Phloretin Alleviates Arsenic Trioxide-Induced Apoptosis of H9c2 Cardiomyoblasts via Downregulation in Ca2+/Calcineurin/NFATc Pathway and Inflammatory Cytokine Release

Prabhakaran, Vineetha Vadavanath; Gopalan, Raghu K.

doi:10.1007/s12012-021-09655-0

Cited by 6 publications

(4 citation statements)

References 61 publications

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“…the enzymatic activity of tyrosinase (J. Chen et al, 2020) or glucose transporters GLUT (Lin et al, 2016; L. Liu et al, 2022), and thus it influences various physiological processes (Casado-Diaz et al, 2021; Vadavanath Prabhakaran and Kozhiparambil Gopalan, 2021; Wu et al, 2018). Molecular docking showed that hydrophobic interaction and hydrogen bonding are the main non-covalent interaction forces between phloretin and tyrosinase (J.…”

Section: Discussionmentioning

confidence: 99%

Allosteric links between the hydrophilic N-terminus and transmembrane core of human Na⁺/H⁺ antiporter NHA2

Velázquez

Průša

Masrati

et al. 2022

Preprint

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The human Na+/H+ antiporter NHA2 (SLC9B2) transports Na+ or Li+ across the plasma membrane in exchange for protons, and is implicated in various pathologies. It is a 537 amino acids protein with an 82 residues long hydrophilic cytoplasmic N-terminus followed by a transmembrane part comprising 14 transmembrane helices. We optimized the functional expression of HsNHA2 in the plasma membrane of a salt-sensitive Saccharomyces cerevisiae strain and characterized a set of mutated or truncated versions of HsNHA2 in terms of their substrate specificity, transport activity, localization and protein stability. We identified a highly conserved proline 246, located in the core of the protein, as being crucial for ion selectivity. The replacement of P246 with serine or threonine resulted in antiporters with altered substrate specificity and increased resistance to the HsNHA2-specific inhibitor phloretin that were not only highly active at an acidic pH of 4.0 (like the native antiporter), but also at neutral pH. We also experimentally confirmed the importance of a putative salt bridge between E215 and R432 for antiporter function and structural integrity. Truncations of the first 50 - 70 residues of the N-terminus doubled the transport activity of HsNHA2, whilst changes in the charge at positions E47, E56, K57, or K58 decreased the antiporter’s transport activity. Thus, the hydrophilic N-terminal part of the protein appears to allosterically autoinhibit its cation transport. Our data also show this in vivo approach to be useful for a rapid screening of SNP’s effect on HsNHA2 activity.

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Section: Discussionmentioning

confidence: 99%

Allosteric links between the hydrophilic N-terminus and transmembrane core of human Na⁺/H⁺ antiporter NHA2

Velázquez

Průša

Masrati

et al. 2022

Preprint

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“…Mutations of proline 246 to G, A, S or T provided the antiporter with highly increased resistance to the Hs NHA2‐specific inhibitor phloretin (Figure 3). It was found to efficiently inhibit for example, the enzymatic activity of tyrosinase 64 or glucose transporters GLUT, 65,66 and thus it influences various physiological processes 67–69 . Molecular docking showed that hydrophobic interaction and hydrogen bonding are the main non‐covalent interaction forces between phloretin and tyrosinase 64 .…”

Section: Discussionmentioning

confidence: 99%

“…It was to efficiently inhibit for example, the enzymatic activity of tyrosinase 64 or glucose transporters GLUT, 65,66 and thus it influences various physiological processes. [67][68][69] Molecular docking showed that hydrophobic interaction and hydrogen bonding are the main noncovalent interaction forces between phloretin and tyrosinase. 64 So far, the molecular mechanism of the phloretin inhibition of HsNHA2 has not been studied.…”

