Journal of Physiological Sciences最新文献

Emery-Dreifuss muscular dystrophy (EDMD), caused by mutations in genes encoding nuclear envelope proteins, is clinically characterized by muscular dystrophy, early joint contracture, and life-threatening cardiac abnormalities. To elucidate the pathophysiological mechanisms underlying striated muscle involvement in EDMD, we previously established a murine model with mutations in Emd and Lmna (Emd^-/-/Lmna^H222P/H222P; EH), and reported exacerbated skeletal muscle phenotypes and no notable cardiac phenotypes at 12 weeks of age. We predicted that lack of emerin in Lmna^H222P/H222P mice causes an earlier onset and more pronounced cardiac dysfunction at later stages. In this study, cardiac abnormalities of EDMD mice were compared at 18 and 30 weeks of age. Contrary to our expectations, physiological and histological analyses indicated that emerin deficiency causes no prominent differences of cardiac involvement in Lmna^H222P/H222P mice. These results suggest that emerin does not contribute to cardiomyopathy progression in Lmna^H222P/H222P mice.

Heat acclimation/acclimatisation (HA) mitigates heat-related decrements in physical capacity and heat-illness risk and is a widely advocated countermeasure for individuals operating in hot environments. The efficacy of HA is typically quantified by assessing the thermo-physiological responses to a standard heat acclimation state test (i.e. physiological biomarkers), but this can be logistically challenging, time consuming, and expensive. A valid molecular biomarker of HA would enable evaluation of the heat-adapted state through the sampling and assessment of a biological medium. This narrative review examines candidate molecular biomarkers of HA, highlighting the poor sensitivity and specificity of these candidates and identifying the current lack of a single 'standout' biomarker. It concludes by considering the potential of multivariable approaches that provide information about a range of physiological systems, identifying a number of challenges that must be overcome to develop a valid molecular biomarker of the heat-adapted state, and highlighting future research opportunities.

Mast cells are present in mucosal and connective tissues throughout the body. They synthesize and release a wide variety of bioactive molecules, such as histamine, proteases, and cytokines. In this study, we found that a population of connective tissue mast cells (CTMCs) stores and releases noradrenaline, originating from sympathetic nerves. Noradrenaline-storing cells, not neuronal fibers, were predominantly identified in the connective tissues of the skin, mammary gland, gastrointestinal tract, bronchus, thymus, and pancreas in wild-type mice but were absent in mast cell-deficient W-sash c-kit mutant Kit^W-sh/W-sh mice. In vitro studies using bone marrow-derived mast cells revealed that extracellular noradrenaline was taken up but not synthesized. Upon ionomycin stimulation, noradrenaline was released. Electron microscopy analyses further suggested that noradrenaline is stored in and released from the secretory granules of mast cells. Finally, we found that noradrenaline-storing CTMCs express organic cation transporter 3 (Oct3), which is also known as an extraneuronal monoamine transporter, SLC22A3. Our findings indicate that mast cells may play a role in regulating noradrenaline concentration by storing and releasing it in somatic tissues.

The regional differences in cerebral oxygen extraction fraction (OEF) in brain were investigated using positron emission tomography (PET) in detail with consideration of systemic errors in PET measurement estimated by simulation studies. The cerebral blood flow (CBF), cerebral blood volume (CBV), OEF, and cerebral metabolic rate of oxygen (CMRO₂) were measured on healthy men by PET with ¹⁵O-labeled gases. The OEF values in the pons and the parahippocampal gyrus were significantly smaller than in the other brain regions. The OEF value in the lateral side of the occipital cortex was largest among the cerebral cortical regions. Simulation studies have revealed that errors in OEF caused by regional differences in the distribution volume of ¹⁵O-labeled water, as well as errors in OEF caused by a mixture of gray and white matter, must be negligible. The regional differences in OEF in brain must exist which might be related to physiological meanings.Article title: Kindly check and confirm the edit made in the article title.I have checked the article title and it is OK as is. Trial registration: The UMIN clinical trial number: UMIN000033382, https://www.umin.ac.jp/ctr/index.htm.

A metabolite of acetaminophen, AM404, which is an anandamide transporter inhibitor, induces analgesia mainly via activation of transient receptor potential channel 1 in the spinal cord, although the role of cannabinoid receptors remains to be studied. The ventral root reflex response induced by stimulation of the dorsal root in in vitro preparations of rat spinal cord is useful to assess the effect of analgesics. We analyzed the effects of AM404 and cannabinoid receptor antagonist AM251 on reflex responses in lumbar spinal cord preparations from newborn rats and found that the amplitude of the slow ventral root potential after administration of 10 µM AM404 was not significantly changed, whereas 10 µM AM251 significantly increased the amplitude. Administration of the cannabinoid receptor 1 agonist WIN55,212-2 (10 µM) did not significantly affect the reflex response. We suggest that endogenous cannabinoids in the spinal cord are involved in the antinociceptive mechanism through suppressive effects.

Introduction: CCN5/WISP2 is prominently manifest in adipose tissue and has been linked to the pathogenesis of obesity, diabetes, and insulin resistance. However, discrepancies exist in previous studies, and little is known about its association with gestational diabetes mellitus (GDM). The current investigation is designed to examine the correlation of WISP2 with risk factors in GDM patients in comparison to healthy pregnant women for the first time.

Methods: This case-control study measured serum levels of CCN5, TNF-α, IL-6, adiponectin, and fasting insulin using ELISA kits in 88 GDM patients and 88 pregnant women.

