Relationship between the severity of pre-frailty and the degree of adaptation of Ninjin'yoeito (NYT) on pre-frailty.

With the global trend towards longer life expectancies, there's an increasing emphasis on not just living longer, but also maintaining health and wellbeing into older age. This study explores the efficacy of Ninjin'yoeito (NYT) in the early stages of frailty, a critical period for preventive interventions. Taking account of the knowledge gap regarding the association between early frailty and NYT, we use data from workplace health checkups to examine the relationship between pre-frailty severity and NYT adaption. The objective of our research is to enhance the comprehension of early treatments using NYT to prevent the progression of frailty. A total of 314 employees of the Kyoto Industrial Health Association who received workplace health checkups between November 2021 and March 2023 and consented to this study were included in the analysis. Information on gender, age, body mass index (BMI), NYT-specific symptoms assessment, the Japanese version of the General Health Questionnaire-12 (GHQ-12), and the Kihon Checklist (KCL) were obtained. The correlation analysis revealed that there was a strong positive correlation between the number of applicable NYT indications and the GHQ-12 score (r = 0.5992, p < 0.0001). Similarly, a moderate positive correlation was observed between the number of applicable NYT indications and the KCL score (r = 0.5030, p < 0.0001). In the multivariate analysis, both GHQ-12 (ß = 0.49, SE = 0.06, t = 7.66, 95% CI: 0.36 to 0.62, p = 0.000) and KCL (ß = 0.54, SE = 0.12, t = 4.29, 95% CI: 0.29 to 0.79, p = 0.000) showed significant positive associations with the variance in the number of applicable NYT indications, indicating that higher scores on these measures were related to a greater number of indications. NYT has the potential to be utilized not only as a therapeutic intervention for frailty, but also as a preventive measure.

The Role of Ion-Transporting Proteins in Human Disease.

This Special Issue focuses on the significance of ion-transporting proteins, such as ion channels and transporters, providing evidence for their significant contribution to bodily and cellular functions via the regulation of signal transduction and ionic environments [...].

Ambroxol-Enhanced Frequency and Amplitude of Beating Cilia Controlled by a Voltage-Gated Ca2+ Channel, Cav1.2, via pHi Increase and [Cl-]i Decrease in the Lung Airway Epithelial Cells of Mice.

Ambroxol (ABX), a frequently prescribed secretolytic agent which enhances the ciliary beat frequency (CBF) and ciliary bend angle (CBA, an index of amplitude) by 30%, activates a voltage-dependent Ca2+ channel (CaV1.2) and a small transient Ca2+ release in the ciliated lung airway epithelial cells (c-LAECs) of mice. The activation of CaV1.2 alone enhanced the CBF and CBA by 20%, mediated by a pHi increasei and a [Cl-]i decrease in the c-LAECs. The increase in pHi, which was induced by the activation of the Na+-HCO3- cotransporter (NBC), enhanced the CBF (by 30%) and CBA (by 15-20%), and a decrease in [Cl-]i, which was induced by the Cl- release via anoctamine 1 (ANO1), enhanced the CBA (by 10-15%). While a Ca2+-free solution or nifedipine (an inhibitor of CaV1.2) inhibited 70% of the CBF and CBA enhancement using ABX, CaV1.2 enhanced most of the CBF and CBA increases using ABX. The activation of the CaV1.2 existing in the cilia stimulates the NBC to increase pHi and ANO1 to decrease the [Cl-]i in the c-LAECs. In conclusion, the pHi increase and the [Cl-]i decrease enhanced the CBF and CBA in the ABX-stimulated c-LAECs.

Physiological roles of chloride ions in bodily and cellular functions.

