Physiological genomicsPub Date : 2025-04-01Epub Date: 2025-02-21DOI: 10.1152/physiolgenomics.00161.2024
Kevin G Burfeind, Yoshio Funahashi, Xiao-Tong Su, Anne E Lackey, Matt W Hagen, Sienna Blanche, Jacqueline M Emathinger, Jessica F Hebert, Alicia A McDonough, Susan B Gurley, Jonathan W Nelson, Michael P Hutchens
{"title":"Kidney cell response to acute cardiorenal and isolated kidney ischemia-reperfusion injury.","authors":"Kevin G Burfeind, Yoshio Funahashi, Xiao-Tong Su, Anne E Lackey, Matt W Hagen, Sienna Blanche, Jacqueline M Emathinger, Jessica F Hebert, Alicia A McDonough, Susan B Gurley, Jonathan W Nelson, Michael P Hutchens","doi":"10.1152/physiolgenomics.00161.2024","DOIUrl":"10.1152/physiolgenomics.00161.2024","url":null,"abstract":"<p><p>Acute cardiorenal syndrome (CRS) represents a critical intersection of cardiac and renal dysfunction with profound clinical implications. Despite its significance, the molecular underpinnings that mediate cellular responses within the kidney during CRS remain inadequately understood. We used single nucleus RNA sequencing (snRNAseq) to dissect the cellular transcriptomic landscape of the kidney following a translational model of CRS, cardiac arrest/cardiopulmonary resuscitation (CA/CPR) in comparison to ischemia-reperfusion injury (IRI). In each dataset, we found that proximal tubule (PT) cells of the kidney undergo significant gene expression changes, with decreased expression of genes critically important for cell identity and function, indicative of dedifferentiation. Based on this, we created a novel score to capture the dedifferentiation state of each kidney cell population and found that certain epithelial cell populations, such as the PT S1 and S2 segments, as well as the distal convoluted tubule, exhibited significant dedifferentiation response. Interestingly, the dedifferentiation response in the distal nephron differed in magnitude between IRI and CA/CPR. Gene set enrichment analysis (GSEA) of PT response to IRI and CA/CPR revealed similarities between the two models and key differences, including enrichment of immune system process genes. Transcriptional changes in both mouse models of acute kidney injury (AKI) highly correlated with a dataset of human biopsies from patients diagnosed with AKI. This comprehensive single-nucleus transcriptomic profiling provides valuable insights into the cellular mechanisms driving CRS.<b>NEW & NOTEWORTHY</b> Cardiac dysfunction is a common cause of acute kidney injury in a malady called acute cardiorenal syndrome. In a mouse model of acute cardiorenal syndrome called cardiac arrest/cardiopulmonary resuscitation, we characterized, for the first time, the kidney transcriptional landscape at the single-cell level. We developed a novel method for quantifying cell response to injury and found that cells adapted through dedifferentiation, the magnitude of which varied depending on cell type.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"266-278"},"PeriodicalIF":2.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468052","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 : 2025-04-01Epub Date: 2025-01-15DOI: 10.1152/physiolgenomics.00040.2024
Alessandro M Zagatto, Rodrigo A B de Poli, Elvis S Malta, Pablo R Fleitas-Paniagua, Fernando Diefenthaeler, Juan M Murias, Alex Castro
{"title":"Is the time to task failure during severe-intensity exercise associated with muscle, blood, and respiratory changes?","authors":"Alessandro M Zagatto, Rodrigo A B de Poli, Elvis S Malta, Pablo R Fleitas-Paniagua, Fernando Diefenthaeler, Juan M Murias, Alex Castro","doi":"10.1152/physiolgenomics.00040.2024","DOIUrl":"10.1152/physiolgenomics.00040.2024","url":null,"abstract":"<p><p>The study aimed to verify the physiological and metabolic parameters associated with the time to task failure (TTF) during cycling exercise performed within the severe-intensity domain. Forty-five healthy and physically active males participated in two independent experiments. In <i>experiment 1</i>, after a graded exercise test, participants underwent constant work rate (CWR) cycling efforts at 115% of peak power output to assess neuromuscular function (potentiated twitch) pre- and postexercise. <i>Experiment 2</i> was similar to <i>experiment 1</i>, but with physiological (respiratory parameters, energetic pathway contribution) and metabolic parameters in the blood (gasometry and blood lactate responses) and vastus lateralis muscle tissue (target metabolomic analysis, glycogen content, muscle pH, and buffering capacity in vitro) measured instead of neuromuscular function. <i>Experiment 1</i> evidenced