Results: The GDM group had remarkably higher serum levels of CCN5 (379.41 ± 83.078 ng/ml) compared to controls (212.02 ± 77.935 ng/ml). In a similar vein, it was observed that patients diagnosed with GDM exhibited elevated levels of pro-inflammatory cytokines such as IL-6 and TNF-α; while conversely, adiponectin levels were found to be significantly lower than those observed in the control group (P < 0.0001). In women with GDM, a positive and significant correlation was observed between CCN5 and BMI, FBG, insulin, HOMA-IR, as well as IL-6 and TNF-α levels. In the adjusted model, the risk of GDM was significantly increased with elevated serum CCN5 level.

Conclusion: Our research indicates a noteworthy and affirmative correlation between the levels of CCN5 in the serum and the risk of developing GDM, along with its associated risk factors such as BMI, insulin resistance index, FBG, and inflammatory cytokines (TNF-α and IL-6). These findings suggest that CCN5 could potentially play a role in the etiology of GDM.

Intracellular calcium (Ca²⁺) signaling regulates many cellular functions, including cell proliferation and migration, in both normal cells and cancer cells. Store-operated Ca²⁺ entry (SOCE) is a major mechanism by which Ca²⁺ is imported from the extracellular space to the intracellular space, especially in nonexcitable cells. Store-operated Ca²⁺ entry (SOCE) is also a receptor-regulated Ca²⁺ entry pathway that maintains Ca²⁺ homeostasis by sensing reduced Ca²⁺ levels in the endoplasmic reticulum (ER). In general, the activation of G protein-coupled receptors (GPCRs) or immunoreceptors, such as T-cell, B-cell and Fc receptors, results in the production of inositol 1,4,5-trisphosphate (IP₃). IP₃ binds to IP₃ receptors located in the ER membrane. The, IP₃ receptors in the ER membrane trigger a rapid and transient release of Ca²⁺ from the ER store. The resulting depletion of ER Ca²⁺ concentrations is sensed by the EF-hand motif of stromal interaction molecule (STIM), i.e., calcium sensor, which then translocates to the plasma membrane (PM). STIM interacts with Orai Ca²⁺ channel subunits (also known as CRACM1) on the PM, leading to Ca²⁺ influx from the extracellular space to increase intracellular Ca²⁺ concentrations. The physiological functions of Orai and STIM have been studied mainly with respect to their roles in the immune system. Based on numerous previous studies, Orai channels (Orai1, Orai2 and Orai3 channels) control Ca²⁺ release-activated Ca²⁺ (CRAC) currents and contribute to SOCE currents in other types of cells, including various cancer cells. There are many reports that Orai1 is involved in cell proliferation, migration, metastasis, apoptosis and epithelial-mesenchymal transition (EMT) in various cancers. We previously found that Orai1 plays important roles in cell apoptosis and migration in melanoma. Recently, we reported novel evidence of Orai1 in human oral squamous cell carcinoma (OSCC) cells and human cardiac fibroblasts (HCFs). In this review, we present multiple physiological functions of Orai1 in various cancer cells and cardiac fibroblasts, including our findings.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have exerted cardioprotective effects in clinical trials, but underlying mechanisms are not fully understood. As mitigating sympathetic overactivity is of major clinical concern in the mechanisms of heart failure treatments, we examined the effects of modulation of glucose handling on baroreflex-mediated sympathetic nerve activity and arterial pressure regulations in rats with chronic myocardial infarction (n = 9). Repeated 11-min step input sequences were used for an open-loop analysis of the carotid sinus baroreflex. An SGLT2 inhibitor, empagliflozin, was intravenously administered (10 mg/kg) after the second sequence. Neither the baroreflex neural nor peripheral arc significantly changed during the last observation period (seventh and eighth sequences) compared with the baseline period although urinary glucose excretion increased from near 0 (0.0089 ± 0.0011 mg min^-1 kg^-1) to 1.91 ± 0.25 mg min^-1 kg^-1. Hence, empagliflozin does not acutely modulate the baroreflex regulations of sympathetic nerve activity and arterial pressure in this rat model of chronic myocardial infarction.

Neural stem cells (NSCs) are maintained in the adult mammalian brain throughout the animal's lifespan. NSCs in the subependymal zone infrequently divide and generate transit amplifying cells, which are destined to become olfactory bulb neurons. When transit amplifying cells are depleted, they are replenished by the quiescent NSC pool. However, the cellular basis for this recovery process remains largely unknown. In this study, we traced NSCs and their progeny after transit amplifying cells were eliminated by intraventricular infusion of cytosine β-D-arabinofuranoside. We found that although the number of neurosphere-forming NSCs decreased shortly after the treatment, they were restored to normal levels 3 weeks after the cessation of treatment. More importantly, the depletion of transit amplifying cells did not induce a significant expansion of the NSC pool by symmetric divisions. Our data suggest that the size of the NSC pool is hardly affected by brain damage due to antimitotic drug treatment.

In this work, we examined the involvement of type 5 adenylyl cyclase (AC5) in cardiac dysfunction induced in mice given Porphyromonas gingivalis lipopolysaccharide (PG-LPS) at a dose equivalent to the circulating levels in periodontitis (PD) patients. Cardiac function was significantly decreased in mice given PG-LPS compared to the control, but treatment for 1 week with the AC5 inhibitor vidarabine ameliorated the dysfunction. Cardiac fibrosis and myocyte apoptosis were significantly increased in the PG-LPS group, but vidarabine blocked these changes. The PG-LPS-induced cardiac dysfunction was associated with activation of cyclic AMP/Ca²⁺-calmodulin-dependent protein kinase II signaling and increased phospholamban phosphorylation at threonine 17. These results suggest that pharmacological AC5 inhibition may be a promising approach to treat PD-associated cardiovascular disease.