Journal of Physiological Sciences最新文献

TRPC3 channels are involved in the physiological and pathological myocardial responses to mechanical loads. However, the involvement of TRPC3 in the response to acute stretch, that is, the Frank-Starling mechanism, has not been comprehensively elucidated. To elucidate this, we analyzed the response to stretch in isolated mouse ventricular cardiomyocytes. Our analysis revealed that TRPC3-deficient cells exhibited significantly lower cellular end-systolic elastance, an index of contractility, than wild-type cells owing to the absence of acute stretch-induced reactive oxygen species (ROS) production. Subsequently, we demonstrated that ATP released from pannexin-1 during stretch activates the TRPC3-NOX2 complex via P2Y signaling, thereby increasing ROS production. The results of this study show that TRPC3 plays a role in the Frank-Starling mechanism by mediating the mechanotransduction pathway of stretch-induced ROS production, which is a novel physiological role for TRPC3 in the heart.

We investigated whether the same sympathetic nerves innervate arteries and neuromuscular junctions and aortic baroreceptor stimulation reduces muscle force in rats. Histological analysis with fluorescent labeling revealed nicotinic acetylcholine receptors, motor nerves, adrenergic nerves, and arteries in gastrocnemius muscle tissue. Whole-mount preparations revealed a potential extension of adrenergic nerves around an artery connected to the neuromuscular junction. Physiological analysis under anesthesia was conducted to examine the effects of baroreceptor activation on muscle contractility and contraction-induced lumbar sympathetic reflex discharges following tetanic motor nerve stimulation. Intravenous phenylephrine injection increased mean arterial pressure to ∼150 mmHg and reduced both tetanic force and sympathetic reflex discharges when the aortic depressor nerves were intact. Bilateral aortic nerve denervation nearly abolished these effects. These findings indicate that aortic baroreceptor afferent signaling decreases hindlimb muscle contractility, most likely by inhibiting the contraction-induced sympathetic reflex. Sympathetic nerves distributed to arteries and neuromuscular junctions may underlie this modulation.

Thirty years from now, society will be transformed by dramatic advances in digital transformation, life infrastructure, and personalized medicine. People will communicate seamlessly in virtual spaces, and older adults will enjoy more fulfilling lives. Nevertheless, increasingly complex lifestyles will place immense pressure on ecosystems, affecting the environment and organisms and leading to serious health challenges. To address these issues, the Japanese Association of Anatomists, the Physiological Society of Japan (PSJ), and the Japanese Pharmacological Society have launched a collaborative initiative on "One Health". This framework aims to integrate the protection of flora and fauna with the health of humans, animals, and the planet, extending even to outer space. In the symposium held at 2025 APPW congress cohosted by PSJ, experts from multiple disciplines discussed how humans can coexist with microbes, xenobiotics, humans, and robots on Earth, fostering a sustainable and resilient future. This article summarizes this One Health symposium.

Diabetic retinopathy (DR), a leading cause of adult blindness, with LAMC1-mediated epithelial-mesenchymal transition (EMT) playing a key role. By analyzing DR-related microarray datasets (GSE60436/GSE102485) from GEO, we identified 685 differentially expressed genes (570 downregulated, 115 upregulated). Functional and WGCNA analyses linked these to PI3K/Akt signaling, revealing 11 diagnostic hub genes, including LAMC1. Western blot analysis confirmed that LAMC1 significantly upregulated in high glucose (HG)-treated ARPE-19 cells and diabetic mouse retinas. In vitro and in vivo experiments confirmed that LAMC1 promotes EMT in retinal pigment epithelial (RPE) cells via PI3K/Akt activation, enhancing migration and invasion. Conversely, LAMC1 knockdown alleviated retinal damage in diabetic mice. Our studies uncovered that LAMC1's role in DR progression through PI3K/Akt-driven EMT, suggesting its potential as a therapeutic target.

We have identified the Podoplanin expression in rat jejunal villi. We aimed to investigate the relationship between the Podoplanin expression in jejunal villi and the pathogenesis of congenital protein-losing enteropathy (PLE), using the Podoplanin heterozygous knock-out (Pdpn-het KO) mice and aspirin-induced inflammation of the jejunum. In the Pdpn-het KO mice the reticular and complexes distribution of Podoplanin was observed in the jejunal villi, resulting in be swollen of lamina propria. To confirm the abnormal distribution of small lymph vessels in the jejunal villi, the LYVE-1 immunohistochemical expression was investigated. The expression of Podoplanin and LYVE-1 in the jejunum of the Pdpn-het KO mice exhibited a distinct pattern. The intravenous administration of Evans blue dye appeared quickly into the mesenteric lymph vessels and lymph nodes in the wild-type but not observed in Pdpn-het KO mice. In the Pdpn-het KO mice, aspirin-induced jejunal inflammation produced a significant leakage of the intravenous administration of FITC-albumin into the jejunal lumen. The hypoalbuminemia in the blood and the marked distribution of FITC-albumin in the jejunal villi were also observed in the mice. In conclusion, we proposed that Pdpn-het KO mice with jejunal inflammation demonstrates a good animal model of the congenital PLE.

