bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of Alcoholic Ketoacidosis in Mice
Authors: Ryu Clara , Rivadeneira Ana , Narayanan Ashwini , Kim Gou Young , Choi Inyeong 
Published: May 2024

Chronic alcohol use depletes glycogen stores in the liver and impairs gluconeogenesis, causing decreased glucose availability and increased reliance on fatty acid breakdown. This also alters counterregulatory hormone balance that further increases free fatty acid breakdown and ketone production, resulting in ketoacidosis. The main features of alcoholic ketoacidosis (AKA) are high ketone bodies, low blood bicarbonate levels, and high anion gaps. This metabolic disorder was first reported in 1940s and pathophysiological data were collected from patients taken several decades ago, which helped to lay the foundation for the current understanding of its pathophysiology, diagnosis, and management. Nonetheless, our understanding of AKA is presently limited and has many challenges. To better understand its biochemical and pathophysiological properties, we induced AKA in mice (8-weeks; male) by modifying the clinically relevant NIH alcohol feeding protocol. Compared to mice pair-fed with control diet, mice fed chronic/binge alcohol under a fasting condition developed low blood HCO3− (20.07 mM for pair-fed vs. 13.04 for EtOH-fed mM; p < 0.05; n = 4-6/group), high β-hydroxybutyrate (0.54 mM for pair-fed vs. 3.62 for EtOH-fed mM; p < 0.05), and high pH anion gap (19.7 for pair-fed vs. 33.3 for EtOH-fed; p < 0.05), all of which are hallmarks for AKA. Blood pH was also low (7.32 for pair-fed vs. 7.14 for EtOH-fed; p<0.05) and base excess was more negative, consistent with metabolic acidosis. Mice subjected to a fasting alone exhibited a mild increase in β-hydroxybutyrate. Furthermore, [HCO3−], anion gap, and blood pH remained unchanged in these fasting-alone mice. In mice with AKA, the NADH/NAD+ ratio in the liver was decreased, consistent with the conversion of acetoacetate to β-hydroxybutyrate. These mice also had decreased glucose and insulin levels, consistent with hormonal changes in response to impaired gluconeogenesis and glycogen depletion. The mice also had increased aspartate transaminase AST levels in the blood. Histopathological analysis of the livers revealed diffuse mixed microvesicular and macrovesicular steatosis and mild lobular inflammation in AKA mice. Few acidophilic bodies (necrosis) and ballooning degeneration were seen. Except for the liver, most organs showed no significant difference between the two groups of mice. In summary, AKA mice showed biochemical parameters that are similar to those in humans diagnosed with AKA. The animal model of AKA will be useful for preclinical studies that search and test prevention strategies to alleviate AKA or evaluate the therapeutic effcacy of drug candidates. This work was supported by the grant from the National Institute of Alcohol Abuse and Alcoholism (R21AA028606). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Cerebrovascular Conductance Responses to Carbon Dioxide are Attenuated by the Presence of Hypertension in Patients with Atrial Fibrillation
Authors: Walsh Harvey , Junejo Rehan , Lip Gregory , Fisher James 
Published: May 2024

The cerebral vasculature is highly sensitive to carbon dioxide (CO2) and cerebrovascular CO2 reactivity (CVRCO2) is widely used to index cerebral vascular health. Some studies have shown that both atrial fibrillation (AF) and hypertension (HTN) are independently associated with reduced CVRCO2. However, it is unknown if these effects on CVRCO2 are synergistic when AF and HTN are present together. In this study we tested the hypothesis that CVRCO2 was lower in patients with both AF and HTN (AF+HTN) compared to normotensive patients with AF. Transcranial Doppler ultrasound was used to measure middle cerebral artery blood velocity (MCA Vm) in AF (n=31) and AF+HTN (n=57) during stepped increases and decreases in end-tidal carbon dioxide (PETCO2). The ratio of MCA Vm and mean arterial pressure (MAP) was defined as