Current research in physiology最新文献

Sodium-glucose co-transporter type 2 (SGLT2) inhibitor therapy to treat type 2 diabetes unexpectedly reduced all-cause mortality and hospitalization due to heart failure in several large-scale clinical trials, and has since been shown to produce similar cardiovascular disease-protective effects in patients without diabetes. How SGLT2 inhibitor therapy improves cardiovascular disease outcomes remains incompletely understood. Metabolic flexibility refers to the ability of a cell or organ to adjust its use of metabolic substrates, such as glucose or fatty acids, in response to physiological or pathophysiological conditions, and is a feature of a healthy heart that may be lost during diabetic cardiomyopathy and in the failing heart. We therefore undertook studies to determine the effects of SGLT2 inhibitor therapy on cardiac metabolic flexibility in vivo in obese, insulin resistant mice using a [U¹³C]-glucose infusion during fasting and hyperinsulinemic euglycemic clamp. Relative rates of cardiac glucose versus fatty acid use during fasting were unaffected by EMPA, whereas insulin-stimulated rates of glucose use were significantly increased by EMPA, alongside significant improvements in cardiac insulin signaling. These metabolic effects of EMPA were associated with reduced cardiac hypertrophy and protection from ischemia. These observations suggest that the cardiovascular disease-protective effects of SGLT2 inhibitors may in part be explained by beneficial effects on cardiac metabolic substrate selection.

External stressors such as alcohol, caffeine, and vigorous exercise are known to alter cellular homeostasis, affecting the autonomic nervous system (ANS) and overall physiological function. However, little direct evidence exists quantifying the impact of these external stressors on physiological testing. We assessed the impact of the above-listed stressors on spontaneous baroreflex sensitivity (BRS), heart rate variability (HRV), heart rate asymmetry (HRA), and systolic blood pressure variability (BPV). Seventeen male university varsity American-style football athletes completed two identical assessments on separate days, once presenting with one or more stressors (recent intake of caffeine, alcohol, or exercise participation; contraindicated assessment) and another with no stressors present (repeat assessment). Both assessments were conducted within one week and at the same time of day. The testing protocol consisted of 5-min of rest followed by 5-min of a squat-stand maneuver (0.05 Hz). Continuous beat-to-beat blood pressure and electrocardiogram measurements were collected and allowed for calculations of BRS, HRV, HRA, and BPV. Significant decreases (p < 0.05) in HRV and HRA metrics (SDNN, SD2, SDNNd, SDNNa, SD2a, SD2d), HRV total power, and BRS-up sequence were found during the contraindicated assessment in comparison to the repeat assessment. When assessing those with exercise as their only stressor, high-frequency HRV and BRS-pooled were significantly decreased and increased, respectively, during the contraindicated assessment. Pre-season physiological baseline testing in sport is becoming increasingly prevalent and thus must consider external stressors to ascertain accurate and reliable data. This data confirms the need for stringent and standardized guidelines for pre-participation baseline physiological testing.

As the number of people travelling to altitude increases, the risk of life threatening medical emergencies also increases. It is important that we have effective strategies to minimize the risk of altitude illness. In this study, an attempt was made to investigate the combined effect of non-pharmacological (Intermittent hypoxia training; IHT) and pharmacological (acetazolamide; ACZ) intervention as a prophylactic strategy in order to minimize the risk of high altitude hypoxic related problems using rats as an animal model. Male Sprague Dawley rats were subjected to IHT for 4 h consecutively for 5 days at 12% FiO₂ under normobaric conditions with and without oral ACZ administration at 25 mg/kg body weight. Validation of the intervention was performed by exposing the rats to extreme hypoxia (EH) at 8% FiO₂ to further assess the effect of IHT and ACZ on hypoxic acclimatization. The principal findings of this study is that the combined effect of IHT and ACZ improves the arterial oxygenation by alterations in hemodynamics and in blood gasometry, thereby resulting into an increase in the oxygen carrying capacity of the blood with increase in SpO₂ (peripheral oxygen saturation). The present study showed that the combined effect of IHT with ACZ could be refined as a prophylactic measure for better outcomes during altitude ascent and rapid altitude acclimatization rather than IHT or ACZ alone.

Network pharmacology is an emerging field which is currently capturing interest in drug discovery and development. Chronic kidney conditions have become a threat globally due to its associated lifelong therapies. Nephrotic syndrome (NS) is a common glomerular disease that is seen in paediatric and adult population with characteristic manifestation of proteinuria, oedema, hypoalbuminemia, and hyperlipidemia. It involves podocyte damage with tubulointerstitial fibrosis and glomerulosclerosis. Till date there has been no specific treatment available for this condition that provides complete remission. Repurposing of drugs can thus be a potential strategy for the treatment of NS. Recently, epigenetic mechanisms were identified that promote progression of many renal diseases. Therefore, in the present study, we investigated two epigenetic drugs valproic acid (VPA) and all-trans retinoic acid (ATRA). Epigenetic drugs act by binging about changes in gene expression without altering the DNA sequence. The changes include DNA methylation or histone modifications. The targets for the two drugs ATRA and VPA were collated from ChEMBL and Binding DB. All the genes associated with NS were collected from DisGeNET and KEGG database. Interacting proteins for the target genes were acquired from STRING database. The genes were then subjected to gene ontology and pathway enrichment analysis using a functional enrichment software tool. A drug-target and drug-potential target-protein interaction network was constructed using the Cytoscape software. Our results revealed that the two drugs VPA and ATRA had 65 common targets that contributed to kidney diseases. Out of which, 25 targets were specifically NS associated. Further, our work exhibited that ATRA and VPA were synergistically involved in pathways of inflammation, renal fibrosis, glomerulosclerosis and possibly mitochondrial biogenesis and endoplasmic reticulum stress. We thus propose a synergistic potential of the two drugs for treating chronic kidney diseases, specifically NS. The outcomes will undoubtedly invigorate further preclinical and clinical explorative studies. We identify network pharmacology as an initial inherent approach in identifying drug candidates for repurposing and synergism.

