Melatonin reduces IL-33 and TSLP expression in human nasal epithelial cells by scavenging ROS directly.

BACKGROUND: Chronic rhinosinusitis (CRS) is a chronic mucosal inflammation of the nasal cavity and sinuses. It is classified into CRS without nasal polyps and CRS with nasal polyps (CRSwNP). CRSwNP has high recurrence, especially CRSwNP with massive eosinophil infiltration which is mediated by type 2 inflammatory response. Melatonin is a hormone secreted by the pineal gland, it has powerful antioxidant and anti-inflammatory effects in addition to regulating biological rhythms. There are no studies on melatonin for the treatment of CRS, so we aimed to explore whether melatonin could be used for the treatment of CRS. MATERIALS AND METHODS: In this study, we used melatonin to treat a cell model of CRS. Subsequently, MTT assay was performed to examine the cell viability of human nasal epithelial cells (HNEpCs), a reactive oxygen species (ROS) kit to detect ROS production, a malondialdehyde (MDA) kit to detect the MDA content in the cell culture supernatant, and an apoptosis kit and Western blot analysis to detect apoptosis. The expressions of Nrf2, HO-1, IL-33, TSLP, and IL-25 were detected by Western blot analysis. RESULTS: Melatonin improved the viability of HNEpCs, reduced lipopolysaccharide-induced ROS, reduced the MDA content, and inhibited their apoptosis. More importantly, melatonin reduced the expression of IL-33 and TSLP, an important phenomenon for the treatment of CRSwNP. CONCLUSION: Melatonin protects HNEpCs from damage in inflammation and reduces IL-33 and TSLP expression of HNEpCs.

HO-1: a new marker for predicting postoperative recurrence of CRSwNP.

BACKGROUND: Chronic rhinosinusitis with polyps (CRSwNP) is a subtype of chronic rhinosinusitis and is highly prone to recurrence; therefore, it is urgent to find appropriate markers to predict recurrence of CRSwNP after surgery. PURPOSE: We aim to investigate the expression of HO-1 in CRSwNP and assess its value of predicting postoperative recurrence of CRSwNP. METHODS: We recruited 77 participants and collected clinical data of all. We use Immunohistochemical staining to determine the expression of HO-1 in tissues. We use Spearman correlation test to analyze the correlation between HO-1 positive cell count and clinical score, and ROC curve to assess the value of HO-1 positive cell count in predicting recurrence of CRSwNP. RESULTS: HO-1 positive cells were macrophages and significantly increased in CRSwNP; HO-1 positive cell count was negatively correlated with preoperative SNOT-22 score; HO-1 can predict postoperative recurrence of CRSwNP, AUC = 0.80, p = 0.004. CONCLUSION: HO-1 is a biochemical marker of CRSwNP and can predict postoperative recurrence of CRSwNP.

Recessive/dominant model: Alternative choice in case-control-based genome-wide association studies.

An additive genetic model is usually employed in case-control-based genome-wide association studies. The model usually encodes "AA", "Aa" and "aa" ("a" represents the minor allele) as three different numbers, implying the contribution of genotype "Aa" to the phenotype is different from "AA" and "aa". From the perspective of biological phenomena, the coding is reasonable since the phenotypes of lives are not "black and white". A case-control based study, however, has only two phenotypes, case and control, which means that the phenotypes are "black and white". It suggests that a recessive/dominant model may be an alternative to the additive model. In order to investigate whether the alternative is feasible, we conducted comparative experiments on several models used in those studies through chi-square test and logistic regression. Our simulation experiments demonstrate that a recessive model is better than the additive model. The area under the curve of the former has increased by 5% compared with the latter, the discrimination of identifying risk single nucleotide polymorphisms has been improved by 61%, and the precision has also reached 1.10 times that of the latter. Furthermore, the real data experiments show that the precision and area under the curve of the former are 16% and 20% higher than the latter respectively, and the area under the curve of dominant model of the former is 13% higher than the latter. The results indicate a recessive/dominant model may be an alternative to the additive model and suggest a new route for case-control-based studies.

Chronic modafinil therapy ameliorates depressive-like behavior, spatial memory and hippocampal plasticity impairments, and sleep-wake changes in a surgical mouse model of menopause.

