Experimental Physiology最新文献

The objective of this work was to investigate the role of ZFP36 in mitral valve prolapse (MVP). Mitral valve and plasma were collected to assess the expression of ZFP36, transforming growth factor β (TGF-β), collagen and elastin and apoptosis rates. Mitral valve interstitial cells (MICs) were transfected with ZFP36 plasmids to observe changes in the secretion of collagen, elastin and matrix metalloproteinases (MMPs) and apoptosis rates. MICs were exposed to TGF-β1 to evaluate the changes in expression of collagen, elastin, MMPs and ZFP36 and apoptosis. Subsequently, after transfection with ZFP36 plasmid, exogenous TGF-β1 was added to the MICs, and the secretion of collagen, elastin and MMPs and apoptosis rate were re-evaluated. Finally, transcriptome and RNA immunoprecipitation (RIP) sequencing was conducted to identify downstream genes of TGF-β1 that could bind to ZFP36. Patients with MVP showed elevated levels of TGF-β1 in plasma and increased rates of apoptosis, along with higher expression of ZFP36, TGF-β1, collagen and elastin in the prolapsed valve. Overexpression of ZFP36 in MICs did not significantly alter the secretion of collagen or elastin or apoptosis rates. TGF-β1 promoted apoptosis of MICs, increased the secretion of collagen, elastin, MMP-3,9, ZFP36 and reduced the expression of MMP-1,2,13. Moreover, overexpression of ZFP36 inhibited the effects of TGF-β1 on MICs. Co-analysis of transcriptome and RIP sequencing identified three genes: CFAP184, GTP binding protein 6 (GBP6) and HERC6. Knockdown of GBP6 reduced the pro-apoptotic effects of TGF-β1 on MICs. ZFP36 exerts a protective role in MVP by inhibiting the effects of TGF-β1 on MICs. Notably, ZFP36 can mitigate the pro-apoptotic effects of TGF-β1 on MICs through the GBP6 pathway.

Acute myocardial infarction is a leading cause of morbidity and mortality, with ischaemia-reperfusion (I/R) injury exacerbating myocardial damage. Vagus nerve stimulation (VNS) has been reported to exert cardioprotective effects, but its efficacy in preconditioning against I/R injury requires further investigation. We evaluated the cardioprotective effects of VNS preconditioning in a rat model of acute myocardial infarction with induced I/R injury. Sixty rats were randomized into Pre-VNS, Control and Sham groups. The Pre-VNS group received 1 week of low-level cervical VNS before induction of I/R injury; stimulation was deactivated 30 min before ischaemia. Survival, echocardiographic function, reperfusion arrhythmias, arrhythmia inducibility, infarct size, apoptosis and inflammatory cytokines were assessed. Survival did not differ significantly between Pre-VNS and Control groups (75.0% vs. 65.0%, p = 0.497). However, Pre-VNS animals exhibited preserved cardiac function, with higher ejection fraction and fractional shortening (p < 0.001). VNS preconditioning reduced the incidence of reperfusion arrhythmia during left anterior descending coronary artery ligature release (p = 0.006) and decreased the arrhythmia index on programmed stimulation (p = 0.003). Infarct size and cardiomyocyte apoptosis were significantly attenuated (p < 0.001), accompanied by markedly lower serum interleukin-1β, interleukin-6 and tumour necrosis factor-alpha levels (p < 0.001). VNS preconditioning effectively mitigates I/R injury by improving cardiac function, reducing infarct size and arrhythmias, and attenuating inflammatory and apoptotic responses.

