{"PubmedArticle":{"MedlineCitation":{"@attributes":{"Status":"MEDLINE","Owner":"NLM","IndexingMethod":"Automated"},"PMID":{"@attributes":{"Version":"1"},"@text":"39442590"},"DateCompleted":{"Year":"2024","Month":"11","Day":"26"},"DateRevised":{"Year":"2025","Month":"06","Day":"01"},"Article":{"@attributes":{"PubModel":"Print-Electronic"},"Journal":{"ISSN":{"@attributes":{"IssnType":"Electronic"},"@text":"1879-260X"},"JournalIssue":{"@attributes":{"CitedMedium":"Internet"},"Volume":"1871","Issue":"1","PubDate":{"Year":"2025","Month":"Jan"}},"Title":"Biochimica et biophysica acta. Molecular basis of disease","ISOAbbreviation":"Biochim Biophys Acta Mol Basis Dis"},"ArticleTitle":"Hyperglycaemia induces diet-dependent defects of the left-right axis by lowering intracellular pH.","Pagination":{"StartPage":"167550","MedlinePgn":"167550"},"ELocationID":[{"@attributes":{"EIdType":"doi","ValidYN":"Y"},"@text":"10.1016\/j.bbadis.2024.167550"},{"@attributes":{"EIdType":"pii","ValidYN":"Y"},"@text":"S0925-4439(24)00544-1"}],"Abstract":{"AbstractText":["Pregestational diabetes is a risk factor for congenital anomalies, including heterotaxy syndrome, a rare birth defect characterized by the abnormal arrangement of organs relative to the left-right (L-R) body axis. To provide insight into the underlying mechanism by which diabetes induces heterotaxy, we here analyzed the L-R axis of mouse embryos of diabetic dams. Various Pitx2 expression patterns indicative of disruption of L-R axis formation were apparent in such embryos. Expression of Nodal at the node, which triggers a Nodal-Pitx2 expression cascade in lateral plate mesoderm, showed marked regression associated with L-R axis malformation. This regression was similar to that apparent in Wnt3a<sup>-\/-<\/sup> embryos, and canonical Wnt signalling was indeed found to be downregulated in embryos of diabetic dams. RNA sequencing revealed dysregulation of glycolysis in embryos of diabetic dams, and high glucose lowered intracellular pH in the primitive streak, leading to the suppression of Wnt signalling and the regression of Nodal expression. Of note, maternal vitamin A intake increased the incidence of L-R axis defects in embryos of diabetic dams, with dysregulation of retinoic acid metabolism being apparent in these embryos and in Wnt3a<sup>-\/-<\/sup> embryos. Our results shed light on the mechanisms underlying embryopathies associated with maternal diabetes and suggest the importance of diet for prevention of heterotaxy."],"CopyrightInformation":"Copyright \u00a9 2024 Elsevier B.V. All rights reserved."},"AuthorList":{"@attributes":{"CompleteYN":"Y"},"Author":[{"@attributes":{"ValidYN":"Y"},"LastName":"Matsuoka","ForeName":"Ryohei","Initials":"R","AffiliationInfo":[{"Affiliation":"Department of Developmental Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Kitajima","ForeName":"Keiko","Initials":"K","AffiliationInfo":[{"Affiliation":"Department of Developmental Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Nii","ForeName":"Takenobu","Initials":"T","AffiliationInfo":[{"Affiliation":"Department of Developmental Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Zou","ForeName":"Zhaonan","Initials":"Z","AffiliationInfo":[{"Affiliation":"Department of Developmental Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Tanaka","ForeName":"Kaori","Initials":"K","AffiliationInfo":[{"Affiliation":"Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Joo","ForeName":"Kunihiko","Initials":"K","AffiliationInfo":[{"Affiliation":"Department of Cardiovascular Surgery, Kyushu University Hospital, Fukuoka 812-8582, Japan."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Ohkawa","ForeName":"Yasuyuki","Initials":"Y","AffiliationInfo":[{"Affiliation":"Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Ohga","ForeName":"Shouichi","Initials":"S","AffiliationInfo":[{"Affiliation":"Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Meno","ForeName":"Chikara","Initials":"C","AffiliationInfo":[{"Affiliation":"Department of Developmental Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. Electronic address: meno.chikara.727@m.kyushu-u.ac.jp."