Depression, cognitive deficits, and sleep disturbances are common and often severe in menopausal women. Hormone replacement cannot effectively alleviate these symptoms and sometimes elicits life-threatening adverse reactions. Exploring effective therapies to target psychological problems is urgently needed. In this work, we developed a mouse model of menopause by bilateral ovariectomies (OVXs) and investigated whether menopausal mental symptoms can be ameliorated by psychostimulant modafinil (MOD) as well as explored the underlying mechanisms. At ~3 weeks after OVXs, mice got daily intraperitoneal administrations of MOD at the beginning of the active phase. Several behavioral tests and electroencephalogram (EEG) recordings were conducted. Electrophysiological and immunohistochemical experiments were carried out to evaluate the synaptic plasticity and neurogenesis, respectively. We found that chronic MOD administration in OVX mice significantly decreased immobility time. The spatial memory performance of OVX mice improved significantly in response to MOD administration in the Morris water-maze test. The OVX mice were characterized by an attenuation of hippocampal synaptic transmission and synaptic long-term potentiation and had fewer 5-ethynyl-2'-deoxyuridine-labeled cells in the dentate gyrus, which were restored after MOD administration. Antagonists of dopamine D1 and D2 receptors and GABAA receptor agonists were involved in MOD-exerted anti-depressant actions and augments of hippocampal neurogenesis in OVX mice. Moreover, night-dosed MOD therapy significantly promoted the night-time delta-band EEG power during wakefulness and the day-time rapid eye movement sleep amount, which were significantly reduced by OVXs. Collectively, these findings suggest that MOD is a promising therapeutic candidate for menopausal women.

Glutamate Activates the Histaminergic Tuberomammillary Nucleus and Increases Wakefulness in Rats.

Glutamate is the major excitatory neurotransmitter in the brain and plays an essential role in regulating wakefulness. Histaminergic neurons, which are exclusively localized in the tuberomammillary nucleus (TMN) of the hypothalamus, have a pivotal role in the regulation of sleep-wake patterns by sending widespread projections into many brain areas implicated in sleep-wake control. The role of glutamate in histaminergic neurons within the TMN and the resulting sleep-wake profile remains unknown. We found that glutamate, NMDA, AMPA or dihydrokainate, a glutamate-uptake inhibitor, dose-dependently increased wakefulness when microinjected into the rat TMN. Glutamate, NMDA, and AMPA also increased the firing rate of action potentials in TMN histaminergic neurons. The arousal-promoting effect of glutamate was inhibited by NMDA and histamine H1 receptor antagonists. Furthermore, MK-801, an NMDA receptor antagonist, inhibited the firing rate of histaminergic neurons and increased non-rapid eye movement sleep after microinjection into rat TMN. Taken together, these findings demonstrated that glutamate activated histaminergic neurons in the TMN and increased wakefulness in rats, possibly via the action of NMDA and histamine H1 receptors.

Caveolin-1: a multifaceted driver of breast cancer progression and its application in clinical treatment.

Human breast cancer is one of the most frequent cancer diseases and causes of death among female population worldwide. It appears at a high incidence and has a high malignancy, mortality, recurrence rate and poor prognosis. Caveolin-1 (Cav1) is the main component of caveolae and participates in various biological events. More and more experimental studies have shown that Cav1 plays a critical role in the progression of breast cancer including cell proliferation, apoptosis, autophagy, invasion, migration and breast cancer metastasis. Besides, Cav1 has been found to be involved in chemotherapeutics and radiotherapy resistance, which are still the principal problems encountered in clinical breast cancer treatment. In addition, stromal Cav1 may be a potential indicator for breast cancer patients' prognosis. In the current review, we cover the state-of-the-art study, development and progress on Cav1 and breast cancer, altogether describing the role of Cav1 in breast cancer progression and application in clinical treatment, in the hope of providing a basis for further research and promoting CAV1 gene as a potential target to diagnose and treat aggressive breast cancers.

The factors associated with the early diagnosis of nasal NK/T-cell lymphoma with prominent ocular symptoms and general nasal NKTL.

