Physiological genomicsPub Date : 2023-10-01Epub Date: 2023-08-07DOI: 10.1152/physiolgenomics.00046.2023
Pavel A Makhnovskii, Egor M Lednev, Alina O Gavrilova, Nadia S Kurochkina, Tatiana F Vepkhvadze, Marina V Shestakova, Daniil V Popov
{"title":"Dysregulation of early gene response to a mixed meal in skeletal muscle in obesity and type 2 diabetes.","authors":"Pavel A Makhnovskii, Egor M Lednev, Alina O Gavrilova, Nadia S Kurochkina, Tatiana F Vepkhvadze, Marina V Shestakova, Daniil V Popov","doi":"10.1152/physiolgenomics.00046.2023","DOIUrl":"https://doi.org/10.1152/physiolgenomics.00046.2023","url":null,"abstract":"<p><p>Obesity- and type 2 diabetes mellitus-induced changes in the expression of protein-coding genes in human skeletal muscle were extensively examined at baseline (after an overnight fast). We aimed to compare the early transcriptomic response to a typical single meal in skeletal muscle of metabolically healthy subjects and obese individuals without and with type 2 diabetes. Transcriptomic response (RNA-seq) to a mixed meal (nutritional drink, ∼25 kJ/kg of body mass) was examined in the vastus lateralis muscle (1 h after a meal) in 7 healthy subjects and 14 obese individuals without or with type 2 diabetes. In all obese individuals, the transcriptome response to a meal was dysregulated (suppressed and altered) and associated with different biological processes compared with healthy control. To search for potential transcription factors regulating transcriptomic response to a meal, the enrichment of transcription factor-binding sites in individual promoters of the human skeletal muscle was examined. In obese individuals, the transcriptomic response is associated with a different set of transcription factors than that in healthy subjects. In conclusion, metabolic disorders are associated with a defect in the regulation of mixed meal/insulin-mediated gene expression-insulin resistance in terms of gene expression. Importantly, this dysregulation occurs in obese individuals without type 2 diabetes, i.e., at the first stage of the development of metabolic disorders.<b>NEW & NOTEWORTHY</b> In skeletal muscle of metabolically healthy subjects, a typical single meal normalized to body mass induces activation of various transcription factors, expression of numerous receptor tyrosine kinases associated with the insulin signaling cascade, and transcription regulators. In skeletal muscle of obese individuals without and with type 2 diabetes, this signaling network is poorly regulated at the transcriptional level, indicating dysregulation of the early gene response to a mixed meal.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41208984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Physiological genomicsPub Date : 2023-09-01Epub Date: 2023-07-24DOI: 10.1152/physiolgenomics.00030.2023
Blair W Perry, Anna L McDonald, Shawn Trojahn, Michael W Saxton, Ellery P Vincent, Courtney Lowry, Brandon D Evans Hutzenbiler, Omar E Cornejo, Charles T Robbins, Heiko T Jansen, Joanna L Kelley
{"title":"Feeding during hibernation shifts gene expression toward active season levels in brown bears (<i>Ursus arctos</i>).","authors":"Blair W Perry, Anna L McDonald, Shawn Trojahn, Michael W Saxton, Ellery P Vincent, Courtney Lowry, Brandon D Evans Hutzenbiler, Omar E Cornejo, Charles T Robbins, Heiko T Jansen, Joanna L Kelley","doi":"10.1152/physiolgenomics.00030.2023","DOIUrl":"10.1152/physiolgenomics.00030.2023","url":null,"abstract":"<p><p>Hibernation in bears involves a suite of metabolical and physiological changes, including the onset of insulin resistance, that are driven in part by sweeping changes in gene expression in multiple tissues. Feeding bears glucose during hibernation partially restores active season physiological phenotypes, including partial resensitization to insulin, but the molecular mechanisms underlying this transition remain poorly understood. Here, we analyze tissue-level gene expression in adipose, liver, and muscle to identify genes that respond to midhibernation glucose feeding and thus potentially drive postfeeding metabolical and physiological shifts. We show that midhibernation feeding stimulates differential expression in all analyzed tissues of hibernating bears and that a subset of these genes responds specifically by shifting expression toward levels typical of the active season. Inferences of upstream regulatory molecules potentially driving these postfeeding responses implicate peroxisome proliferator-activated receptor gamma (PPARG) and other known regulators of insulin sensitivity, providing new insight into high-level regulatory mechanisms involved in shifting metabolic phenotypes between hibernation and active states.