}]}]},"Language":["eng"],"PublicationTypeList":{"PublicationType":[{"@attributes":{"UI":"D016428"},"@text":"Journal Article"},{"@attributes":{"UI":"D013485"},"@text":"Research Support, Non-U.S. Gov't"}]},"ArticleDate":[{"@attributes":{"DateType":"Electronic"},"Year":"2024","Month":"10","Day":"21"}]},"MedlineJournalInfo":{"Country":"Netherlands","MedlineTA":"Biochim Biophys Acta Mol Basis Dis","NlmUniqueID":"101731730","ISSNLinking":"0925-4439"},"ChemicalList":{"Chemical":[{"RegistryNumber":"0","NameOfSubstance":{"@attributes":{"UI":"D060509"},"@text":"Wnt3A Protein"}},{"RegistryNumber":"0","NameOfSubstance":{"@attributes":{"UI":"D018398"},"@text":"Homeodomain Proteins"}},{"RegistryNumber":"184787-43-7","NameOfSubstance":{"@attributes":{"UI":"D000097577"},"@text":"Homeobox Protein PITX2"}},{"RegistryNumber":"0","NameOfSubstance":{"@attributes":{"UI":"C555511"},"@text":"Wnt3a protein, mouse"}},{"RegistryNumber":"0","NameOfSubstance":{"@attributes":{"UI":"D014157"},"@text":"Transcription Factors"}},{"RegistryNumber":"0","NameOfSubstance":{"@attributes":{"UI":"D055457"},"@text":"Nodal Protein"}}]},"CitationSubset":["IM"],"MeshHeadingList":{"MeshHeading":[{"DescriptorName":{"@attributes":{"UI":"D000818","MajorTopicYN":"N"},"@text":"Animals"}},{"DescriptorName":{"@attributes":{"UI":"D051379","MajorTopicYN":"N"},"@text":"Mice"}},{"DescriptorName":{"@attributes":{"UI":"D005260","MajorTopicYN":"N"},"@text":"Female"}},{"DescriptorName":{"@attributes":{"UI":"D011247","MajorTopicYN":"N"},"@text":"Pregnancy"}},{"DescriptorName":{"@attributes":{"UI":"D060509","MajorTopicYN":"Y"},"@text":"Wnt3A Protein"},"QualifierName":[{"@attributes":{"UI":"Q000378","MajorTopicYN":"N"},"@text":"metabolism"},{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"}]},{"DescriptorName":{"@attributes":{"UI":"D018398","MajorTopicYN":"Y"},"@text":"Homeodomain Proteins"},"QualifierName":[{"@attributes":{"UI":"Q000378","MajorTopicYN":"N"},"@text":"metabolism"},{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"}]},{"DescriptorName":{"@attributes":{"UI":"D006943","MajorTopicYN":"N"},"@text":"Hyperglycemia"},"QualifierName":[{"@attributes":{"UI":"Q000378","MajorTopicYN":"N"},"@text":"metabolism"},{"@attributes":{"UI":"Q000473","MajorTopicYN":"N"},"@text":"pathology"}]},{"DescriptorName":{"@attributes":{"UI":"D006863","MajorTopicYN":"N"},"@text":"Hydrogen-Ion Concentration"}},{"DescriptorName":{"@attributes":{"UI":"D000097577","MajorTopicYN":"N"},"@text":"Homeobox Protein PITX2"}},{"DescriptorName":{"@attributes":{"UI":"D060449","MajorTopicYN":"N"},"@text":"Wnt Signaling Pathway"}},{"DescriptorName":{"@attributes":{"UI":"D014157","MajorTopicYN":"N"},"@text":"Transcription Factors"},"QualifierName":[{"@attributes":{"UI":"Q000378","MajorTopicYN":"N"},"@text":"metabolism"},{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"}]},{"DescriptorName":{"@attributes":{"UI":"D019521","MajorTopicYN":"N"},"@text":"Body Patterning"},"QualifierName":[{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"}]},{"DescriptorName":{"@attributes":{"UI":"D018507","MajorTopicYN":"N"},"@text":"Gene Expression Regulation, Developmental"}},{"DescriptorName":{"@attributes":{"UI":"D004032","MajorTopicYN":"N"},"@text":"Diet"}},{"DescriptorName":{"@attributes":{"UI":"D003921","MajorTopicYN":"N"},"@text":"Diabetes Mellitus, Experimental"},"QualifierName":[{"@attributes":{"UI":"Q000378","MajorTopicYN":"N"},"@text":"metabolism"},{"@attributes":{"UI":"Q000473","MajorTopicYN":"N"},"@text":"pathology"}]},{"DescriptorName":{"@attributes":{"UI":"D018345","MajorTopicYN":"N"},"@text":"Mice, Knockout"}},{"DescriptorName":{"@attributes":{"UI":"D055457","MajorTopicYN":"N"},"@text":"Nodal Protein"},"QualifierName":[{"@attributes":{"UI":"Q000378","MajorTopicYN":"N"},"@text":"metabolism"},{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"}]},{"DescriptorName":{"@attributes":{"UI":"D008810","MajorTopicYN":"N"},"@text":"Mice, Inbred C57BL"}}]},"KeywordList":[{"@attributes":{"Owner":"NOTNLM"},"Keyword":[{"@attributes":{"MajorTopicYN":"N"},"@text":"Heterotaxy"},{"@attributes":{"MajorTopicYN":"N"},"@text":"L-R axis formation"},{"@attributes":{"MajorTopicYN":"N"},"@text":"Pregestational diabetes"},{"@attributes":{"MajorTopicYN":"N"},"@text":"Retinoic acid signalling"},{"@attributes":{"MajorTopicYN":"N"},"@text":"Wnt signalling"}]}],"CoiStatement":"Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."},"PubmedData":{"History":{"PubMedPubDate":[{"@attributes":{"PubStatus":"received"},"Year":"2024","Month":"8","Day":"6"},{"@attributes":{"PubStatus":"revised"},"Year":"2024","Month":"10","Day":"2"},{"@attributes":{"PubStatus":"accepted"},"Year":"2024","Month":"10","Day":"17"},{"@attributes":{"PubStatus":"medline"},"Year":"2024","Month":"11","Day":"27","Hour":"0","Minute":"21"},{"@attributes":{"PubStatus":"pubmed"},"Year":"2024","Month":"10","Day":"24","Hour":"0","Minute":"22"},{"@attributes":{"PubStatus":"entrez"},"Year":"2024","Month":"10","Day":"23","Hour":"19","Minute":"22"}]},"PublicationStatus":"ppublish","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"39442590"},{"@attributes":{"IdType":"doi"},"@text":"10.1016\/j.bbadis.2024.167550"},{"@attributes":{"IdType":"pii"},"@text":"S0925-4439(24)00544-1"}]}}}}