Body Water Research Articles

Effects of dapagliflozin on body composition and its relation to hemodynamics in heart failure with preserved ejection fraction: the CAMEO-DAPA randomized clinical trial

Abstract Background Excess fat, particularly visceral fat, plays an important role in the development of heart failure with preserved ejection fraction (HFpEF). Sodium glucose cotransporter-2 inhibitors improve hemodynamics, reduce symptom severity, and decrease risk of hospitalization, but their impact on body composition, as well as potential relationships between changes in body composition and hemodynamic effects, are unknown in HFpEF. Purpose Evaluate the effect of dapagliflozin on body and blood composition and examined the potential correlation of such changes on cardiac hemodynamics. Methods The CAMEO-DAPA trial, a single-center, double-blind, randomized, placebo-controlled study, showed that 24 weeks of dapagliflozin reduced resting and exercise pulmonary capillary wedge pressures (PCWP) in patients with HFpEF. This prespecified secondary analysis reports the effects of dapagliflozin on body composition using dual energy x-ray absorptiometry (DEXA), blood composition (radiolabeled iodinated albumin), and cardiac hemodynamics using high-fidelity micromanometers. Analysis was performed based on the intention-to-treat. Relative change was calculated by dividing the absolute change on the baseline value. Results Overall, 37 patients (67 years, 65% women, 70% with obesity, 27% overweight) completed the trial. As compared with baseline, dapagliflozin decreased total body fat compared with placebo [mean (SD) absolute change: -2.29 (2.94) kg vs -0.32 (1.84) in placebo, p=0.03; relative change: -4.6% (5.4) vs -0.8% (4.3), p=0.02], Figure 1. This was primarily due to greater loss of upper body trunk fat [absolute change: -1.53 (1.70) kg vs +0.31 (0.99) in placebo, p<.001; relative change: -5.2% (5.6) vs +1.1% (4.1), p<.001], Figure 1. Reductions in trunk fat were correlated with decreases in PCWP (r=0.41, p=0.03), Figure 2. Total body fat-free mass (FFM) tended to decrease in the dapagliflozin group [absolute change: -0.63 (1.85) kg vs +0.34 (1.76), p=0.12]; reductions in leg, android, and gynoid FFM were all greater than placebo (p<0.05). Dapagliflozin reduced plasma volume [absolute change: -170 (343) ml vs +112 (346), p=0.02] compared with placebo, and the decrease in plasma volume was correlated with the reduction in FFM (r=0.47, p=0.006), Figure 2. Treatment with dapagliflozin had no effect on resting metabolic rate but was associated with modest reduction in bone mineral content [-16 (47) g vs +26 (61), p=0.03]. Conclusions In patients with HFpEF, dapagliflozin decreases body fat, particularly trunk fat, suggesting greater effect on visceral adipose, which is correlated with favorable hemodynamic effects. Dapagliflozin also tends to reduce FFM, which may relate to reduction in total body water with or without reduction is muscle mass, in tandem with modest decreases in bone mineral content.Figure 1:Relative change in fat massFigure 2

Effect of Fontan circulation on body composition and correlation with exercise capacity

Abstract Background There is growing attention to body composition in Fontan patients (FP) and preliminary results suggest that FP have an increased fat mass and a decreased muscle mass compared to the healthy population. FP also have reduced exercise capacity compared to health peers. However, data are still limited. Purpose The aim of our study was to compare the body composition (BC) of adult patients with Fontan circulation and healthy controls and to assess the correlation with functional capacity. Material and Methods Case control study on adult patients with Fontan circulation (FP) and age and gender matched healthy controls (HC). The following characteristics were recorded: age, gender, morphology of the systemic ventricle, type of Fontan circulation, level of physical activity (PAR, 0-7 points, 0 = sedentary - 7 = running > 3hours/week). S-score muscle, T-score bone, fat mass (FM%), intra-muscular adipose tissue (IMAT), abdominal adipose tissue (AAT), intracellular water (ICW), extracellular water (ECW), total body water (TBW), were measured through multi-frequency bioelectrical impedance technology in the FP and in the HC. Correlation was made for FP between body composition and oxygen consumption at peak exercise (VO2 peak), VE/VCO2 slope and NYHA class as indicator of functional capacity. Results Thirty Fontan patients (FP, mean age 24±6 yrs, 70% males) and 30 matched healthy controls (HC) were recruited in the study. The systemic ventricle was dominant left in 14 patients (47%), dominant right in 16 (53%). Four patients had atrio-pulmonary connection, the remaining were palliated with a lateral tunnel (n=26, 87%). The analysed parameters are summarised in Table 1. PAR was reduced in FP compared to HC (median 4.0 points in FP versus 7.0 points in HC, p 0.024). There was no difference in the BMI, fat mass, and body water between FP and HC. However, FP showed significantly lower S and T scores compared to the HC (S-score: -0,75 in FP versus 0,0 in HC, p 0.003. T-score: -0.9 in FP versus -0.25 in HC, p 0.001). In FP, NYHA Class was I in 28 patients (93%), II in 1 (3,5%) and III in 1 (3.5%) patient. The mean VO2 was 23.4±5.4mlO2/kg/min and mean VE/VCO2 slope 32±7. There was a direct correlation between VO2 peak and the PAR (rho 0.443, p 0.044). No correlation was found between the VO2 peak, the VE/VCO2 slope or the NYHA Class and the analysed parameters of body composition. Conclusion FP have reduced muscle mass, and bone density compared to HC. In addition to the known reduced efficiency of the cardiac pump during exercise in FP, the lower level of conditioning contributes to the reduced exercise capacity in this population. Programs aiming to encourage physical activity are key and should be part of patients’ care.