a significant decrease in muscle force with instauration of peripheral fatigability indices and no change in central fatigue indices. Severe-intensity domain exercise in <i>experiment 2</i> was accompanied by changes in physiological and metabolic parameters and in blood and muscle parameters. However, the TTF was associated with oxidative contribution (r = 0.811, <i>P</i> < 0.001), as well as anaerobic capacity (r = 0.554, <i>P</i> = 0.027), muscle buffering capacity (r = 0.792, <i>P</i> = 0.035), phosphagen energy contribution (r = 0.583, <i>P</i> = 0.017), and carnitine changes (r = 0.855, <i>P</i> = 0.016), but not correlated with electromyographic response, blood acid-base balance, and muscular glycogen content and pH. TTF during CWR exercise within the severe-intensity domain is likely explained by a combination of interacting mechanisms, with oxidative and phosphagen contributions, and muscle buffering capacity suggested as the main peripheral limiting factors to exercise within this exercise-intensity domain.<b>NEW & NOTEWORTHY</b> For the first time, a metabolomic analysis confirms that the cycling time to task failure (TTF) within the severe-intensity domain can be explained by muscle buffering capacity (62.2%), oxidative pathways contribution (65%), and muscle carnitine changes (71.9%), beyond some correlations with anaerobic capacity, tricarboxylic acid cycle intermediates, and phosphagen pathway contribution. The muscle glycogen content, muscle or blood pH, electromyography, and cardiorespiratory responses were not associated with TTF.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"227-239"},"PeriodicalIF":2.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984565","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 : 2025-04-01Epub Date: 2025-02-25DOI: 10.1152/physiolgenomics.00142.2024
Camila J Cuellar, Esraa A Ismail, McKenzie L J Haimon, Quinn A Hoorn, Fahong Yu, Maria Belen Rabaglino, Peter James Hansen
{"title":"Interactions between type of culture medium and addition of serum on development and gene expression of bovine blastocysts produced in vitro.","authors":"Camila J Cuellar, Esraa A Ismail, McKenzie L J Haimon, Quinn A Hoorn, Fahong Yu, Maria Belen Rabaglino, Peter James Hansen","doi":"10.1152/physiolgenomics.00142.2024","DOIUrl":"10.1152/physiolgenomics.00142.2024","url":null,"abstract":"<p><p>Serum is commonly added to culture medium to improve the production of bovine embryos in vitro. The main goals were to verify the actions of serum to increase blastocyst yield and test the hypothesis that fetal bovine serum alters blastocyst gene expression in a manner that could affect competence to establish pregnancy and dysregulate fetal development. Media used were synthetic oviduct fluid medium bovine embryo 2 (SOF-BE2) and a commercial medium from IVF Biosciences termed here as IVFB. Three experiments were conducted in which either adult or fetal bovine serum (10%, vol/vol) was added at <i>day 1</i> or <i>5</i> of development. Overall, serum increased blastocyst production. Gene expression in blastocysts was measured in the experiment in which fetal bovine serum was added at <i>day 5</i>. Serum resulted in 215 differentially expressed genes for embryos cultured in SOF-BE2 and 194 genes for embryos cultured in IVFB (adjusted <i>P</i> value of <0.05 and a |log<sub>2</sub>| fold change >1). Only 24 genes were regulated by serum similarly for both media, including several transcription factors, imprinted genes, <i>PSAT1</i> implicated in fetal growth in mice, and genes dysregulated in cloned embryos. Serum largely eliminated differences in gene expression between media. Expression data on eight biomarker genes were also used to calculate an embryo competence index previously related to embryo survival. Serum lowered the embryo competence index for both media. In conclusion, actions of fetal bovine serum on the preimplantation embryo include changes in gene expression indicative of reduced embryo competence and possible alterations in fetal development.<b>NEW & NOTEWORTHY</b> Serum is commonly added to the culture medium to improve the production of bovine embryos in vitro, but its molecular consequences for the resultant embryo are unclear. Here, we showed that blastocysts produced in serum experienced changes in gene expression, including transcription factors and imprinted genes. An embryo competence index that predicts embryo's ability to establish pregnancy based on gene expression was reduced by serum, suggesting serum can reduce embryo survivability.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"256-265"},"PeriodicalIF":2.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143493200","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 : 2025-04-01Epub Date: 2025-02-28DOI: 10.1152/physiolgenomics.00204.2024