AIM: This study explored the clinical features of nasal natural killer/T-cell lymphoma (NKTL) in patients with prominent ocular symptoms and those with general nasal NKTL to improve the early diagnosis of nasal NKTL. METHOD: A retrospective cohort study was performed with 278 patients with nasal NKTL admitted to the First Affiliated Hospital of Zhengzhou University between January 2011 and December 2017. Of these cases, 56 presented with nasal NKTL and prominent ocular symptoms, and 222 presented with general nasal NKTL. RESULTS: No significant differences in gender and age distribution were found between patients with general nasal NKTL and those with nasal NKTL and prominent ocular symptoms (p > 0.05). Cases of nasal NKTL and prominent ocular symptoms were usually complicated with B symptoms(48.2% vs 32.9%, p < 0.05). Patients with nasal NKTL and prominent ocular symptoms were more likely to progress to stage III disease (p < 0.01). The median time from first onset to diagnosis was 2.5 months. Most patients with general nasal NKTL had a longer history (69.6% vs 45.0%, p < 0.01). The misdiagnosis rate of the first visit of patients with general nasal NKTL was 29.3%, and that of patients with prominent ocular symptoms was 51.8%; this difference was significant (p < 0.01). Patients with nasal NKTL and prominent ocular symptoms showed a higher positive rate of EBV DNA (p < 0.01), which was significantly associated with staging (p < 0.01). CONCLUSIONS: Compared with patients with general nasal NKTL, the early diagnosis of patients with prominent ocular symptoms is difficult and easy to misdiagnose. Patients with nasal NKTL and prominent ocular symptoms mostly present with advanced disease stages, and most patients have B symptoms and a high positive rate of EBV DNA.

The rostromedial tegmental nucleus is essential for non-rapid eye movement sleep.

The rostromedial tegmental nucleus (RMTg), also called the GABAergic tail of the ventral tegmental area, projects to the midbrain dopaminergic system, dorsal raphe nucleus, locus coeruleus, and other regions. Whether the RMTg is involved in sleep-wake regulation is unknown. In the present study, pharmacogenetic activation of rat RMTg neurons promoted non-rapid eye movement (NREM) sleep with increased slow-wave activity (SWA). Conversely, rats after neurotoxic lesions of 8 or 16 days showed decreased NREM sleep with reduced SWA at lights on. The reduced SWA persisted at least 25 days after lesions. Similarly, pharmacological and pharmacogenetic inactivation of rat RMTg neurons decreased NREM sleep. Electrophysiological experiments combined with optogenetics showed a direct inhibitory connection between the terminals of RMTg neurons and midbrain dopaminergic neurons. The bidirectional effects of the RMTg on the sleep-wake cycle were mimicked by the modulation of ventral tegmental area (VTA)/substantia nigra compacta (SNc) dopaminergic neuronal activity using a pharmacogenetic approach. Furthermore, during the 2-hour recovery period following 6-hour sleep deprivation, the amount of NREM sleep in both the lesion and control rats was significantly increased compared with baseline levels; however, only the control rats showed a significant increase in SWA compared with baseline levels. Collectively, our findings reveal an essential role of the RMTg in the promotion of NREM sleep and homeostatic regulation.

Regulating Cdc42 and Its Signaling Pathways in Cancer: Small Molecules and MicroRNA as New Treatment Candidates.

Despite great improvements in the diagnosis and treatment of neoplasms, metastatic disease is still the leading cause of death in cancer patients, with mortality rates still rising. Given this background, new ways to treat cancer will be important for development of improved cancer control strategies. Cdc42 is a member of the Rho GTPase family and plays an important role in cell-to-cell adhesion, formation of cytoskeletal structures, and cell cycle regulation. It thus influences cellular proliferation, transformation, and homeostasis, as well as the cellular migration and invasion processes underlying tumor formation. Cdc42 acts as a collection point for signal transduction and regulates multiple signaling pathways. Moreover, recent studies show that in most human cancers Cdc42 is abnormally expressed and promoting neoplastic growth and metastasis. Regarding possible new treatments for cancer, miRNA and small molecules targeting Cdc42 and related pathways have been recently found to be effective on cancer. In this review, we analyze the newly recognized regulation mechanisms for Cdc42 and Cdc42-related signal pathways, and particularly new treatments using small molecules and miRNAs to inhibit the abnormal overexpression of Cdc42 that may slow down the metastasis process, improve cancer therapy and lead to novel strategies for development of antineoplastic drugs.

