Effects of Sleep Reactivity on Sleep Macro-Structure, Orderliness, and Cortisol After Stress: A Preliminary Study in Healthy Young Adults.

Purpose: To investigate changes and links of stress and high sleep reactivity (H-SR) on the macro-structure and orderliness of sleep and cortisol levels in good sleepers (GS). Patients and Methods: Sixty-two GS (18-40 years old) were recruited, with 32 in the stress group and 30 in the control group. Each group was further divided into H-SR and low SR subgroups based on the Ford Insomnia Response to Stress Test. All participants completed two nights of polysomnography in a sleep laboratory. Before conducting polysomnography on the second night, the stress group completed the Trier Social Stress Test and saliva was collected. Results: The duration of NREM sleep stages 1, 2 (N1, N2) and rapid eye movement sleep (REM) decreased, and the values of approximate entropy, sample entropy, fuzzy entropy, and multiscale entropy increased under stress and SR effects. Stress increased rapid eye movement density, and H-SR increased cortisol reactivity. Conclusion: Stress can damage the sleep and increase cortisol release in GS, especially those with H-SR. N1, N2 and REM sleep are more easily affected, while NREM sleep stage 3 sleep is relatively stable.

A dual-channel fluorescent nanoprobe for accurate cancer diagnosis by sequential detection of adenosine triphosphate and sulfur dioxide.

Cancer is one of the major diseases that seriously endanger the health of all mankind. Accurate diagnosis of early cancer is the most promising way to reduce cancer harm and improve patient survival. However, many developed fluorescent probes for cancer imaging only have the function of identifying one marker, which cannot meet the needs of accurate diagnosis. Here, a fluorescent nanoprobe (CPH@ZIF-90) utilizing ZIF-90 to encapsulate SO2-sensitive dye (CPH) is synthesized for the sequential detection of ATP and SO2. The nanoprobe first interacts with ATP to release CPH, thus increasing the fluorescence at 685 nm and realizing the near-infrared (NIR) fluorescence detection of ATP. Then, SO2 acts on the released CPH through nucleophilic addition, affecting the π-conjugated structure of CPH and resulting in enhanced fluorescence at 580 nm. CPH@ZIF-90 exhibits satisfactory sensitivity and selectivity for sequential detection of ATP and SO2. Excitedly, CPH@ZIF-90 can sequentially image the endogenous ATP and SO2 in cells, showing sensitive fluorescence changes in dual channels (red and green). Due to the NIR emission properties of CPH@ZIF-90 and its ability to enrich in tumor, it is applied to monitor ATP and SO2 in mice and distinguish normal mice from tumor mice. The ability of CPH@ZIF-90 to sequentially detect two cancer-related biomarkers makes it provide meaningful assistance in accurate early diagnosis of cancer.

Near-Infrared Fluorescent Nanoprobes for Adenosine Triphosphate-Guided Imaging in Cancer and Fatty Liver Mice.

Adenosine triphosphate (ATP), as an indispensable biomolecule, is the main energy source of cells and is used as a marker for diseases such as cancer and fatty liver. It is of great significance to design a near-infrared fluorescent nanoprobe with excellent performance and apply it to various disease models. Here, a near-infrared fluorescent nanoprobe (ZIF-90@SiR) based on a zeolitic imidazole framework is proposed. The fluorescent nanoprobes are synthesized by encapsulating the dye (SiR) into the framework of ZIF-90. Upon the addition of ATP, the structure of the ZIF-90@SiR nanoprobe is disrupted and SiR is released to generate near-infrared fluorescence at 670 nm. In the process of ATP detection, ZIF-90@SiR shows high sensitivity and good selectivity. Moreover, the ZIF-90@SiR nanoprobe has good biocompatibility due to its low toxicity to cells. It is used for fluorescence imaging of ATP in living cells and thus distinguishing normal cells and cancer cells, as well as distinguishing fatty liver cells. Due to excellent near-infrared fluorescence properties, the ZIF-90@SiR nanoprobe can not only distinguish normal mice and tumor mice but also differentiate normal mice and fatty liver mice for the first time.