Yan Zhang, Yanfeng Wang, Jiankun Yang, Lei Ji, Yuhua Yao, Dan Ren, Jian Zhang
{"title":"Landscape of the intratumoral microbiota acting on the tumor immune microenvironment in LUAD and LUSC.","authors":"Yan Zhang, Yanfeng Wang, Jiankun Yang, Lei Ji, Yuhua Yao, Dan Ren, Jian Zhang","doi":"10.1152/physiolgenomics.00204.2024","DOIUrl":"10.1152/physiolgenomics.00204.2024","url":null,"abstract":"<p><p>Although the intratumoral microbiota has been discovered to have a close connection with tumor immunity, the specific role played by intratumoral microbiota in regulating the tumor immune microenvironment (TIME) of lung cancer remains largely unexplored. Here, we comprehensively investigated the association between intratumoral microbiota and the TIME in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). First, we found that intratumoral microbiota and host transcriptome profile significantly differed between LUAD and LUSC. Moreover, there were strong associations between the abundance of intratumoral microbes and the expression of host genes in both LUAD and LUSC. Furthermore, we found an association between intratumoral <i>Lachnoclostridium</i> and chemokine expression, suggesting a role for these species of microbiota in modulating tumor immunity. In addition, we found that tumors harbor distinct relative abundance of <i>Lachnoclostridium</i> presented variation in response to immunotherapy and sensitivity to potential drug candidates. Our study provided important insights into the regulation of intratumoral microbiota on the TIME in LUAD and LUSC, which may serve as a precursor for a hypothesis-driven study to better understand the causational relationship of intratumoral microbiota in lung cancer.<b>NEW & NOTEWORTHY</b> LUAD and LUSC exhibited significant differences in intratumoral microbiome and the TIME profile. The relative abundance of intratumoral <i>Lachnoclostridium</i> correlated with the tumor immune infiltration in both LUSC and LUAD. Intratumoral <i>Lachnoclostridium</i> impacted the patients' sensitivity to potential targeted drugs, especially in LUSC.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"279-291"},"PeriodicalIF":2.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528175","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}
{"title":"Colonic responses to aspirin treatment - transcriptome effects by dose, time and ancestry.","authors":"Victor Guryev","doi":"10.1152/physiolgenomics.00043.2025","DOIUrl":"https://doi.org/10.1152/physiolgenomics.00043.2025","url":null,"abstract":"","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701284","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}
Roman O Bokov, Kristina A Sharlo, Natalia A Vilchinskaya, Sergey A Tyganov, Olga V Turtikova, Sergey V Rozhkov, Ruslan M Deviatiiarov, Oleg A Gusev, Elena S Tomilovskaya, Boris S Shenkman, Oleg I Orlov
{"title":"Molecular insights into human soleus muscle atrophy development: long-term dry immersion effects on the transcriptomic profile and post-translational signaling.","authors":"Roman O Bokov, Kristina A Sharlo, Natalia A Vilchinskaya, Sergey A Tyganov, Olga V Turtikova, Sergey V Rozhkov, Ruslan M Deviatiiarov, Oleg A Gusev, Elena S Tomilovskaya, Boris S Shenkman, Oleg I Orlov","doi":"10.1152/physiolgenomics.00196.2024","DOIUrl":"https://doi.org/10.1152/physiolgenomics.00196.2024","url":null,"abstract":"<p><p><b>Background:</b> Muscle disuse results in complex signaling alterations followed by structural and functional changes, such as atrophy, force decrease and slow-to-fast fiber-type shift. Little is known about human skeletal muscle signaling alterations under long-term muscle disuse. <b>Methods:</b> In this study, we describe the effects of 21-day dry immersion on human postural soleus muscle. We performed both transcriptomic analysis and Western blots to describe the states of the key signaling pathways regulating soleus muscle fiber size, fiber-type, and metabolism. <b>Results:</b> 21-day dry immersion resulted in both slow-type and fast-type myofibers atrophy, downregulation of rRNA content, and mTOR signaling. 21-day dry immersion also leads to slow-to-fast fiber-type and gene expression shift, upregulation of p-eEF2, p-CaMKII, p-ACC content and downregulation of NFATc1 nuclear content. It also caused massive gene expression alterations associated with calcium signaling, cytoskeletal parameters, and downregulated mitochondrial signaling (including fusion, fission, and marker of mitochondrial density).</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615994","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 : 2025-03-01Epub Date: 2025-02-10DOI: 10.1152/physiolgenomics.00135.2024