cerebrovascular conductance index (CVCi). CVRCO2 was taken as the linear slope for MCA Vm and MCA CVCi versus PETCO2. As expected, baseline MAP was higher in AF+HTN than AF (107±9 vs. 98±9 mmHg, respectively; p<0.001). Baseline MCA Vm was numerically lower in AF+HTN than AF, but this did not reach statistical significance (50 [44-60] vs. 52 [45-63] cm.s−1, respectively; p=0.075), while baseline CVCi was lower in AF+HTN compared to AF (0.46 [0.42-0.57] vs. 0.54 [0.44-0.63] cm.s−1.mmHg−1; p<0.001). MCA Vm CVRCO2 was not different between groups (1.70 [1.47-2.19] and 1.74 [1.54-2.52] cm/s/mmHg−2 for AF+HTN and AF, respectively; p=0.221), whereas MCA CVCi CVRCO2 was 13% lower in AF+HTN compared to AF (0.013 ± 0.004 vs. 0.015 ± 0.005 cm.s.mmHg−2; p=0.047). Stepwise linear regression analysis identified that cardiac rhythm during data acquisition (AF or normal sinus rhythm) was a predictor of baseline MCA CVCi and MCA CVCi CVRCO2. In summary, our results demonstrate impaired MCA CVCi CVRCO2 in AF+HTN and suggest that the presence of HTN worsens cerebrovascular function in AF. Such cerebrovascular alterations may be important for the development of cognitive decline and diminished brain health in AF. Funding provided by Bristol-Myers Squibb/Pfizer Alliance Project Grant (CV185-481), British Heart Foundation Project Grant (PG/15/45/31579) and the National Institute of Health Research Clinical Research Network (NIHR CRN). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Trimethylamine-N-oxide aggravated sympathetic activation in D-galactose induced aging rats by down-regulating P2Y12 receptor in microglia
Authors: Wu Yuming , Wang Ping , Mi Yuan , Yu Hao , Teng Xu , Jin Sheng , Xiao Lin 
Published: May 2024

This study aimed to determine whether trimethylamine N-oxide (TMAO) was involved in sympathetic activation in aging and the underline mechanisms. Our hypothesis is that TMAO reduces P2Y12 receptor and induces microglia-mediated inflammation in the paraventricular nucleus, then leading to sympathetic activation in aging. Eighteen young adults (20-40 years old) and sixteen old adults (65-90 years old) were involved in the study. Aging rats were established by injecting D-galactose (200 mg/kg/d) subcutaneously for 12 weeks. TMAO (120 mg/kg/d) or 1% 3, 3-dimethyl-l-butanol (DMB, a structural analog of choline, inhibiting TMA formation) was administrated in drinking water for 12 weeks to investigate their effects on neuroinflammation and sympathetic activation in aging rats. Heart rate variability was analyzed by 24 h ambulatory ECG multichannel recording system (CT-083S Holter ECG recorder, BENEWARE, Hangzhou) in young and old adults. The PowerLab 15T data acquisition system (AD Instruments, Australia) was used to record blood pressure and renal sympathetic nerve activity in the rats. Plasma levels of TMAO, noradrenaline, and IL-1β in old adults were higher than those in young group. In addition, standard deviation of all normal to normal intervals and standard deviation of the average of normal to normal intervals were lower in old adults and negative correlated with TMAO, which indicating sympathetic activation in old adults and related to the increased TMAO. Rats treatment with D-gal showed increased senescence-associated protein, microglia-mediated inflammation levels and decreased P2Y12 receptor in the paraventricular nucleus. Plasma levels of TMAO, noradrenaline, and IL-1β were increased, accompanied by enhanced renal sympathetic nerve activity. While TMAO supplementation aggravated the above phenomenons, and DMB abated them. These findings suggested that TMAO might contribute to the sympathetic hyperactivity of aging via downregulating P2Y12 receptor in microglia and increasing inflammation in the paraventricular nucleus. These results may provide a new target for the prevention and treatment of aging and aging-related diseases. This work was supported by the Program for the National Natural Science Foundationof China (32271155 and 31671185), the Science and Technology Project of the Hebei Education Department (ZD2021076), the Youth Top Talent Foundation of Hebei Province of China and the Program of Clinical Medicine Innovation Research Team of Hebei Medical University (2022LCTD-A1). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