[Effect of electroacupuncture on visceral sensitivity and colonic NGF, TrkA, TRPV1 expression in IBS-D rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Tianshu" (ST 25) and "Shangjuxu" (ST 37) on mental state, visceral sensitivity and protein expression of nerve growth factor (NGF), tyrosine kinase receptor A (TrkA) and transient receptor potential vanilloid 1 (TRPV1) of colonic tissue in diarrhea-predominant irritable bowel syndrome (IBS-D) rats, and to explore its possible mechanism on treating IBS-D. METHODS: A total of 36 male SD rats of SPF grade were randomized into a blank group, a model group, an EA group and a western medication group, 9 rats in each group. In the model group, the EA group and the western medication group, IBS-D model was established by enema of dinitrobenzene sulfonic acid (DNBS) combined with chronic restraint stress method. In the EA group, EA was applied at "Tianshu" (ST 25) and "Shangjuxu" (ST 37), with disperse-dense wave, in frequency of 2 Hz/100 Hz, 20 min each time, once a day for 7 days. In the western medication group, pinaverium bromide suspension was given by gavage (15 mg•kg-1•d-1) for 7 days. Before and after model establishment, and after intervention, the body mass, 24 h food intake and fecal water content were observed, the visceral sensitivity was detected by abdominal withdrawal reflex (AWR); after intervention, the mental state was evaluated by elevated plus maze (EPM) test, the protein expression of NGF, TrkA and TRPV1 was detected by immunohistochemistry and Western blot in the 4 groups. RESULTS: After model establishment, compared with the blank group, the body mass and 24 h food intake were decreased (P<0.05), first systolic latency of AWR was shortened and number of contraction wave of AWR was increased (P<0.05), and fecal water content was increased (P<0.05) in the model group, the EA group and the western medication group. After intervention, compared with the blank group, open arm residence time ratio (OT%) of EPM was decreased (P<0.05) and protein expression of NGF, TrkA, TRPV1 in colonic tissue was increased in the model group (P<0.05); compared with the model group, the body mass and 24 h food intake were increased (P<0.05), first systolic latency of AWR was lengthened and number of contraction wave of AWR was decreased (P<0.05), the fecal water content was decreased (P<0.05), OT% of EPM was increased (P<0.05), and protein expression of NGF, TrkA, TRPV1 in colonic tissue was decreased (P<0.05) in the EA group and the western medication group. CONCLUSION: Electroacupuncture at "Tianshu" (ST 25) and "Shangjuxu" (ST 37) can relieve the anxiety and depression-like behaviors in IBS-D rats, down-regulate the protein expression of NGF, TrkA, TRPV1 in colonic tissue, so as to reduce the visceral sensitivity and relieve symptoms.

A Dual-Channel Fluorescent Nanoprobe for Sequential Detection of ATP and Peroxynitrite to Accurately Distinguish between Normal Cells and Cancer Cells.

Cancer is one of the biggest public enemies of global health with its high morbidity and mortality. Achieving early diagnosis is the most effective means of reducing cancer harm, which requires the use of powerful tools to accurately identify biomarkers. However, most of the reported fluorescent probes for cancer diagnosis can only detect one substance, which makes it difficult to meet the requirements of high accuracy. Here, a fluorescent nanoprobe (CPQ@ZIF-90) for sequential detection of ATP and ONOO- is constructed by encapsulating the ONOO- sensitive unit CPQ within ZIF-90. CPQ@ZIF-90 first reacts with ATP to release CPQ, which greatly enhances the fluorescence at 740 nm. Then, the released CPQ continues to react with ONOO- and is oxidatively cleaved by ONOO- to form a coumarin product with a small π-conjugated structure, which significantly enhances the fluorescence at 510 nm. CPQ@ZIF-90 shows high sensitivity and selectivity for the detection of ATP and then ONOO-. Moreover, CPQ@ZIF-90 has good biocompatibility and successfully realizes the sequential detection of a dual-channel fluorescence change of ATP and ONOO- in living cells and zebrafish and accurately distinguishes normal cells from cancer cells. CPQ@ZIF-90 is expected to be a potential tool for accurate cancer diagnosis through sequential detection of two cancer markers.

