The epithelial zinc transporter ZIP10 epigenetically regulates human epidermal homeostasis by modulating histone acetyltransferase activity.

BACKGROUND: The skin is the first organ that manifests changes in response to zinc deficiency. However, the molecular mechanism underlying how zinc is involved in skin homeostasis, especially its epigenetic regulation, is largely unknown. OBJECTIVES: In this study we demonstrate the importance of zinc levels and the zinc transporter ZIP10 in the epigenetic maintenance of human epidermal homeostasis. METHODS: Adult human skin, including skin appendages, were stained with anti-ZIP10 antibody. Histone acetyltransferase (HAT) activity was assessed after treating human keratinocytes with ZIP10 small interfering (si)RNAs or the zinc chelator TPEN. ZIP10- or HAT-regulated genes were analysed based on limma bioinformatics analysis for keratinocytes treated with ZIP10 siRNAs or a HAT inhibitor, or using a public database for transcription factors. A reconstituted human skin model was used to validate the role of ZIP10 in epidermal differentiation and the functional association between ZIP10 and HAT. RESULTS: ZIP10 is predominantly expressed in the interfollicular epidermis, epidermal appendages and hair follicles. ZIP10 depletion resulted in epidermal malformations in a reconstituted human skin model via downregulation of the activity of the epigenetic enzyme HAT. This decreased HAT activity, resulting from either ZIP10 depletion or treatment with the zinc chelator TPEN, was readily restored by zinc supplementation. Through bioinformatics analysis for gene sets regulated by knockdown of SLC39A10 (encoding ZIP10) and HAT inhibition, we demonstrated that ZIP10 and HATs were closely linked with the regulation of genes related to epidermal homeostasis, particularly filaggrin and metallothionein. CONCLUSIONS: Our study suggests that ZIP10-mediated zinc distribution is crucial for epidermal homeostasis via HATs. Therefore, zinc-dependent epigenetic regulation could provide alternatives to maintaining healthy skin or alleviating disorders with skin barrier defects.

Evaluation of circadian phenotypes utilizing fibroblasts from patients with circadian rhythm sleep disorders.

We evaluated the circadian phenotypes of patients with delayed sleep-wake phase disorder (DSWPD) and non-24-hour sleep-wake rhythm disorder (N24SWD), two different circadian rhythm sleep disorders (CRSDs) by measuring clock gene expression rhythms in fibroblast cells derived from individual patients. Bmal1-luciferase (Bmal1-luc) expression rhythms were measured in the primary fibroblast cells derived from skin biopsy samples of patients with DSWPD and N24SWD, as well as control subjects. The period length of the Bmal1-luc rhythm (in vitro period) was distributed normally and was 22.80±0.47 (mean±s.d.) h in control-derived fibroblasts. The in vitro periods in DSWPD-derived fibroblasts and N24SWD-derived fibroblasts were 22.67±0.67 h and 23.18±0.70 h, respectively. The N24SWD group showed a significantly longer in vitro period than did the control or DSWPD group. Furthermore, in vitro period was associated with response to chronotherapy in the N24SWD group. Longer in vitro periods were observed in the non-responders (mean±s.d.: 23.59±0.89 h) compared with the responders (mean±s.d.: 22.97±0.47 h) in the N24SWD group. Our results indicate that prolonged circadian periods contribute to the onset and poor treatment outcome of N24SWD. In vitro rhythm assays could be useful for predicting circadian phenotypes and clinical prognosis in patients with CRSDs.

Amelioration of lacrimal gland inflammation by oral administration of K-13182 in Sjögren's syndrome model mice.

Regulation of the adhesion of mononuclear cells to endothelial cells is considered to be a critical step for the treatment of inflammatory diseases, including autoimmune diseases. K-13182 was identified as a novel inhibitor for these adhesions. K-13182 inhibited the expression of vascular cell adhesion molecule-1 (VCAM-1, CD106) on human umbilical vein endothelial cells (HUVECs) and on mouse vascular endothelial cell line (MAECs) induced by tumour necrosis factor (TNF)-alpha. K-13182 also inhibited the adhesion of mononuclear cells to these HUVECs and MAECs, indicating that K-13182 suppressed these adhesions mediated by cellular adhesion molecules including VCAM-1. To evaluate the therapeutic effect in autoimmune disease model mice, K-13182 was orally administered to non-obese diabetic (NOD) mice as Sjögren's syndrome (SS) model mice. Severe destructive inflammatory lesions were observed in the lacrimal glands of vehicle-treated control mice; however, 8-week administration of K-13182 inhibited the mononuclear cell infiltration into the inflammatory lesions of the lacrimal glands. In K-13182-treated mice, the decrease in tear secretion was also prevented compared to the control mice. In addition, the apoptosis and the expression of FasL (CD178), perforin, and granzyme A was suppressed in the lacrimal glands of K-13182-treated mice. Therefore, K-13182 demonstrated the possibility of therapeutic efficacy for the inflammatory region of autoimmune disease model mice. These data reveal that VCAM-1 is a promising target molecule for the treatment of autoimmune diseases as a therapeutic strategy and that K-13182 has the potential as a new anti-inflammatory drug for SS.