SLC26A6 Deficiency Differentially Alters the Expression of MicroRNAs and RNA Binding Proteins in the Intestine
Authors: Natarajan Anbazhagan Arivarasu , Husain Nazim , Kapoor Shaunik , Kulkarni Neelkanth , Kumar Anoop , Jayawardena Dulari , Liqyanah Tala 
Published: May 2024

BACKGROUND: Putative anion transporter 1 (PAT1, SLC26A6), expressed at the luminal membrane of the intestinal epithelial cells, plays a key role in oxalate homeostasis and bicarbonate secretion. Additionally, we have recently shown that PAT1 knockout mice (PKO) exhibit compromised barrier integrity, gut dysbiosis and enhanced susceptibility to colitis. As defective PAT1 function and/or expression alters intestinal vulnerability to inflammation and miRNAs and RNA binding proteins are implicated in pathophysiology of gut inflammation, the focus of the current study was to investigate if loss of PAT1 modulates the expression of these post transcriptional regulators. Methods: microRNA was extracted from the colonic mucosa of age-matched PKO and wild type (WT) littermates (Qiagen miRNeasy mini kit) and subjected to miRNA expression profiling by Nanostring nCounter Mouse miRNA panel. Acquired raw data was further analyzed using the nSolver Analysis Software and ROSALIND online software platform to identify the differential gene expression. RT-PCR and western blotting was used to analyze the mRNA and protein expression of RNA binding proteins. Results: Genetic deficiency of PAT-1 resulted in differential expression of miRNAs compared to WT mice, where 60 miRNAs were notably upregulated, and 5 miRNAs were significantly downregulated in the colon. miR-150, known to be downregulated in ulcerative colitis patients, showed the maximum decrease (~6.9-fold change, P< 0.02) in PKO mice. Of note, miR-767 (known to promote tumor progression) was the top upregulated miRNA (~5.2-fold change, p<0.01). Interestingly, in silico analysis using TargetScan revealed that most of the upregulated miRNAs have been associated with the decrease in gut barrier function as previously shown in PKO mice. Further, a remarkable decrease in the protein expression of RNA binding proteins, HUR (0.82 ± 0.07 WT vs 0.49 + 0.03 PKO, P< 0.5) and CUGBP-1(0.37 ± 0.08 WT vs 0. 0.12 ± 0.03 PKO, P< 0.5) was also noted in PKO compared to WT mice. CONCLUSION: Our data provide evidence that PAT-1 deficiency in mice results in differential expression of several posttranscriptional regulators including miRNAs and RNA binding proteins with gene targets implicated in maintenance of epithelial barrier integrity. We speculate that altered expression of posttranscriptional regulators may potentially contribute to altered gut homeostasis observed in diseases associated with PAT1 deficiency. Supported by VA/NIH. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Effect of intermittent hypoxia on glucose tolerance in adults with type 2 diabetes
Authors: Zhao Jiahui , Stray-Gundersen Sten , Lalande Sophie 
Published: May 2024

Hypoxia stimulates glucose uptake through an insulin-independent pathway. The purpose of this single-blind randomized study was to determine the acute effect of intermittent hypoxia, consisting of alternating short bouts of breathing hypoxic and normoxic air, on glucose and insulin concentrations during an oral glucose tolerance test in adults with type 2 diabetes. It was hypothesized that intermittent hypoxia would attenuate the increase in glucose and insulin concentrations during an oral glucose tolerance test. Six adults with type 2 diabetes (5 men, age: 51±15 years, HbA1c: 7.3±1.5%) visited the laboratory on two occasions. On both visits, a 2-hour oral glucose tolerance test was performed, with venous blood samples collected 0, 30, 60, 90, and 120 min after ingestion of a high-glucose drink. Following ingestion of the