Paracelsus proceedings of experimental medicine最新文献

{"title":"Trimethylamine N-Oxide (TMAO): a Unique Counteracting Osmolyte?","authors":"Paul H. Yancey","doi":"10.33594/000000661","DOIUrl":"https://doi.org/10.33594/000000661","url":null,"abstract":"Cells of many organisms facing osmotic shrinkage or swelling undergo homeostatic volume regulation using osmolytes—inorganic ions (Na+, K+, Cl-) in transient disturbances, but special organic osmolytes in long-term disturbances. Neutral amino acids, methylamines and polyols are key examples. Widely termed 'compatible' cosolutes/cosolvents, they—unlike inorganic ions—do not perturb membrane potential nor (supposedly) macromolecules. Indeed, most enhance protein stability in part through preferential exclusion; i.e., they 'dissolve' poorly in proteins' hydration layer and reduce water availability for hydrating unfolding proteins. However, these concepts imply that organic osmolytes are all 'compatible' and interchangeable in this way. Instead, most have unique non-osmotic cytoprotective properties such as antioxidation, and some may have stabilizing features not universal among osmolytes. The latter is exemplified by trimethylamine N-oxide (TMAO), an osmolyte high in chondrichthyans (sharks and rays), and that increases with depth in many marine animals. First, TMAO is the strongest enhancer of protein folding among common osmolytes, but unlike most osmolytes, exhibits some preferential binding with proteins. Second, unlike other common osmolytes such as glycine, TMAO is not found in nature in the absence of a protein destabilizer—notably urea (primary osmolyte of chondrichthyans) and hydrostatic pressure, both counteracted by TMAO. Without a destabilizer, TMAO can over-stabilize proteins causing non-functional aggregates; i.e., it is not 'compatible'. Third, TMAO 'hardens' water structure and reduces water compressibility (again unlike other osmolytes). Under high pressure in the deep sea, these 'piezolyte' properties reduce both protein unfolding and cell volume compression.","PeriodicalId":74396,"journal":{"name":"Paracelsus proceedings of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135014564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduced Hepatocyte Bicarbonate Output Accelerates Periductal Inflammation and Fibrosis in mdr2-/- Mouse Liver","authors":"","doi":"10.33594/000000634","DOIUrl":"https://doi.org/10.33594/000000634","url":null,"abstract":"Background/Aims: Mice deficient for the canalicular phospholipid transporter MDR2 (ABCB4) develop sclerosing cholangitis due to high biliary concentrations of monomeric bile acids. This study determines whether a selective reduction in biliary bicarbonate output, secondary to the deletion of the hepatocyte-expressed carbonic anhydrase CAXIV (Car14) aggravates the bile acid-induced damage observed in the mdr2-/- mouse model. Methods: Bile flow was measured gravimetrically and HCO3- output by microtitration before and during stimulation with intravenously applied tauroursodesoxycholic acid (TUDCA) in car14-/-mdr2-/- (abcb4-/-), car14-/-/mdr2+/+, car14+/+/mdr2-/- and wt mice. Cholangiocyte proliferation, hepatic inflammation and fibrosis was studied by gene and/or protein expression for proinflammatory and profibrotic cytokines, cholangiocyte proliferation markers, and by (immuno) histochemical assessment. The impact of Car14 deficiency was also assessed in a xenobiotic cholangitis model. Results: TUDCA stimulated HCO3-output was significantly increased in 6 week old mdr2-/- mice, and significantly decreased in both car14-/- as well as car14-/-/mdr2-/-mice, compared to wt, while bile flow was unaltered. Both bile flow and HCO3- output were significantly decreased in 11 week old mdr2-/-, and more so in car14-/-/mdr2-/- mice. Loss of Car14 significantly increased inflammatory liver injury and cholangiocyte proliferation, and aggravated liver fibrosis in car14-/-/mdr2-/- mice compared to mdr2-/- mice. In contrast, the absence of Car14 did not affect the hepatic functional and morphological alterations in 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) fed mice. Conclusions: Car14 deletion reduced biliary HCO3- output and aggravated the functional, inflammatory and morphological alterations in the liver of mdr2-/-mice. These results demonstrate the importance of sufficient hepatocellular bicarbonate output in the protection of the hepatobiliary epithelium against toxic bile acids.","PeriodicalId":74396,"journal":{"name":"Paracelsus proceedings of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48793978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intracellular Potassium in Cell Growth and Proliferation of Human Mesenchymal Stem Cells and Blood