Acute Effects Research Articles

Acute right-sided transcutaneous vagus nerve stimulation improves cardio-vagal baroreflex gain in patients with chronic heart failure.

The aim of this paper is to investigate the acute effects of short-term transcutaneous vagus nerve stimulation (tVNS) on cardio-vagal baroreflex gain and heart rate variability in patients with chronic heart failure (CHF). A total of 16 adults with CHF and left ventricular ejection fraction (LVEF) < 50% in sinus rhythm were enrolled (65 ± 8years, 63% men, LVEF 40 ± 5%, 88% on beta-blockers, 50% on quadruple CHF therapy). Over a single experimental session, after a 10-min baseline recording, each patient underwent two trials of 10-min tVNS (Parasym Device, 200µs, 30Hz, 1mA below discomfort threshold) at either the right or left tragus in a randomized order, separated by a 10-min recovery. Compared with baseline, tVNS did not affect heart rate, blood pressure, and respiratory rate (p > 0.05), and no patients complained of discomfort or any adverse effect. Right-sided tVNS was associated with a significant increase in cardio-vagal baroreflex gain (from 5.6 ± 3.1 to 7.5 ± 3.8ms/mmHg, ∆ 1.9 ± 1.6ms/mmHg, p < 0.001), while no change was observed with left-sided tVNS (∆ 0.5 ± 2.0ms/mmHg, p = 0.914). These findings were independent of stimulation-side order (excluding any carry-over effect) and consistent across sex, LVEF category, and HF etiology subgroups (p-value for interaction > 0.05). Acute right-sided tVNS increases cardio-vagal baroreflex gain in patients with CHF and LVEF < 50%, with no tolerability concerns.

Acute effect of resistive aquatic high-intensity interval training on metabolic costs in adults.

The effects of Aquatic High-Intensity Interval Training (AHIIT) and resistive AHIIT (Resistive AHIIT) to improve metabolic responses were not yet known. This study was to compare the metabolic responses and perceived effort in young healthy adults in a single session of AHIIT and resistive AHIIT. 20 healthy subjects (9 females, 11 males) performed a stationary running at a matched exercise intensity prior AHIIT and resistive AHIIT [10 × 1-min bouts of stationary running at 90% maximum heart rate (HR max) separated by 1-min active recovery] to examine the metabolic and cardiometabolic outcomes. Mixed effects models were applied to analyze the effects of group, time, and the interaction between group and time on both outcomes. The level of correlations between metabolic variables was checked by Pearson's linear correlation. There are significant differences on pre and post resting energy expenditure (REE) within both AHIIT and resistive AHIIT groups (p < 0.01) respectively as well as the subjective rate of perceived exertion (RPE) (p < 0.01) within RAHIIT group. A moderate correlation found on respiratory exertional ratio (RER) and RPE in resistive AHIIT (r = 0.534). No significant differences between groups in terms of HR max, mean heart rate (HR mean), peak oxygen consumption (VO2 peak) and total energy expenditure (TEE) (p = 0.50, p = 0.48, p = 0.81, p = 0.59). Resistive AHIIT provides comparable benefits of metabolic outcomes with AHIIT. Comparable results allowed AHIIT and resistive AHIIT prescriptions precisely.

The impact of antidepressant discontinuation prior to treatment with psilocybin for treatment-resistant depression

It has been suggested that the recent use and discontinuation of antidepressant drugs compromises the action of psilocybin. As evidence is only available from small or uncontrolled samples, this post hoc analysis investigated this using data from the largest, phase II, randomized controlled trial of psilocybin treatment to date. Data from 233 participants with treatment-resistant depression (TRD) who received 25 mg, 10 mg, or 1 mg of investigational drug COMP360 psilocybin (a proprietary, pharmaceutical-grade synthetic psilocybin formulation, developed by the sponsor, Compass Pathfinder Ltd.), administered with psychological support, were compared for groups of participants who either discontinued one or more antidepressant drugs during screening or entered the trial antidepressant drug free. Measures of depression symptom severity change during the antidepressant drug discontinuation period, baseline suicidality, acute subjective psychedelic effects, and the study's primary endpoint (change in depression symptom severity between Baseline and Week 3) are described for both groups. Antidepressant drug discontinuation was not related to worsening of depression severity before Baseline. Suicidality was comparable between groups at Baseline. Psilocybin treatment efficacy and the subjective psychedelic experience did not appear to be compromised by antidepressant drug discontinuation. Thus, it does not limit the feasibility of psilocybin treatment for the future. These findings also support the overall homogeneity of our findings with psilocybin treatment as a monotherapy for TRD. The prior contradictory reports may come to appear misleading.