Water deprivation induces a systemic pro-catabolic state that differentially affects oxidative and glycolytic skeletal muscles in male mice.

Dehydration, characterized by the loss of total body water and/or electrolytes due to diseases or inadequate fluid intake, is prevalent globally but often underestimated. Its contribution to long-term chronic diseases and sarcopenia is recognized, yet the mechanisms involved in systemic and muscle protein metabolism during dehydration remain unclear. This study investigated metabolic adaptations in a 36-hour water deprivation (WD) model of mice. Male C57BL/6 mice underwent 36-h WD or pair-feeding at rest, with assessments of motor skills along with biochemical, and metabolic parameters. Dehydration was confirmed by hypernatremia, body mass loss, hyporexia, and increased activity of vasopressinergic and oxytocinergic neurons compared to controls. These results were associated with liver mass loss, decreased glycaemia, and increased cholesterolemia. Additionally, increased VO2 and a decreased respiratory exchange ratio indicated reduced carbohydrate consumption and potentially increased protein use during dehydration. Thus, skeletal muscle protein metabolism was evaluated due to its high protein content. In the oxidative muscles of the WD group, total and proteasomal proteolysis increased, which was associated with decreased Akt-mediated intracellular signaling. Interestingly, there was an increase in fiber cross-sectional area, likely due to higher muscle water content caused by increased intracellular osmolality induced by protein catabolism products. Conversely, no changes were observed in protein turnover or water content in glycolytic muscles. These findings suggest that short-term WD imposes a pro-catabolic state, depleting protein content in skeletal muscle. However, skeletal muscle may respond differently to dehydration based on its phenotype and might adapt for a limited time.

An Elevated FIB-4 Score is associated with the severity of heart failure

Abstract Background Liver disease and heart failure (HF) are known to be closely associated. Non-invasive tests (NIT), such as the FIB-4 score, have been recommended by different guidelines to rule out advanced liver fibrosis and to stratify the risk of liver-related outcomes in patients with chronic liver diseases. Purpose Thus, our goal was to evaluate the connection between the FIB-4 index, heart failure, associated comorbidities, and cardiological biomarkers that predict the risk of liver fibrosis in patients with heart failure. Methods HF patients hospitalized in the cardiology department were divided into a group with an FIB-4 index <1.3 (indicating a low risk of liver fibrosis) (n=53) and a group with an FIB-4 index ≥1.3 (indicating intermediate and high risk of fibrosis) (n=59). Clinical examinations, laboratory results, echocardiography with Vivid E95-GE Healthcare, non-invasive body mass analysis with Body Composition Analyzer (Tanita Pro), and measurements of NT-proBNP, growth differentiation factor 15 (GDF-15), galectin-3, fatty acid-binding protein (FABP), copeptin, and vascular endothelial growth factor (VEGF) concentrations were performed. Results The patients with an FIB-4 index ≥1.3 had significantly higher: left ventricular volume index (LAVI) (p=0.004), E/E’ ratio (p=0.004) and lower left ventricular ejection fraction (p=0.003) compared to group with low risk of liver fibrosis. There were no differences in body mass compartments between groups except for ECW/TBW (%) - an index of body water distribution, which was lower in low-risk liver fibrosis group (p=0.0002). Patients with an FIB-4 index ≥1.3 had also lower: GFR MDRD (median 59.95 vs 85.1 mL/min/1.73 m²; p<0.001), total cholesterol (116.5 vs 15 mg/dL; p=0.002), LDL cholesterol (median 56 vs 93 mg/dL; p<0.0001) and HDL cholesterol (median 39 vs 47 mg/dL; p=0.03). Regarding heart failure biochemical biomarkers, patients with low risk of liver fibrosis had significantly lower level of NT-proBNP (median 37 vs 161 pg/ml; p<0.0001), GDF-15 (median 399.6 vs 898.9 pg/ml; p<0.0001) and FABP (median 101 vs 264,7 pg/ml; p=0.04). In a multiple logistic regression model the factors that were independently associated with the risk of liver fibrosis in HF patients based on an FIB-4 index were GDF-15 >724 pg/ml (OR 33.7, 95%CI: 6.5-174.2; p=0.0001), and NT-proBNP >129 pg/ml (OR 19.9, 95% CI: 3.8-103; p=0.0001) (Figure 1) Conclusion Our study suggests association between an elevated FIB-4 score and heart functions, and kidney impairment with fluid overload but not with higher total and low density cholesterols fractions or percentage of fat. Higher GDF-15 and NT-proBNP levels are independently associated with the risk of liver fibrosis based on an FIB-4 index. FIB-4 index in HF patients is an easy method to monitor the risk of liver fibrosis and might help to predict the HF progression and CVD complications.