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10642923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10047108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Physiological genomicsPub Date : 2023-09-01Epub Date: 2023-07-17DOI: 10.1152/physiolgenomics.00013.2023
Colleen G Julian, Julie A Houck, Sahand Fallahi, Litzi Lazo-Vega, Christopher J Matarazzo, Breea Diamond, Valquiria Miranda-Garrido, Bernardo J Krause, Lorna G Moore, Jonathan A Shortt, Lilian Toledo-Jaldin, Ramón A Lorca
{"title":"Altered placental ion channel gene expression in preeclamptic high-altitude pregnancies.","authors":"Colleen G Julian, Julie A Houck, Sahand Fallahi, Litzi Lazo-Vega, Christopher J Matarazzo, Breea Diamond, Valquiria Miranda-Garrido, Bernardo J Krause, Lorna G Moore, Jonathan A Shortt, Lilian Toledo-Jaldin, Ramón A Lorca","doi":"10.1152/physiolgenomics.00013.2023","DOIUrl":"10.1152/physiolgenomics.00013.2023","url":null,"abstract":"<p><p>High-altitude (>2,500 m) residence increases the risk of pregnancy vascular disorders such as fetal growth restriction and preeclampsia, each characterized by impaired placental function. Genetic attributes of highland ancestry confer relative protection against vascular disorders of pregnancy at high altitudes. Although ion channels have been implicated in placental function regulation, neither their expression in high-altitude placentas nor their relationship to high-altitude preeclampsia has been determined. Here, we measured the expression of 26 ion-channel genes in placentas from preeclampsia cases and normotensive controls in La Paz, Bolivia (3,850 m). In addition, we correlated gene transcription to maternal and infant ancestry proportions. Gene expression was assessed by PCR, genetic ancestry evaluated by <i>ADMIXTURE</i>, and ion channel proteins localized by immunofluorescence. In preeclamptic placentas, 11 genes were downregulated (<i>ABCC9</i>, <i>ATP2A2</i>, <i>CACNA1C</i>, <i>KCNE1</i>, <i>KCNJ8</i>, <i>KCNK3</i>, <i>KCNMA1</i>, <i>KCNQ1</i>, <i>KCNQ4</i>, <i>PKD2</i>, and <i>TRPV6</i>) and two were upregulated (<i>KCNQ3</i> and <i>SCNN1G</i>). <i>KCNE1</i> expression was positively correlated with high-altitude Amerindian ancestry and negatively correlated with non-high altitude. <i>SCNN1G</i> was negatively correlated with African ancestry, despite minimal African admixture. Most ion channels were localized in syncytiotrophoblasts (Cav1.2, TRPP2, TRPV6, and Kv7.1), whereas expression of Kv7.4 was primarily in microvillous membranes, Kir6.1 in chorionic plate and fetal vessels, and MinK in stromal cells. Our findings suggest a role for differential placental ion channel expression in the development of preeclampsia. Functional studies are needed to determine processes affected by these ion channels in the placenta and whether therapies directed at modulating their activity could influence the onset or severity of preeclampsia.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10642922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10057015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Physiological genomicsPub Date : 2023-09-01Epub Date: 2023-07-17DOI: 10.1152/physiolgenomics.00032.2023
Brandon M Bauer, Supriyo Bhattacharya, Elizabeth Bloom-Saldana, Jose M Irimia-Dominguez, Patrick T Fueger
