Physiological Reports最新文献

Sex steroid hormones play a regulatory role in various metabolic processes, including glucose homeostasis via the orexinergic system and lactose synthesis. This review consolidates experimental findings on the mechanisms by which these hormones regulate these two pathways. A systematic search of PubMed, Scopus, and Web of Science identified 15 controlled studies involving animals and humans that investigated the effects of sex steroid hormones on both pathways. Estradiol enhanced orexin neuron excitability and increased orexin-1 receptor expression in a cyclical, phase-dependent manner within the orexinergic-glucose axis, promoting glucose utilization during estrogen-dominant phases. Progesterone reduced this activity, which is consistent with the conservation of energy during the luteal phase. Testosterone diminished orexin-A neuronal activation during glucose deficit, suggesting a suppressive effect on orexin-driven glucose mobilization. Also, estradiol promoted lactogenesis after progesterone withdrawal, whereas progesterone sustained prepartum inhibition of α-lactalbumin and casein gene transcription. In conclusion, the influence of sex steroid hormones on orexinergic-glucose regulation is hormone-specific and phase-dependent, with estradiol acting as a stimulant, progesterone as an inhibitor, and testosterone having a largely suppressive effect. The postpartum decrease in progesterone level triggers estradiol to support milk production. Studies are needed to investigate the role of sex steroid hormones on lactase expression, activity, and lactose tolerance.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are cornerstone therapies for heart failure and chronic kidney disease. Clinical trials have demonstrated that the estimated glomerular filtration rate (eGFR) typically declines within the first few weeks after SGLT2i initiation. One proposed mechanism of the acute eGFR dip is the reduced intraglomerular pressure through tubuloglomerular feedback (TGF). Adenosine is a key mediator in TGF signaling, and caffeine, a nonselective adenosine receptor antagonist, may influence this process. We conducted a retrospective cohort study at SSM Health Saint Louis University Hospital to examine whether caffeine intake influences the initial eGFR dip following SGLT2i initiation. Eligible patients completed a caffeine consumption survey, and chart reviews assessed creatinine and proteinuria at baseline and 1 month post-initiation. Data from 62 patients (mean age 60.1 ± 12.4 years; median eGFR 50.0 [IQR 37.2-66.9] mL/min/1.73 m²) revealed a negative correlation between caffeine intake and eGFR dip at 1 month (r = -0.31, p = 0.02). Multivariable regression showed caffeine intake and baseline creatinine were independently associated with the eGFR dip. These findings suggest high caffeine consumption may attenuate the early eGFR decline seen with SGLT2i therapy. Further research is warranted to explore its impact on long-term renal outcomes.

Breast cancer progression is influenced by tumor subtype, metabolic environment, and patient factors, including menopausal status and BMI. In this study, we utilized publicly available data to investigate the prognostic relevance of PPARγ gene's expression across different subgroups. We also examined adipose tissue proliferation in patients with various tumor subtypes and phenotypic cohorts. We analyzed RNA-seq data from primary breast cancer patients in the TCGA-BRCA cohort, stratifying patients by PPARγ expression, menopausal status, and tumor receptor subtype. Kaplan-Meier analyses revealed that high PPARγ expression was associated with improved overall survival, particularly in premenopausal patients. Complementing this, we analyzed PET-CT scans from breast cancer patients in the ACRIN-6888 trial, focusing on standardized uptake value (SUV) metrics of a cell cycle tracer, 3'-deoxy-3'-[18F]-fluorothymidine (¹⁸F-FLT) in visceral and subcutaneous adipose tissue. Postmenopausal patients had lower visceral adipose tissue SUV_mean, and patients with ER+ or non-TNBC tumors showed lower SUV_peak and SUV_max of both adipose tissue types, indicating metabolic/proliferative reprogramming of adipose tissue based on tumor subtype. We hypothesize that PPARγ expression and adipose proliferation differentially affect survival across subtypes and menopausal status, providing deeper insight into PPARγ as a therapeutic target in breast cancer and the potential implications for precision medicine treatments.