[Effect of electroacupuncture on colonic motility and RhoA and ROCK protein expression in IBS-D rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) of "Tianshu"(ST25) and "Shangjuxu"(ST37)on gastrointestinal motility, psychological abnormality and expression of RhoA and ROCK protein in rats with diarrhea predominant irritable bowel syndrome (IBS-D), so as to explore its underlying mechanism in improving IBS-D. METHODS: Thirty-six male rats were randomly and equally divided into control, model, EA and medication groups (n=9 in each group). The IBS-D model with psychological abnormality was established by gavage of dinitrobenzene sulfonic acid (DNBS) + chronic restraint stress. EA (2 Hz/100 Hz, 0.3 mA) was applied to bilateral ST25 and ST37 for 20 min, once a day for 7 days. Rats of the medication group received gavage of pinaverium bromide solution (15 mg/kg), once a day for 7 days. The rats' food intake in 24 h, body mass and colonic contraction waves were recorded. The anhedonia-related behavior was measured using the sucrose consumption test. The elevated plus maze test (the open-arm residence time ratio) was used to assess the anxiety-like behavior. The small intestinal propulsion rate test was used to assess the intestinal motility. The expression levels of RhoA and ROCK proteins in the colonic tissue were measured by Western blot. RESULTS: After modeling, the body mass, food consumption, sucrose preference index, the open-arm residence time ratio andlatency of colonic contraction waves were significantly decreased (P<0.05), and the number of contraction waves, intestinal propulsive rate, and the expression levels of RhoA and ROCK proteins considerably increased (P<0.01，P<0.05) in the model group relevant to the control group. Following the interventions, the decrease of body mass, food consumption, sucrose preference index, open-arm residence time ratio and latency of contraction waves, and the increase of the contraction waves, intestinal propulsive rate, and the expression levels of RhoA and ROCK proteins were all reversed by both EA and medication (P<0.05，P<0.01). The effect of EA was significantly superior to that of medication in increasing the sucrose pre-ference index (P<0.05). CONCLUSION: EA can improve both colonic motility and psychological disorders in IBS-D rats with psychological disorder, which may be related to its function in down-regulating the expression of colonic RhoA and ROCK proteins.

Aquaporin-4, Connexin-30, and Connexin-43 as Biomarkers for Decreased Objective Sleep Quality and/or Cognition Dysfunction in Patients With Chronic Insomnia Disorder.

Objectives: To examine serum concentrations of aquaporin-4 (AQP4), connexin-30 (CX30), connexin-43 (CX43), and their correlations with cognitive function in the patients with chronic insomnia disorder (CID). Methods: We enrolled 76 subjects with CID and 32 healthy controls (HCs). Serum levels of AQP4, CX30, and CX43 were measured by enzyme-linked immunosorbent assays. Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and polysomnography, and mood was evaluated with 17-item Hamilton Depression Rating Scale and 14-item Hamilton Anxiety Rating Scale. Cognitive function was evaluated by the Chinese-Beijing Version of Montreal Cognitive Assessment (MoCA-C) and Nine Box Maze Test. Results: The serum levels of AQP4, CX43, and CX30 were significantly reduced in the CID group compared to the HCs. Partial correlation analysis showed that the biomarkers showed no significant correlations with PSQI score, AHI, ODI and TS90, but AQP4, CX43, and CX30 were positively associated with the percentage and total time of slow wave sleep in the CID group. Serum concentrations of AQP4 and CX30 were positively associated with MoCA-C score in the CID group, and AQP4 level negatively correlated with spatial working memory errors. Conclusions: Subjects with CID patients have decreased serum levels of AQP4, CX30, and CX43 indicating astrocyte dysfunction, which could be related to poor objective sleep quality and/or cognition dysfunction.

Changed serum levels of CD62E+, angiotensin II and copeptin in patients with chronic insomnia disorder: a link between insomnia and stroke?

BACKGROUND: Epidemiological and observational clinical studies have found that insomnia is a risk factor for stroke and that, accordingly, insomnia is likely to cause changes of stroke-related biomarkers. There is substantial evidence that stroke is closely related to endothelial dysfunction and hypertension. The aim of this study is to investigate whether there is alteration of endothelial dysfunction (CD62E+) and hypertension (angiotensin II and copeptin) biomarkers in patients with chronic insomnia disorder (CID). METHODS: The CID patients (N = 54) and the good sleepers (GS, N = 32) were enrolled. Pittsburgh sleep quality index (PSQI), pre-sleep arousal scale (PSAS) and polysomnography were used to assess their sleep and neuropsychological function. Serum levels of CD62E+, angiotensin II and copeptin were determined using a quantitative sandwich ELISA. RESULTS: The CID group had higher serum levels of CD62E+, angiotensin II, and copeptin than the GS group. After controlling for sex, age, depression and apnea-hypopnea index, the partial correlation analysis revealed that the levels of CD62E+ and copeptin correlated positively with the PSAS score and negatively with the objective sleep quality. Angiotensin II levels negatively correlated with objective sleep onset latency. Moreover, there was a positive correlation between CD62E+ and angiotensin II. Principal components analysis revealed that CD62E+ and copeptin had a substantial correlation with parameters of subjective and objective sleep. CONCLUSION: Patients with CID exhibit endothelial activation, over-activated renin-angiotensin system and increased sympathetic excitability, as indicated by increased serum levels of CD62E+, angiotensin II and copeptin, with linking to poor sleep quality.

[Acupuncture and moxibustion treatment for dry eye disease: a network Meta-analysis of rando-mized controlled trial].