Section: Discussionmentioning

confidence: 99%

“…Chen et al, 2020) or glucose transporters GLUT (Lin et al, 2016;L. Liu et al, 2022), and thus it influences various physiological processes (Casado-Diaz et al, 2021;Vadavanath Prabhakaran and Kozhiparambil Gopalan, 2021;Wu et al, 2018). Molecular docking showed that hydrophobic interaction and hydrogen bonding are the main non-covalent interaction forces between phloretin and tyrosinase (J.…”

Section: Mutations Of Proline 246 To G a S Or T Provided The Antiport...mentioning

confidence: 99%

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Allosteric links between the hydrophilic N‐terminus and transmembrane core of human Na⁺/H⁺ antiporter NHA2

et al. 2022

View full text Add to dashboard Cite

The human Na + /H + antiporter NHA2 (SLC9B2) transports Na + or Li + across the plasma membrane in exchange for protons, and is implicated in various pathologies. It is a 537 amino acids protein with an 82 residues long hydrophilic cytoplasmic N-terminus followed by a transmembrane part comprising 14 transmembrane helices. We optimized the functional expression of HsNHA2 in the plasma membrane of a salt-sensitive Saccharomyces cerevisiae strain and characterized a set of mutated or truncated versions of HsNHA2 in terms of their substrate specificity, transport activity, localization and protein stability. We identified a highly conserved proline 246, located in the core of the protein, as being crucial for ion selectivity. The replacement of P246 with serine or threonine resulted in antiporters with altered substrate specificity and increased resistance to the HsNHA2-specific inhibitor phloretin that were not only highly active at an acidic pH of 4.0 (like the native antiporter), but also at neutral pH. We also experimentally confirmed the importance of a putative salt bridge between E215 and R432 for antiporter function and structural integrity. Truncations of the first 50 -70 residues of the Nterminus doubled the transport activity of HsNHA2, whilst changes in the charge at positions E47, E56, K57, or K58 decreased the antiporter's transport activity. Thus, the hydrophilic N-terminal part of the protein appears to allosterically autoinhibit its cation transport. Our data also show this in vivo approach to be useful for a rapid screening of SNP´s effect on HsNHA2 activity.

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Potential of natural products in combination with arsenic trioxide: Investigating cardioprotective effects and mechanisms

Wang¹,

Liu²,

Hu³

et al. 2023

Biomedicine & Pharmacotherapy

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Phloretin Alleviates Arsenic Trioxide-Induced Apoptosis of H9c2 Cardiomyoblasts via Downregulation in Ca2+/Calcineurin/NFATc Pathway and Inflammatory Cytokine Release

Cited by 6 publications

References 61 publications

Allosteric links between the hydrophilic N-terminus and transmembrane core of human Na⁺/H⁺ antiporter NHA2

Allosteric links between the hydrophilic N-terminus and transmembrane core of human Na⁺/H⁺ antiporter NHA2

Allosteric links between the hydrophilic N‐terminus and transmembrane core of human Na⁺/H⁺ antiporter NHA2

Potential of natural products in combination with arsenic trioxide: Investigating cardioprotective effects and mechanisms

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Phloretin Alleviates Arsenic Trioxide-Induced Apoptosis of H9c2 Cardiomyoblasts via Downregulation in Ca2+/Calcineurin/NFATc Pathway and Inflammatory Cytokine Release

Cited by 6 publications

References 61 publications

Allosteric links between the hydrophilic N-terminus and transmembrane core of human Na+/H+ antiporter NHA2

Allosteric links between the hydrophilic N-terminus and transmembrane core of human Na+/H+ antiporter NHA2

Allosteric links between the hydrophilic N‐terminus and transmembrane core of human Na+/H+ antiporter NHA2

Potential of natural products in combination with arsenic trioxide: Investigating cardioprotective effects and mechanisms

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Product

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Allosteric links between the hydrophilic N-terminus and transmembrane core of human Na⁺/H⁺ antiporter NHA2

Allosteric links between the hydrophilic N-terminus and transmembrane core of human Na⁺/H⁺ antiporter NHA2

Allosteric links between the hydrophilic N‐terminus and transmembrane core of human Na⁺/H⁺ antiporter NHA2