Change of total body water dependent on age and nutritional status

Change of total body water dependent on age and nutritional status

Selected somatic parameters and body composition as predictors of cardiorespiratory fitness among Polish adolescents aged 11–14

The aim of the study was to verify whether selected somatic parameters and components of body composition were significant predictors of cardiorespiratory fitness (CRF) among a potentially healthy Polish population of adolescents aged 11–14 years. The cross-sectional study was conducted on a group of 375 subjects (164 girls, and 211 boys). A 20 m shuttle run test (20 m SRT) was used to assess CRF. The total number of rounds was taken into account. Basic somatic parameters were measured: body mass (BM), body height (BH), waist circumference (WC), hip circumference (HC), body mass index (BMI), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR), and body composition components: body fat percentage (FM%), fat mass (FM kg), total body water (TBW), fat-free mass (FFM). Statistical analyses included basic statistical measures (mean and standard deviation) and Spearman rank correlation coefficient. Multiple linear regression analysis was performed to detect significant predictors of CRF. In each proposed model, the dependent variable was the number of rounds, and the independent variables were selected somatic parameters and components of body composition. More than half (65%) of the subjects had an average or lower level of CRF, and 35% of the population presented a good or above good level of CRF. The study showed a statistically significant negative correlation between BM, FM%, FM kg, HC, WC, BMI, WHR, WHtR and the number of laps in the total sample. The strongest correlation in the group of girls was noted for age (r = 0.34) and in the group of boys for FM% (r = -0.52\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$-0.52$$\\end{document}). Each regression model presented proved to be statistically significant, and the significant predictors of CRF in the group of girls were age (R2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$R^2$$\\end{document} = 16%) and FM% (R2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$R^2$$\\end{document} = 6%). In the group of boys, the significant predictors of CRF were WHtR (R2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$R^2$$\\end{document} = 8%) and age (R2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$R^2$$\\end{document} = 2%). Estimating body fat distribution is useful in assessing cardiorespiratory fitness, and this in turn indicates its usefulness in preventive screening of school-aged adolescents.

Impedance Spectroscopy Measures of Whole and Segmental Skeletal Muscle Quantity Associated With Strength and Power in Collegiate Ice Hockey Players.

Otremba, JR, Heesch, AJ, Morgan, RM, Poolman, MA, Schindler, GD, and Fitzgerald, JS. Bioelectrical impedance spectroscopy measures of whole and segmental skeletal muscle quantity associated with strength and power in collegiate ice hockey players. J Strength Cond Res XX(X): 000-000, 2024-Bioelectrical impedance spectroscopy (BIS) is a promising monitoring tool for body water compartment assessment, particularly intracellular water (ICW), in which acute decreases are associated with increased muscle damage and reduced function, and chronic changes are associated with muscle quantity. Because little is known about the predictive utility of BIS-derived measures in athletes, this study aimed to assess the association between whole-body and segmental compartment water measured by BIS and maximal-intensity exercise performance in athletes. Twenty-five National Collegiate Athletic Association Division I collegiate hockey players completed 2 consecutive testing sessions. Body water and composition were assessed using a SOZO BIS device. Strength and explosive strength were measured on a force platform during the isometric belt squat and squat jump, respectively. Peak power was assessed using the 6-Second Test on a Wattbike. Pearson's r and partial correlation were used to assess relationships. Select body water and composition BIS variables were strong correlates of strength ( r = 0.51-0.63, p < 0.05), moderate correlates of power ( r = 0.41-0.44, p < 0.05), and lacked association with explosive strength. Segmental leg variables tended to be the strongest correlates of strength and power. Body water and traditional lean mass variables expressed similar predictive utility. Intracellular water/extracellular water lacked associated with exercise performance in bivariate and adjusted models. We provide evidence of the criterion validity of whole-body (i.e., ICW, fat-free mass, skeletal muscle mass [SMM]) and segmental (i.e., leg ICW, leg SMM) BIS variables, related to the quantity of SMM, to predict body-size dependent maximal-intensity exercise performance. Practitioners can use this information to determine which variables to track for performance readiness monitoring.

Cuticular hydrocarbons promote desiccation resistance by preventing transpiration in D. melanogaster.

