Journal of Physiological Sciences最新文献

TRPA1 was first identified as a noxious cold receptor in mice in 2003. Multiple TRPA1 genes have since been isolated, indicating that TRPA1 emerged early in evolution and showing the existence of TRPA1 variants in a range of species, including insects. Although TRPA1 channels in insects to birds (endotherms) show heat-dependent activation that indicates the importance of TRPA1 for detecting ambient warm to hot temperatures, in mammals TRPA1 temperature sensitivity remains controversial. Analyses of insect TRPA1 highlighted several important structural motifs, but the structural basis of heat-evoked activation is still unclear. Furthermore, atomic-level structures of TRPA1 solved using single particle analysis with cryo-electron microscopy did not reveal a basis for TRPA1 thermosensitivity. Recent studies did demonstrate that human TRPA1 has bimodal thermosensitivity and mouse TRPA1 is involved in noxious heat sensitivity, but additional systematic analyses are needed to determine the general mechanism of mammalian TRPA1 thermosensitivity.

Developing strategies to enhance cardiac vagal activity (CVA) is essential for improving mood and managing stress. Although hypoxia inhalation may boost CVA, the optimal acute hypoxic conditions remain unclear. Therefore, we aimed to achieve a comprehensive understanding of the hypoxic conditions required to improve CVA and mood following hypoxia. Twenty-one healthy adults participated in both normobaric hypoxic (NH; FIO₂: 13.5 %) and normoxic (NN; FIO₂: 20.9 %) conditions. We monitored heart rate variability (HRV), percutaneous oxygen saturation (SpO₂), and mood across pre-, hypoxia, and post-sessions and assessed psychophysiological stress using the Baevsky Stress Index (SI). Under hypoxia, SpO₂ decreased to 88.1 %, accompanied by reductions in vagally-mediated HRV, followed by supercompensation post-hypoxia. Additionally, mood declined during hypoxia but rapidly rebounded, correlating with CVA and SI fluctuations. These results indicate that acute low-dose hypoxic gas inhalation at FIO₂: 13.5 % enhances CVA and mood post-hypoxia, offering a practical method for building resilience.

Fenestration has been reported to enhance Fontan hemodynamics in several cases of Fontan circulation. However, the indication criteria for fenestration remain under discussion. To assess the effectiveness of fenestration in Fontan circulation, we conducted a theoretical analysis using a computational model of the fenestrated Fontan circulation. The cardiac chambers and vascular systems were modeled using the time-varying elastance model and the modified Windkessel model, respectively. When the pulmonary vascular resistance index was 4.01 Wood units m², fenestration significantly reduced central venous pressure from 18.0 to 16.1 mmHg and decreased stressed blood volume from 610 to 555 ml. However, in the models with reduced ventricular end-systolic elastance, increased ventricular stiffness constant, or heightened systemic vascular resistance, the advantages of fenestration were diminished. Thus, fenestration may effectively improve the hemodynamics of Fontan circulation in patients with elevated pulmonary vascular resistance.

Over the last decade, therapeutic advances in cancer immunotherapy have rapidly progressed, leading to an expansion of clinical trials and the development of novel immune checkpoint inhibitors (ICIs) and combination treatments. While ICIs offer substantial clinical benefits, they are also associated with various side effects, notably concerning endocrine function and potential gonadal damage following the initiation of immunotherapy. Exercise has demonstrated promise in enhancing treatment efficacy, including symptom reduction in cancer patients. Research has also established the benefits of exercise in managing fertility and reproductive health. However, there is limited data on the effectiveness of exercise in mitigating fertility-related side effects specifically in patients undergoing ICIs therapy. Given that a significant number of cancer patients are of reproductive age, it is crucial to address potential sexual side effects and offer fertility preservation options. Ensuring that patients are well-informed and supported in their reproductive health decisions is vital. This review reports the prevalence of immune-related adverse effects linked to fertility in cancer patients undergoing ICIs, explores the potential mechanisms by which ICIs may impact reproductive health, and emphasizes the role of exercise in mitigating these adverse effects.

Physical inactivity, which is a global issue, reduces physical and mental vitality, particularly impairing prefrontal-cortex-based mental health. This may trigger social withdrawal and depression, hindering the ability to have an active lifestyle. However, we have identified a beneficial agent, a vitamin B₁ derivative called thiamine tetrahydrofurfuryl disulfide (TTFD), that enhances physical activity through dopaminergic regulation in the medial prefrontal cortex (mPFC) of rats. Since the brain dopaminergic system also regulates the sleep-wake cycle via the ascending arousal system, we postulated that TTFD may promote arousal. To test this, we performed electroencephalograms and electromyograms in rats, monitoring their physical activity and sleep-wake cycles after TTFD injection. Analysis revealed that TTFD acutely promotes arousal, reduces slow-wave sleep (SWS) and rapid eye movement (REM) sleep, and promotes increased physical activity. TTFD not only promotes physical activity but also increases arousal, thereby potentially contributing to enhanced mental health.