Lymphocytes","authors":"","doi":"10.33594/000000635","DOIUrl":"https://doi.org/10.33594/000000635","url":null,"abstract":"Many data show that K+ ions are essential for cell proliferation. In this brief review, we summarize our own studies and literature data that characterize the relationship between modulations of intracellular K+ content and the intensity of cell proliferation. Using flame emission assay we compared the transport of monovalent cations in transformed cells and in human mesenchymal stem cells in growing cultures, as well as during stress-induced cell cycle arrest and transition from monolayer (2D) to three-dimensional (3D) spheroids. A decrease in the intracellular content of K+ (evaluated as the ratio of the content of K+ in cells to the mass of cellular protein) associated with the accumulation of G1 cells in the population and accompanied by a stop in proliferation was revealed. The relationship between intracellular K+ and initiation of cell proliferation was further analyzed in human blood lymphocytes (HBL) as a model for the transition of cells from quiescence to proliferation. In HBL stimulated to proliferate, the content of K+ in cells increases during the transition G0/G1/S, accompanying the growth of small lymphocytes into blasts. Cellular water content, calculated from buoyant cell density, is higher in proliferating HBLs and in Jurkat leukemic T cells than in resting HBL. Available data suggest that intracellular K+ is important for successful cell proliferation as the main intracellular ion involved in the regulation of cell volume during the transition from quiescence to proliferation, and high K+ content and associated high water content in the cell are a characteristic feature of cell proliferation and transformation.","PeriodicalId":74396,"journal":{"name":"Paracelsus proceedings of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47000983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Insights on Shigellosis: How the Interaction Between Invasin IpaA and Vinculin Hijacks Cellular Mechanotransduction","authors":"Cristina Bertocchia, Nicole Moralesa, Andrea Ravasiob","doi":"10.33594/000000631","DOIUrl":"https://doi.org/10.33594/000000631","url":null,"abstract":"With 270 million infections annually and nearly half a million death a year, shigellosis is a severe intestinal infection caused by bacteria of the Shigella family. Appearance and spread of drug-resistant strains renewed global concerns for public health and finding novel targets for treatment is fast becoming a priority. To this end, invasins are a potentially good candidate. Also called Ipa(s), which is the short for Invasion Plasmid Antigen, invasins play a key role in mediating bacterial invasion and infection of the host cell. Importantly, they have been reported to hijack inbuilt mechanical capability of the host cells such as cell adhesion and active processes mediated by the actin cytoskeleton to enable bacterial ingress into the host cells. IpaA is an invasin of particular interest as it presents three motifs that mimic vinculin binding sites and thus it allows IpaA to interact with vinculin, which is one of the most critical regulators of cellular and tissue mechanics. Using a mechanobiology point-of-view, we aim to provide an overview of Shigella´s infection mechanism, to highlight recently discovered molecular mechanisms of IpaA/vinculin interaction and to finally discuss their consequences for epithelial cell and tissue mechanical homeostasis that may result in the symptomatic outcomes seen in severe shigellosis.","PeriodicalId":74396,"journal":{"name":"Paracelsus proceedings of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43778248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computation of the Balance of Monovalent Ion Fluxes in the U937 Cell as an Example of a Proliferating Animal Cell","authors":"Valentina Yurinskaya, Emily Zook, Igor Vereninov, Alexey Vereninov","doi":"10.33594/000000630","DOIUrl":"https://doi.org/10.33594/000000630","url":null,"abstract":"This paper was prepared by Alexey A. Vereninov for an online presentation in connection with his 90th birthday. Unfortunately, his health did not allow him to take part in this online meeting, but he hoped that his presentation would still be published. To our deep regret, he passed away on July 5, 2022. All his life, A. Vereninov worked at the Institute of Cytology of the Russian Academy of Sciences where, from 1986 to 2019, he headed the Laboratory of Cell Physiology. Alexey Vereninov was interested in answering the fundamental questions regarding ionic homeostasis in animal cells. In the last years of his life, he became particularly interested in the quantitative analysis of monovalent ion fluxes through the cell membrane. The