Diminished melatonin secretion in the elderly caused by insufficient environmental illumination.

The pineal hormone melatonin has some circadian regulatory effects and is assumed to have a close relation with sleep initiation and maintenance. Many previous reports have described age-related decreases in melatonin levels, especially in elderly insomniacs (EIs), which may act as causal or exacerbating factors in sleep disturbances in the elderly. Ten elderly residents with psychophysiological insomnia (mean age, 74.2 yr), 10 healthy residents of the same home [elderly control (EC) group; mean age, 72.7 yr], and 10 healthy young control subjects (mean age, 20.9 yr) living at home participated in this study. The elderly persons, especially the EIs, were exposed to significantly less environmental light and simultaneously suffered from significantly diminished nocturnal melatonin secretion. Supplementary exposure to 4 h (1000 to 1200 h, 1400 to 1600 h) of midday bright light in the EI group significantly increased melatonin secretion to levels similar to those in the young control group without circadian phase-shifting. There was a tendency for the magnitude of the increase in nocturnal melatonin secretion stimulated by bright light to parallel amelioration of sleep disturbances in these subjects. The present findings suggest that we need to pay attention to elderly individuals who suffer under conditions of poor environmental light resulting in disorganized circadian rhythms, including the sleep-wake cycle.

Supplementary administration of artificial bright light and melatonin as potent treatment for disorganized circadian rest-activity and dysfunctional autonomic and neuroendocrine systems in institutionalized demented elderly persons.

Increased daytime napping, early morning awakening, frequent nocturnal sleep interruptions, and lowered amplitude and phase advance of the circadian sleep-wake rhythm are characteristic features of sleep-waking and chronobiological changes associated with aging. Especially in elderly patients with dementia, severely fragmented sleep-waking patterns are observed frequently and are associated with disorganized circadian rhythm of various physiological functions. Functional and/or organic deterioration of the suprachiasmatic nucleus (SCN), decreased exposure to time cues such as insufficient social interaction and reduced environmental light, lowered sensitivity of sensory organs to time cues, and reduced ability of peripheral effector organs to express circadian rhythms may cause these chronobiological changes. In many cases of dementia, the usual treatments for insomnia do not work well, and the development of an effective therapy is an important concern for health care practitioner and researchers. Recent therapeutical trials of supplementary administration of artificial bright light and the pineal hormone melatonin, a potent synchronizer for mammalian circadian rhythm, have indicated that these treatments are useful tools for demented elderly insomniacs. Both bright light and melatonin simultaneously ameliorate disorganized thermoregulatory and neuroendocrine systems associated with disrupted sleep-waking times, suggesting a new, potent therapeutic means for insomnia in the demented elderly. Future studies should address the most effective therapeutic design and the most suitable types of symptoms for treatment and investigate the use of these tools in preventive applications in persons in early stages of dementia.

Double-blind test on the efficacy of methylcobalamin on sleep-wake rhythm disorders.

The therapeutic effect of methylcobalamin (Met-12) on sleep-wake rhythm disorders was examined in a double-blind test. In the test group which was given a large dosage, a higher percentage of improvement was found compared to the control group with a small dosage, although the difference was not significant. The test group inconsistently showed significant improvement in both the sleep-wake cycle parameters and in clinical symptoms. The tendency was for the results to show a beneficial effect of Met-12 on rhythm disorders. However, because the percentage of improvement was low and significant improvement was inconsistent, Met-12 might be considered to have a low therapeutic potency and possible use as a booster for other treatment methods of the disorders.

Expandable metallic stent treatment for malignant colorectal strictures.

Four patients were treated by placement of an expandable metallic stent (two Gianturco Z-stents, two Ultraflex stents) for malignant colorectal strictures. All four patients were able to defecate after stent placement. Stent migration was recognized in one patient. Two patients suffered from tenesmus after stent placement.

Randomized, dim light controlled, crossover test of morning bright light therapy for rest-activity rhythm disorders in patients with vascular dementia and dementia of Alzheimer's type.

The authors compared the therapeutic effect of morning bright and dim light exposure on rest-activity (R-A) rhythm disorders in patients with vascular dementia (VD) and patients with dementia of Alzheimer's type (DAT). Participants in this study were 12 patients with VD (M/F = 5/7; average age = 81 years) and 10 patients with DAT (M/F = 4/6; average age = 78 years). They were exposed to 2 weeks of bright light (BL; 5000-8000 lux) and 2 weeks of dim light (DL; 300 lux) in the morning (09:00-11:00) in a randomized crossover design in which the 2-week treatment period took place between pretreatment (1 week) and posttreatment (1 week) periods. Continuous R-A monitoring was performed at 1-minute intervals throughout the study using an actigraph around the nondominant wrist. The BL exposure for 2 weeks induced a significant reduction in both nighttime activity and percentages of nighttime activity to total activity compared with the pretreatment period, as well as compared with the DL condition in the VD group, but not in the DAT group. These findings support the assumption that the therapeutic efficacies of morning BL exposure are prominent in VD patients and are mainly due to its photic effect rather than nonphotic effects such as the intensification of social interaction accompanying light therapy.