Treatment preferences of patients with muscle invasive bladder cancer: A discrete choice experiment

AbstractBackgroundWhen faced with treatment options, patients are asked to participate in decision‐making. We sought to determine which treatment aspects matter most for individuals treated for muscle invasive bladder cancer (MIBC), with an aim to improve understanding of patient preferences and what trade‐offs patients are willing to accept. Our study consisted of a discrete choice experiment (DCE): a type of questionnaire used to elicit preferences in the absence of real‐world choice.MethodsThe DCE had five attributives, each with three levels. Participants were asked to complete a questionnaire in which they were asked to choose between two hypothetical MIBC treatments. The data were analysed using a conditional logit model, and preferences for, and trade‐offs between, attributes were estimated.ResultsWe recruited patients with MIBC who had either already completed, were undergoing or had yet to commence radical treatment for MIBC (n = 60). Participants indicated a strong preference for treatments that increased their life expectancy (p = &lt;0.001), had a lower risk of long‐term complications (p = &lt;0.001) and less changes to their body image (p = &lt;0.001). Changes to sexual wellbeing (p = 0.09) or an increase in acute side effects (p = 0.99) did not influence preferences. Patients were willing to accept treatments with higher risk of long‐term complications to improve their life expectancy or body image.ConclusionWhen deciding on the type of treatment, increased life expectancy is the most important consideration for people with MIBC. The risk of long‐term complications and changes to overall body image as a result of treatment are also important. Our study also highlighted that patients are willing to accept a higher risk of long‐term complications to improve other treatment outcomes. Understanding patient preferences is important for shared decision‐making, which has an impact on quality of care for people living with MIBC.

Acute Effect of Three Aerobic Exercise Intensities on Glomerular Filtration Rate in Healthy Older Adults.

To assess the immediate effects of three aerobic exercise intensities on the estimated glomerular filtration rate (eGFR) in healthy, sedentary older adults. Eighteen healthy, sedentary older adults (ten men and eight women) voluntarily participated in this study. The participants underwent three standardized aerobic exercise tests (100%, 80%, and 60% of the maximal heart rate) on a bicycle ergometer. Blood samples were collected to determine cholesterol, triacylglycerols, glucose, serum creatinine (Cr), Cystatin C (CysC) concentrations, and eGFR. eGFR and serum concentrations of Cr and CysC were not modified at any exercise intensity. There was a negative correlation between blood total cholesterol vs. eGFR (R = -0.512, R = -0.582, R = -0.531; p < 0.05) at rest, 60%, and 100% of the maximal heart rate, respectively. In addition, a negative correlation existed for age vs. eGFR at 60% of the maximal heart rate (R = -0.516; p < 0.05). Short-duration aerobic exercise of low, moderate, and vigorous intensity did not significantly affect eGFR and is considered safe for kidney function in healthy, sedentary older adults. However, regular monitoring of kidney function in older people engaged in moderate- and high-intensity exercise is advised.

Driving performance and ocular activity following acute administration of 10 mg methylphenidate: A randomised, double-blind, placebo-controlled study.

Methylphenidate is a routinely prescribed treatment for attention-deficit/hyperactivity disorder with misuse potential owing to its perceived performance-enhancing and euphoric properties. Although clinically effective, there is limited understanding of how methylphenidate affects safety-sensitive tasks such as driving when used by healthy individuals. Explore the acute effects of 10 mg methylphenidate on driving performance and gaze behaviour. Twenty-five fully licensed, healthy adults (mean age = 33.5 ± 7.8 years, 64% male) took part in two 40-min simulated highway drives with simultaneous eye movements monitored using a proprietary automotive-grade driver monitoring system (Seeing Machines). Driving performance was assessed using the standard deviation of lateral position, standard deviation of speed and steering variability. Visual scanning efficiency was determined using ocular metrics, such as fixation duration and rate, gaze transition entropy, and stationary gaze entropy, were assessed to determine visual scanning efficiency. Methylphenidate significantly improved driving performance by reducing lane weaving and speed variation, particularly in the latter half of the drive. Although a significant reduction in fixation duration was observed, all other ocular metrics remained unchanged. Methylphenidate mitigates performance decrements typically associated with prolonged and monotonous driving. The absence of pronounced oculomotor effects suggests that a single 10 mg dose of methylphenidate has no deleterious impact on visual scanning behaviour during driving tasks with low-to-moderate cognitive demand. Future research should investigate the effects of methylphenidate under various dosing and driving conditions to better understand its impact. ACTRN12620000499987.