{"title":"Dose-dependent progression of multiple low-dose streptozotocin-induced diabetes in mice.","authors":"Brandon M Bauer, Supriyo Bhattacharya, Elizabeth Bloom-Saldana, Jose M Irimia-Dominguez, Patrick T Fueger","doi":"10.1152/physiolgenomics.00032.2023","DOIUrl":"10.1152/physiolgenomics.00032.2023","url":null,"abstract":"<p><p>This study investigated the effects of different multiple low doses of streptozotocin (STZ), namely 35 and 55 mg/kg, on the onset and progression of diabetes in mice. Both doses are commonly used in research, and although both induced a loss of beta cell mass, they had distinct effects on whole glucose tolerance, beta cell function, and gene transcription. Mice treated with 55 mg/kg became rapidly glucose intolerant, whereas those treated with 35 mg/kg had a slower onset and remained glucose tolerant for up to a week before becoming equally glucose intolerant as the 55 mg/kg group. Beta cell mass loss was similar between the two groups, but the 35 mg/kg-treated mice had improved glucose-stimulated insulin secretion in gold-standard hyperglycemic clamp studies. Transcriptomic analysis revealed that the 55 mg/kg dose caused disruptions in nearly five times as many genes as the 35 mg/kg dose in isolated pancreatic islets. Pathways that were downregulated in both doses were more downregulated in the 55 mg/kg-treated mice, whereas pathways that were upregulated in both doses were more upregulated in the 35 mg/kg-treated mice. Moreover, we observed a differential downregulation in the 55 mg/kg-treated islets of beta cell characteristic pathways, such as exocytosis or hormone secretion. On the other hand, apoptosis was differentially upregulated in 35 mg/kg-treated islets, suggesting different transcriptional mechanisms in the onset of STZ-induced damage in the islets. This study demonstrates that the two STZ doses induce distinctly mechanistic progressions for the loss of functional beta cell mass.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10642924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10112805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Physiological genomicsPub Date : 2023-09-01Epub Date: 2023-07-17DOI: 10.1152/physiolgenomics.00128.2022
Sharmila Ahmad, Markus Hodal Drag, Suraya Mohamad Salleh, Zexi Cai, Mette Olaf Nielsen
{"title":"Gene coexpression network analysis reveals perirenal adipose tissue as an important target of prenatal malnutrition in sheep.","authors":"Sharmila Ahmad, Markus Hodal Drag, Suraya Mohamad Salleh, Zexi Cai, Mette Olaf Nielsen","doi":"10.1152/physiolgenomics.00128.2022","DOIUrl":"10.1152/physiolgenomics.00128.2022","url":null,"abstract":"<p><p>We have previously demonstrated that pre- and early postnatal malnutrition in sheep induced depot- and sex-specific changes in adipose morphological features, metabolic outcomes, and transcriptome in adulthood, with perirenal (PER) as the major target followed by subcutaneous (SUB) adipose tissue. We aimed to identify coexpressed and hub genes in SUB and PER to identify the underlying molecular mechanisms contributing to the early nutritional programming of adipose-related phenotypic outcomes. Transcriptomes of SUB and PER of male and female adult sheep with different pre- and early postnatal nutrition histories were used to construct networks of coexpressed genes likely to be functionally associated with pre- and early postnatal nutrition histories and phenotypic traits using weighted gene coexpression network analysis. The modules from PER showed enrichment of cell cycle regulation, gene expression, transmembrane transport, and metabolic processes associated with both sexes' prenatal nutrition. In SUB (only males), a module of enriched adenosine diphosphate metabolism and development correlated with prenatal nutrition. Sex-specific module enrichments were found in PER, such as chromatin modification in the male network but histone modification and mitochondria- and oxidative phosphorylation-related functions in the female network. These sex-specific modules correlated with prenatal nutrition and adipocyte size distribution patterns. Our results point to PER as a primary target of prenatal malnutrition compared to SUB, which played only a minor role. The prenatal programming of gene expression and cell cycle, potentially through epigenetic modifications, might be underlying mechanisms responsible for observed changes in PER expandability and adipocyte-size distribution patterns in adulthood in both sexes.