Physiological Reports最新文献

The use of genetically diverse mouse models offers a more accurate reflection of human genetic variability, improving the translatability of findings to heterogeneous human populations. This approach is particularly valuable in understanding diverse immune responses to disease by environmental exposures. This study investigates the inflammatory responses to acute exposures to mainstream cigarette smoke (CS) and environmental tobacco smoke (ETS) in two genetically diverse mouse strains, CC002/UncJ (UNC) & Diversity Outbred (J:DO). The UM-HET3 (HET3) mouse strain, typically used in aging intervention studies, has also been used to evaluate the translatability of this model for age-associated pathologies. The study involves a comprehensive approach, including BALF cytokine analysis, evaluation of lung tissue architecture, assessment of macrophages and its associated proteins (MMP9 & MMP12) abundance. Several cytokines/chemokines were found to be upregulated across three strains. Notably, the UNC strain exclusively showed upregulation of TNF-α, IL-17A, and IL-13, whereas the J:DO showed an upregulation in KC. The number of alveolar macrophages in the lungs of UNC mice was very low at baseline compared to other strains studied in this study, which is indicative of some inherent shift in the pulmonary immune profiles of these inbred mice. In contrast, the J:DO strain, characterized by genetic outbreeding, showed a much more robust lung macrophage response comparable to C57BL/6J. The findings provide valuable insight into how genetic diversity affects immune responses in response to acute CS/ETS exposure, with implications for understanding diverse human responses to environmental stressors in studying lung pathophysiology.

Cancer is a complex disease with profound societal and economic impacts, especially in metastatic cases where treatment challenges arise due to the absence of reliable biomarkers and effective therapies. While P21-activated kinases (PAKs) play a key role in cancer progression, their potential as predictive markers for metastasis and therapeutic targets has not been fully explored. We hypothesized that genetic alterations in PAK isoforms could be linked to reduced overall patient survival. To investigate this, we used data from the cBioPortal for Cancer Genomics, analyzing several randomized, multicentered phase-3 clinical trial datasets. The analysis revealed significant genetic alterations in PAK genes, particularly in cancers such as breast, prostate, pancreatic, and lung. Notably, elevated PAK expression was associated with poorer survival outcomes in prostate and breast cancer patients. In pancreatic and lung cancers, although a trend of poorer survival with PAK alterations was observed, it was not statistically significant. Our findings underscore the importance of PAK isoforms as potential biomarkers and therapeutic targets, particularly in metastatic cancers. Further research could lead to improved patient outcomes through targeted interventions aimed at PAK-related pathways, with PAK serving as a reliable biomarker for the precise diagnosis, monitoring, and personalization of treatment strategies.

Type 2 diabetes (T2D) is a common metabolic disorder in which only 25% of patients meet management targets. While the primary care setting is positioned to provide lifestyle management education, studies are lacking which integrate behavior interventions in this setting utilizing clinic staff. Thus, we evaluated a 90-day lifestyle intervention for management of glycemia at a family practice clinic administered by clinic medical assistants. Twenty patients with non-insulin-dependent T2D completed a 90-day intervention driven by patient choices of nutrition and physical activity. Medical assistants were trained by members of the study team and administered the intervention under nurse practitioner supervision. HbA1c trended toward significant reduction 8.59 ± 0.9% to 8.15 ± 1.2% (p = 0.051, 95% CI: -0.88 to 0.003). Modest reductions were observed for waist circumference (115.5 ± 12.6 vs. 112.5 ± 15.2 cm; p = 0.014, 95% CI: -5.66 to -0.26), body weight (97.7 ± 21.9 vs. 95.6 ± 23.9 kg; p = 0.016. 95% CI: -3.84 to -0.31), and BMI (33.7 ± 7.2 vs. 32.8 ± 7.5 kg/m²; p = 0.028, 95% CI: -1.29 to -0.12). This 90-day, patient choice-intervention was successful at lowering HbA1c in patients with T2D. Our study is limited by a lack of control group, and results should be interpreted as such. These data have implications for team-based care models in clinic settings to improve health outcomes in patients with T2D.