calculation algorithm was developed by Alexey together with his brother Igor A. Vereninov, professor at St. Petersburg State Polytechnical University. The results of their work in recent years are summarized in this paper.","PeriodicalId":74396,"journal":{"name":"Paracelsus proceedings of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44284217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ion Transporters Involved in Dissipation of Transmembrane Na+ and K+ Gradients in C2C12 Myotubes Triggered by Electrical Pulse Stimulation","authors":"Svetlana V. Sidorenkoa, Elizaveta A. Klimanovaa, Eugene G. Maksimova, Olga D. Lopinaa, Sergei N. Orlov","doi":"10.33594/000000629","DOIUrl":"https://doi.org/10.33594/000000629","url":null,"abstract":"Background/Aims: Cultured skeletal muscle cells subjected to electrical pulse stimulation (EPS) are widely employed as an in vitro model of exercising skeletal muscle. Numerous studies demonstrated that sustained excitation of skeletal muscle results in the dissipation of the transmembrane gradient of monovalent cations. During exercises the impending loss of excitability has to be counterbalanced by rapid restoration of the Na+i/K+i ratio. To understand mechanisms of the maintenance of muscle contractility, it is necessary to know which transporters are participated in the dissipation of Na+i and K+i gradients and how to activate Na,K-ATPase for its regeneration. This study was aimed at the identification of ion transporters involved in the dissipation of the transmembrane gradients of Na+ and K+induced by EPS, and Na,K-ATPase isoforms involved in its restoration. Methods: The differentiated C2C12 myotubes were subjected to electrical pulse stimulation in the presence or absence of different ion transport systems inhibitors followed by measurement of intracellular monovalent cations by flame atomic absorption spectrometry. Results: Electrical pulse stimulation of C2C12 myotubes results in the dissipation of Na+i/K+i gradient, which is maintained by α2-Na,K-ATPase. Na-K-2Cl cotransporter (NKCC), voltage-gated Na+ (Nav), and large conductance Ca2+-activated K+ channels (BKCa), and Na/H exchanger (NHE) are involved in the dissipation of this gradient. Suppression of calmodulin-dependent protein kinase II (CaMKII) increases Na+ efflux in EPS-treated C2C12 myotubes. Conclusion: NKCC, Nav, BKCa, and NHE are involved in the dissipation of Na+i/K+i gradient in EPS-treated C2C12 myotubes.","PeriodicalId":74396,"journal":{"name":"Paracelsus proceedings of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48512926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apelin Regulation of K-Cl Cotransport in Vascular Smooth Muscle Cells as a Potential Target for Cardiovascular Disease","authors":"Neelima Sharma","doi":"10.33594/000000627","DOIUrl":"https://doi.org/10.33594/000000627","url":null,"abstract":"Background/Aims: Apelin and its signaling through the G-protein coupled receptor (APJ, gene symbol APLNR) regulate cardiovascular function via two mechanisms: 1) By promoting nitric oxide (NO)-mediated vasodilation, impaired by oxidized low-density lipoproteins (oxLDL); and 2) By inducing cell proliferation via the phosphatidylinositol-3-kinase (PI3K)/protein kinase B/Akt pathway (PI3K/Akt) and mitogen activated protein kinase (MAPK) pathways. The potassium chloride cotransporter (KCC1,3,4; SLC12A4,6,7) controls cell volume, and regulates cardiovascular function through proliferation, migration, and blood pressure control. Importantly, KCC regulatory mechanisms and apelin/APJ signaling pathways overlap placing KCC as a potential target for apelin/APJ to elicit its cardioprotective effects. Therefore, apelin’s action on KCC activity was examined in contractile and synthetic rat aortic vascular smooth muscle cells (VSMCs). Methods: KCC activity was measured by atomic absorption spectrophotometry in chloride (Cl-) and Cl--free medium with sulfamate (Sf-) as Cl- replacement, and with rubidium (Rb+) as a potassium (K+) congener. The calculated difference between Rb+ transport in the presence of chloride (Cl-) and sulfamate (Sf-) is the Cl--dependent Rb+ influx (i.e., K-Cl cotransport activity). Apelin-13 (1 µM) was added either during flux (acute effect) and/or in the growth media (chronic effect) based on the experimental goals. KCC activity was characterized with respect to the VSMC phenotypes, in the presence or absence of apelin and corresponding inhibitors of the signaling pathways, oxLDL, and as a function of various physiological factors described below. Results: The APJ receptor was expressed in both contractile and synthetic VSMC phenotypes, the former also possessing the soluble guanylyl cyclase-coupled protein kinase G (PKG) receptor, critical for NO-mediated