The genetic predisposition to high glucose-induced peritoneal membrane (PM) injury during peritoneal dialysis (PD) and its mechanisms are of substantial clinical interest. We compared PD-induced peritoneal injury between two closely related mouse substrains, C57BL/6J and C57BL/6N, which differ in the function of the mitochondrial enzyme nicotinamide nucleotide transhydrogenase (NNT). Nnt(+/+) C57BL/6N mice exhibited significantly greater susceptibility, as indicated by mesothelial cell loss, fibrosis, neoangiogenesis, inflammation, M1 macrophage infiltration, and reduced ultrafiltration. To further investigate NNT's role, we silenced NNT in vitro. Knockdown prevented mitochondrial ROS accumulation, reduced pro-inflammatory mediator release in mesothelial cells, inhibited M1 polarization in macrophages, and impaired fibroblast proliferation under high glucose. We also observed a reverse NNT reaction in fibroblasts, contributing to glucose-induced ROS. Our findings indicate reduced genetic susceptibility of Nnt(-/-) C57BL/6J mice to PD-induced PM damage and identify NNT as a potential therapeutic target for PD-associated peritoneal injury.

This study examines sex-specific effects of developmental sertraline exposure on cardiac function and gene expression before and after myocardial infarction (MI) in mice. Female C57BL/6 mice (10 weeks) received intraperitoneal sertraline (5 mg/kg/day, n = 37) or saline (n = 20) before mating, during pregnancy, and postnatally to pups (1.5 mg/kg/day, postnatal Days 0-14). MI in offspring was induced at 10 weeks by left coronary artery ligation. Randomly chosen offspring (sham n = 8 and MI n = 26 per sex) underwent baseline echocardiography and at 10 weeks post-MI if surviving. Serotonin- and estrogen-related gene expression was analyzed. Before MI, sertraline-exposed females had lower heart rate (649.1 ± 102.0 vs. 692.9 ± 38.4 bpm, n = 34), increased end-systolic volume, and reduced ejection fraction (80.7 ± 6.3% vs. 83.9 ± 3.5%; p < 0.05). Exposed males also had lower heart rates (665.9 ± 32.7 vs. 683.3 ± 47.9 bpm, n = 34, p < 0.05). Post-MI, both sexes remodeled similarly (scar size, ischemic-zone fraction); sertraline-exposed males had higher scar-zone collagen (p < 0.05) and a nonsignificant lower survival trend than females. Sertraline altered serotonin-related gene expression (Htr2a, Htr2b, Slc6a4), particularly in male sham mice. Developmental sertraline exposure induces sex-specific cardiac changes, potentially affecting post-MI outcomes, with males showing more structural and survival impairments.

Carbon monoxide (CO), a gas endogenously produced in mammalian tissues, exerts vasodilatory, anti-ischemic, and anti-inflammatory effects. These properties have prompted the development of CO-releasing molecules (CO-RMs) for therapeutic purposes. Among this class of compounds is CORM-A1, a boron-based carboxylic acid, which generates controlled amounts of CO under physiological conditions. In this proof-of-principle study we explored the potential of CORM-A1 to protect kidneys from warm ischemia and reperfusion (WI/R) injury in rat and swine models. We found that intravenous administration of CORM-A1 significantly increased blood carboxyhemoglobin (COHb) levels while facilitating CO accumulation in renal tissue, thus confirming its ability to deliver CO to peripheral organs. In rats subjected to 45- and 60-min WI/R, administration of CORM-A1 improved renal function at reperfusion, as shown by decreased serum creatinine and urea levels. Histopathological analysis revealed substantial protection against tubular damage, cell infiltration, and inflammation, especially after 60-min ischemia. Protection was dose-dependent, with higher doses offering enhanced effects. In a swine kidney auto-transplantation model, CORM-A1 significantly improved graft function, reduced fibrosis and necrosis, and extended graft survival. These findings position CORM-A1 as a promising CO prodrug, with translational relevance for clinical applications in kidney transplantation and other ischemia-related conditions.

We utilized non-invasive methods and novel computational approaches to examine the effects of acutely varying fractional inspired O₂ (FIO₂) on convective and diffusive steps of O₂ transport and muscle tissue (de)oxygenation during incremental cycling to exhaustion in 10 Tier 3 and 4 endurance athletes breathing either 0.152, 0.209, or 0.298 FIO₂. At submaximal work rates (100-275 W) in hypoxia, higher cardiac output compensated for lower arterial O₂ content. At maximal work rate, convective O₂ transport was lower in hypoxia (mean [95%CI]: 5.37 [5.14-5.59] L/min, q < 0.0001) and higher in hyperoxia (6.84 [6.50-7.18] L/min, q = 0.043) compared to normoxia (6.56 [6.16-6.95] L/min), whereas O₂ diffusive conductance did not differ between conditions (94 [82-106], 98 [83-112], 98[87-109] mL/min/mmHg for hypoxia, normoxia and hyperoxia, respectively, p = 0.490). Consequently, maximal O₂ uptake (V̇O_2max) was lower in hypoxia (4.06 [3.85-4.27] L/min, q < 0.0001) and higher in hyperoxia (5.02 [4.85-5.19] L/min, q = 0.003) compared to normoxia (4.83 [4.63-5.02] L/min). In hypoxia, muscle tissue saturation index was 1%-4%-units lower compared to normoxia and hyperoxia during submaximal cycling but similar at maximal work rate. In summary, central and peripheral compensatory mechanisms maintained O₂ uptake despite altered FIO₂ at submaximal work rates. At maximal work rate the effects of hypoxia and hyperoxia on V̇O_2max were mediated through convective O₂ transport.