Existential feelings as a phenomenological framework for psychedelic therapy

ABSTRACT This article provides a phenomenological account of the role of existential feelings in the acute and lasting effects of psychedelic therapy and attempts to elucidate phenomenologically why certain psychedelic experiences in specific contexts have the potential of providing long-term relief from mental suffering. First, we explain Matthew Ratcliffe’s theory of existential feelings and use it to highlight shared phenomenological characteristics between various mental disorders. Next, we discuss the phenomenology of oceanic feelings to specify the kind of existential feeling that is involved in acute psychedelic experiences and connect this to the existential reorientation that may occur after the use of psychedelics. Following this, we show how this framework of existential feelings allows us to (1) characterize the phenomenological process that takes during therapeutic use of psychedelics, and (2) describe various conditions required for a successful therapeutic psychedelic experience.

Acute inflammatory and metabolic effect of high fructose intake in normal-weight women: A randomized, double-masked, crossover trial

We aimed to evaluate the acute effect of a fructose-rich single meal on metabolic and inflammatory biomarkers RESEARCH METHODS AND PROCEDURES: This single-center, double-masked, randomized crossover trial recruited females aged 20 to 47 with a normal body mass index and was conducted at Hospital das Clínicas (Belo Horizonte, MG, Brazil). Participants received a standardized meal with either sucrose, glucose, or a fructose overload. Blood samples were collected after overnight fasting (baseline) and at 30, 60, 120, and 240 minutes postprandial. Serum levels of glucose, triglycerides (primary outcome), total cholesterol, alanine aminotransferase, aspartate aminotransferase, adiponectin, leptin, resistin, interleukin (IL)-2, IL-4, IL-5, IL-6, IL-10, IL-17, interferon-gamma, tumor necrosis factor, eotaxin, and total blood leukocytes were measured. This trial was completed with 25 enrolled participants, and three dropped out. The per-protocol analysis included 22 participants. As expected, postprandial glycemia increased 30 minutes after consuming meals rich in sucrose (P = 0.045) or glucose (P < 0.001). Triglyceride and leucocyte concentrations increased only at 240 minutes after consuming a high-fructose meal (P < 0.05). Regardless of the type of carbohydrate overload, leptin concentrations decreased postprandially compared to baseline at all time points (P < 0.05). Four participants reported adverse events after consuming the standardized meal with glucose or fructose, including nausea and malaise. Our findings indicate that a fructose-rich single meal leads to a more significant increase in triglyceride and leukocyte concentrations compared to glucose and sucrose in healthy women. These findings support concerns regarding the potential inflammatory and metabolic dysfunction associated with frequent consumption of high-fructose meals.

RNA m6A methyltransferase activator affects anxiety-related behaviours, monoamines and striatal gene expression in the rat.

Modification of mRNA by methylation is involved in post-transcriptional regulation of gene expression by affecting the splicing, transport, stability and translation of mRNA. Methylation of adenosine at N6 (m6A) is one of the most common and important cellular modification occurring in the mRNA of eukaryotes. Evidence that m6A mRNA methylation is involved in regulation of stress response and that its dysregulation may contribute to the pathogenesis of neuropsychiatric disorders is accumulating. We have examined the acute and subchronic (up to 18 days once per day intraperitoneally) effect of the first METTL3/METTL14 activator compound CHMA1004 (methyl-piperazine-2-carboxylate) at two doses (1 and 5 mg/kg) in male and female rats. CHMA1004 had a locomotor activating and anxiolytic-like profile in open field and elevated zero-maze tests. In female rats sucrose consumption and swimming in Porsolt's test were increased. Nevertheless, CHMA1004 did not exhibit strong psychostimulant-like properties: CHMA1004 had no effect on 50-kHz ultrasonic vocalizations except that it reduced the baseline difference between male and female animals, and acute drug treatment had no effect on extracellular dopamine levels in striatum. Subchronic CHMA1004 altered ex vivo catecholamine levels in several brain regions. RNA sequencing of female rat striata after subchronic CHMA1004 treatment revealed changes in the expression of a number of genes linked to dopamine neuron viability, neurodegeneration, depression, anxiety and stress response. Conclusively, the first-in-class METTL3/METTL14 activator compound CHMA1004 increased locomotor activity and elicited anxiolytic-like effects after systemic administration, demonstrating that pharmacological activation of RNA m6A methylation has potential for neuropsychiatric drug development.