Studies of animals native to high altitude can provide valuable insight into physiological mechanisms and evolution of performance in challenging environments. We investigated how mechanisms controlling cardiovascular function may have evolved in deer mice (Peromyscus maniculatus) native to high altitude. High-altitude deer mice and low-altitude white-footed mice (P. leucopus) were bred in captivity at sea level, and first-generation lab progeny were raised to adulthood and acclimated to normoxia or hypoxia. We then used pharmacological agents to examine the capacity for adrenergic receptor stimulation to modulate heart rate (f_H) and mean arterial pressure (P_mean) in anaesthetized mice, and used cardiac pressure-volume catheters to evaluate the contractility of the left ventricle. We found that highlanders had a consistently greater capacity to increase f_H via pharmacological stimulation of β₁-adrenergic receptors than lowlanders. Also, whereas hypoxia acclimation reduced the capacity for increasing P_mean in response to α-adrenergic stimulation in lowlanders, highlanders exhibited no plasticity in this capacity. These differences in highlanders may help augment cardiac output during locomotion or cold stress, and may preserve their capacity for α-mediated vasoconstriction to more effectively redistribute blood flow to active tissues. Highlanders did not exhibit any differences in some measures of cardiac contractility (maximum pressure derivative, dP/dt_max, or end-systolic elastance, E_es), but ejection fraction was highest in highlanders after hypoxia acclimation. Overall, our results suggest that evolved changes in sensitivity to adrenergic stimulation of cardiovascular function may help deer mice cope with the cold and hypoxic conditions at high altitude.

Background

Efficient reproductive function is an important characteristic that has evolved through natural selection. Nutrition can modulate reproductive activities at different levels, and its effect on reproduction is deemed complex and less predictable.

Objective

This study aims at investigating the underlying effect of persistent dietary protein deficiency during early life on reproductive parameters of subsequent (F₁ and F₂) generations.

Method

Rats in group of four (4) were fed daily, different ration of protein diet (PD) formulated as: 21% protein diet, 10%protein diet, 5%protein diet and control diet (rat chow, containing 16–18% protein). They were fed ad libitum before mating, throughout gestation and lactation, and next generations were weaned to the maternal diet. Reproductive function analysis (which include; gestation and pubertal hormonal profiling, onset of puberty, oestrus cyclicity, sexual response) and morphometric analysis of the ovarian structure were carried out to assess associated consequences.

Results

There was significant reduction in the fertility index (Control; 85.8%., 21%PD; 88.43%., as compared to 10%PD; 65.9%., 5%PD; 35.78%.,) at F_1, also recurring in F₂ respectively as a consequence of altered reproductive function in the protein deficient models at P ≤ 0.05. Low protein diet posed suboptimal intrauterine condition, which was linked to increased prenatal morbidity and mortality (control; 11.3%., 21%PD; 3.3%., 10%PD; 27.4%., 5%PD; 32.9%), low birthweight (control; 5.29, 4.9 g., 21%PD; 5.5, 5.06 g., 10%PD; 4.05, 3.86 g., 5%PD; 2.7, 2.5 g) at F₁ and F₂ respectively, delayed onset of puberty (with average pubertal age set at: control; PND 36, 21%PD; PND 38 while 10%PD; PND 62., and 5%PD; PND 67), followed by induced cycle irregularity, altered follicular maturation and endocrine dysfunction, more severe in 5%PD.

Conclusion

Reproductive status of a female organism depends on the maintenance of ovarian structure and function that has been associated with the hypothalamic pituitary-gonadal axis, hormonal events and sexual maturity. There is therefore an association between persistent early life protein deficiency and reproductive response which mechanistically involves life-long changes in key ovarian cytoarchitecture and function.

Purpose

This study aimed to investigate the long-term effects of multiple concussions on prefrontal cortex oxygenation during a neurovascular coupling activating task using near infrared spectroscopy (NIRS).