signaling. In general, KCC activity was higher in synthetic vs. contractile VSMCs, consistent with enhanced migration and proliferation in the former. In addition, apelin-mediated activation of KCC was modulated by extracellular sodium [Na+]o, osmolality, length of apelin treatment (acute or chronic) and VSMC phenotype (contractile vs synthetic). Based on selective inhibitors, apelin activated KCC through the (NO)/soluble guanylate cyclase (sGC)/protein kinase G (PKG) (NO/sGC/PKG)-, PI3K/Akt- and MAPK-dependent pathway(s). Furthermore, apelin rescued the inhibition of KCC by oxLDL. Altogether, results suggest apelin/APJ as an important modulator of KCC activity to sustain cell volume regulation and cardiovascular function. More recently, the apelinergic system has been proposed as a novel target for the treatment of Corona virus disease 2019 (COVID-19) and, given the significant overlap between the regulatory mechanisms of this system and KCC, and their role in cardiovascular disease (CVD), this study opens new avenues to identify potential targets for diverse implementation strategies","PeriodicalId":74396,"journal":{"name":"Paracelsus proceedings of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49485041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Internal Impermeant Anion, Its Mean Valence and Osmolarity-Charge Asymmetry","authors":"A. Dmitriev, R. Linsenmeier","doi":"10.33594/000000602","DOIUrl":"https://doi.org/10.33594/000000602","url":null,"abstract":"Background/Aims: For many years experimental and theoretical studies of the processes controlling the transmembrane potential of living cells and their volume were focused on ions, first of all Na+, K+, and Cl-, that can be moved in and out of the cell by various active and passive mechanisms. But recently more and more attention has been directed toward the internal impermeant anion (Xz-) – a complex entity that is comprised of many very different molecules. The most intriguing feature of the internal impermeant anion is that its amount and, importantly, its mean valence can be changed during the metabolic activity of the cell. The aim of this paper is to computationally investigate how changes in the amount and the mean valence of the internalimpermeant anion influence the concentration of the main ions, the membrane potential, and the cell volume. Methods: The computational analyses were performed using our charge-difference model describe earlier. Results and Conclusion: The results of computational simulations confirm previous results that changes in the amount of Xz- influence nothing but the cell volume if z remains constant, although transient disturbances of concentrations and Em happen and their extent depends on the speed of Xz- changes. Changes of z have more serious consequences. A decrease of |z| leads to a decrease of concentrations of cations ([K+]i and [Na+]i), to an increase of the concentrations of anions ([Cl-]I and [Xz-]i), and to depolarization of the cell membrane; an increase of |z| leads to changes in the opposite directions. Interestingly, even in conditions when Xz- remains unchanged, the normal electrophysiological activity expressed in changes of Em will affect [Cl-]i and consequently [Xz-]i (due to volume changes), inducing feedback effects on the cation concentrations and Em. Accordingly, Xz- is viewed as an important but not the only component of a broader concept of osmolarity-charge asymmetry. The basic physical reasons that determine the interrelations between Xz- on one hand and ionic concentrations, Em, and the cell volume on the other hand are discussed.","PeriodicalId":74396,"journal":{"name":"Paracelsus proceedings of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44672732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paracelsus 10,000: An Observational Cohort Study About the Health Status of the Population of Salzburg, Austria. Rationale, Objectives and Study Design","authors":"V. Frey, P. Langthaler, Emanuel Raphaelis, Susanne Ring-Dimitriou, L. Kedenko, E. Aigner, Jennifer Martinz, Isabella Gostner, Arne C. Bathke, Paul Sungler, Michael Studnicka, Elisabeth Haschke-Becher, Eugen Trinka, B. Iglseder, Bernhard Paulweber","doi":"10.33594/000000600","DOIUrl":"https://doi.org/10.33594/000000600","url":null,"abstract":"Background/Aims: Paracelsus 10,000 is an observational cohort study with the objective to investigate the health status of the population in and around the city of Salzburg. The focus lies on common non-communicable diseases, mainly cardiovascular, cerebrovascular, and metabolic diseases, and their risk factors. The aim of the study is to establish a large database enabling to study associations between life style, genetic factors and development of common