drink, participants were exposed to either an intermittent hypoxia (IH) protocol, consisting of eight 4-min hypoxic cycles at a targeted arterial oxygen saturation of 80% interspersed with breathing room air to resaturation, or an intermittent normoxia (IN) protocol consisting of eight 4-min normoxic cycles interspersed with breathing room air. By design, oxygen saturation was lower during intermittent hypoxia than intermittent normoxia (81±3 vs. 97±1%, p<0.01). Relative changes in plasma glucose concentrations in response to the oral glucose tolerance tests were not different between conditions (IH vs. IN: 30: 42±15 vs. 35±15; 60: 57±26 vs. 65±30; 90: 73±32 vs. 88±30; and 120: 78±26 vs. 83±29 mg/dl, interaction effect: p=0.13). Similarly, the relative changes in insulin concentrations in response to the oral glucose tolerance tests were not different between conditions (IH vs. IN: 30: 14±17 vs. 25±17; 60: 42±36 vs. 48±35; 90: 70±58 vs. 86±60; and 120: 103±72 vs. 125±94 ulU/ml, main effect for condition: p=0.12). While these preliminary results did not reach statistical significance, the observed trends for reduced glucose concentrations in combination with lower insulin concentrations during intermittent hypoxia suggest that short bouts of hypoxia improve glucose tolerance by stimulating glucose uptake independently from the action of insulin. Data from a larger sample size of adults with type 2 diabetes are needed to confirm these preliminary findings. None. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Plasma Branched-Chain Fatty Acids Reflect Dairy-Fat Intake in a Pilot Clinical Trial in Individuals with Prediabetes
Authors: Taormina Victoria , Eisenhardt Simonne , Gilbert Matthew , Poynter Matthew , Kien C. Lawrence , Kraft Jana 
Published: May 2024

Epidemiological studies often rely on fatty acid (FA) biomarkers of dairy-fat intake to represent diet history and to establish associations with cardiometabolic risk factors. However, a more robust body of direct research is needed to validate the currently utilized FA biomarkers as accurate representations of dairy-fat intake. Thus, our objectives were to i) compare the plasma FA profile of individuals with prediabetes following the consumption of a diet with full-fat (3.25%) yogurt (FFY diet) or non-fat yogurt (NFY diet) to evaluate their validity of currently utilized biomarkers and ii) identify additional FAs to serve as potential biomarkers. We hypothesized that the proportion of the unique dairy-derived FAs including odd-chain FAs (13:0, 15:0, 17:0, 19:0, 21:0, 23:0), branched-chain FAs ( iso-13:0, anteiso-13:0, iso-14:0, iso-15:0, anteiso-15:0, iso-16:0, iso-17:0, anteiso-17:0, iso-18:0), and the trans-FAs 16:1 trans-9 and 18:1 trans-11 would increase in plasma total lipids following the consumption of three daily servings of full-fat yogurt for three weeks. Our 8-week randomized, double-masked, controlled crossover study included six men and seven women aged 45-75 years old. Each experimental diet period, NFY diet and FFY diet, was three weeks in length. The arithmetic difference in fat (8% energy) between the NFY diet (30% fat) and the FFY diet (38% fat) was solely due to the dairy fat in the full-fat yogurt. Following each experimental diet period, fasting plasma samples were taken and analyzed for FA composition of plasma total lipids using gas-liquid chromatography. Consumption of the FFY diet resulted in no change in the proportion of total odd-chain FAs or the individual FAs 16:1 trans-9 and 18:1 trans-11, but the proportion of total branched-chain FAs was greater in response to the FFY diet ( P < 0.01). For individual odd-chain and branched-chain FAs, the proportions of iso-17:0 and anteiso-17:0 were greater in response to the FFY diet ( P < 0.01 for both); however, there were no differences in anteiso-15:0 or iso-15:0 proportions by diet. Results from this pilot trial suggest that commonly utilized FA biomarkers may not be suffciently robust to represent dairy-fat intake. Branched-chain FAs should be further explored for alternatives. Funding for this project was provided by National Dairy Council Nutrition Research Funding, a USDA Agriculture and Food Research Initiative National Institute of Food and Agriculture Predoctoral Fellowship, and a fellowship from the University of Vermont’s Food Systems Research Center. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