Suppression of the postprandial hyperglycemia in patients with type 2 diabetes by a raw medicinal herb powder is weakened when consumed in ordinary hard gelatin capsules: A randomized crossover clinical trial.

Contradictory claims about the efficacy of several medicinal plants to promote glycemic control in patients with type 2 diabetes mellitus (T2DM) have been explained by divergences in the administration form and by extrapolation of data obtained from healthy individuals. It is not known whether the antidiabetic effects of traditional herbal medicines are influenced by gelatin capsules. This randomized crossover trial aimed to evaluate the acute effect of a single dose of raw cinnamon consumed orally either dissolved in water as a beverage or as ordinary hard gelatin capsules on postprandial hyperglycemia (>140 mg/dL; >7.8 mmol/L) in T2DM patients elicited by a nutritionally-balanced meal providing 50 g of complex carbohydrates. Fasting T2DM patients (n = 19) randomly ingested a standardized meal in five experimental sessions, one alone (Control) and the other after prior intake of 3 or 6 g of crude cinnamon in the form of hard gelatin capsules or powder dissolved in water. Blood glucose was measured at fasting and at 0.25, 0.5, 0.75, 1, 1.5 and 2 hours postprandially. After each breakfast, its palatability scores for visual appeal, smell and pleasantness of taste were assessed, as well as the taste intensity sweetness, saltiness, bitterness, sourness and creaminess. The intake of raw cinnamon dissolved in water, independently of the dose, decreased the meal-induced large glucose spike (peak-rise of +87 mg/dL and Δ1-hour glycemia of +79 mg/dL) and the hyperglycemic blood glucose peak. When cinnamon was taken as capsules, these anti-hyperglycemic effects were lost or significantly diminished. Raw cinnamon intake did not change time-to-peak or the 2-h post-meal glycaemia, but flattened the glycemic curve (lower iAUC) without changing the shape that is typical of T2DM patients. This cinnamon's antihyperglycemic action confirms its acarbose-like property to inhibit the activities of the carbohydrate-digesting enzymes α-amylases/α-glucosidases, which is in accordance with its exceptionally high content of raw insoluble fiber. The efficacy of using raw cinnamon as a diabetes treatment strategy seems to require its intake at a specific time before/concomitantly the main hyperglycemic daily meals. Trial registration: Registro Brasileiro de Ensaios Clínicos (ReBEC), number RBR-98tx28b.

Endothelial Dysfunction Does Not Occur after Acute, Elevated Homocysteine Exposure of the Lumen of the Iliac Artery of the Anaesthetised Pig

Introduction: Elevated luminal homocysteine has been linked with cardiovascular disease; however, whether there is a direct effect of homocysteine on blood vessel endothelium is not clear. In this study, the acute effect of luminal homocysteine on iliac artery endothelial function was assessed in the anaesthetised pig. Methods: Hyperhomocysteinaemic blood was injected into an occluded segment of the iliac in the anaesthetised pig for 20 min, and the effect on atrial diameter during the occlusion and during the reactive hyperaemia assessed. Results: No significant changes in arterial diameter or pressure were observed during the incubation period at homocysteine concentrations of 10, 20, 40 and 100 µM. There was also no difference in the magnitude of the iliac diameter increase in the response to reactive hyperaemia when the incubation period was completed. Conclusion: There is no evidence of endothelial dysfunction in response to an acute 20-min elevation in homocysteine in an intact conduit artery.