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10642927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10057012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Endothelial to mesenchymal transition in neonatal hyperoxic lung injury: role of sex as a biological variable.","authors":"Abiud Cantu, Manuel Cantu Gutierrez, Yuhao Zhang, Xiaoyu Dong, Krithika Lingappan","doi":"10.1152/physiolgenomics.00037.2023","DOIUrl":"10.1152/physiolgenomics.00037.2023","url":null,"abstract":"<p><p>Bronchopulmonary dysplasia (BPD) is characterized by an arrest in alveolarization, abnormal vascular development, and variable interstitial fibroproliferation in the premature lung. Endothelial to mesenchymal transition (EndoMT) may be a source of pathological fibrosis in many organ systems. Whether EndoMT contributes to the pathogenesis of BPD is not known. We tested the hypothesis that pulmonary endothelial cells will show increased expression of EndoMT markers upon exposure to hyperoxia and that sex as a biological variable will modulate differences in expression. Wild-type (WT) and Cdh5-PAC CreERT2 (endothelial reporter) neonatal male and female mice (C57BL6) were exposed to hyperoxia (0.95 [Formula: see text]) either during the saccular stage of lung development (95% [Formula: see text]; <i>postnatal day 1-5</i> [<i>PND1-5</i>]) or through the saccular and early alveolar stages of lung development (75% [Formula: see text]; <i>PND1-14</i>). Expression of EndoMT markers was measured in whole lung and endothelial cell mRNA. Sorted lung endothelial cells (from room air- and hyperoxia-exposed lungs) were subjected to bulk RNA-Seq. We show that exposure of the neonatal lung to hyperoxia leads to upregulation of key markers of EndoMT. Furthermore, using lung sc-RNA-Seq data from neonatal lung we were able to show that all endothelial cell subpopulations including the lung capillary endothelial cells show upregulation of EndoMT-related genes. Markers related to EndoMT are upregulated in the neonatal lung upon exposure to hyperoxia and show sex-specific differences. Mechanisms mediating EndoMT in the injured neonatal lung can modulate the response of the neonatal lung to hyperoxic injury and need further investigation.<b>NEW & NOTEWORTHY</b> We show that neonatal hyperoxia exposure increased EndoMT markers in the lung endothelial cells and this biological process exhibits sex-specific differences.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10625841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9970956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mohannad Khandakji, Hind Hassan Ahmed Habish, Nawal Bakheet Salem Abdulla, Sitti Apsa Albani Kusasi, Nema Mahmoud Ghobashy Abdou, Hajer Mahmoud M A Al-Mulla, Reem Jawad A A Al Sulaiman, Salha M Bu Jassoum, Borbala Mifsud
{"title":"<i>BRCA1</i>-specific machine learning model predicts variant pathogenicity with high accuracy.","authors":"Mohannad Khandakji, Hind Hassan Ahmed Habish, Nawal Bakheet Salem Abdulla, Sitti Apsa Albani Kusasi, Nema Mahmoud Ghobashy Abdou, Hajer Mahmoud M A Al-Mulla, Reem Jawad A A Al Sulaiman, Salha M Bu Jassoum, Borbala Mifsud","doi":"10.1152/physiolgenomics.00033.2023","DOIUrl":"https://doi.org/10.1152/physiolgenomics.00033.2023","url":null,"abstract":"<p><p>Identification of novel <i>BRCA1</i> variants outpaces their clinical annotation which highlights the importance of developing accurate computational methods for risk assessment. Therefore our aim was to develop a <i>BRCA1</i>-specific machine learning model to predict the pathogenicity of all types of <i>BRCA1</i> variants and to apply this model and our previous <i>BRCA2-</i>specific model to assess <i>BRCA</i> variants of uncertain significance (VUS) among Qatari patients with breast cancer. We developed an XGBoost model that utilizes variant information such as position frequency and consequence as well as prediction scores from numerous in silico tools. We trained and tested the model with <i>BRCA1</i> variants that were reviewed and classified by the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium. In