Poor maternal nutrition and excessive gestational weight gain predict future development of obesity in offspring. Preclinically, maternal obesity induced by a high-fat, high-sugar diet (HFHSD) induces hyperphagia and obesity in offspring. We hypothesized that this might, in part, reflect reduced peripheral gastric vagal afferent (GVA) satiety signalling. Female Glu Venus mice were fed a standard laboratory diet (SLD) or HFHSD for 11 weeks before mating and throughout pregnancy and lactation. Offspring were weaned onto a SLD, then housed in metabolic cages at 6-7 weeks old to assess feeding behaviour. In vitro single-fibre GVA recordings were conducted on tissue collected from 8-week-old mice. Before mating, HFHSD dams were 13% heavier, with 66% higher relative fat mass compared with SLD dams. Maternal diet had no impact on total food intake or offspring weight. Meal size during the light phase was 14% larger in HFHSD than control offspring. Meal duration was longer in HFHSD than control offspring of both sexes across 24 h and the dark phase, and in females during the light phase. HFHSD offspring ate fewer meals than control offspring across all time periods. Tension-sensitive GVAs responded less to stretch in male, but not female, HFHSD than SLD offspring. Mucosal GVA responses to mucosal stroking were unaffected by maternal diet or offspring sex. In conclusion, exposure in utero and during lactation to elevated maternal adiposity and maternal HFHSD consumption induces male-specific programming of reduced GVA responses to stretch. Meal size was increased in both sexes only during the light phase, suggesting programming of other appetite-regulatory pathways by this exposure.

The magnitude of progressive augmentation (PA) and ventilatory long-term facilitation (vLTF) are two forms of respiratory plasticity that are enhanced in some humans with obstructive sleep apnoea (OSA). This response might be linked to repeated nocturnal exposure to intermittent hypoxia or other traits connected to OSA. A meta-analysis was completed using data from 91 OSA participants who completed one of two mild intermittent hypoxia protocols during wakefulness. Two iterations of a subset regression analysis were completed to identify the best model that predicted the magnitude of PA or vLTF. Novel (e.g., arousal and hypoxic burden) or standard indicators of sleep apnoea (e.g., apnoea/hypopnoea index), anthropometric variables, protocol elements and physiological variables measured during wake and sleep were included as independent variables. After model selection, a multiple linear regression analysis was used to identify the most impactful variables in the model. The hypoxic ventilatory response (HVR) alone (R = 0.589, P < 0.001) or in combination with the arousal index (R = 0.625, P < 0.015 for both variables) predicted the magnitude of PA, whilst the HVR in combination with the arousal burden (R = 0.602, P < 0.001) or arousal index (R = 0.593, P < 0.002 for all variables) predicted the magnitude of vLTF. The HVR and markers of arousal are strong predictors of the magnitude of PA and vLTF. In contrast, markers of apnoea severity, including the hypoxic burden, did not add to the ability to predict the magnitude of PA or vLTF.

Prolonged sitting inherent to long-haul air travel can acutely decrease lower-limb blood flow and increase brachial blood pressure. Healthy motion seating (HMS), which passively alters sitting interface pressure and posture, is a promising technology which may attenuate the deleterious effects of long-haul air travel. The aim of this study was to determine the impact of an innovative airplane passenger seat motion feature, aerospace HMS, on lower-limb blood flow and blood pressure in response to 6.5 h of simulated long-haul air travel. In a randomised cross-over design, 19 healthy adults completed a 6.5 h long-haul flight simulation in aerospace seating equipped with (HMS) and without (CON) healthy motion technology. Superficial femoral artery blood flow, brachial blood pressure, and perceptions of mood disturbance, pain and discomfort were measured before and after flight simulation. In linear mixed models there was a significant interaction (condition × time) effect for superficial femoral artery blood flow, with a decrease in lower-limb blood flow in CON (-22.4 mL/min; 95% CI: -2.41, -42.39; P = 0.032) but not HMS (3.7 mL/min; 95% CI: -16.3, 23.67; P = 0.720) across the 6.5 h flight simulation. There were no interaction, group nor time effects for blood pressure. Mood, pain and discomfort all worsened across the 6.5 h flight simulation (time, all P < 0.05), but there were no interaction nor group effects. The passive alterations in sitting interface pressure, posture and movement created by aerospace HMS can prevent prolonged sitting-induced reductions in local lower-limb blood flow typical of long-haul air travel.