Methods

Self-reported physically active males who previously participated in contact team sports at various levels of competition and who previously had experienced at least 3 concussions (n = 55; mTBI) or had no history of concussions (n = 29; CTRL) were recruited. Participants completed a 5 min “Where's Waldo” object identification protocol which consisted of participants closing their eyes for 20-s followed by 40-s (repeated 5 times over 5-min) of searching a computer screen for “Waldo” hidden in a field of distractors. NIRS (μM) was used to measure right and left prefrontal cortex cerebral oxygenation. Oxygenated (O₂Hb), deoxygenated (HHb), total (tHb) haemoglobin, and haemoglobin difference (HbDiff) were analysed through the change in average maximal and minimal values (ΔMAX), Z-scores, and standard deviations.

Results

There were no significant differences in the relative change in cerebral oxygenation of the right prefrontal cortex between groups. In mTBI, left prefrontal cortex HHb ΔMAX (p = 0.031) and tHb ΔMAX (p = 0.044) were significantly lower than in the CTRL group. Within-group, right vs. left prefrontal cortex differences showed significantly lower values in left HbDiff Z-scores (p = 0.019) in only the mTBI group while the CTRL group showed significantly lower values in left HbDiff SD (p = 0.045).

Conclusion

This preliminary study suggests that there are changes in prefrontal cortex oxygenation in males who had a history of experiencing multiple concussions in their past during a neurovascular coupling activating task. These changes may represent potential long-term effects in the brain's ability to adapt cerebral oxygenation during increased neural activity.

Researchers from different fields have studied the causes of obesity and associated comorbidities, proposing ways to prevent and treat this condition by using a common animal model of obesity to create a profound energy imbalance in young adult rodents. However, to confirm the harmful effects of consuming a high-fat and hypercaloric diet, it is common to include normolipidic and normocaloric control groups in the experimental protocols. This study compared the effect of three experimental diets described in the literature – namely, a high-fat diet, a high-fat and high-sucrose diet, and a high-fat and high-fructose diet – to induce obesity in C57BL/6 J mice with the standard AIN-93G diet as a control. We hypothesize that the AIN diet formulation is not a good control in this type of experiment because this diet promotes weight gain and metabolic dysfunctions similar to the hypercaloric diet. The metabolic data of animals fed the AIN-93G diet were similar to those of the high-calorie groups (development of steatosis and hyperlipidemia). However, it is important to emphasize that the group fed a high-fat diet had a higher percentage of total fat (p = 0.0002) and abdominal fat (p = 0.013) compared to the other groups. Also, the high-fat group responded poorly to glucose and insulin tolerance tests, showing a picture of insulin resistance. As expected, the intake of the AIN-93G diet promotes metabolic alterations in the animals like the high-fat formulations. Therefore, although this diet continues to be used as the gold standard for growth and maintenance, it warrants a reassessment of its composition to minimize the metabolic changes observed in this study, thus updating its fitness as a normocaloric model of a standard rodent diet.

The passive mechanical properties of the vertebrate heart are controlled in part by the composition of the extracellular matrix (ECM). Changes in the ECM, caused by increased blood pressure, injury or disease can affect the capacity of the heart to fill with blood during diastole. In mammalian species, cardiac fibrosis caused by an increase in collagen in the ECM, leads to a loss of heart function and these changes in composition are considered to be permanent. Recent work has demonstrated that the cardiac ventricle of some fish species have the capacity to both increase and decrease collagen content in response to thermal acclimation. It is thought that these changes in collagen content help maintain ventricle function over seasonal changes in environmental temperatures. This current work reviews the cellular mechanisms responsible for regulating collagen deposition in the mammalian heart and proposes a cellular pathway by which a change in temperature can affect the collagen content of the fish ventricle through mechanotransduction. This work specifically focuses on the role of transforming growth factor β1, MAPK signaling pathways, and biomechanical stretch in regulating collagen content in the fish ventricle. It is hoped that this work increases the appreciation of the use of comparative models to gain insight into phenomenon with biomedical relevance.

Current researches aim at identifying modifiable risk factors for infertility, particularly dietary lifestyle. Abelmoschus esculentus is one of the important vegetables in the human diet with reported valuable nutrients but has been linked with reproductive dysfunction in males. This study investigated the reproductive effects of Abelmoschus esculentus fruit methanol extract in female Wistar rats. Dried Abelmoschus esculentus fruit was extracted with methanol. Fifteen female Wistar rats (180–200 g) grouped into three (n = 5) received 1.0 mL/kg/day distilled water (control), 70 and 200 mg/kg/day of the extract once daily for 21 days via oral gavage. The estrous cycle was assessed using Marcondes and Papanicolaou methods. The histology of the tissues was evaluated by microscopy. Serum follicle-stimulating hormone, luteinizing hormone, and estrogen levels were measured using an enzyme-linked immunosorbent assay. Tissue antioxidant activities and malondialdehyde levels were assayed by spectrophotometry. Data were analyzed using the Analysis of variance at a significance of p < 0.05. The estrous cycle of the Abelmoschus esculentus fruit methanol extracts treated rats showed normal cellular characteristics. Though Abelmoschus esculentus fruit methanol extract increased the antioxidant activities, it reduced the body weight and follicle-stimulating hormone level and caused severe inflammation and fibrosis of the ovary and uterus. Abelmoschus esculentus fruit methanol extract adversely altered the reproductive functions of female Wistar rats by disrupting the ovarian and uterine cytology and reducing hormone levels.