Dicarbonyl stress, protein glycation and the unfolded protein response
<p>The reactive dicarbonyl metabolite, methylglyoxal (MG), is increased in obesity and diabetes and is implicated in the development of insulin resistance, type 2 diabetes mellitus and vascular complications of diabetes. Dicarbonyl stress is the metabolic state of abnormal high MG concentratio...
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| منشور في: |
2022
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| _version_ | 1864513568262586368 |
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| author | Naila Rabbani (291722) |
| author2 | Mingzhan Xue (3607649) Paul J. Thornalley (291723) |
| author2_role | author author |
| author_facet | Naila Rabbani (291722) Mingzhan Xue (3607649) Paul J. Thornalley (291723) |
| author_role | author |
| dc.creator.none.fl_str_mv | Naila Rabbani (291722) Mingzhan Xue (3607649) Paul J. Thornalley (291723) |
| dc.date.none.fl_str_mv | 2022-11-22T21:11:14Z |
| dc.identifier.none.fl_str_mv | 10.1007/s10719-021-09980-0 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Dicarbonyl_stress_protein_glycation_and_the_unfolded_protein_response/21592353 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biochemistry and cell biology Medicinal and biomolecular chemistry Cell Biology Molecular Biology Biochemistry |
| dc.title.none.fl_str_mv | Dicarbonyl stress, protein glycation and the unfolded protein response |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p>The reactive dicarbonyl metabolite, methylglyoxal (MG), is increased in obesity and diabetes and is implicated in the development of insulin resistance, type 2 diabetes mellitus and vascular complications of diabetes. Dicarbonyl stress is the metabolic state of abnormal high MG concentration. MG is an arginine-directed glycating agent and precursor of the major advanced glycation endproduct, arginine-derived hydroimidazolone MG-H1. MG-H1 is often formed on protein surfaces and an uncharged hydrophobic residue, inducing protein structural distortion and misfolding. Recent studies indicate that dicarbonyl stress in human endothelial cells and fibroblasts in vitro induced a proteomic response consistent with activation of the unfolded protein response (UPR). The response included: increased abundance of heat shock proteins and ubiquitin ligases catalysing the removal of proteins with unshielded surface hydrophobic patches and formation of polyubiquitinated chains to encapsulate misfolded proteins; and increased low grade inflammation. Activation of the UPR is implicated in insulin resistance. An effective strategy to counter increased MG is inducing increased expression of glyoxalase-1 (Glo1). An optimized inducer of Glo1 expression, trans-resveratrol and hesperetin combination, normalized increased MG concentration, corrected insulin resistance and decreased low grade inflammation in overweight and obese subjects. We propose that dicarbonyl stress, through increased formation of MG-glycated proteins, may be an important physiological stimulus of the UPR and Glo1 inducers may provide a route to effective suppression and therapy. With further investigation and validation, this may provide key new insight into physiological activators of the UPR and association with dicarbonyl stress.</p><h2>Other Information</h2> <p> Published in: Glycoconjugate Journal<br> License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="http://dx.doi.org/10.1007/s10719-021-09980-0" target="_blank">http://dx.doi.org/10.1007/s10719-021-09980-0</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_b13cd125c39d240a08a8e3407dc703f2 |
| identifier_str_mv | 10.1007/s10719-021-09980-0 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/21592353 |
| publishDate | 2022 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Dicarbonyl stress, protein glycation and the unfolded protein responseNaila Rabbani (291722)Mingzhan Xue (3607649)Paul J. Thornalley (291723)Biochemistry and cell biologyMedicinal and biomolecular chemistryCell BiologyMolecular BiologyBiochemistry<p>The reactive dicarbonyl metabolite, methylglyoxal (MG), is increased in obesity and diabetes and is implicated in the development of insulin resistance, type 2 diabetes mellitus and vascular complications of diabetes. Dicarbonyl stress is the metabolic state of abnormal high MG concentration. MG is an arginine-directed glycating agent and precursor of the major advanced glycation endproduct, arginine-derived hydroimidazolone MG-H1. MG-H1 is often formed on protein surfaces and an uncharged hydrophobic residue, inducing protein structural distortion and misfolding. Recent studies indicate that dicarbonyl stress in human endothelial cells and fibroblasts in vitro induced a proteomic response consistent with activation of the unfolded protein response (UPR). The response included: increased abundance of heat shock proteins and ubiquitin ligases catalysing the removal of proteins with unshielded surface hydrophobic patches and formation of polyubiquitinated chains to encapsulate misfolded proteins; and increased low grade inflammation. Activation of the UPR is implicated in insulin resistance. An effective strategy to counter increased MG is inducing increased expression of glyoxalase-1 (Glo1). An optimized inducer of Glo1 expression, trans-resveratrol and hesperetin combination, normalized increased MG concentration, corrected insulin resistance and decreased low grade inflammation in overweight and obese subjects. We propose that dicarbonyl stress, through increased formation of MG-glycated proteins, may be an important physiological stimulus of the UPR and Glo1 inducers may provide a route to effective suppression and therapy. With further investigation and validation, this may provide key new insight into physiological activators of the UPR and association with dicarbonyl stress.</p><h2>Other Information</h2> <p> Published in: Glycoconjugate Journal<br> License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="http://dx.doi.org/10.1007/s10719-021-09980-0" target="_blank">http://dx.doi.org/10.1007/s10719-021-09980-0</a></p>2022-11-22T21:11:14ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1007/s10719-021-09980-0https://figshare.com/articles/journal_contribution/Dicarbonyl_stress_protein_glycation_and_the_unfolded_protein_response/21592353CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/215923532022-11-22T21:11:14Z |
| spellingShingle | Dicarbonyl stress, protein glycation and the unfolded protein response Naila Rabbani (291722) Biochemistry and cell biology Medicinal and biomolecular chemistry Cell Biology Molecular Biology Biochemistry |
| status_str | publishedVersion |
| title | Dicarbonyl stress, protein glycation and the unfolded protein response |
| title_full | Dicarbonyl stress, protein glycation and the unfolded protein response |
| title_fullStr | Dicarbonyl stress, protein glycation and the unfolded protein response |
| title_full_unstemmed | Dicarbonyl stress, protein glycation and the unfolded protein response |
| title_short | Dicarbonyl stress, protein glycation and the unfolded protein response |
| title_sort | Dicarbonyl stress, protein glycation and the unfolded protein response |
| topic | Biochemistry and cell biology Medicinal and biomolecular chemistry Cell Biology Molecular Biology Biochemistry |