Physiological roles of Cl-, a major anion in the body, are not well known compared with those of cations. This review article introduces: (1) roles of Cl- in bodily and cellular functions; (2) the range of cytosolic Cl- concentration ([Cl-]c); (3) whether [Cl-]c could change with cell volume change under an isosmotic condition; (4) whether [Cl-]c could change under conditions where multiple Cl- transporters and channels contribute to Cl- influx and efflux in an isosmotic state; (5) whether the change in [Cl-]c could be large enough to act as signals; (6) effects of Cl- on cytoskeletal tubulin polymerization through inhibition of GTPase activity and tubulin polymerization-dependent biological activity; (7) roles of cytosolic Cl- in cell proliferation; (8) Cl--regulatory mechanisms of ciliary motility; (9) roles of Cl- in sweet/umami taste receptors; (10) Cl--regulatory mechanisms of with-no-lysine kinase (WNK); (11) roles of Cl- in regulation of epithelial Na+ transport; (12) relationship between roles of Cl- and H+ in body functions.

Variability of serum CYFRA 21 - 1 and its susceptibility to clinical characteristics in individuals without cancer: a 4-year retrospective analysis.

BACKGROUND: CYFRA 21 - 1 is a useful marker for diagnosing and monitoring lung cancer. However, its stability remains unclear. Moreover, while its applicability to screening is now being investigated, CYFRA 21 - 1 levels in individuals without cancer, who are targets for cancer screening, have not yet been the focus of research. Therefore, the present study investigated variability in and the factors increasing serum CYFRA 21 - 1 levels. METHODS: This retrospective study recruited 951 individuals undergoing annual medical examinations for six years. We used data obtained in the first four years. Variability in serum CYFRA 21 - 1 levels over a period of four years were investigated. CYFRA 21 - 1 was categorized as normal (≤ 3.5 ng/ml) or elevated (> 3.5 ng/ml). The rate of an elevated level in one visit and the transition from an elevated to normal level between visits were visualized. A multiple logistic regression model was used to study the relationships between the frequency of elevated CYFRA 21 - 1 levels and clinical characteristics, such as age, sex, body mass index, weight changes, and the smoking status. RESULTS: Approximately 5% of subjects had elevated CYFRA 21 - 1 levels once in five tests over four years, while 15% had elevated CYFRA 21 - 1 levels once or more. Among subjects with elevated CYFRA 21 - 1 levels in one blood test, between 63 and 72% had normal levels in the next test. The median CYFRA 21 - 1 level in subjects with elevations in one blood test significantly decreased in the next test at all four time points. The frequency of elevated CYFRA 21 - 1 levels was associated with an older age [odds ratio (OR) = 6.99, 95% confidence interval (CI) = 3.01-16.2], current heavy smoking (OR = 3.46, 95% CI = 1.52-7.9), and weight loss (OR = 1.86, 95% CI = 1.07-3.24). CONCLUSIONS: Variability in and the factors increasing serum CYFRA 21 - 1 levels beyond the cut-off value need to be considered when interpretating CYFRA 21 - 1 test results. The future application of CYFRA 21 - 1 to lung cancer screening may require more than a single measurement.

Therapeutic potential of multifunctional myricetin for treatment of type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia, insulin resistance, and insufficient insulin secretion. It is considered that chronic hyperglycemia causes serious problems due to diabetic complications such as retinopathy, nephropathy, and neuropathy. Primarily, treatment in T2DM is pharmacologically tried by using drugs that are insulin sensitizers, insulin secretagogues, α-glucosidase inhibitors, and glucose transporter inhibitors. However, long-term application of these drugs frequently induces various harmful side effects, suggesting that the importance of taking advantage of natural products like phytochemicals. Accordingly, flavonoids, a group of phytochemicals, have attracted attention as components of natural products which are effective in the treatment of several diseases containing T2DM and are strongly recommended as food supplements to ameliorate T2DM-related complications. Several well-studied flavonoids such as quercetin and catechin are known to have anti-diabetic, anti-obesity, and anti-hypertensive actions, although a huge number of flavonoids are still under investigation and their actions are not fully understood. In this situation, myricetin is being shown to be a multiple bioactive compound to prevent and/or suppress hyperglycemia through inhibiting digestion and uptake of saccharides and enhancing insulin secretion as a possible GLP-1 receptor agonist, and to ameliorate T2DM-related complications by protecting endothelial cells from oxidative stress induced by hyperglycemia. In this review, we summarize the multiple effects of myricetin on the targets of T2DM treatment, comparing with different flavonoids.