[Clinical experience of autologous blood transfusion and fibrin glue in neurosurgery].

Clinical experience of autologous blood preservation on 83 patients and transfusion on 43 patients were reported. When drawing blood, 14 patients whose hemoglobin level was below 13 g/dl (body weight < 70 kg) or 14 g/dl (body weight > 70 kg) received subcutaneous recombinant human erythropoietin injection (s.c.) to facilitate erythropoiesis, according to the internal standard protocol. Hemoglobin levels of all the patients recovered to more than 10 g/dl by the time they were admitted to the hospital, which value would not interfere with general neurosurgical procedures. The injection of erythropoietin did not cause any side effects. Autologous blood transfusion was performed in 43 patients but, in 3 patients, additional homologous transfusion was required because of excessive bleeding. Except in cases with meningioma, postoperative hemoglobin values were identical with preoperative values, indicating that autologous blood transfusion was enough to replace intraoperative blood loss. Autologous fibrin glue was applied in 74 patients. In 70 cases including 55 with skull base surgery, the glue was applied to ensure dural closure. The incidence of cerebrospinal fluid leakage was 16.4% (5 patients) in skull base surgery. This incidence was identical to or less than that in previous reports. The glue was also effective in transposing and fixing offending vessels in 4 cases which received microvascular decompression. As a conclusion, procedures for autologous blood preservation and transfusion were safely performed in neurosurgical cases. Review of the literature was also presented to discuss the advantages and problems to be solved in the future.

Amelioration by aniracetam of abnormalities as revealed in choice reaction performance and shuttle behavior.

To delineate the possible effects of aniracetam PO on abnormal behaviors, we analyzed disrupted shuttle behavior and choice reaction (CR) performance in both aged and juvenile animals subjected to an ischemic (permanent occlusion of both carotid arteries)-hypoxic (17-min exposure to 93% N2 and 7% O2 mixture gas) or ischemic (20-min occlusion of both carotid arteries) insult and/or treated with methamphetamine given IP. Aniracetam at single PO doses of 10 and 30 mg/kg significantly decreased the number of incorrect lever pressings induced by IP methamphetamine in young adult rats subjected to the CR test battery. A 21-day PO regimen with aniracetam (30 mg/kg/day) resulted in an increase in the number of correct responses and a decrease in the CR latency as detected in the CR task with young adult rats inflicted with an ischemic-hypoxic insult. Aniracetam (1-100 mg/kg PO) was also evaluated in the electrostimulation-induced hyperreactivity assay (an increase in the number of shuttle responses) in both juvenile and aged mice subjected to a 20-min ischemic insult; there again a significant improvement of performance was clearly observed. The outcomes of these behavioral pharmacological analyses suggest that aniracetam has the ability to normalize the disrupted behavior, cognition, and self-regulation or decision-making process in a comprehensive way.

Morning bright light therapy for sleep and behavior disorders in elderly patients with dementia.

Fourteen inpatients with dementia showing sleep and behavior disorders (average age = 75 years), and 10 control elderly people (average age = 75 years) were carefully observed for 2 months. Four weeks of morning light therapy markedly improved sleep and behavior disorders in the dementia group. The measurement of sleep time and the serum melatonin values suggests that sleep and behavior disorders in the dementia group are related to decreases in the amplitude of the sleep-wake rhythm and decreases in the levels of melatonin secretions. Morning light therapy significantly increased total and nocturnal sleep time and significantly decreased daytime sleep time. These results indicate that morning bright light is a powerful synchronizer that can normalize disturbed sleep and substantially reduce the frequency of behavior disorders in elderly people with dementia.

Reappraisal of the corticothalamic and thalamocortical interactions that contribute to the augmenting response in the rat.

In urethane-anesthetized rats, low frequency electrical stimulation of the thalamic radiation (TR) evoked an augmenting response in the somatosensory cortex (SCx) which was followed by rhythmic slow waves. The augmenting response mainly consists of the incremental secondary response (II-response). Simultaneously, augmentation also occurs in the ventrobasal nucleus of thalamus (VB) on the late component responses, C- and D-waves, to TR stimulation. The latencies of these augmented responses were shorter for the C-wave and the accompanying unit discharges in the VB relay neurons than for the D-wave and the II-response. We hypothesized that the thalamo-cortico-thalamic reverberating circuit was crucial in generating the augmenting response in the SCx. To test this hypothesis, an attempt was made to block temporarily the corticothalamic glutamatergic transmission by means of microinjections of kynurenate (KYN), an antagonist of glutamate, into the VB with a dose of more than 2 mM. This local procedure blocked all of the augmenting phenomena completely with a full recovery after the duration that depended on the dose of KYN. Besides, in the stage of complete blocking of the II-response to the test TR stimuli, the augmentation was able to be restored by adding a short train of high frequency TR stimuli that mimicked a burst discharge of VB relay neurons. These results in support of the hypothesis would reappraise the functional significance of the reverberating circuit in augmentation that has recently been controversial.