The left ventricle (LV) is the primary pumping chamber of the heart, generating high systolic pressure to sustain systemic circulation. LV contractile dysfunction is a hallmark of various cardiovascular diseases and is associated with mitochondrial dysfunction, characterised by decreased oxidative phosphorylation (OXPHOS) capacity and increased oxidative stress. While our understanding of cardiac mitochondrial physiology has been gained from studies on LV tissues in animal models or atrial tissues in human studies, findings are often generalised across cardiac regions. Given that fundamental differences in anatomical structure, physiological function and metabolic demands exist between the LV and left atrium (LA), this study aimed to compare mitochondrial bioenergetics between LV and LA tissues from healthy rat hearts. Using high-resolution respirometry coupled with fluorimetry, we assessed mitochondrial respiration, ATP production and hydrolysis, and reactive oxygen species (ROS) production rates. Protein expression of mitochondrial respiratory complexes and antioxidant enzymes was quantified using western blotting. Our results showed that per tissue mass, LV tissues exhibited greater mitochondrial OXPHOS respiration, ATP production and hydrolysis rates, ROS production rate, and higher protein levels of mitochondrial complexes and antioxidant enzymes, consistent with higher citrate synthase activity as a marker of mitochondrial content. However, when normalised to mitochondrial content, LV tissues exhibited lower OXPHOS respiration and ATP production, expression of mitochondrial complexes and antioxidant proteins compared to LA. This study provides new insights into chamber-specific differences in mitochondrial function under physiological conditions, suggesting the importance of considering regional mitochondrial profiles in studies of cardiac mitochondrial function in health and disease.

Older adults with reduced thermoregulatory capabilities are increasingly at risk of heat-related pathophysiological outcomes (e.g., acute kidney injury, heatstroke) due to increasingly frequent, prolonged and intense heatwaves. Foot immersion and neck cooling have been proposed as practical, non-electrical cooling strategies for protecting older adults during heatwaves, though evidence supporting their efficacy is limited. This study evaluated the effect of foot immersion with or without neck cooling on systemic proteins associated with acute kidney injury (NGAL, KIM-1), intestinal enterocyte damage (IFABP), immune activation (sCD14) and systemic inflammation (IL-6, TNF-α, CRP) in older adults. Seventeen participants (nine females; median [IQR] age 72 [69-74] years) completed three randomized 6-h passive heat exposures (38°C, 35% relative humidity) with no-cooling, foot immersion in 20°C water, or foot immersion with neck cooling via wet towels. Thermal and cardiovascular strain were measured throughout exposures, with venous blood samples collected pre- and post-exposure. Body core temperature increased by ∼1.1°C (P < 0.001) with no changes in any measured systemic proteins (all P > 0.05) across conditions. Foot immersion with or without neck cooling modestly reduced heart rate, mean skin temperature, whole-body sweat rate and fluid consumption (P < 0.05), but had no effect on body core temperature or systemic protein concentrations (all P > 0.05) relative to no-cooling. These findings do not support the efficacy of these interventions for mitigating hyperthermia in older adults during heatwaves. Further research is warranted to evaluate their efficacy for protecting against heat-related acute kidney injury, intestinal enterocyte damage, immune activation, or systemic inflammation under more severe exposure conditions.

The antihypertensive mechanism of sodium-glucose cotransporter 2 (SGLT2) inhibitors has been traditionally attributed to osmotic diuresis. However, emerging evidence reveals multifaceted mechanisms beyond diuresis, including regulation of the renin-angiotensin-aldosterone system, sympathetic nervous system suppression, ion homeostasis restoration, anti-inflammatory/antioxidant actions, weight loss and improved vascular function. These synergistic pathways collectively reduce blood pressure and provide cardiorenal protection in cardiovascular-kidney-metabolic (CKM) syndrome patients. Elucidating these multi-target antihypertensive effects holds critical implications for optimizing therapeutic strategies, mitigating cardiorenal risks and establishing SGLT2 inhibitors as adjunctive antihypertensive therapy in CKM syndrome patients.