Molecular Mechanisms of Obesity-Induced Development of Insulin Resistance and Promotion of Amyloid-ß Accumulation: Dietary Therapy Using Weak Organic Acids via Improvement of Lowered Interstitial Fluid pH.

Insulin resistance is one of the etiologies of type 2 diabetes mellitus (T2DM) and has been suggested to contribute to the development of Alzheimer's disease by promoting amyloid-ß accumulation. Various causes of insulin resistance have been suggested; however, mechanisms of insulin resistance development remain to be elucidated in many respects. Elucidating the mechanisms underlying the development of insulin resistance is one of the key factors in developing methods to prevent the onset of T2DM and Alzheimer's disease. It has been suggested that the body pH environment plays an important role in the control of cellular functions by regulating the action of hormones including insulin and the activity of enzymes and neurons, thereby maintaining homeostatic conditions of the body. This review introduces: (1) Mitochondrial dysfunction through oxidative stress caused by obesity-induced inflammation. (2) Decreased pH of interstitial fluid due to mitochondrial dysfunction. (3) Development of insulin resistance due to diminution of insulin affinity to its receptor caused by the lowered interstitial fluid pH. (4) Accelerated accumulation of amyloid-ß due to elevated activities of ß- and γ-secretases caused by the lowered interstitial fluid pH. (5) Diet therapies for improving insulin resistance with weak organic acids that act as bases in the body to raise the pH of lowered interstitial fluid and food factors that promote absorption of weak organic acids in the gut.

A big data-based prediction model for prostate cancer incidence in Japanese men.

To define a normal range for PSA values (ng/mL) by age and create a prediction model for prostate cancer incidence. We conducted a retrospective analysis using 263,073 observations of PSA values in Japanese men aged 18-98 years (2007-2017), including healthy men and those diagnosed with prostate cancer. Percentiles for 262,639 PSA observations in healthy men aged 18-70 years were calculated and plotted to elucidate the normal fluctuation range for PSA values by age. Univariable and multivariable logistic regression analyses were performed to develop a predictive model for prostate cancer incidence. PSA levels and PSA velocity increased with age in healthy men. However, there was no difference in PSA velocity with age in men diagnosed with prostate cancer. Logistic regression analysis showed an increased risk of prostate cancer for PSA slopes ranging from 0.5 to 3.5 ng/mL/year. This study provides age-specific normal fluctuation ranges for PSA levels in men aged 18-75 years and presents a novel and personalized prediction model for prostate cancer incidence. We found that PSA slope values of > 3.5 ng/mL/year may indicate a rapid increase in PSA levels caused by pathological condition such as inflammation but are unlikely to indicate cancer risk.

Mumefural prevents insulin resistance and amyloid-beta accumulation in the brain by improving lowered interstitial fluid pH in type 2 diabetes mellitus.

The present study tried to clarify if mumefural would prevent hyperglycemia, one of the typical symptoms of type 2 diabetes mellitus (T2DM), since mumefural is an extract from Japanese apricots preventing hyperglycemia. To clarify if mumefural would prevent T2DM pathogenesis, we used Otsuka Long-Evans Tokushima fatty (OLETF) rats, T2DM model. Mumefural diminished hyperglycemia, HOMA-IR and plasma triglyceride concentration in OLETF rats under fasting conditions. In addition, mumefural elevated protein expression of sodium-coupled monocarboxylate transporter 1 (SMCT1) in the distal colon participating in absorption of weak organic acids, which behave as bases but not acids after absorption into the body. Mumefural also increased the interstitial fluid pH around the brain hippocampus lowered in OLETF rats compared with non-T2DM LETO rats used as control for OLETF rats. Amyloid-beta accumulation in the brain decreased in accordance with the pH elevation. On the one hand, mumefural didn't affect plasma concentrations of glucagon, GLP-1, GIP or PYY under fasting conditions. Taken together, these observations indicate that: 1) mumefural would be a useful functional food improving hyperglycemia, insulin resistance and the lowered interstitial fluid pH in T2DM; 2) the interstitial fluid pH would be one of key factors influencing the accumulation of amyloid-beta.