Polycystic kidney diseases (PKD) are genetic disorders which disrupt kidney architecture and function. Autosomal recessive PKD (ARPKD) is a rare form of PKD, caused by mutations in PKHD1, and clinically more severe than the more common autosomal dominant PKD (ADPKD). Prior studies have implicated Hedgehog (Hh) signaling in ADPKD, with increased levels of Hh components in experimental ADPKD and reduced cystogenesis following pharmacological Hh inhibition. In contrast, the role of the Hh pathway in ARPKD is poorly understood. We hypothesized that Hh pathway activity would be elevated during ARPKD pathogenesis, and its modulation may slow disease progression. We utilized Cpk mice which phenocopy ARPKD and generated a PKHD1-mutant spheroid model in human collecting ducts. Significantly elevated levels of the Hh transcriptional effector Gli3 were found in Cpk mice, a finding replicated in PKHD1-mutant spheroids. In Cpk mice, total GLI3 and GLI3 repressor protein levels were also increased. Reduction of increased Gli3 levels via heterozygous genetic deletion in Cpk mice did not affect cyst formation. Additionally, lowering GLI3 transcripts to wildtype levels did not influence PKHD1-mutant spheroid size. Collectively, these data suggest attenuation of elevated Gli3 does not modulate murine and human models of ARPKD.

This study investigated sex differences in the development of pulmonary edema and exercise-induced arterial hypoxemia (EIAH) in well-trained endurance athletes during near-maximal exercise in a real-world setting. Twenty participants (10M vs. 10F; V̇O₂peak: 69.3 (8.8) vs. 50.7 (4.1) ml∙kg^-1∙min^-1) underwent a maximal incremental treadmill test (visit 1) and a time trial on a steep trail (~2.5 km, ~800 m elevation gain) in North Vancouver (visit 2). Pulmonary edema was evaluated using handheld lung ultrasound ~10-15 min post-exercise and oxygen saturation (SpO₂) was monitored using finger pulse oximetry. Males completed the time trial significantly faster than females (M: 31.5 (6.5) vs. F: 40.4 (7.5) min, p = 0.006), while females sustained a higher percentage of their visit 1 heart rate (M: 94 (1) vs. F: 96 (1) %max, p = 0.02). All participants developed EIAH, with no sex differences in end-exercise SpO₂ (M: 89 (4) % vs. F: 90 (3) %, respectively, p = 0.35). There was no evidence of pulmonary edema, assessed through ultrasound b-line scores, with no differences between sexes (M: 0.3 (1.0) vs. F: 0.5 (1.5), respectively, p = 0.60). Pulmonary edema is an unlikely contributor to EIAH in endurance athletes performing near-maximal time trial exercise in a real-world setting.

The twin testosterone transfer (TTT) hypothesis posits that females with male co-twins (opposite-sex, OS) might develop male-typical traits due to higher prenatal testosterone exposure. This study explored whether females of OS have lower 2D:4D digit ratios and higher testosterone levels compared to females of same-sex (SS) twin pairs. Conducted in Tamale from January to December 2022, the study included 40 participants aged 18-27 years: 10 males of OS, 10 females of OS, and 20 females of SS twin pairs. Digit ratios (2D:4D) and serum testosterone levels were measured using computer-assisted analysis and ELISA, respectively. Results showed no significant differences in 2D:4D ratios between females of OS and SS twin pairs for either the right hand (0.960 ± 0.049 vs. 0.955 ± 0.042; p = 0.766) or the left hand (0.966 ± 0.048 vs. 0.968 ± 0.047; p = 0.908). Serum testosterone levels were lower in females of OS than females of SS twin pairs (0.4 ± 0.1 vs. 0.67 ± 0.34 nmol/L; p = 0.013), but this result was not significant after multiple testing corrections (p > 0.050). The findings indicate that the TTT hypothesis may not apply, or its effects on digit ratios and testosterone levels in females of OS twin pairs are weak and not statistically significant. Further studies involving larger samples are however, recommended.

Cisplatin is a widely used anticancer drug, but its accumulation in renal tubular epithelial cells (TECs) can cause acute kidney injury. Phosphoseryl-tRNA kinase (PSTK) is an intermediate product produced under oxidative stress conditions. This study aimed to elucidate whether PSTK could protect TECs and its possible mechanisms. We found that PSTK levels decreased after cisplatin treatment, but PSTK overexpression using lentivirus vectors protected TEC viability. Overexpression of PSTK increased selenoprotein concentrations and reduced intracellular ROS levels. Additionally, PSTK overexpression inhibited the BAX/BCL2/Caspase 3 pathway after cisplatin stimulation, suggesting its potential role in preventing cell apoptosis. Taken together, this study suggests that PSTK could protect TEC viability from cisplatin-induced injury, possibly by inhibiting mitochondrial apoptosis. The study is significant for developing therapeutic strategies that could manipulate PSTK to delay AKI progression.