Phytotoxicity of single and mixed rare earth element (La, Nd and Sm) exposures on Lactuca sativa seed germination and growth.

The mode of action, bioaccumulation potential and toxicity of Rare Earth Elements (REE), with several applications in the technology, medical and agricultural fields, are still understudied. The nitrates acute effects on single exposures, binary and ternary mixtures of lanthanum (La), neodymium (Nd) and samarium (Sm) on Lactuca sativa lettuce seed germination and wet biomass in an artificial soil (AS) and an Ultisol were assessed. Germination (EC50), wet biomass (IC50) and germination inhibition (% GI) were evaluated. EC50 values show La was the most toxic in Ultisol, Sm in AS, and Nd appears with intermediate values on both substrates. The IC50, both single and mixed, decreased from 3- to 181-fold with increasing test concentrations in relation to the control in AS, while increases in Ultisol were observed, followed by decreases at higher doses which may be associated with the low-dose stimulation effect (hormesis). Our findings may be used to subsidize REE risk assessment studies and reinforce the hormesis effect to prevent the use of high application of REE fertilizers, avoiding the accumulation of REE in agricultural soils.

Indirect markers of muscle damage in military physical training session with neuromuscular and aerobic exercises in circuit (Cross operational): acute effects and recoverability

The Brazilian army recently developed the military physical training “Cross Operational” (CO), composed of four different difficulty levels. The moderate/high intensity character of CO can damage the muscle fibers, characterized by alterations at the cellular level, which can be evaluated indirectly by intramuscular proteins showing up in the bloodstream. In this context, the analysis of muscle damage biomarkers can be used as part of an initial injury prevention tool and in the evaluation of training progression and post-exercise recovery. This study aimed to observe the acute effect of CO on indirect markers of muscle damage in military personnel of the Brazilian army. Twenty-four male recruits aged between 18 and 26 years participated in the study. The four sessions corresponding to the CO levels were performed in cross-design, with a seven-day washout period, and blood samples were collected at rest, immediately after, 24 and 48 hours after each training session. The measured markers were creatine kinase (CK), myoglobin (Mb) and lactate dehydrogenase (LDH). In all CO levels, CK had a significant increase 24 hours after CO, whereas Mb and LDH incresead immediately after CO. Regarding recovery time, LDH returned to baseline values within 48 hours in all levels, whereas CK and Mb, after 48 hours of recovery, reduced but did not return to baseline in level 4. The serum elevations of the biomarkers studied, like those found in studies with other consolidated physical training methods, suggest that CO can contribute to the improvement of the physical training of military personnel.

Compensatory reactions of B cells in response to chronic HIV-1 Tat exposure.

Patients infected with human immunodeficiency virus-1 (HIV-1) have an increased incidence of B-cell lymphoma, even though HIV-1 does not infect B cells. The development of B-cell lymphomas appears to be related to the action of the HIV-1 transactivator protein (Tat), which is released from HIV-infected cells and penetrates uninfected B cells, affecting host cell gene expression. Upon chronic HIV-1 infection, Tat acts on the cells for a long time, probably allowing the cells to adapt to the presence of the viral protein. The aim of this work was to identify and study the mechanism of adaptation of cells to prolonged (chronic) exposure to HIV-1 Tat. We performed a comparative analysis of cells expressing Tat under the action of either an inducible promoter or a constitutive promoter, allowing us to model acute and chronic Tat effects, respectively. We found that the acute action of Tat leads to the suppression of cell proliferation, probably due to the downregulation of genes associated with replication and protein synthesis. In the case of chronic action of Tat, cell proliferation was restored and the expression of genes associated with the implementation of protective (antiviral) functions of the cell was increased. Analysis using proteasome inhibitors showed that in the case of chronic action, intense Tat proteolysis occurred, which could be the main mechanism of B-cell adaptation. Thus, B cells have a powerful mechanism to adapt to the entry of HIV-1 Tat, the efficiency of which may determine the frequency of lymphomagenesis in HIV-1-infected patients.