Ambroxol-enhanced ciliary beating via voltage-gated Ca2+ channels in mouse airway ciliated cells.

Ambroxol (ABX) facilitates the mucociliary clearance (MC) by enhancing ciliary beating in airways. In this study, we focused on airway ciliary beating enhanced by ABX. However, little is known about the ABX-stimulated Ca2+ signalling activating airway ciliary beating. Airway ciliated cells isolated from mice lungs were observed by a high-speed video microscope, and the activities of beating cilia were assessed by CBF (ciliary beat frequency) and CBD (ciliary bend distance, an index of amplitude). ABX (10 µM) enhanced the CBF and CBD by 30%, and the enhancement was inhibited by nifedipine (20 µM, a L-type voltage-gated Ca2+ channel (CaV) inhibitor), or a Ca2+-free solution (approximately 50%). Pre-treatment with BAPTA-AM (10 µM, a chelator of intracellular Ca2+) abolished ABX-stimulated increases in CBF, CBD and [Ca2+]i. Thus, ABX increases [Ca2+]i (intracellular Ca2+ concentration) by stimulating Ca2+ release from the internal stores and nifedipine-sensitive Ca2+ entry. A previous study demonstrated the expression of CaV1.2 in airway cilia. ABX enhanced CBF, CBD and [Ca2+]i even in a high extracellular K+ concentration (155.5 mM), suggesting that it activates CaV1.2 except by depolarization. These enhancements were inhibited by nifedipine. In conclusion, ABX, which increases [Ca2+]i by stimulating Ca2+ release from internal stores and Ca2+ entry through CaV1.2s, enhanced CBF and CBD in airway ciliated cells. ABX is a novel agonist that modulates CaV1.2 of airway beating cilia to enhance CBF and CBD.

TRPV3-ANO1 interaction positively regulates wound healing in keratinocytes.

Transient receptor potential vanilloid 3 (TRPV3) belongs to the TRP ion channel super family and functions as a nonselective cation channel that is highly permeable to calcium. This channel is strongly expressed in skin keratinocytes and is involved in warmth sensation, itch, wound healing and secretion of several cytokines. Previous studies showed that anoctamin1 (ANO1), a calcium-activated chloride channel, was activated by calcium influx through TRPV1, TRPV4 or TRPA1 and that these channel interactions were important for TRP channel-mediated physiological functions. We found that ANO1 was expressed by normal human epidermal keratinocytes (NHEKs). We observed that ANO1 mediated currents upon TRPV3 activation of NHEKs and mouse skin keratinocytes. Using an in vitro wound-healing assay, we observed that either a TRPV3 blocker, an ANO1 blocker or low chloride medium inhibited cell migration and proliferation through p38 phosphorylation, leading to cell cycle arrest. These results indicated that chloride influx through ANO1 activity enhanced wound healing by keratinocytes.

Transforming Growth Factor-ß1 and Bone Morphogenetic Protein-2 Inhibit Differentiation into Mature Ependymal Multiciliated Cells.

Ependymal cilia play pivotal roles in cerebrospinal fluid flow. In the primary culture system, undifferentiated glial cells differentiate well into ependymal multiciliated cells (MCCs) in the absence of fetal bovine serum (FBS). However, the substances included in FBS which inhibit this differentiation process have not been clarified yet. Here, we constructed the polarized primary culture system of ependymal cells using a permeable filter in which they retained ciliary movement. We found that transforming growth factor-ß1 (TGF-ß1) as well as Bone morphogenetic protein (BMP)-2 inhibited the differentiation with ciliary movement. The inhibition on the differentiation by FBS was recovered by the TGF-ß1 and BMP-2 inhibitors in combination.

Secondary bile acid lithocholic acid attenuates neurally evoked ion transport in the rat distal colon.