Activation of the ventral tegmental area increased wakefulness in mice.

The ventral tegmental area (VTA) is crucial for brain functions, such as voluntary movement and cognition; however, the role of VTA in sleep-wake regulation when directly activated or inhibited remains unknown. In this study, we investigated the effects of activation or inhibition of VTA neurons on sleep-wake behavior using the pharmacogenetic "designer receptors exclusively activated by designer drugs (DREADD)" approach. Immunohistochemistry staining was performed to confirm the microinjection sites, and combined with electrophysiological experiments, to determine whether the VTA neurons were activated or inhibited. The hM3Dq-expressing VTA neurons were excited confirmed by clozapine-N-oxide (CNO)-driven c-Fos expression and firing in patch-clamp recordings; whereas the hM4Di-expressing VTA neurons inhibited by reduction of firing. Compared with controls, the activation of VTA neurons at 9:00 (inactive period) produced a 120.1% increase in the total wakefulness amount for 5 h, whereas NREM and REM sleep were decreased by 62.5 and 92.2%, respectively. Similarly, when VTA neurons were excited at 21:00 (active period), the total wakefulness amount increased 81.5%, while NREM and REM sleep decreased 64.6 and 93.8%, respectively, for 8 h. No difference of the amount and EEG power density of the NREM sleep was observed following the arousal effects of CNO. The inhibition of VTA neurons during active or inactive periods gave rise to no change in the time spent in the wakefulness, REM, and NREM sleep compared with control. The results indicated that VTA neurons activated pharmacogentically played important roles in promoting wakefulness.

Determinants of crease width in inherent double eyelid of Asian young women.

BACKGROUND: The creation of a superior palpebral crease has been the most popular plastic surgery procedure in Asians for several decades. The most important criterion for judging the success of this procedure is the achievement of the desired size and shape of this crease or the perfect crease width. However, the determinants of crease width remain unclear, which may account for the high rate of unsatisfactory results. METHODS: Standard images were used to study the anatomic parameters, including crease width, crease height, and upper eyelid movement distance (ULMD) at the midpupillary axis, of the inherent double eyelid crease in 32 Chinese women aged 19-26 years. The thickness of the eyelid tissue at 5, 7.5, 10, and 15 mm from the lid margin was measured in the oblique sagittal direction by magnetic resonance imaging (MRI) at the central axis of the optic nerve. Multiple linear regression was used to analyze the relationship between crease width and crease height, ULMD, and eyelid thickness. RESULTS: Multiple linear regression revealed that crease height, crease thickness, and ULMD were significantly associated with crease width (partial regression coefficients: 0.67, -0.33, and -0.29 respectively). The determination coefficient R2 was 0.667 in the regression model, and the result of analysis of variance (ANOVA) showed that the regression model was significant (F = 16.04, p = 0.000). CONCLUSIONS: In performing upper blepharoplasty, it is important to consider eyelid thickness and movement distance of the upper eyelid margin rather than relying on crease height alone. Attention to these factors will help to achieve the desired size and shape of the crease.

Paeoniflorin exerts analgesic and hypnotic effects via adenosine A1 receptors in a mouse neuropathic pain model.

RATIONAL: Neuropathic pain is frequently comorbid with sleep disturbances. Paeoniflorin, a main active compound of total glucosides of paeony, has been well documented to exhibit neuroprotective bioactivity. OBJECTIVE: The present study evaluated effects of paeoniflorin on neuropathic pain and associated insomnia and the mechanisms involved. METHODS: The analgesic and hypnotic effects of paeoniflorin were measured by mechanical threshold and thermal latency, electroencephalogram (EEG) and electromyogram, and c-Fos expression in a neuropathic pain insomnia model. RESULTS: The data revealed that paeoniflorin (50 or 100 mg/kg, i.p.) significantly increased the mechanical threshold and prolonged the thermal latency in partial sciatic nerve ligation (PSNL) mice. Meanwhile, paeoniflorin increased non-rapid eye movement (NREM) sleep amount and concomitantly decreased wakefulness time. However, pretreatment with l,3-dimethy-8-cyclopenthylxanthine, an adenosine A1 receptor (R, A1R) antagonist, abolished the analgesic and hypnotic effects of paeoniflorin. Moreover, paeoniflorin at 100 mg/kg failed to change mechanical threshold and thermal latency and NREM sleep in A1R knockout PSNL mice. Immunohistochemical study showed that paeoniflorin inhibited c-Fos overexpression induced by PSNL in the anterior cingulate cortex and ventrolateral periaqueductal gray. CONCLUSIONS: The present findings indicated that paeoniflorin exerted analgesic and hypnotic effects via adenosine A1Rs and might be of potential use in the treatment of neuropathic pain and associated insomnia.