Acute effects of swimming goggle wearing on intraocular pressure, anterior chamber biometrics, and optic nerve head morphology

Swimming goggles (SG) are widely used in water sports, and this study aimed to evaluate the acute effects of wearing SG on intraocular pressure (IOP), anterior chamber biometrics, axial length (AL), and optic nerve head (ONH) morphology. Twenty-eight healthy young adults participated in this cross-sectional study, with assessed parameters including IOP, central corneal thickness (CCT), anterior chamber depth (ACD), anterior chamber angle (ACA), AL, and optical coherence tomography (OCT) imaging of the ONH, specifically Bruch membrane opening (BMO), Bruch membrane opening-minimum rim width (BMO-MRW), lamina cribrosa depth (LCD), and prelaminar tissue (PLT). Measurements were taken at four time points: before wearing SG, at the 1st and 10th minutes of wearing, and immediately after removal. The results showed a significant increase in IOP at the 1st and 10th minutes of SG wear compared to pre-wear and post-removal values. Additionally, decreases in CCT, ACD, and ACA, along with an increase in AL, were observed while wearing SG. However, these changes reverted to baseline after the goggles were removed. No significant alterations were detected in ONH parameters during the study. The findings suggest that wearing SG induces an acute rise in IOP and changes in anterior segment parameters, likely due to oculopression, but does not appear to affect ONH morphology in the short term. Further studies are needed to investigate any potential long-term effects.

The acute effect of heart rate monitor projection on exercise effort in school students

Heart rate (HR) monitoring during exercise represents a potentially useful strategy for teachers delivering physical education lessons. This study examined how projecting HR monitor data onto a screen acutely affected school students’ exercise intensity during a high-intensity interval training (HIIT) session. Twenty students (12.3 ± 0.9 years, male = 8, female = 12) from one primary school volunteered to participate. Using a randomised crossover design within a 4-week period, participants completed four sessions of HIIT with HR projection and four sessions of HIIT with no ability to view HR. During the HR projection condition all participants viewed their HR on a class screen in real-time, with a changing colour according to HR level. Target intensity was 90% of age-predicted maximum HR. Peak HR and time above 90% HR (RED) were collected in all sessions. Student focus groups and teacher interviews were conducted to gain perceptions around the effects of the projection. Peak HR ( p = 0.005, η2 effect size = 0.049) and RED ( p = 0.000, η2 effect size = 0.083) were significantly greater during the projected condition. Qualitative data indicated that projection improved student motivation to reach the target, and ignited competition amongst peers to work harder. Projecting HR data onto a screen can increase the acute exercise intensity of school students during HIIT. HR projection therefore represents a useful strategy for the delivery of exercise sessions with an emphasis on intensity, within physical education classes.

Acute Effects of Citrulline Malate Supplementation on Nocturnal Blood Pressure Dipping After Exercise in Hypertensive Patients: A Randomized, Placebo-Controlled Trial

Background Citrulline malate (CM), especially when used in conjunction with physical exercise, has demonstrated potential as a non-pharmacological adjunct in the management of hypertension. Nevertheless, its impact on nocturnal blood pressure dipping remains unexplored. Objective Evaluate the impact of a single dose of CM on nocturnal blood pressure dipping after exercise in hypertensive individuals. Methods In a double-blind, placebo-controlled, parallel-group clinical trial, twenty hypertensive adults (55 ± 16 years) were randomly assigned to either a CM (6 g) or placebo (6 g of corn starch) group (PLA). Resting blood pressure was measured after a 20-min period of comfortable seating in a calm environment. Both groups underwent 40 min of treadmill running/walking at an intensity of 60–70% of their reserve heart rate, 120 min after ingesting the substances. Ambulatory blood pressure monitoring was employed to measure blood pressure over 24 h. Results No significant differences in systolic blood pressure values were observed between the CM and PLA groups at rest, during wakefulness, sleep, or over a 24-h period. However, CM exhibited a significant reduction in diastolic blood pressure in several metrics: delta 24 h (-14 mmHg vs −6 mmHg, p = 0.047), delta wakefulness (-12 mmHg vs −4 mmHg, p = 0.024), percent delta 24 h (-16% vs −6%, p = 0.024), and percent delta wakefulness (-14% vs −4%, p = 0.013). No significant differences were found between CM and PLA in terms of systolic and diastolic nocturnal absolute reductions (-13 mmHg vs −12 mmHg, p = 0.808, and −13 mmHg vs −8 mmHg, p = 0.273, respectively) or nocturnal percentage decrease (-9.9% vs −9.4%, p = 0.844, and −15.3% vs −11.7%, p = 0.399, respectively). Conclusions The study found no significant changes in the post-exercise nocturnal blood pressure dip following a single dose of CM supplementation. However, a notable reduction in diastolic blood pressure was observed during the waking period and over the average 24-h monitoring period. Clinical trial registry number and website ClinicalTrials.gov platform (NCT03378596).