The inhibitory action of the secondary bile acid lithocholic acid (LCA) on neurally evoked Cl-/HCO3- secretion was investigated using the Ussing-chambered mucosal-submucosal preparation from the rat distal colon. Electrical field stimulation (EFS) evoked cholinergic and noncholinergic secretory responses in the rat distal colon. The responses were almost completely blocked by TTX (10-6 M) but not atropine (10-5 M) or hexamethonium (10-4 M). The selective antagonist for VIP receptor 1 (VPAC1) greatly reduced the EFS-evoked response. Thus, the rat distal colon may be predominantly innervated by noncholinergic VIP secretomotor neurons. Basolateral addition of 6 × 10-5 M LCA inhibited the EFS-evoked response. The inhibitory action of LCA was partly rescued by the Y2R antagonist BIIE0246. The bile acid receptor TGR5 agonist INT-777 mimicked the LCA-induced inhibitory action. Immunohistochemical staining showed the colocalization of TGR5 and PYY on L cells. TGR5 immunoreactivity was also found in VIP-immunoreactive submucosal neurons which also expressed the PYY receptor, Y2R. These results suggest that LCA inhibits neurally evoked Cl-/HCO3- secretion through the activation of TGR5 on L cells and cholinergic- and VIP-secretomotor neurons in the submucosal plexus. Furthermore, the inhibitory mechanism may involve TGR5-stimulated PYY release from L cells and Y2R activation in VIP-secretomotor neurons.

Detection and categorization of severe cardiac disorders based solely on heart period measurements.

Cardiac disorders are common conditions associated with a high mortality rate. Due to their potential for causing serious symptoms, it is desirable to constantly monitor cardiac status using an accessible device such as a smartwatch. While electrocardiograms (ECGs) can make the detailed diagnosis of cardiac disorders, the examination is typically performed only once a year for each individual during health checkups, and it requires expert medical practitioners to make comprehensive judgments. Here we describe a newly developed automated system for alerting individuals about cardiac disorders solely by measuring a series of heart periods. For this purpose, we examined two metrics of heart rate variability (HRV) and analyzed 1-day ECG recordings of more than 1,000 subjects in total. We found that a metric of local variation was more efficient than conventional HRV metrics for alerting cardiac disorders, and furthermore, that a newly introduced metric of local-global variation resulted in superior capacity for discriminating between premature contraction and atrial fibrillation. Even with a 1-minute recording of heart periods, our new detection system had a diagnostic performance even better than that of the conventional analysis method applied to a 1-day recording.

Association between 3-Year Repetitive Isolated Hematuria and eGFR Deterioration in an Apparently Healthy Population: A Retrospective Cohort Study.

Microscopic hematuria is being increasingly recognized as a major indicator of kidney deterioration. Persistent hematuria may better detect estimated glomerular filtration rate (eGFR) deterioration and potential glomerulonephritis. We conducted a retrospective cohort study to investigate the associations between persistent hematuria: the frequency or consistency of positive dipstick hematuria defined by the preceding 3 years urinalyses, and eGFR deterioration over 5 years and abnormal urinalyses suggesting potential glomerulonephritis (hematuria 1+ or higher, 2+ or higher, proteinuria, and hematuria and proteinuria) 5 years later, among adult participants with positive dipstick hematuria at baseline in a large-scale Japanese health checkup setting (n = 2104). There was no significant association between persistent hematuria and eGFR deterioration over 5 years. The higher the frequency of preceding hematuria, the greater the RR of hematuria 5 years later; RRs of hematuria with preceding thrice, twice, or once hematuria were 3.64 [95% CI, 3.11-4.25], 2.97 [95% CI, 2.52-3.51], or 1.91 [95% CI, 1.58-2.30] for "hematuria 1+ or higher," and 7.13 [95% CI, 5.17-9.83], 4.26 [95% CI, 3.02-6.02], or 2.23 [95% CI, 1.52-3.27] for "hematuria 2+ or higher". The presence of both hematuria and proteinuria 5 years later was only associated with preceding thrice hematuria (RR: 2.35 [95% CI, 1.37-4.03]). In conclusion, persistent hematuria for 3 years was associated with hematuria and proteinuria that were suggesting glomerulonephritis, but not associated with eGFR deterioration over 5 years. Multiple dipstick urinalyses over years can add some values to detect potential glomerulonephritis as an early sign of chronic kidney diseases.