Heart rate variability (HRV) is controlled mainly by the autonomic nervous system (ANS). The aim of our prospective study was to investigate whether respiratory control influences changes in ANS activity, as reflected by HRV parameters. The analyzed parameters were compared in different sessions and by anxiety or depression score. The root mean square of the mean squared differences of successive NN intervals (rMSSD) and the high frequency power (HF) was lower in anxious females. As compared with rest, in sessions that involved respiratory control, the standard deviation of NN intervals (SDNN) and low frequency power (LF) were higher, whereas the ratio between very low frequency (VLF) and total power (TP) had lower values. LF/HF expressed the highest variation in all analyzed groups, increasing in all situations compared to the rest, without differences between sexes. Normalized coherence (NCoh) peaked during heart-focused breathing and was lowest at rest. NCoh increased during respiratory control in anxious females. The NCoh-LF/HF correlation was observed in all sessions in subjects without anxiety. Respiratory control improved HRV parameters and cardiorespiratory coherence, with significant differences between sexes and individuals with and without anxiety.

Data suggest that skeletal muscles have an internal clock that dictates training-related adaptations, which could generate different health benefits in response to exercise timing. However, limited data exist on the impact of blood flow restriction (BFR) training timing on health outcomes. To investigate the impact of 6 weeks of BFR training performed at different times of day on body composition, performance measures, and irisin and PGC1-α4 expression. Participants (n = 31; aged 19-30) who performed 6 weeks of BFR resistance training were categorized into morning (n = 16; 05:00-11:00) or afternoon (n = 15; 11:00-17:00) groups. A sub-analysis of responders and non-responders (top and bottom 25% of muscle strength or lean mass change) was performed. Primary outcomes were changes in body composition, muscle strength, isokinetic measures, and irisin and PGC1-α4 expression. Time effects were observed for changes in lean mass (p < 0.001), relative lean mass (p < 0.001), body fat percentage (p = 0.02), and all performance measures (ps ≤ 0.015). A negative correlation was observed between lean mass change and irisin change (r = -0.18; p = 0.57). No group or time × group interactions were reported for any outcomes. Six weeks of BFR training provided improvements in body composition and performance outcomes and no changes in irisin and PGC1-α4 irrespective of timing.

Volumetric muscle loss (VML) injury results in the irrecoverable loss of muscle mass and strength and alters the metabolic capacity of the remaining muscle tissue. The primary objective of this retrospective study was to leverage existing RNA-seq datasets to investigate mitochondria and metabolic transcriptome changes after VML injury. The datasets were extracted from publicly available sources and included a bulk RNA-seq dataset (Rattus norvegicus) and a single-cell RNA-seq dataset (Mus musculus) that combined provided a transcriptional landscape out to 42 days post-injury (dpi). The Broad Institute's MitoCarta3.0 database was used to identify mitochondrial-associated genes and pathways for the analysis. There was a robust downregulation of genes in the bulk RNA-seq dataset out to 28 dpi. Gene set enrichment analysis revealed that these genes contributed to oxidative phosphorylation, fatty-acid oxidation, and carbohydrate metabolism. A changing metabolic transcriptional landscape was evident in the single-cell RNA-seq dataset as several cell types (e.g., satellite cells, macrophages, and fibro-adipogenic cells) had upregulated gene sets (e.g., oxidative phosphorylation) that switched to downregulated after 14 dpi. Results from this study complement physiological studies that report dysfunctional mitochondrial bioenergetics, particularly for carbohydrate and free-fatty acid carbon sources, both immediately and chronically after VML injury. These findings also provide targets for monitoring the success of future interventions or directly manipulating in attempts to improve whole-muscle metabolic function.