12440 Exploring The Potential Protective Role Of The Bacterial-derived Metabolite Indole-3-propionic Acid Against Obesogenic Insults In Placenta Cell Lines

Abstract Disclosure: J. Ernst: None. L. Conlon: None. R. Gupta: None. L. Kang: None. M.E. Heard-Lipsmeyer: None. Obesity during pregnancy is associated with detrimental changes in placental function that lead to the development of complications such as gestational diabetes and preeclampsia as well as altered metabolism in the offspring. With the incidence of obesity reaching epidemic levels world-wide, it is imperative to find mechanisms to mitigate these risks during pregnancy. The gut-microbiome is a diverse system that regulates numerous body functions through the secretion of specific metabolites. Gut dysbiosis has recently emerged as one mechanism that contributes to placental dysfunction and clear associations between obesity and gut dysbiosis are evident. Indole-3-propionic acid (IPA) is a gut microbiome-derived metabolite that has anti-inflammatory, anti-oxidative stress and glucose regulatory functions, all of which are dysregulated in obesity. Previous studies have found diminished levels of IPA in serum of women with overweight/obesity. However, it remains unknown what the physiological functions of IPA are in the placenta and if it could have potential protective effects against perturbations caused by obesity. The objective of this study is to determine what physiological role IPA plays in the placenta and if IPA can protect against obesogenic insults that contribute to placental pathology. For this study, we developed an in vitro model of obesity where two human placental cell lines, BeWo (choriocarcinoma) and HTR8 (normal immortalized trophoblasts) were cultured in media conditioned by mature human adipocytes (ACM). RNA sequencing (RNAseq) analysis was used to determine acute effects of IPA treatment after 24 hours in the presence and absence of ACM. We further examined the influence of IPA on insulin signaling with physiological and hyperinsulinemia levels of insulin at 24 and 72 hours utilizing QPCR and western blot analyses. RNAseq analysis revealed treatment with physiological levels of IPA induced changes in genes associated with normal placental function, autophagy and inflammatory mediated processes and other pathways. Our RNAseq analysis offers initial insight into the molecular mechanisms of IPA in placental cells. Future analyses will investigate the potential role of insulin signaling, glucose homeostasis and oxidative stress. Collectively, this study highlights the importance of a healthy gut microbiome and potentially serves as a window of opportunity to mitigate the onset or severity of pregnancy-related disorders such as gestational diabetes by enhancing the gut microbiome prior to pregnancy. Presentation: 6/1/2024