Age and Smoking Status Affect Serum Cytokeratin 19 Fragment Levels in Individuals Without Cancer.

BACKGROUND/AIM: Lung cancer is a frequent and fatal cancer that is difficult to diagnose in the early stages. CYFRA 21-1 is a serological marker currently used to diagnose and monitor lung cancer; however, its clinical use for screening is controversial. Therefore, the present study investigated the relationship between serum CYFRA 21-1 levels and clinical confounders. PATIENTS AND METHODS: We recruited 3,674 individuals who had never been diagnosed with any cancer. The relationships between high serum CYFRA 21-1 levels (≥3.5 ng/ml) and age, sex, body mass index, and smoking status were investigated. RESULTS: High serum CYFRA 21-1 levels (≥3.5 ng/ml) were detected in 5.1% of all subjects. High serum CYFRA 21-1 levels were observed in 7.3% of current smokers and 4.3% of non-smokers. The proportion of subjects with high serum CYFRA 21-1 levels was markedly higher in the older group (65 years and older, 11%) than in the younger group (younger than 45 years, 2.0%). High serum CYFRA 21-1 levels (≥3.5 ng/ml) were associated with older age [odds ratio (OR)=3.39, 95% confidence interval (CI)=1.79-6.41 for 55-64 years vs. <45 years, and OR=7.34, 95% CI=3.86-13.9 for ≥65 years vs. <45 years, respectively] and current smoking (OR=2.09, 95% CI=1.38-3.15 for current smoker vs. non-smoker). CONCLUSION: High serum CYFRA 21-1 levels were associated with an older age and current smoking, which may be considered as factors influencing CYFRA 21-1 levels.

Enhancement of airway ciliary beating mediated via voltage-gated Ca2+ channels/α7-nicotinic receptors in mice.

Acetylcholine (ACh), which activates muscarinic ACh receptors (mAChRs) and nicotinic ACh receptors (nAChRs), enhances airway ciliary beating by increasing the intracellular Ca2+ concentration ([Ca2+]i). The mechanisms enhancing airway ciliary beating by nAChRs have remained largely unknown, although those by mAChRs are well understood. In this study, we focused on the effects of α7-nAChRs and voltage-gated Ca2+ channels (CaVs) on the airway ciliary beating. The activities of ciliary beating were assessed by frequency (CBF, ciliary beat frequency) and amplitude (CBD, ciliary bend distance) measured by high-speed video microscopy. ACh enhanced CBF and CBD by 25% mediated by an [Ca2+]i increase stimulated by mAChRs and α7-nAChRs (a subunit of nAChR) in airway ciliary cells of mice. Experiments using PNU282987 (an agonist of α7-nAChR) and MLA (an inhibitor of α7-nAChR) revealed that CBF and CBD enhanced by α7-nAChR are approximately 50% of those enhanced by ACh. CBF, CBD, and [Ca2+]i enhanced by α7-nAChRs were inhibited by nifedipine, suggesting activation of CaVs by α7-nAChRs. Experiments using a high K+ solution with/without nifedipine (155.5 mM K+) showed that the activation of CaVs enhances CBF and CBD via an [Ca2+]i increase. Immunofluorescence and immunoblotting studies demonstrated that Cav1.2 and α7-nAChR are expressed in airway cilia. Moreover, IL-13 stimulated MLA-sensitive increases in CBF and CBD in airway ciliary cells, suggesting an autocrine regulation of ciliary beating by CaV1.2/α7-nAChR/ACh. In conclusion, a novel Ca2+ signalling pathway in airway cilia, CaV1.2/α7-nAChR, enhances CBF and CBD and activates mucociliary clearance maintaining healthy airways.

Association Between Cerebral Microbleeds and Circulating Levels of Mid-Regional Pro-Adrenomedullin.