Desiccation is a fundamental challenge confronted by all terrestrial organisms, particularly insects. With a relatively small body size and large surface-to-volume ratio insects are susceptible to rapid evaporative water loss and dehydration. To counter these physical constraints, insects have acquired specialized adaptations, including a hydrophobic cuticle that acts as a physical barrier to transpiration. We previously reported that genetic ablation of the oenocytes - specialized cells required to produce cuticular hydrocarbons (HCs) - significantly reduced survivorship under desiccative conditions in the fruit fly, Drosophila melanogaster. Although increased transpiration - resulting from the loss of the oenocytes and HCs - was hypothesized to be responsible for the decrease in desiccation survival, this possibility was not directly tested. Here we investigate the underlying physiological mechanisms contributing to the reduced survival of oenocyte-less (oe-) flies. Using flow-through respirometry we show that oe- flies, regardless of sex, exhibited an increased rate of transpiration relative to wild-type controls, and that coating oe- flies with fly-derived HC extract restored the rate to near wild-type levels. Importantly, total body water stores, including metabolic water reserves, as well as dehydration tolerance, measured as the percent of total body water lost at time of death, were largely unchanged in oe- flies. Together, our results directly demonstrate the critically important role played by the oenocytes and cuticular HCs to promote desiccation resistance.

Sex differences in the adrenal circadian clock: A role for BMAL1 in the regulation of urinary aldosterone excretion and renal electrolyte balance in mice.

Brain and muscle ARNT-Like 1 (BMAL1) is a circadian clock transcription factor that regulates physiological functions. Male adrenal-specific Bmal1 (ASCre/+::Bmal1) KO mice displayed blunted serum corticosterone rhythms, altered blood pressure rhythm, and altered timing of eating, but there is a lack of knowledge in females. This study investigates the role of adrenal BMAL1 in renal electrolyte handling and urinary aldosterone levels in response to low salt in male and female mice. Mice were placed in metabolic cages to measure 12-hour urinary aldosterone after a standard diet and 7 days low salt diet, as well as daily body weight, 12-hour food and water intake, and renal sodium and potassium balance. Adrenal glands and kidneys were collected at ZT0 or ZT12 to measure expression of aldosterone synthesis genes and clock genes. Compared to littermate controls, ASCre/+::Bmal1 KO male and female mice displayed increased urinary aldosterone in response to a low salt diet, although mRNA expression of aldosterone synthesis genes was decreased. Timing of food intake was altered in ASCre/+::Bmal1 KO male and female mice, with a blunted night/day ratio. ASCre/+::Bmal1 KO female mice displayed decreases in renal sodium excretion in response to low salt, but both male and female KO mice had changes in sodium balance that were time-of-day-dependent. In addition, sex differences were found in adrenal and kidney clock gene expression. Notably, this study highlights sex differences in clock gene expression that could contribute to sex differences in physiological functions.

Relationship Between Mediterranean Diet Adherence and Body Composition Parameters in Older Adults from the Mediterranean Region

In recent decades, the rapid spread of various communication media has led to changes in traditional eating habits. In the Mediterranean region, the classic (Mediterranean) dietary pattern has been lost as a result. This has led to a shift in eating habits towards unhealthy eating patterns, which in turn has resulted in an inadequate distribution of body composition. It is known that, among other things, the number of non-communicable diseases increases with the inadequate distribution of body composition. The aim of our study was to examine the level of adherence to the Mediterranean diet (MD) of older adults in the Mediterranean region in relation to specific body composition parameters. This study included 521 older adults with a mean age of 69.6 ± 6.3 years. Body composition was measured using the BIA 101 Anniversary device (Akern s.r.l., Florence, Italy) and adherence to the MD was assessed using the MEDLIFE index questionnaire. This study found significant differences in body composition between males and females. The mean adherence to the MD was 17.0 ± 3.3 points among the participants and there was higher adherence in females (p = 0.002, ηp2 = 0.019). A multiple linear regression was performed to assess the relationship between the body composition parameters and MD. Multiple linear regression models were significant for reactance, fat mass (%), fat-free mass (%), skeletal muscle index, and total body water (%), with specific individual MEDLIFE items such as the consumption of processed meat, meat, white meat, fruit, vegetables, olive oil and limiting snacks between meals. Moreover, promising correlations were found between certain MD characteristics and BIA parameters, but the overall health effects of the MD remain unclear.

Habitual water intake impacted the body composition of young male athletes in free-living conditions: a cross-sectional study

