effects of curcumin because the concentration-dependent curve evidently shifted in the presence of AA. In this study, we elucidated the food–drug interaction via OATP4C1 and indicated the utility of antioxidant usage. Our findings will provide essential information regarding food–drug interactions for both clinical practice and the commercial development of supplements. Full article
(This article belongs to the Special Issue Transport of Nutrients and Ions Relevant to Human Pathophysiology)
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15 pages, 3218 KiB  
Article
Unique Substrate Recognition and Sodium–Substrate Binding Stoichiometry in a Bacterial Serotonin Transporter, TuriSERT
by Mu Li, Xintong Zhang, Sixiang Chen, Hanhe Liu and Yuan-Wei Zhang
Int. J. Mol. Sci. 2023, 24(23), 17112; https://doi.org/10.3390/ijms242317112 - 4 Dec 2023
Cited by 1 | Viewed by 1279
Abstract
All resolved high-resolution structures of the transporters in the neurotransmitter sodium symporter (NSS) family revealed that the NSS members share common structural and mechanistic features for substrate and ion binding and transport. However, a recently reported bacterial orthologue of the human serotonin transporter [...] Read more.
All resolved high-resolution structures of the transporters in the neurotransmitter sodium symporter (NSS) family revealed that the NSS members share common structural and mechanistic features for substrate and ion binding and transport. However, a recently reported bacterial orthologue of the human serotonin transporter (hSERT), TuriSERT, possesses a structural characteristic specific for amino acid substrate binding but does transport a biogenic amine. The unique structural feature of TuriSERT requires a novel configuration for coordinating its substrate and ions. In the present study, we characterized TuriSERT expressed in Escherichia coli cells with a fluorescent substrate by biochemical, structural, and pharmacological approaches. Substrate transport by TuriSERT requires Na+ but not Cl−. Replacement of Asp262 by asparagine renders TuriSERT Cl−-dependent. Substitutions of the corresponding Na1 residues did not alter Na+ dependence on substrate transport, whereas the mutation of a Na2 site residue led to a loss of transport activity, suggesting that Na+ binds only to the Na2 site in TuriSERT. In addition, substitutions of several residues essential for recognizing 5-hydroxytryptamine (5-HT) in hSERT had little effect on 5-HT displacement potency in transport assay for TuriSERT. In contrast, mutations of the residues that are proposed to coordinate with 5-HT in our docking model dramatically reduced 5-HT displacement. Furthermore, our results indicated that all tested antidepressants showed a weak inhibitory effect on TuriSERT. The present study demonstrated the existence of a unique substrate binding site and 1:1 stoichiometry of sodium–substrate binding in TuriSERT, a novel structural finding for the NSS transporters. Full article
(This article belongs to the Special Issue Transport of Nutrients and Ions Relevant to Human Pathophysiology)
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Review

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19 pages, 940 KiB  
Review
Role of Divalent Cations in Infections in Host–Pathogen Interaction
by John A. D’Elia and Larry A. Weinrauch
Int. J. Mol. Sci. 2024, 25(18), 9775; https://doi.org/10.3390/ijms25189775 - 10 Sep 2024
Viewed by 962
Abstract
With increasing numbers of patients worldwide diagnosed with diabetes mellitus, renal disease, and iatrogenic immune deficiencies, an increased understanding of the role of electrolyte interactions in mitigating pathogen virulence is necessary. The levels of divalent cations affect host susceptibility and pathogen survival in [...] Read more.
With increasing numbers of patients worldwide diagnosed with diabetes mellitus, renal disease, and iatrogenic immune deficiencies, an increased understanding of the role of electrolyte interactions in mitigating pathogen virulence is necessary. The levels of divalent cations affect host susceptibility and pathogen survival in persons with relative immune insufficiency. For instance, when host cellular levels of calcium are high compared to magnesium, this relationship contributes to insulin resistance and triples the risk of clinical tuberculosis. The movement of divalent cations within intracellular spaces contributes to the host defense, causing apoptosis or autophagy of the pathogen. The control of divalent cation flow is dependent in part upon the mammalian natural resistance-associated macrophage protein (NRAMP) in the host. Survival of pathogens such as M tuberculosis within the bronchoalveolar macrophage is also dependent upon NRAMP. Pathogens evolve mutations to control the movement of calcium through external and internal channels. The host NRAMP as a metal transporter competes for divalent cations with the pathogen NRAMP in M tuberculosis (whether in latent, dormant, or active phase). This review paper summarizes mechanisms of pathogen offense and patient defense using inflow and efflux through divalent cation channels under the influence of parathyroid hormone vitamin D and calcitonin. Full article
(This article belongs to the Special Issue Transport of Nutrients and Ions Relevant to Human Pathophysiology)
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