Vaishali Singh, Ryan J Adam, Mark R Paterson, Alison J Kriegel
{"title":"Vacuole membrane protein 1 and acute response to renal ischemia and ischemia/reperfusion.","authors":"Vaishali Singh, Ryan J Adam, Mark R Paterson, Alison J Kriegel","doi":"10.1152/physiolgenomics.00135.2024","DOIUrl":"10.1152/physiolgenomics.00135.2024","url":null,"abstract":"<p><p>Ischemia-reperfusion (I/R) injury is an important initiating cause of chronic kidney disease and renal failure. Changes in proximal tubule (PT) morphology, including brush border loss, occur rapidly in response to ischemic stress and I/R injury. Vacuole membrane protein 1 (VMP1) is a compelling target for ischemia-associated renal damage because it is a necessary regulator of autophagy, and the genomic location of hypoxia-responsive microRNA <i>miR-21</i> lies within an intronic region of the <i>Vmp1</i> gene. Autophagy is reported to have protective and pathological effects on I/R injury. In this study, we find that VMP1 is rapidly upregulated in renal cortex tissue in response to 15 and 30 min of ischemia. Intravenous delivery of <i>Vmp1-</i>targeting GameR or a scrambled GapmeR was performed on adult male Sprague-Dawley rats for 2 days before either 30 min of renal ischemia, 30 min of ischemia followed by 24 h of reperfusion (I/R), or corresponding control procedures. Autophagy markers and PT morphology were assessed in the renal cortex. Suppression of ischemia-induced upregulation of VMP1 attenuated PT brush border loss following 30 min of ischemia and 24 h post-I/R. Our study reveals a novel and mechanistically important dissociation between VMP1 expression, miR-21-5p expression, autophagy markers, and I/R tubular injury in the renal cortex.<b>NEW & NOTEWORTHY</b> The impact of autophagy on renal ischemia/reperfusion injury (IRI) remains unclear. VMP1 promotes autophagy through interaction with beclin-1 and subsequent localization to the endoplasmic reticulum. In this study, GapmeR-mediated suppression of VMP1 in rats and attenuated proximal tubule damage following 30 min of ischemia or following 24 h of reperfusion, without altering autophagy markers following reperfusion. This new insight suggests that increased VMP1 did not afford autophagy-mediated protection from IRI in proximal tubules.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"172-178"},"PeriodicalIF":2.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391507","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 : 2025-03-01Epub Date: 2025-01-17DOI: 10.1152/physiolgenomics.00181.2024
Pedro M Guerreiro, Adelino V M Canário
{"title":"Off the shelf: Regulation of fish blood pH through ionocyte membrane remodelling and protein translocation without additional synthesis.","authors":"Pedro M Guerreiro, Adelino V M Canário","doi":"10.1152/physiolgenomics.00181.2024","DOIUrl":"10.1152/physiolgenomics.00181.2024","url":null,"abstract":"","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"146-147"},"PeriodicalIF":2.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009732","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 : 2025-03-01Epub Date: 2025-01-27DOI: 10.1152/physiolgenomics.00063.2024
Siriluck Ponsuksili, Frieder Hadlich, Shuaichen Li, Nares Trakooljul, Henry Reyer, Michael Oster, Yosef Amsalu Abitew, Vera Sommerfeld, Markus Rodehutscord, Klaus Wimmers
{"title":"DNA methylation dynamics in the small intestine of egg-selected laying hens along egg production stages.","authors":"Siriluck Ponsuksili, Frieder Hadlich, Shuaichen Li, Nares Trakooljul, Henry Reyer, Michael Oster, Yosef Amsalu Abitew, Vera Sommerfeld, Markus Rodehutscord, Klaus Wimmers","doi":"10.1152/physiolgenomics.00063.2024","DOIUrl":"10.1152/physiolgenomics.00063.2024","url":null,"abstract":"<p><p>Decades of artificial selection have markedly enhanced egg production efficiency, yet the epigenetic underpinnings, notably DNA methylation dynamics in the gut, remain largely unexplored. Here, we investigate how breeds and developmental stages influence DNA methylation profiles in laying hens, and their potential relationship to laying performance and gut health. We compared two highly selected laying hen strains, Lohmann Brown-Classic (LB) and Lohmann Selected Leghorn-Classic (LSL), which exhibited similar egg production but divergent physiological, metabolic, and immunological