The study aimed to explore the associations between water intake and body composition and differences of body composition in different water itake and hydration statuses among young male athletes. A cross-sectional study was conducted among 111 young male athletes in Beijing, China. Total drinking fluids (TDF) and water from food were assessed using a 7-day, 24-h fluid intake record questionnaire and the duplicate portion method, respectively. The osmolality of 24-hour urine and blood samples was tested. Body composition was measured using a bioelectrical impedance analyzer twice at 5-min intervals. Participants were divided into two groups based on the recommendations of total water intake (TWI) and TDF in China, as well as into three groups based on 24-h urine osmolality. Pearson's correlation coefficients were calculated to determine the relationship between water intake and body composition. Chi-square tests and Student's t-tests were used to compare differences. A total of 109 participants completed the study. TDF (r = 0.230, p = 0.016; r = 0.234, p = 0.014; r = 0.242, p = 0.011) and TWI (r = 0.275, p = 0.004; r = 0.243, p = 0.011; r = 0.243, p = 0.011) were positively correlated with total body water (TBW), intracellular water (ICW), and extracellular water (ECW). TBW/body weight (BW) was positively associated with TDF percentage of BW (TDF/BW) (r = 0.267, p = 0.005), water from food percentage of BW (r = 0.217, p = 0.024), and TWI percentage of BW (TWI/BW) (r = 0.316, p = 0.001). Participants who met the TDF recommendation of China had 1.3 kg higher skeletal muscle mass (SMM), 0.9 kg higher ICW, and 0.5% higher TBW/BW than those who did not (all p &amp;lt; 0.05), with fat-free mass (FFM) and TBW being higher (p = 0.051; p = 0.050). Those who met the TWI recommendation of China had 1.3 kg higher SMM, 2.4 kg higher FFM, 1.1 kg higher ICW, 0.6 kg higher ECW, and 1.7 kg higher TBW than their counterparts (all p &amp;lt; 0.05). Moderate associations were found between water intake and body composition. No significant differences were observed among participants in three hydration statuses (all p &amp;gt; 0.05). Participants who met the TWI or TDF recommendations had better body composition distribution than their counterparts. Thus, habitual water intake, not hydration status, affects body composition among athletes in free-living conditions.

Hypoxia reduces mouse urine output via HIF1α–mediated up–regulation of renal AQP1

Introduction: Patients with acute mountain sickness (AMS) due to hypoxia at high altitudes often exhibit abnormal water metabolism. Hypoxia-inducible factors (HIFs) are major regulators of adaptive responses to hypoxia. As transcription factors, HIFs are involved in the regulation of erythropoiesis, iron metabolism, angiogenesis, energy metabolism, and cell survival by promoting the transcriptional expression of hundreds of target genes. Roxadustat, a novel drug for the treatment of anemia associated with chronic kidney disease, acts by inhibiting the degradation of HIFs to increase their protein levels. However, the clinical use of roxadustat is frequently associated with peripheral edema, suggesting the involvement of HIFs in regulating the body's water balance possibly by modulating water reabsorption in the kidney. Methods: we first evaluated the effect of hypoxia (8% O2) on mouse urine output. We then performed in vitro experiments using hypoxia (1% O2) and roxadustat on mouse primary proximal tubular cells (mPTCs). The qPCR, western blot, and immunofluorescence were used to assess AQP1 mRNA and protein expression levels. Luciferase, CHIP, and EMSA were used to investigate the transcriptional regulation of AQP1 by HIF1α. Results: We found that mice exposed to hypoxia (8% O2) had significantly reduced urine volume compared to mice exposed to normoxia (21% O2). Hypoxia significantly elevated AQP1 expression at both mRNA and protein levels. In vitro experiments using mouse primary cultured proximal tubular cells (mPTCs) revealed that both hypoxia and roxadustat increased AQP1 expression. Mechanistically, overexpression of HIF1α, but not HIF2α, markedly increased AQP1 protein expression. Furthermore, the up-regulation of AQP1 by hypoxia and roxadustat can be blocked by the HIF1α inhibitor PX-478 in mPTCs. Finally, we found that the AQP1 gene promoter contains a putative hypoxia response element (HRE) and confirmed that AQP1 is a target gene of HIF1α using Luciferase reporter, CHIP, and EMSA assays. Conclusion: This study demonstrates that hypoxia can reduce the urine volume of mice via upregulating AQP1 expression by HIF1α in the proximal tubular epithelial cells. Our findings also suggest a potential mechanism involved in water metabolism disorders in patients with AMS and in patients with chronic kidney disease (CKD) receiving roxadustat treatment.

A systematic review of lithium biology and pharmacology and toxicological evaluation of new organic lithium salts

Objective: to systematize scientific data on biomedical studies investigating trace element lithium over the past 70 years; evaluate toxic properties of lithium ascorbate (LiAsc) as an important promising candidate molecule.Material and methods. An analysis of 49,959 publications on lithium biomedical research retrieved from PubMed/MEDLINE database was carried out using modern data mining methods developed within the framework of topological approach to recognizing (Yu.I. Zhuravlev scientific school). Publications found by experts and not indexed in PubMed/MEDLINE were used in discussing the results of a systematic analysis of publications array retrieved from PubMed/MEDLINE. An experimental study of chronic 180 day-long LiAsc (at doses of 5, 50 and 150 mg/kg) toxicity was performed on 36 “Soviet chinchilla” rabbits by assessing local irritant action. Intoxication clinical picture, body weight dynamics, water and food intake as well as physiological, hematological and biochemical parameters were analyzed.Results. Classification and systematization of all currently available publications on lithium biology and medicine were performed. It was shown that pharmacological applications of lithium salts in mental disorders as well as lithium effects on simple sugars metabolism, lipid metabolism, blood pressure regulation, hematopoiesis, inflammation and tumor growth inhibition, neurotransmitter homeostasis, neurotrophic and neuroprotective molecular mechanisms as well as homeostasis of other electrolytes comprised promising fields of lithium drug research. The prospects for using organic lithium salts, particularly LiAsc, for various therapeutic goals were also discussed. 180-day-long oral administration of LiAsc at doses of 5, 50, 150 mg/kg resulted in no macroscopic signs of local inflammatory reaction while examining its local irritant effect.Conclusion. The lithium-ion effect on neurotransmitters promotes neuroprotection and reduces a risk of addiction. The antihypertensive, antiatherosclerotic, antidiabetic, antitumor and neurotrophic effects related to organic lithium salts may be beneficial in various therapeutic applications.