BACKGROUND: Mid-regional pro-adrenomedullin (MR-proADM) is a novel biomarker for cognitive decline based on its association with cerebral small vessel disease (SVD). Cerebral microbleeds (MBs) are characteristic of SVD; however, a direct association between MR-proADM and MBs has not been explored. OBJECTIVE: We aimed to examine whether circulating levels of MR-proADM are associated with the identification of MBs by brain magnetic resonance imaging (MRI) and whether this association could be linked with cognitive impairment. METHODS: In total, 214 participants (mean age: 75.9 years) without history of cerebral infarction or dementia were prospectively enrolled. All participants underwent brain MRI, higher cognitive function testing, blood biochemistry evaluation, lifestyle examination, and blood MR-proADM measurement using a time-resolved amplified cryptate emission technology assay. For between-group comparisons, the participants were divided into two groups according to whether their levels of MR-proADM were normal (< 0.65 nmol/L) or high (≥0.65 nmol/L). RESULTS: The mean MR-proADM level was 0.515±0.127 nmol/L. There were significant between-group differences in age, hypertension, and HbA1c levels (p < 0.05). In the high MR-proADM group, the MR-proADM level was associated with the identification of MBs on brain MR images and indications of mild cognitive impairment (MCI). In participants with ≥3 MBs and MCI, high MR-proADM levels remained a risk factor after multivariate adjustment (OR: 2.94; p < 0.05). CONCLUSION: High levels of MR-proADM may be a surrogate marker for the early detection of cognitive decline associated with the formation of cerebral MBs. This marker would be valuable during routine clinical examinations of geriatric patients.

Ezrin knockdown reduces procaterol-stimulated ciliary beating without morphological changes in mouse airway cilia.

Mucociliary clearance, which is conducted by beating cilia cooperating with the surface mucous layer, is a major host defense mechanism of the airway epithelium. Ezrin, a crosslinker between membrane proteins and the actin cytoskeleton, is located in microvilli and around the basal bodies in airway ciliary cells. It is also likely that ezrin plays an important role in apical localization of ß2 adrenergic receptor (ß2AR) in airway ciliary cells. Here, we studied the physiological roles of ezrin by using trachea and airway epithelial cells prepared from ezrin-knockdown (Vil2kd/kd) mice. The trachea and airway ciliary cells of Vil2kd/kd mice presented a normal morphology and basal body orientation, suggesting that ezrin is not directly involved in development and planar cell polarity of cilia. Procaterol stimulates ciliary beating (frequency and amplitude) via ß2AR in the airway ciliary cells. In the Vil2kd/kd mice, airway ciliary beating stimulated with procaterol was partly inhibited due to the impairment of cell surface expression of ß2AR. These results suggest that ezrin regulates the beating of airway ciliary cells by promoting the apical surface localization of ß2AR. This article has an associated First Person interview with the first author of the paper.

Minimum biological domain of xenin-25 required to induce anion secretion in the rat ileum.

Xenin-25 has a variety of physiological functions in the gastrointestinal tract, including ion transport and motility. Xenin-25 and neurotensin show sequence homology, especially near their C-terminal regions. The sequence similarity between xenin-25 and neurotensin indicates that the effects of xenin-25 is mediated by the neurotensin receptor but some biological actions of xenin-25 are independent. We have previously reported that xenin-25 modulates intestinal ion transport and colonic smooth muscle activity. However, minimal biological domain of xenin-25 to induce ion transport was not clear. To improve the mechanistic understanding of xenin-25 and to gain additional insights into the functions of xenin-25, the present study was designed to determine the minimal biological domain of xenin-25 required for ion transport in the rat ileum using various truncated xenin fragments and analogues in an Ussing chamber system. The present results demonstrate that the minimum biological domain of xenin-25 to induce Cl-/HCO3- secretion in the ileum contains the C-terminal pentapeptide. Furthermore, Arg at position 21 is important to retain the biological activity of xenin-25 and induces Cl-/HCO3- secretion in the rat ileum.