addition we tested the model's performance on an independent set of missense variants of uncertain significance with experimentally determined functional scores. The model performed excellently in predicting the pathogenicity of ENIGMA-classified variants (accuracy: 99.9%) and in predicting the functional consequence of the independent set of missense variants (accuracy: 93.4%). Moreover it predicted 2 115 potentially pathogenic variants among the 31 058 unreviewed <i>BRCA1</i> variants in the <i>BRCA</i> exchange database. Using two <i>BRCA</i>-specific models we did not identify any pathogenic <i>BRCA1</i> variants among those found in patients in Qatar but predicted four potentially pathogenic <i>BRCA2</i> variants, which could be prioritized for functional validation.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10393322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9914591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Physiological genomicsPub Date : 2023-08-01Epub Date: 2023-06-12DOI: 10.1152/physiolgenomics.00166.2022
Nethika R Ariyasinghe, Roberta de Souza Santos, Andrew Gross, Arwin Aghamaleky-Sarvestany, Simion Kreimer, Sean Escopete, Sarah J Parker, Dhruv Sareen
{"title":"Proteomics of novel induced pluripotent stem cell-derived vascular endothelial cells reveal extensive similarity with an immortalized human endothelial cell line.","authors":"Nethika R Ariyasinghe, Roberta de Souza Santos, Andrew Gross, Arwin Aghamaleky-Sarvestany, Simion Kreimer, Sean Escopete, Sarah J Parker, Dhruv Sareen","doi":"10.1152/physiolgenomics.00166.2022","DOIUrl":"10.1152/physiolgenomics.00166.2022","url":null,"abstract":"<p><p>The vascular endothelium constitutes the inner lining of the blood vessel, and malfunction and injuries of the endothelium can cause cardiovascular diseases as well as other diseases including stroke, tumor growth, and chronic kidney failure. Generation of effective sources to replace injured endothelial cells (ECs) could have significant clinical impact, and somatic cell sources like peripheral or cord blood cannot credibly supply enough endothelial cell progenitors for multitude of treatments. Pluripotent stem cells are a promising source for a reliable EC supply, which have the potential to restore tissue function and treat vascular diseases. We have developed methods to differentiate induced pluripotent stem cells (iPSCs) efficiently and robustly across multiple iPSC lines into nontissue-specific pan vascular ECs (iECs) with high purity. These iECs present with canonical endothelial cell markers and exhibit measures of endothelial cell functionality with the uptake of Dil fluorescent dye-labeled acetylated low-density lipoprotein (Dil-Ac-LDL) and tube formation. Using proteomic analysis, we revealed that the iECs are more proteomically similar to established human umbilical vein ECs (HUVECs) than to iPSCs. Posttranslational modifications (PTMs) were most shared between HUVECs and iECs, and potential targets for increasing the proteomic similarity of iECs to HUVECs were identified. Here we demonstrate an efficient robust method to differentiate iPSCs into functional ECs, and for the first time provide a comprehensive protein expression profile of iECs, which indicates their similarities with a widely used immortalized HUVECs, allowing for further mechanistic studies of EC development, signaling, and metabolism for future regenerative applications.<b>NEW & NOTEWORTHY</b> We have developed methods to differentiate induced pluripotent stem cells (iPSCs) across multiple iPSC lines into nontissue-specific pan vascular ECs (iECs) and demonstrated the proteomic similarity of these cells to a widely used endothelial cell line (HUVECs). We also identified posttranslational modifications and targets for increasing the proteomic similarity of iECs to HUVECs. In the future, iECs can be used to study EC development, signaling, and metabolism for future regenerative applications.