characteristics. Our sampling encompassed key developmental stages: the pullet stage (10 and 16 wk old), peak production (24 and 30 wk old), and later stage (60 wk old) (<i>n</i> = 99; 10 per group), allowing us to elucidate the temporal dynamics of epigenetic regulation. Our findings highlight a crucial window of epigenetic modulation during the prelaying period, characterized by stage-specific methylation alterations and the involvement of predicted transcription factor motifs within methylated regions. This observation was consistent with the expression patterns of DNA methyltransferases (DNMTs), including <i>DNMT1</i>, <i>DNMT3A</i>, and <i>DNMT3B</i>. In addition, a higher methylation level was observed in specific loci or regions in the LSL compared with the LB strain. Notably, we uncover strain-specific differences in methylation levels, particularly pronounced in genomic regions associated with intestinal integrity, inflammation, and energy homeostasis. Our research contributes to the multidisciplinary framework of epigenetics and egg-laying performance, offering valuable implications for poultry production and welfare.<b>NEW & NOTEWORTHY</b> Our study reveals key methylation changes in the jejunum mucosa of laying hens across developmental stages and between strains, with implications for gut health, immune function, and egg production. These findings highlight a crucial role of epigenetic regulation in optimizing performance.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"125-139"},"PeriodicalIF":2.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047560","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 : 2025-03-01Epub Date: 2025-01-15DOI: 10.1152/physiolgenomics.00015.2024
Hina Usman, David Witonsky, Margaret C Bielski, Kristi M Lawrence, Bharathi Laxman, Sonia S Kupfer
{"title":"Genomic and cellular responses to aspirin in colonic organoids from African- and European-Americans.","authors":"Hina Usman, David Witonsky, Margaret C Bielski, Kristi M Lawrence, Bharathi Laxman, Sonia S Kupfer","doi":"10.1152/physiolgenomics.00015.2024","DOIUrl":"10.1152/physiolgenomics.00015.2024","url":null,"abstract":"<p><p>Aspirin (ASA) is a proven chemoprotective agent for colorectal cancer (CRC), though interindividual responses and cellular mechanisms are not well characterized. Human organoids are ideal to study treatment responses across individuals. Here, colonic organoids from African-Americans (AA) and European-Americans (EA) were used to profile genomic and cellular ASA responses. Colonic organoids from 67 participants, 33 AA and 34 EA, were treated with 3 mM ASA or vehicle control for 24 h. Gene expression was assessed by RNA-seq, and differentially responsive genes were analyzed by condition, population, and for gene set enrichment. Top differentially responsive genes were assessed by time and ASA doses in independent organoids. Expression quantitative trait loci (eQTL) mapping was performed to identify variants associated with condition-specific responses. Apoptosis and necrosis assays were performed, and apoptosis gene expression was measured in organoids. Overall, 8,343 genes were differentially responsive to ASA with differences between AA and EA. Significant enrichment for fatty acid oxidation (FAO) and peroxisome proliferator-activated receptor (PPAR) signaling was found. Significant treatment eQTLs were identified for relevant genes involved in FAO, apoptosis, and prostaglandin metabolism. ASA-induced apoptosis and secondary necrosis were confirmed with the identification of significant differential responses of apoptotic genes to ASA. Results demonstrate large transcriptional responses to ASA treatment with differences in responses between individuals. Genomic and cellular results suggest that ASA effects on the mitochondria are key mechanisms of action that could underlie clinical effects. These results could be used to assess clinical treatment responses for chemoprevention in the future.<b>NEW & NOTEWORTHY</b> Aspirin treatment in colonic organoids from diverse individuals revealed significant transcriptome-wide responses, especially for genes in lipid and apoptosis signaling pathways. In normal organoids, apoptosis was induced by aspirin, providing one possible mechanism of colorectal cancer chemoprevention. Our results are a first step toward implementation of personalized medicine for aspirin in colorectal cancer prevention.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"103-114"},"PeriodicalIF":2.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984471","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}