12548 Mammary De Novo Lipogenesis During A Hyperinsulinemic-euglycemic Clamp

Abstract Disclosure: T.M. Fordham: None. M. Ramos-Roman: None. E.J. Parks: Consulting Fee; Self; Simply Good Foods. Stock Owner; Self; Sagimet Biosciences. Other; Self; Past President of The Obesity Society. Introduction: The mammary produces large amounts of medium-chain saturated fatty acids. Long-chain saturated fatty acids found in human milk primarily derive from the maternal diet or from the mobilization of stored triglycerides. Previous studies have established the importance of insulin in stimulating mammary differentiation, milk synthesis, and lipogenesis. However, no studies have assessed how changes in insulin concentrations alter human mammary de novo lipogenesis (DNL) nor what effect gestational diabetes may have on insulin’s relationship to lipogenesis during lactation. Through the utilization of stable isotopes and the hyperinsulinemic-euglycemic clamp technique, we tested the differing concentrations of insulin to stimulate mammary DNL. Methods: Eight women (32±4 yrs) with (GDM, n=4) or without (NGT, n=4) recent gestational diabetes and overweight or obesity (28.2±2.9 kg/m2) were recruited to participate in this study at 6 weeks postpartum. The night before the study, participants orally consumed 3 doses of 70% deuterated water to label newly made fatty acids. Participants arrived in the morning for IV placement and immediately pumped milk contralaterally for 20 minutes. Milk was pumped two hours later, again at the end of step 1 of the clamp (10 mU/m2/min) and once more after step 2 (either 20 or 40 mU/m2/min). Milk triglycerides were extracted and prepared for analysis by gas chromatography-mass spectrometry. The incorporation of deuterium into milk triglyceride-fatty acids was the primary outcome. Results: Fasting insulin concentrations were significantly associated with newly-made 16:0 in milk triglycerides (r=0.85, P=0.01). Of all measured triglyceride 16:0, 1.6±1.0% were made de novo. This percentage increased 1.5-fold by the end of step 2 of the clamp (P=0.06). Fasting milk DNL 14:0 was 12.3±4.8% which was significantly greater than DNL 16:0 (P&amp;lt;0.01). DNL 14:0 increased 1.7-fold during step 2 (P=0.04). For both milk triglyceride 12:0 and 14:0 derived from DNL, a significant effect across clamp-stage was observed (P&amp;lt;0.001 for both), but not an effect of group (P=0.12, P=0.11, respectively). Bonferroni posthoc analyses revealed that the insulin effect was significant for both groups for 12:0 (GDM, P=0.02; NGT, P &amp;lt;0.01) and 14:0 (GDM, P&amp;lt;0.01; NGT, P=0.01). Interpretation: The present study is the first to assess the acute effect of a hyperinsulinemic-euglycemic clamp on the synthesis of newly-made triglyceride fatty acids in human milk. These results suggest that the increases in mammary DNL may be fatty acid specific, favoring that of lauric and myristic acids, but not longer chain fatty acids like palmitate. Mammary lipogenesis was stimulated by insulin in all subjects regardless of recent gestational diabetes diagnosis. The role mammary DNL plays in overall milk fat content deserves further investigation. Presentation: 6/3/2024

12440 Exploring The Potential Protective Role Of The Bacterial-derived Metabolite Indole-3-propionic Acid Against Obesogenic Insults In Placenta Cell Lines

Abstract Disclosure: J. Ernst: None. L. Conlon: None. R. Gupta: None. L. Kang: None. M.E. Heard-Lipsmeyer: None. Obesity during pregnancy is associated with detrimental changes in placental function that lead to the development of complications such as gestational diabetes and preeclampsia as well as altered metabolism in the offspring. With the incidence of obesity reaching epidemic levels world-wide, it is imperative to find mechanisms to mitigate these risks during pregnancy. The gut-microbiome is a diverse system that regulates numerous body functions through the secretion of specific metabolites. Gut dysbiosis has recently emerged as one mechanism that contributes to placental dysfunction and clear associations between obesity and gut dysbiosis are evident. Indole-3-propionic acid (IPA) is a gut microbiome-derived metabolite that has anti-inflammatory, anti-oxidative stress and glucose regulatory functions, all of which are dysregulated in obesity. Previous studies have found diminished levels of IPA in serum of women with overweight/obesity. However, it remains unknown what the physiological functions of IPA are in the placenta and if it could have potential protective effects against perturbations caused by obesity. The objective of this study is to determine what physiological role IPA plays in the placenta and if IPA can protect against obesogenic insults that contribute to placental pathology. For this study, we developed an in vitro model of obesity where two human placental cell lines, BeWo (choriocarcinoma) and HTR8 (normal immortalized trophoblasts) were cultured in media conditioned by mature human adipocytes (ACM). RNA sequencing (RNAseq) analysis was used to determine acute effects of IPA treatment after 24 hours in the presence and absence of ACM. We further examined the influence of IPA on insulin signaling with physiological and hyperinsulinemia levels of insulin at 24 and 72 hours utilizing QPCR and western blot analyses. RNAseq analysis revealed treatment with physiological levels of IPA induced changes in genes associated with normal placental function, autophagy and inflammatory mediated processes and other pathways. Our RNAseq analysis offers initial insight into the molecular mechanisms of IPA in placental cells. Future analyses will investigate the potential role of insulin signaling, glucose homeostasis and oxidative stress. Collectively, this study highlights the importance of a healthy gut microbiome and potentially serves as a window of opportunity to mitigate the onset or severity of pregnancy-related disorders such as gestational diabetes by enhancing the gut microbiome prior to pregnancy. Presentation: 6/1/2024