[Physiological Effect of Vallisneria natans Under Different Concentrations of Nitrogen, Phosphorus and Chloramphenicol].

The effects of peroxidase(POD), superoxide dismutase(SOD) activities and malondialdehyde(MDA), soluble proteins and chlorophyll in the leaves of Vallisneria natans exposed to different concentrations of nitrogen and phosphorus in the eutrophication water body and chloramphenicol after 7 days were investigated in the study. The soluble protein content increased significantly in group eutrophic water and 0.2 µg.L-1 chloramphenicol, and the concentration of protein was 2.38 times of that in group 0 µg.L-1 chloramphenicol. In group of eutrophic water and 0. 2 µg.L-1 chloramphenicol, POD activities decreased significantly to 33. 84% of that in group 0 µg.L-1 chloramphenicol. With the increasing of the joint concentration, SOD activities decreased. SOD activities in group of mesotrophic and 0. 2 µg.L-1 chloramphenicol was 28. 59% of that in group of 0 µg.L-1 chloramphenicol.

[Role of stress in depression insomnia and sleep characteristics of commonly used animal stress models].

Depression and insomnia are intimately related. Depressed patients usually manifest sleep discontinuity and early awakening, reduced or no slow wave sleep (SWS) and shortened latency of rapid eye movement (REM) sleep. These sleep abnormalities are very similar to those caused by over activated hypothalamic-pituitary-adrenal (HPA) axis with stress. Therefore, the animal models developed by post-traumatic stress disorder or chronic unpredictable mild stress could be used to evaluate drugs which have effects of both anti-depression and improvement of sleep quality, and to provide a more reliable platform for further studis on the mechanisms of depression and accompanied insomnia. This review mainly focuses on the typical features of sleep disturbance of depression, possible pathophysiological mechanisms, establishment of animal stress models and analysis of their abnormal sleep characteristics.

[Distribution of Hg in mangrove plants and correlation with Hg speciation in sediments].

Plant is an important role in biogeochemical cycle of Hg. The aim of this study is to ascertain Hg accumulation in several kinds of mangrove plants, and to discuss relationship among Hg concentrations in mangrove plants and different Hg speciation in sediments. Contents of total mercury (THg) in mangrove plants and sediments were determined. Hg speciation was determined with a modified Tessier's method. Contents of THg of the mangrove plants were in the range of 817.5-3 197.6 ng/g. In detail, Hg concentration was (1 579.4 +/- 1 326.8) ng/g in Kandelia candel, (2 115.1 +/- 1 892.3) ng/g in Aegiceras corniculatum, (2 159.3 +/- 1 678.7) ng/g in Avicennia marina, (2 566.5 +/- 821.6) ng/g in Bruguiera gymnorrhiza, (2 104.3 +/- 1 661.8) ng/g in Excoecaria agallocha, (3 197.6 +/- 2 782.8) ng/g in Sonneratia apetala, (817.5 +/- 632.3) ng/g in Acanthus ilicifolius, (1 801.8 +/- 1 255.4) ng/g in Rhizophora. stylosa, respectively. There are obvious interspecific variation, and organic variation in THg contents of mangrove plants, which is closely related to environment and physiological characteristics of mangrove plants. Enrichment of THg in mangrove plants was inhomogeneous, following the order of Sonneratia apetala > Bruguiera gymnorrhiza > Avicennia marina > Aegiceras corniculatum > Excoecaria agallocha > Rhizophora stylosa > Kandelia candel > Acanthus ilicifolius. Mercury exists mainly in volatile form in most mangrove wetlands, but mainly in the form of residue in sediments from Shenzhen mangrove wetlands. Significantly positive correlations were found among Hg concentrations in leaves and stems of Sonneratia apetala and volatile Hg, exchangeable Hg of sediments. Significantly positive correlations were also found among Hg concentrations in leaves of Excoecaria agallocha and volatile Hg, exchangeable Hg of sediments. But, there is no significant correlation between Hg concentrations of most mangrove plants and different Hg speciation in sediments. It showed that plants assimilate Hg from different sources, such as water, sediment and air, and that Hg assimilated by plants could transfer among different plant organics.