KPs improve renal function and blood vessels function by balance the sFlt-1:PlGF ratio in L-NAME-induced SHRSP preeclampsia rats
Authors: Chen Yu-Hsuan , Chen Chuan-Mu 
Published: May 2024

Preeclampsia (PE) is one of the major problems for global healthy burden. It affects 2 to 8% of all pregnancies and causes both maternal and infant morbidity and mortality. Kefir peptides are products from many kinds of prebiotic fermentation in whole milk by kefir grain. In this study, we used the N(ω)-nitro-L-arginine methyl ester (L-NAME) in drinking water to mimic the preeclampsia in spontaneous hypertension rat stroke-prone (SHRSP) pregnant rats, the rats were assigned to five treatment groups: the normal group, untreated group, L-NAME group, L-NAME+KPs (LD and HD dose diets) for 20-day experiment. Data showed that rats only gave the L-NAME group induced severe high blood pressure, urine protein, placenta damage, and embryo reabsorption. After KPs pre-administration significantly reduced urine protein production and generalized vessel endothelial dysfunction, anti-oxidative, and anti-inflammation levels in SHRSP rats placenta. In conclusion, kefir peptides is a multipurpose peptide that can suppress oxidative stress, HIF-1a, anti-TNF-α and IL-6 inflammation levels, reducing urine protein production and generalized vessel endothelial dysfunction and balance the sFlt-1:PlGF ratio through blocking eNOS/NO. KPs might be a promising protective nutraceutical agent for early pregnancies. The Higher Education Sprout Project by the Ministry of Education (MOE-112-S-0023) in Taiwan. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Renal upregulation of NCC counteracts empagliflozin-mediated NHE3 inhibition in normotensive but not in hypertensive rats
Authors: Coelho Paulo , Santos-Rios Thiago , Martins Flavia , Crajoinas Renato , Caetano Marcos , Luchi Weverton , McCormick James 
Published: May 2024

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce blood pressure (BP) in hypertensive patients. However, the underlying molecular mechanisms remain largely unknown. Proximal tubule (PT) NHE3-mediated sodium reabsorption is inhibited by SGLT2i in normotensive rodents, yet no BP-lowering effect is observed under this scenario. This study examined the effect of empagliflozin (EMPA) on renal tubular sodium transport in normotensive and spontaneously hypertensive rats (SHRs). It also tested the hypothesis that EMPA-mediated PT NHE3 inhibition in normotensive rats is associated with upregulation of distal nephron apical sodium transporters. Administration of EMPA for 14 days reduced BP in 12-week-old SHRs but not in age-matched Wistar rats. PT NHE3 was inhibited by EMPA treatment in both Wistar and SHRs. EMPA increased NCC expression and phosphorylation levels in Wistar but not SHRs. SHRs exhibited higher cortical and medullary NKCC2 and β-ENaC subunit mRNA and higher medullary α-ENaC expression levels than Wistar rats, none of which were affected by EMPA. Another set of male Wistar rats was treated with EMPA, the NCC inhibitor hydrochlorothiazide (HCTZ), EMPA combined with HCTZ or vehicle for 14 days. In these rats, BP was reduced in response to EMPA and HCTZ combined but not by EMPA or HCTZ alone. Altogether, these data suggest that upregulation of NCC counteracts EMPA-mediated inhibition of PT NHE3 in male normotensive rats, thereby maintaining their baseline BP. Moreover, reducing NHE3 activity without further upregulation of the main apical sodium transporters beyond the PT may contribute to the BP-lowering effect of SGLT2i in experimental models and patients with hypertension. FAPESP 2016/22140-7 and 2021/14534-3. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.