Brain temperature is strictly regulated by various endogenous mechanisms and significantly contributes to brain function in homeothermic animals, making it an important factor for health. Thermosensitive transient receptor potential (TRP) channels convert temperature information into electrical signals through cation influx. In particular, TRPV4 is involved in the regulation of brain function. TRPV4, constitutively active in neurons through its activation by brain temperature, increases neuronal firing. TRPV4KO mice have electroencephalogram abnormalities, resulting in depression-like and social behavioral abnormalities. This basic function of TRPV4, as a translator of brain temperature information, has been implicated in several diseases, including epilepsy and stress-induced depression. In addition to its neuronal functions, TRPV4 has many key functions in glia and vasculature that depend on brain temperature and contribute to brain activity. In this review, I summarize the importance of TRPV4 activities in relation to brain temperature and focus on how hyperthermia-induced TRPV4 dysfunction exacerbates brain diseases.

We investigated the effects of a centrally penetrant ghrelin agonist, RQ-00538053, on colorectal motility in female rats in comparison with that in male rats. Intravenous administration of RQ-00538053 enhanced colorectal motility in female rats. However, approximately tenfold higher doses were required to induce responses in female rats similar to those in male rats. Higher doses were required even when the agonist was intrathecally administered to the lumbosacral spinal cord in female rats. The results of RT-qPCR showed that the level of ghrelin receptor expression in the lumbosacral spinal cord was lower in female rats than in male rats, suggesting that the lower expression level of the receptor may contribute, at least in part, to the sex differences in the action of RQ-00538053. The sexually dimorphic action of a ghrelin agonist will be important for future works aiming to utilize ghrelin agonists as novel drugs to improve constipation.

Mechanical circulatory support is a potential treatment for failing Fontan patients. In this study, we performed a theoretical analysis using a computational model to clarify the effects of systemic ventricular assist device (VAD) in failing Fontan patients. Cardiac chambers and vascular systems were described using the time-varying elastance model and modified Windkessel model, respectively. A VAD was simulated as a nonlinear function. In systolic and diastolic ventricular dysfunction and atrioventricular valve regurgitation models, systemic VAD increased the cardiac index and decreased the central venous pressure (CVP). However, in the high pulmonary vascular resistance model, CVP became extremely high above 15 mmHg to maintain the cardiac index when the pulmonary vascular resistance index (PVRI) was above 5 Wood units m². In Fontan patients with ventricular dysfunction or atrioventricular valve regurgitation, systemic VAD efficiently improves the hemodynamics. In Fontan patients with PVRI of > 5 Wood units m², systemic VAD seems ineffective.

The effect and molecular regulatory mechanism of A Disintegrin and Metalloproteinase 8 (ADAM8) were explored in alcoholic liver fibrosis (ALF). C57BL/6N male mice were randomly divided into control, alcohol, and ADAM8-sgRNA3 plasmid groups. The control group received control liquid diet, while the alcohol and ADAM8-sgRNA3 plasmid groups were given alcohol liquid feed diet combined with ethanol gavage treatment for 8 weeks to induce ALF modeling. In addition, the ADAM8-sgRNA3 plasmid group was injected with the effective ADAM8-sgRNA3 plasmid, while the alcohol and control group mice were injected with an equivalent amount of physiological saline. LX-2 human hepatic stellate cells were divided into control, alcohol, si-ADAM8-2, and si-ADAM8-NC groups and induced for 48 h for model establishment in vitro. Serological detection, pathological staining, Western blotting, qRT-PCR and CCK8 assay were performed for experiments. Compared with the alcohol group, ADAM8 mRNA, protein and, positive area rate, serological indicators, pathological changes, and the expression of liver fibrosis marker and MAPK signaling pathway-related factors in the ADAM8-sgRNA3 plasmid group significantly decreased in vivo. Compared with the alcohol group, ADAM8 mRNA and protein expression, cell viability, and the expression of liver fibrosis markers and MAPK signaling pathway-related factors (p-ERK1/2, PCNA, Bcl-2, p-c-Jun, TGFβ1, p-p38 MAPK and HSP27) reduced significantly in the si-ADAM8-2 group. Therefore, ADAM8 promotes ALF through the MAPK signaling pathway, a promising target for treating ALF.