Journal of Physiological Sciences最新文献

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.

Uncontrolled hypertension is a global health issue with 40 % of hypertensive patients not achieving blood pressure control with current therapies. Previously, we demonstrated renal macrophage infiltration during hypertension development with macrophage depletion leading to reduced blood pressure and renal fibrosis. However, the effect of macrophage depletion in existing hypertension has not been evaluated. We induced hypertension in mice then depleted macrophages and assessed blood pressure and renal fibrosis. Separately induced hypertension and assessed renal macrophage population and fibrosis early in hypertension. Results showed increased renal macrophage, Acta2 early in hypertension development. Macrophage depletion led to reduced blood pressure in the hypertensive mice, decreased kidney Col1a1, Acta2, Col3a1 and Fn1. This study shows that renal macrophage infiltration and fibrosis begin early in hypertension development and depleting macrophages in hypertension reduces blood pressure and suppress renal fibrosis. This shows macrophages are a potential target in treatment of hypertension.

Risk-taking behavior is crucial to increase potential outcomes and alter arousal states in the brain and body represented by heart rates. In this study, we monitored changes in heart rate as rats performed a 50:50 gambling task in which they selected either a certain outcome with 100 % probability (sure option) or a double outcome with 50 % probability (risky option). When rats selected risky options, they exhibited significantly greater decreases in their heart rates before selection than when they selected certain options. In addition, we observed significantly larger increases in heart rates when the rats recognized larger outcomes after selecting the risky options than the sure options. Similar dynamic changes in heart rates were observed in a 25:75 gambling condition with different reward magnitudes and probabilities. These results demonstrate that animals can dynamically alter their heart rates in response to risky selection and outcomes.

We investigated the propagation of extending waves along twitching muscle fibers triggered by the internal shortening of early local contraction in the end-plate region. Bullfrog sartorius muscles were minimally stimulated, and the displacement of carbon particles attached to the muscle surface was captured using a high-speed camera. We found an extending wave along the fiber at a velocity of 5.35 ± 0.33 m·s⁻¹, faster than the conduction of action potentials at 3.04 ± 0.31 m·s⁻¹. Local compression of the muscle surface blocked the propagation of the extending wave, indicating its mechanical nature. Muscle stretching increased the extending wave velocity. These findings provide direct evidence that mechanically transmitted extending waves originate from early local contractions in the end-plate region and propagate along muscle fibers ahead of the contraction wave.

Heightened central and peripheral chemoreflex sensitivity are associated with poor outcomes, but therapeutic approaches to target them are lacking. Endurance and resistance exercise training improve a multitude of physiological outcomes, but their effects on ventilatory chemoreflex sensitivity are unclear. Accordingly, the cardiorespiratory responses to steady-state isocapnic hypoxia (10 % O₂, 5-minutes) and hyperoxic hypercapnic rebreathing (5 % CO₂-95 % O₂) were compared in endurance, resistance, and untrained groups. Central chemoreflex sensitivity was taken as the slope of the relationship between minute ventilation (V̇_E) and end-tidal partial pressure of CO₂. Peripheral chemoreflex sensitivity was determined from the absolute increase in V̇_E from baseline to peak V̇_E expressed relative to the fall in oxygen saturation. Neither central (P = 0.093) nor peripheral (P = 0.847) ventilatory chemoreflex sensitivities were different between groups. Future investigations should seek to understand whether exercise training modality influences central and peripheral chemoreflex sensitivity in older and clinical populations.

Oxidative stress caused by poor oral condition is associated with systemic diseases, including cardiovascular disease. In this work, therefore, we examined the effect of allopurinol, an inhibitor of the reactive oxygen species (ROS)-producing enzyme xanthine oxidase, on cardiac dysfunction in our bite-opening (BO) mouse model, in which a suitable appliance is cemented onto the mandibular incisior. After two weeks, we confirmed that cardiac function was significantly decreased in the BO group compared to the control, while allopurinol ameliorated the dysfunction. The impairment of cardiac function in BO mice was associated with increased production of ROS by xanthine oxidase, leading to the activation of calmodulin kinase II, and altered phosphorylation of ryanodine receptor 2 and phospholamban. These changes were also suppressed by allopurinol. Our results suggest that oxidative stress might play an important role in the development of cardiac dysfunction, and further indicate that allopurinol is protective against BO-induced cardiac dysfunction.

Glioblastoma cells are known to regulate their cellular plasticity in response to their surrounding microenvironment, but it is not fully understood what factors contribute to the cells' changing plasticity. Here, we found that glioblastoma cells alter the expression level of adrenoreceptors depending on their differentiation stage. Catecholamines are abundant in the central nervous system, and we found that noradrenaline, in particular, enhances the stemness of glioblastoma cells and promotes the dedifferentiation potential of already differentiated glioblastoma cells. Antagonist and RNAi experiments revealed that signaling through α1D-adrenoreceptor is important for noradrenaline action on glioblastoma cells. We also found that high α1D-adrenoreceptor expression was associated with poor prognosis in patients with gliomas. These data suggest that glioblastoma cells increase the expression level of their own adrenoreceptors to alter the surrounding tumor microenvironment favorably for survival. We believe that our findings will contribute to the development of new therapeutic strategies for glioblastoma.

Some thermosensitive transient receptor potential (TRP) channels form a protein complex with anoctamin 1 (ANO1, also called TMEM16A). TRP channels have high calcium permeability, and the calcium entering cells through TRP channel activation activates ANO1, a calcium-activated chloride channel, involved in many physiological and pathological conditions. The physiological significance of TRP channels is often mediated by their ability to activate ANO1, which controls chloride flux across the plasma membrane. This review summarizes the latest understanding on the interactions between ANO1 and thermosensitive TRP channels, including TRPV1, TRPV3, and TRPV4, which are involved in pain sensitization in primary sensory neurons, proliferation and migration of human keratinocytes, and fluid secretion such as sweat, respectively.