Exploring the Potential Antidiabetic Effects of Alkannin (A Naphthoquinone Compound): In Vivo and In Silico Studies

Background It is estimated that the plant has been utilized in India’s traditional medical system for close to 2,500 years. Alkanin is a key active component in Boraginaceae medicinal plant roots. Many scientists are interested in this tiny molecule due to its biological potential. Purpose To examine the hypoglycemic effects of alkannin (a naphthoquinone pigment). Methods Initially, we determined the dosage of alkannin by conducting an acute oral toxicity study per Organisation for Economic Co-operation and Development guidelines. Subsequently, streptozocin was used to induce diabetes in mice, and we chose several parameters such as body weight, food and water intake, blood glucose level, and biochemical estimation for the in vivo evaluation. The enhanced pharmacokinetic features of alkannin, such as its better cytochromes P450 metabolism profiles and higher intestinal absorption as compared to glimepiride, were validated by in silico investigations utilizing Swiss ADME (Absorption, Distribution, Metabolism, and Excretion) and AutoDock Vina. Results In particular, blood glucose levels and body weight in the alkannin-treated group drastically decreased to 138 ± 1.45 mg/dL and 27.9±0.54 g, respectively, as compared with the diabetic-treated group. Moreover, alkaline phosphatase levels dropped to 57.26 ± 3.05 U/L in the alkannin group, suggesting enhanced liver and kidney functions. Creatinine levels also decreased from 1.44 ± 0.10 mg/dL to 0.92 ± 0.09 mg/dL, and serum glutamic oxaloacetic transaminase/aspartate aminotransferase levels decreased from 64.16 ± 3.14 U/L to 47.85 ± 2.01 U/L. Additionally, diabetic controls maintained cholesterol levels between 102.1 ± 11.46 mg/dL and 93.53 ± 2.61 mg/dL. With a considerable binding score of –9.2 kcal/mol for alkannin, molecular docking demonstrated a high degree of binding efficiency and robust interaction with biological targets. The docking results revealed that alkannin exhibits drug-like properties. In addition, it satisfies the lead likeness requirement and has a lower synthetic accessibility score compared to glimepiride. Conclusion The results revealed the promising characteristics and positive outcomes of alkannin, underscoring its potential as a viable candidate for further investigation and prospective advancement as a treatment drug for diabetes.

Combretum micranthum G. Don (Combretaceae): Its physiological effects on hydro-electrolyte metabolism, renal tubular function and blood pressure

BackgroundHydro-electrolyte balance is necessary to maintain body homeostasis and blood pressure values within narrow limits. This is accomplished, in part, by renal responses. We conducted this study to determine the effects of Combretum micranthum on hydro-electrolyte metabolism, renal function and arterial blood pressure. Subjects and methodsWe conducted a pilot study including 40 subjects: 10 control subjects, 10 subjects under Combretum micranthum G. Don (400 mg/day), 10 subjects under furosemide (120 mg/day), and 10 subjects under spironolactone (50 mg/day).Anthropobiometric, cardiovascular parameters and the body composition were collected from each subject. Blood and 24-hour urine samples were collected for biological tests. ResultsAt baseline, clinical and biological parameters were comparable for all groups. Consumers of combretum micranthum had a significant decrease in global body fat percentage (−1.63 %; p = 0.045). In the group of combretum micranthum consumers, the body water mass (BWM) is significantly evolved in the direction of an increase (4.37; p = 0.023) and similar to what was observed in the group of subjects treated with spironolactone (0.67; p = 0.042). Consumption of combretum micranthum showed a marked reduction in hypertension indices (systolic blood pressure, diastolic blood pressure and heart rate) identical to that induced by consumption of furosemide or spironolactone. The consumption of combretum micranthum resulted in a significant reduction in kaliemia (−1.07; p < 0.0001) and without any notable effect on natremia (p = 0.119) and chloremia (p = 0.708). In contrast, furosemide and spironolactone caused a significant decrease in natremia (respectivly, −0.80; p = 0.022 and −0.50; p = 0.009). In the combretum micrathum group, the kaliuresis and the chloruresis were significantly increased (respectively, 373.9; p = 0.005 and 441.3; p = 0.028), interestingly, we found a remarkable decrease in natriuresis (−193.3; p = 0.074). In the group of furosemide consumers, the kaliuresis and the chloruresis were significantly increased (respectively, 380.24; p = 0.013 and 425.5; p = 0.013), but with a tendency to increase natriuresis. In the group of subjects taking spironolactone, the urinary concentrations of the three electrolytes studied (natriuresis, kaliuresis and chloruresis) was increased significantly (respectively, 357.5; p = 0.037 and 222.5; p = 0.005 and 563.4; p = 0.007). ConclusionCombretum micranthum would have constituents involved in the maintenance of hydro-electrolyte homeostasis and in the regulation of blood pressure through the involvement of several mechanisms, especially at the renal level. These actions would be attributable to its polyphenolic components. A broader study is needed to better understand the physiological mechanisms underlying these effects.