To investigate whether incomplete Circle of Willis (Incomplete CoW) affects neuropsychological outcomes in patients with primary hypertension, a cross-sectional study was conducted involving 150 patients diagnosed with primary hypertension, a population at increased risk for neurovascular compromise. Magnetic Resonance Angiography was used to classify patients into two groups: Complete CoW (n = 41) and Incomplete CoW (n = 85). Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI), and cognitive function was evaluated using the Mini-Mental State Examination (MMSE). PSQI scores were significantly higher in the Incomplete CoW group compared to the Complete CoW group, indicating poorer sleep quality in patients with an Incomplete CoW. A significant negative correlation was found between PSQI and MMSE scores in the Incomplete CoW group, linking poor sleep quality with cognitive impairment. These findings suggest that the incompleteness of the CoW may contribute to neuropsychological impairments in patients with hypertension, potentially mediated by enhanced inflammatory responses. DATA AVAILABILITY: The data used to support the findings of this study are available from the corresponding author upon request.

Menopausal women frequently report contradictory thermoregulatory symptoms (hot flashes and chills), believed to result from declining estradiol (E₂) levels; however, mechanisms remain unclear. TWIK-related (TREK) potassium channels function as cold receptors. Although E₂ enhances TREK1 activity in vitro, its effect on TREK-mediated thermoregulation has not been investigated in vivo. This study investigated whether E₂ facilitated TREK-mediated thermoregulation in ovariectomized rats using ostruthin, a TREK agonist. Rats were ovariectomized and implanted with silastic tubes with or without E₂, followed by ostruthin or vehicle injection. We measured thermoregulatory parameters, plasma hormones (triiodothyronine and thyroxine), and mRNA expression of cold receptors in dorsal root ganglia. Ventral root responses were examined in vitro. Ostruthin increased body temperature in E₂(+) versus E₂(-) groups, with increased triiodothyronine and upregulation of Trek1, Vgf, and Nos1. Ostruthin enhanced ventral root responses. These findings demonstrate that E₂ potentiates TREK-mediated thermoregulation through enhanced cold sensing, providing insights into menopausal disorders.

Temporomandibular joint (TMJ) disorders are common orofacial pain conditions influenced by multiple factors. This study examined how vagotomy and endogenous opioids affect TMJ-responsive neurons in the trigeminal subnucleus caudalis/cervical junction (Vc/C_1-2) in female rats under different estrogen levels. Under low estrogen, cervical vagotomy enhanced TMJ unit responses to levels seen in high estrogen conditions but had no additional effect under high estrogen. Vagotomy did not change chemical stimulation (ATP) thresholds or spontaneous activity, suggesting a central neural mechanism. Responses to mechanical stimulation of the skin over the TMJ were unaffected. Naloxone increased ATP-evoked responses under low estrogen but had no added effect after vagotomy or under high estrogen. Naloxone also did not alter spontaneous activity or mechanical responses. These findings indicate that vagal input and endogenous opioids significantly modulate TMJ neuron activity under low estrogen, while high estrogen levels limit further excitation, implying estrogen-dependent regulation of vagus and opioid effects on Vc/C_1-2 neurons.

Osteoarthritis (OA) is a common degenerative joint disease characterized by cartilage destruction and inflammation. This study reveals that activating transcription factor 4 (ATF4) is upregulated in IL-1β-treated chondrocytes and promotes ferroptosis, a form of programmed cell death. Knockdown of ATF4 alleviated cartilage damage and reduced ferroptosis in both cell and mouse models. Mechanistically, ATF4 directly binds to the promoter of nuclear protein 1 (NUPR1) and activates its transcription. Overexpression of NUPR1 reversed the protective effects of ATF4 knockdown, confirming the critical role of the ATF4-NUPR1 axis in mediating ferroptosis and OA progression. These findings identify ATF4 as a key driver of OA via ferroptosis regulation and suggest that targeting the ATF4-NUPR1 pathway may offer a promising therapeutic strategy.

Background: To investigate the mechanisms underlying sevoflurane-induced POCD, C57BL/6 J mice and SH-SY5Y cells were treated with sevoflurane for model establishment.

Methods: After the treatment with sevoflurane, CCK-8, EdU and flow cytometry were employed to detect cell damage. The levels of N6-methyladenosine (m6A), METTL14 and DUSP6 were determined by qPCR and Western blot. The interaction between METTL14 and DUSP6 was analyzed using RIP-qPCR and Me-RIP methodologies. The cognitive function in mice were assessed by water maze test.

Results: After sevoflurane treatment, the cell viability, cell proliferation and METTL14 expression were markedly suppressed, while apoptosis was significantly enhanced. METTL14 overexpression elevated the levels of m6A and DUSP6, increased the binding level of METTL14 to DUSP6 mRNA, reducing damage to cells and cognitive dysfunction of mice. Knockdown of DUSP6 negated the beneficial effects observed with METTL14 overexpression.

Conclusion: Sevoflurane induced POCD by regulating METTL14/DUSP6 through m6A methylation.