diseases. Extensive phenotyping and biobanking constitute a basis for preventive measures, multi-omics and precision medicine. Methods: Inhabitants of the city of Salzburg and the surrounding areas were randomly selected and underwent a detailed investigation: The program included medical examinations, as well as assessments on mental disorders and life style including nutrition and physical activity. From all study participants biological samples were stored in a biobank at -80°C enabling future investigations of biomarkers and utilization of the whole spectrum of multi-omics. Results: Between the years 2013 and 2020, 10,044 participants, 5,176 women and 4,868 men aged between 40 and 77 years, completed a baseline assessment. Special emphasis was put on participants between 50 and 59 years old, representing an age group especially prone to changes in health status. In this group, 2,606 participants underwent an extended investigation program. Conclusion: The Paracelsus 10,000 study has the potential to gain new insight into the role of associations between genetic predisposition and life style factors for disease development in the Salzburg population. This report describes rationale, objectives and design of the study and provides insight into the main characteristics of the study cohort.","PeriodicalId":74396,"journal":{"name":"Paracelsus proceedings of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42788516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Change in Metabolomic Profile Associated with an Average Increase in Plain Water Intake of >+ 1 L/Day, Sustained Over 4 Weeks, in Healthy Young Men with Initial Total Water Intake Below 2 L/Day.","authors":"Jodi D Stookey,&nbsp;Bernhard Paulweber,&nbsp;Thomas K Felder,&nbsp;Florian Lang,&nbsp;Dieter Häussinger,&nbsp;David W Killilea,&nbsp;Frans A Kuypers,&nbsp;Markus Ritter","doi":"10.33594/000000619","DOIUrl":"https://doi.org/10.33594/000000619","url":null,"abstract":"<p><strong>Background/aims: </strong>Cells adapt to chronic extracellular hypotonicity by altering metabolism. Corresponding effects of sustained hypotonic exposure at the whole-person level remain to be confirmed and characterized in clinical and population-based studies. This analysis aimed to 1) describe changes in urine and serum metabolomic profiles associated with four weeks of sustained > +1 L/d drinking water in healthy, normal weight, young men, 2) identify metabolic pathways potentially impacted by chronic hypotonicity, and 3) explore if effects of chronic hypotonicity differ by type of specimen and/or acute hydration condition.</p><p><strong>Materials: </strong>Untargeted metabolomic assays were completed for specimen stored from Week 1 and Week 6 of the Adapt Study for four men (20-25 years) who changed hydration classification during that period. Each week, first-morning urine was collected after overnight food and water restriction, and urine (t+60 min) and serum (t+90 min) were collected after a 750 mL bolus of drinking water. Metaboanalyst 5.0 was used to compare metabolomic profiles.</p><p><strong>Results: </strong>In association with four weeks of > + 1 L/d drinking water, urine osmolality decreased below 800 mOsm/kg H₂O and saliva osmolality decreased below 100 mOsm/kg H₂O. Between Week 1 and Week 6, 325 of 562 metabolic features in serum changed by 2-fold or more relative to creatinine. Based on hypergeometric test p-value <0.05 or Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway impact factor >0.2, the sustained > + 1 L/d of drinking water was associated with concurrent changes in carbohydrate, protein, lipid, and micronutrient metabolism, a metabolomic pattern of carbohydrate oxidation <i>via</i> the tricarboxylic acid (TCA) cycle, instead of glycolysis to lactate, and a reduction of chronic disease risk factors in Week 6. Similar metabolic pathways appeared potentially impacted in urine, but the directions of impact differed by specimen type.</p><p><strong>Conclusion: </strong>In healthy, normal weight, young men with initial total water intake below 2 L/d, sustained > + 1 L/d drinking water was associated with profound changes in serum and urine metabolomic profile, which suggested normalization of an aestivation-like metabolic pattern and a switch away from a Warburg-like pattern. Further research is warranted to pursue whole-body effects of chronic hypotonicity that reflect cell-level effects and potential beneficial effects of drinking water on chronic disease risk.</p>","PeriodicalId":74396,"journal":{"name":"Paracelsus proceedings of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10253256/pdf/nihms-1892731.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9623698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}