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10396221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9933695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Retraction for Huang et al., PEA15-HKII, stabilized by U2AF2, form a molecular switch governing cellular fate after spinal cord injury via MAPK pathway.","authors":"","doi":"10.1152/physiolgenomics.00049.2022","DOIUrl":"https://doi.org/10.1152/physiolgenomics.00049.2022","url":null,"abstract":"Spinal cord injury (SCI) is a devastating disease with poor prognosis. In this study, we sought to investigate the effects of proliferation and apoptosis adaptor protein 15 (PEA15) and hexokinase-Ⅱ (HKⅡ) on neuron cells after SCI. Firstly, we established the in vitro SCI model and cultured its neuron cells. Western blot detected the levels of autophagy- and apoptosis-related proteins in SCI neuron cells, and found high levels of LC3-Ⅱ, p62 and CASP12 in SCI neuron cells. Quantitative real time RT-PCR (RT-qPCR) showed the high levels of PEA15 and HKⅡ in SCI neuron cells. Functional experiments verified the positive regulation of PEA15 and HKⅡ on cell apoptosis. Furthermore, PEA15 and HKⅡ promote SCI neuron cell apoptosis by activating mitogen-activated protein kinase (MAPK) pathway. Co-immunoprecipitation (CoIP) and GST pull down assays showed that HKⅡ could interact with phosphorylated PEA15 in SCI neuron cells. Then the interaction of HKⅡ and PEA15-pSer116 was demonstrated to restrain cell apoptosis after SCI. Simultaneously, U2 small nuclear RNA auxiliary factor 2 (U2AF2) could stabilize the mRNA stability of PEA15 and HKⅡ. In summary, PEA15-HKII form a molecular switch to regulate the apoptosis of SCI neuron cells by regulating MAPK pathway, providing a new direction for SCI study.","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10000395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Physiological genomicsPub Date : 2023-08-01Epub Date: 2023-06-19DOI: 10.1152/physiolgenomics.00017.2023
Thomas J LaRocca, Meghan E Smith, Kaitlin A Freeberg, Daniel H Craighead, Timothy Helmuth, Matthew M Robinson, K Sreekumaran Nair, Angela D Bryan, Douglas R Seals
{"title":"Novel whole blood transcriptome signatures of changes in maximal aerobic capacity in response to endurance exercise training in healthy women.","authors":"Thomas J LaRocca, Meghan E Smith, Kaitlin A Freeberg, Daniel H Craighead, Timothy Helmuth, Matthew M Robinson, K Sreekumaran Nair, Angela D Bryan, Douglas R Seals","doi":"10.1152/physiolgenomics.00017.2023","DOIUrl":"10.1152/physiolgenomics.00017.2023","url":null,"abstract":"<p><p>Maximal aerobic exercise capacity [maximal oxygen consumption (V̇o<sub>2max</sub>)] is one of the strongest predictors of morbidity and mortality. Aerobic exercise training can increase V̇o<sub>2max</sub>, but inter-individual variability is marked and unexplained physiologically. The mechanisms underlying this variability have major clinical implications for extending human healthspan. Here, we report a novel transcriptome signature related to ΔV̇o<sub>2max</sub> with exercise training detected in whole blood RNA. We used RNA-Seq to characterize transcriptomic signatures of ΔV̇o<sub>2max</sub> in healthy women who completed a 16-wk randomized controlled trial comparing supervised, higher versus lower aerobic exercise training volume and intensity (4 training groups, fully crossed). We found significant baseline gene expression differences in subjects who responded to aerobic exercise training with robust versus little/no ΔV̇o<sub>2max</sub>, and differentially expressed genes/transcripts were mostly related to inflammatory signaling and mitochondrial function/protein translation. Baseline gene expression signatures associated with robust versus little/no ΔV̇o<sub>2max</sub> were also modulated by exercise training in a dose-dependent manner, and they predicted ΔV̇o<sub>2max</sub> in this and a separate dataset. Collectively, our data demonstrate the potential utility of using whole blood transcriptomics to study the biology of inter-individual variability in responsiveness to the same exercise training stimulus.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10396280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9930785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}