Effects of Chitosan and N-Succinyl Chitosan on Metabolic Disorders Caused by Oral Administration of Olanzapine in Mice.

The issue of human mental health is gaining more and more attention nowadays. However, most mental disorders are treated with antipsychotic drugs that cause weight gain and metabolic disorders, which include olanzapine (OLZ). The search for and development of natural compounds for the prevention of obesity when taking antipsychotic drugs is an urgent task. The biopolymer chitosan (Chi) and its derivatives have lipid-lowering and anti-diabetic properties, which makes them potential therapeutic substances for use in the treatment of metabolic disorders. The purpose of this work was to analyze the effect of the natural biopolymer Chi, its derivative N-succinyl chitosan (SuChi), and Orlistat (ORL) as a control on the effects caused by the intake of OLZ in a mouse model. Mice were fed with pearl barley porridge mixed with OLZ or combinations OLZ + Chi, OLZ + SuChi, or OLZ + ORL for 2 months. The weight, lipid profile, blood chemokines, expression of genes associated with appetite regulation, and behavior of the mice were analyzed in dynamics. For the first time, data were obtained on the effects of Chi and SuChi on metabolic changes during the co-administration of antipsychotics. Oral OLZ increased body weight, food and water intake, and glucose, triglyceride, and cholesterol levels in blood. ORL and SuChi better normalized lipid metabolism than Chi, decreasing triglyceride and cholesterol levels. OLZ decreased the production of all chemokines tested at the 4th week of treatment and increased CXCL1, CXCL13, and CCL22 chemokine levels at the 7th week. All of the supplements corrected the level of CXCL1, CXCL13, and CCL22 chemokines but did not recover suppressed chemokines. SuChi and ORL stimulated the expression of satiety associated proopiomelanocortin (POMC) and suppressed the appetite-stimulating Agouti-related protein (AgRP) genes. All supplements improved the locomotion of mice. Taken collectively, we found that SuChi more than Chi possessed an activity close to that of ORL, preventing metabolic disorders in mice fed with OLZ. As OLZ carries positive charge and SuChi is negatively charged, we hypothesized that SuChi's protective effect can be explained by electrostatic interaction between OLZ byproducts and SuChi in the gastrointestinal tract.

Ameliorative Effects of Phyto-estrogen ‘Genistein’, Homeopathic Combination ‘R-85’and Captopril on Body Weight, Organ Weight, Feed and Water Intake in L-NAME Induced Hypertensive Wistar Rats

Hypertension is associated with the development and progression of severe damage to organs. Meager studied has been found on the effect of Phyto-estrogen ‘genistein’ and homeopathic combination ‘R-85’ as antihypertensive action which may aid in main therapy of hypertension. Thus, present study aims to evaluate the effect of ‘genistein’, ‘R-85’ and ‘captopril’ on body weight, organ weight feed and water intake in Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) induced hypertensive male wistar rats. After acclimatization, the male wistar rats were divided into 5 groups of 5 rats in each group. The rats except control group (group-I) were treated with L-NAME (@50mg/kg, in drinking water, group-II), L-NAME + Genistein (@50mg/kg, per os, group-III), L-NAME + R-85 (@ 5 drops, twice daily, group-IV) and L-NAME + Captopril (@50 mg/kg, per os, group-V) daily for 42 days. The study was conducted for a period of 42 days. During the experimental period, weight of rats, feed intake and water intake was measured weekly. At the end of the experimental period, rats were sacrificed andheart, kidneys and liver were weighed. After treatment with genistein, R-85 and captopril an increase in body weight was found as compared to L-NAME group. On similar treatment there was an increase in feed intake per 100 g of rat was found compared to L-NAME hypertensive group per week. Unlike feed intake, treatments decrease the water intake per 100 g of rat compared to L-NAME group per week. A significant increase in the relative weights of the liver and kidney was found in L-NAME group compared to control. Whereas, treatment with R-85 and captopril significantly decreased the relative weight of liver and kidney as compared to L-NAME group. Thus finding of the present study discloses ameliorative effect of genistein, R-85 and captopril on hypertensive rats.