Intravenously administered BMSCs reduce neuronal apoptosis and promote neuronal proliferation through the release of VEGF after stroke in rats.

BACKGROUND: Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) could ameliorate neurological deficits after stroke in the rodent. OBJECTIVE: The purpose of this study was to investigate the potential mechanisms underlying the neuroprotective effects of implanted BMSCs. METHODS: Ischemic stroke was induced by permanent middle cerebral artery occlusion (MCAo) in Sprague-Dawley rats. BMSCs were intravenously transplanted at 24 hours after MCAo. Neurological function was evaluated using modified neurological severity score and Morris water maze test. Immunohistochemistry and terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling staining were performed to detect neuronal apoptosis and proliferation. The protein and mRNA levels of vascular endothelial growth factor (VEGF) were determined by ELISA and reverse transcriptase polymerase chain reaction, respectively. RESULTS: Significant improvement of neurological deficits was found in BMSC-treated rats compared with control animals at 14 and 28 days after MCAo (p<0.05). Histological evaluation showed that BMSCs treatment significantly promoted neuronal survival and proliferation in the ischemic boundary area. The expression of VEGF was predominantly increased in the ischemic hemisphere of BMSC-treated rats compared with the other groups. On the other hand, transduction of VEGF RNAi lentivirus partially attenuated the above described beneficial effects of systemically administered BMSCs. CONCLUSION: Our data suggest that intravenously administrated BMSCs facilitate neurological function, reduce neuronal apoptosis and promote neuronal proliferation through the release of VEGF.

[Distribution of mercury in surficial sediments from main mangrove wetlands of China].

Surficial sediment samples were collected from main mangrove wetlands of China, mercury, pH, salinity, organic matters, grain size, Fe/Hg, Mn/Hg were analyzed. Mercury content ranges from 2.3 to 903.6 ng x g(-1), with a average of (197 +/- 137.6) ng x g(-1). Compared with local background level, serious Hg pollution with high Hg content was found in 7 areas, including Luoyangqiao [(467.5 +/- 68.8) ng x g(-1)], Fugong [(438.2 +/- 147.0) ng x g(-1)], Ewan [(264.3 +/- 89.2) ng x g(-1)], Yaojiayu [(125.4 +/- 27.1) ng x g(-1)], Fujian Province; Sanya [(164.8 +/- 143.9) ng x g(-1)], Dongzhaigang [(314.1 +/- 335.7) ng x g(-1)], Hainan Province, Shenzhen [(179.9 +/- 7.7) ng x g(-1)], Guangdong Province. Hg content was similar with background value in the other 6 areas, including Yunxiao [(63.3 +/- 43.9)ng x g(-1)], Fujian Province; Gaoqiao [(178.6 +/- 127.0) ng x g(-1)], Guangdong Province; Daguansha [(26.1 +/- 18.8) ng x g(-1)], Shankou [(73.8 +/- 21.1) ng x g(-1)], Beilun estuary [(117.8 +/- 51.4) ng x g(-1)], Qinzhou Bay [(147.5 +/- 107.6) ng x g(-1)], Guangxi Autonomous Region. Discrepancy of total Hg concentrations in mangrove wetlands is due to many environmental factors and human activities. Parameters such as grain size, pH, organic matter, Fe/Hg, Mn/Hg are significantly correlated with total Hg respectively. Clay and Fe/Hg are obvious factors influencing total Hg concentration. Impact of environmental factors on mercury can be showed by regression equation.