Maximal oxygen uptake (VO₂max) in healthy subjects is primarily limited by systemic oxygen delivery. In chronic kidney disease (CKD), VO₂max is potentially reduced by both central and peripheral factors. We aimed to investigate the effect on VO₂peak of adding arm exercise to leg exercise. Ten individuals with CKD stages 3-5 and 10 healthy controls, matched for age, sex, body size, and physical activity level, were included. Subjects performed two maximal exercise tests, one with legs only (L exercise) and one test where arm exercise was added to leg exercise (LA exercise). The increase in VO₂peak, when comparing LA exercise with L exercise, was significantly higher in CKD (0.20 ± 0.18 L/min or 2.31 ± 1.78 mL/(kg·min)) than in controls (0.019 ± 0.12 L/min or 0.26 ± 1.62 mL/(kg·min); p = 0.02 and 0.01, respectively). The decrease in peak leg workload, when comparing L exercise with LA exercise, was larger in controls than in CKD, in absolute terms (p = 0.002) and relative to body weight (p = 0.01). VO₂max in individuals with CKD is dependent on the active muscle mass, supporting a peripheral limitation to VO₂max in CKD. By contrast, the control group appeared to have a more central limitation to VO₂max.

Time-restricted feeding (TRF) and aerobic exercise are lifestyle interventions to prevent or manage different metabolic diseases. How these interventions interact, including the impact of meal timing, is not well understood. The aim of this study was to examine the influence of TRF on fat oxidation during exercise, whereby participants performed an 8-week fat_max-training program either in the fasted state or after a carbohydrate-based snack. 36 participants were randomized into three groups. (1) Training sessions were performed in the fasted state; (2) Training sessions were performed after consuming a standardized carbohydrate-based snack; (3) Exercise training with an ad libitum diet as a control group. Pre- and post-tests included anthropometric measurements and a fat_max-cycle-ergometry protocol to measure substrate oxidation. Data were analyzed as workload-matched and maximal fat oxidation using a series of mixed ANOVAs. Workload-matched (p = 0.038) and maximal (p < 0.001) fat oxidation improved in all groups. No significant group × time interactions were found in substrate utilization. Time had a significant effect on body weight (p = 0.011), fat mass (p < 0.001), and muscle mass (p < 0.001). Results suggest that fat_max exercise training leads to improvements in fat oxidative capacity independent of fed or fasted state.

Knowledge of muscle contractile properties, physical fitness, and their associations with perceived fatigue may provide insights into mechanisms inducing fatigue and treatment targets. We aimed to identify differences in contractile properties and physical fitness between populations, and examine associations with perceived fatigue. We pooled data on perceived fatigue, physical fitness, and contractile properties from six studies, including a control group (n = 90), cancer survivors (n = 27), patients with chronic obstructive pulmonary disease (COPD; n = 16), chronic myeloid leukemia (CML; n = 20), and statin users (n = 64). We evaluated differences between populations, and associations of contractile properties and physical fitness with perceived fatigue. Compared with the control group, we found differences in contractile properties of patients with COPD (larger muscle force decline: β = -10.5%, 95% CI = -16.7; -4.2, increase in early relaxation time (Rt): β = 84.4%, 95% CI = 51.7; 117.0, increase in half Rt: β = 83.1%, 95% CI = 45.5; 120.7, muscle force rise (MFR): β = 0.2%/ms, 95% CI = 0.1; 0.3, and decrease in MFR: β = -24.3%, 95% CI = -35.7; -13.0) and statin users (early Rt: β = -5.4 ms, 95% CI = -10.0; -0.8, increase in early Rt: β = 19.8%, 95% CI = 2.5; 37.1). Associations between contractile properties and perceived fatigue varied across populations. Longer relaxation times were associated with higher perceived fatigue in hemato-oncological populations. To conclude, contractile properties were impaired in patients with COPD and statin users. Associations between contractile properties and perceived fatigue varied across populations. In hemato-oncological populations, impaired muscle relaxation was associated with higher perceived fatigue.