Evaluation of the chronic oral toxicity of the classical ancient prescription Kai-Xin-San

Ethnopharmacological relevanceThe Kai-Xin-San (KXS), as an ancient classic prescription, has been used for the treatment of amnesia for thousands of years. Modern clinical and non-clinical pharmacological studies have found that it has significant therapeutic effects on dementia and depression, but there are relatively few studies on its safety. Aim of the studySubacute and chronic toxicity studies were conducted to investigate the symptoms, severity, target organs, development and recovery of toxic reactions, as well as the toxic dose. These studies provide technical data for ensuring the safety of KXS. Materials and methodsIn the sub-acute toxicity study, rats were orally administered KXS at doses of 0.80, 1.61, 3.22, and 6.43 g/kg body weight for a duration of 4 weeks. In the chronic toxicity study, rats were orally administered KXS at doses of 0.27, 0.81, and 2.43 g/kg body weight for a duration of 26 weeks, and a withdrawal study was conducted for a period of 4 weeks after the treatment.The rats were observed daily for clinical signs and mortality. Changes in body weight, food consumption, and water consumption were periodically monitored. Additionally, urinalysis results, hematological and biochemical parameters, relative organ weights, and pathology were monitored at specific observation time points. ResultsIn the sub-acute toxicity study, necropsy of dead and moribund rats revealed evident distension and swelling of the gastrointestinal tract, as well as thinning of the intestinal wall. The main adverse reactions observed included flatulence, piloerection, abnormal breathing sounds, and emaciation. Doses of 1.61 g/kg and below did not cause animal death. The gastrointestinal system is the main target organ of toxicity. In the chronic toxicity study, the no-observed-adverse-effect-level (NOAEL) of KXS was 0.27 g/kg, and its toxic effects were primarily concentrated in the gastrointestinal system. This led to secondary pathological changes in the immune system, hematopoietic system, and heart, suggesting that relevant indicators should be monitored when large doses are used clinically for an extended period of time. ConclusionsDuring the rodent toxicity evaluation, severe gastrointestinal damage was observed when KXS, powdered with crude drugs, was administered. The NOAEL for rats was found to be 0.27 g/kg/day.

SGLT2i and GLP1-RA exert additive cardiorenal protection with a RAS blocker in uninephrectomized db/db mice.

Diabetic Kidney Disease (DKD) is the main cause of end-stage renal disease in the developed world. The current treatment of the DKD with renin-angiotensin system (RAS) blockade does not totally halt the progression to end stage kidney disease. Currently, several drugs have shown to delay DKD progression such as sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like-1 receptor agonists (GLP-1RA). We hypothesized that by combining several drugs that prevent DKD progression on top of RAS blockade a synergistic effect would be achieved in terms of cardiorenal protection. In the present study, we analysed if the combination of a RAS blocker (ramipril) with a SGLT2i (empagliflozin) and/or GLP-1RA (semaglutide) in a type 2 diabetic mouse model could have add-on effects in kidney and heart protection. Male and female uninephrectomized type 2 diabetic db/db mice were treated with empagliflozin and/or semaglutide on top of ramipril during 8weeks. During the study body weight, water and food intake were weekly monitored, glycaemia biweekly and albuminuria and glomerular filtration rate (GFR) before and after the treatment. At the end of the experiment, kidney and heart were isolated for histological and gene expression studies as well as for intrarenal RAS state assessment. Semaglutide combined with ramipril and/or empagliflozin significantly decreased albuminuria but only when combined with both compounds, semaglutide further decreased blood glucose, glomerular hyperfiltration in male mice and glomerular mesangial matrix expansion. In kidney, only the triple treatment with empagliflozin, semaglutide and ramipril reduced the expression of the proinflammatory and profibrotic genes ccl2 and TGFß1. In addition, the combination of empagliflozin and semaglutide on top of RAS blockade was superior in decreasing cardiomyocyte hypertrophy and heart fibrosis in db/db mice. Our results suggest that the combination of SGLT2i with GLP-1RA is superior in cardiorenal protection in DKD than the drugs administered alone on top of RAS blockade.

Disruption of mitochondrial electron transport impairs urinary concentration via AMPK-dependent suppression of aquaporin-2.

Urinary concentration is an energy-dependent process that minimizes body water loss by increasing aquaporin-2 (AQP2) expression in collecting duct (CD) principal cells. To investigate the role of mitochondrial (mt) ATP production in renal water clearance, we disrupted mt electron transport in CD cells by targeting ubiquinone (Q) binding protein QPC (UQCRQ), a subunit of mt complex III essential for oxidative phosphorylation. QPC-deficient mice produced less concentrated urine than controls, both at baseline and after type 2 vasopressin receptor stimulation with desmopressin. Impaired urinary concentration in QPC-deficient mice was associated with reduced total AQP2 protein levels in CD tubules, while AQP2 phosphorylation and membrane trafficking remained unaffected. In cultured inner medullary CD cells treated with mt complex III inhibitor antimycin A, the reduction in AQP2 abundance was associated with activation of 5' adenosine monophosphate-activated protein kinase (AMPK) and was reversed by treatment with AMPK inhibitor SBI-0206965. In summary, our studies demonstrated that the physiological regulation of AQP2 abundance in principal CD cells was dependent on mt electron transport. Furthermore, our data suggested that oxidative phosphorylation in CD cells was dispensable for maintaining water homeostasis under baseline conditions, but necessary for maximal stimulation of AQP2 expression and urinary concentration.