OBJECTIVE: A network Meta-analysis based on Bayesian theory was used to evaluate efficacy and safety of acupuncture and moxibustion in the treatment of dry eye disease(DED), so as to provide evidence-based research basis for clinical application. METHODS: Randomized controlled trials (RCT) for acupuncture and moxibustion treatment of DED published from the inception of database to November 25, 2020 were searched from PubMed, Embase, Cochrane Library, Web of Science, Sinomed, CNKI, Wanfang and VIP Database. Two reviewers independently screened the literatures, extracted the data. The quality of the included literature was evaluated, and network Meta-analysis was performed by using Stata14.0 and R4.0.3 software. RESULTS: A total of 71 literatures were identified, including 5 536 patients with DED, covering 11 different interventions. Network Meta-analysis showed that acupuncture+traditional Chinese medicine+artificial tears was the best treatment option in terms of the clinical effective rate, breakup time of tear film (BUT), Schirmer I test (SIT) with surface under cumulative ranking area value. Acupuncture+traditional Chinese medicine+artificial tears was better than artificial tears in the clinical effective rate (odds ratio［OR］=12.34, 95% confidence interval［CI］［4.72, 36.89］), BUT(mean differenc［MD］=2.76, 95%CI［0.16, 5.40］), SIT(MD=4.76, 95%CI［1.23, 8.29］). CONCLUSION: Acupuncture and moxibustion in the treatment of DED are generally better than artificial tears, and acupuncture-moxibustion combined with other traditional Chinese medicine therapy has the best effect.

Relationships Between a Range of Inflammatory Biomarkers and Subjective Sleep Quality in Chronic Insomnia Patients: A Clinical Study.

PURPOSE: To examine whether associations exist between chronic insomnia disorder (CID) and overlooked inflammatory factors (Serum amyloid protein A [SAA]), tumor necrosis factor [TNF]-α, granulocyte-macrophage colony-stimulating factor [GM-CSF], and regulated on activation and normal T cell expressed and presumably secreted [RANTES]). PATIENTS AND METHODS: A total of 65 CID patients and 39 sex- and age-matched good sleeper (GS) controls participated in this study. They completed a baseline survey to collect data on demographics, and were elevated sleep and mood by Pittsburgh Sleep Quality Index (PSQI), Athens Insomnia Scale (AIS), 17-item Hamilton Depression Rating Scale (HAMD-17) and 14-item Hamilton Anxiety Rating Scale (HAMA-14), respectively. The blood samples were collected and tested the serum levels of SAA, TNF-α, GM-CSF and RANTES. RESULTS: The CID group had higher serum levels of SAA, TNF-α, and GM-CSF and a lower level of RANTES than the GS group. In the Spearman correlation analysis, SAA and GM-CSF positively correlated with the PSQI and AIS scores. After controlling for sex, HAMD-17 score, and HAMA-14 score, the partial correlation analysis showed that GM-CSF was positively correlated with PSQI score. Further stepwise linear regression analyses showed that GM-CSF was positively associated with the PSQI and AIS scores, while RANTES was negatively associated with them, and SAA was positively associated with just the AIS score. CONCLUSION: The serum levels of inflammatory mediators (SAA, TNF-α, and GM-CSF) were significantly elevated and the level of RANTES was significantly decreased in CID patients and, to some extent, the changes are related to the severity of insomnia. These findings may help us to improve interventions to prevent the biological consequences of CID by inhibiting inflammation, thereby promoting health.

Are Anti-Inflammatory Cytokines Associated with Cognitive Impairment in Patients with Insomnia Comorbid with Depression? A Pilot Study.

BACKGROUND: To distinguish insomnia comorbid with depression (ICD) from chronic insomnia disorder (CID) by exploring the relationship between serum levels of frequently overlooked anti-inflammatory cytokines and cognitive function. METHODS: A total of 42 ICD patients, 63 CID patients, and 42 healthy control subjects were enrolled in the study. The Pittsburgh Sleep Quality Index and Hamilton Depression Rating Scale were used to assess sleep quality and depression severity, respectively. The Chinese-Beijing version of Montreal Cognitive Assessment scale (MoCA-C) and Nine-Box Maze Test (NBMT) were used to assess cognitive function. Serum levels of anti-inflammatory interleukins (IL-1RA, IL-4, IL-5, IL-10, IL-13, and IL-28A), transforming growth factor (TGF)-ß1, granulocyte-macrophage colony-stimulating factor, interferon-γ, and the chemokine regulated upon activation, normal T cell expressed and secreted (RANTES) were measured by enzyme-linked immunosorbent assay. RESULTS: The ICD group had significantly more errors in the spatial reference task (H=2.55, Ps=0.03) and spatial working memory task (H=5.67, Ps<0.01) of the NBMT, as well as lower levels of IL-1RA (H=-2.85, Ps=0.01), IL-4 (H=-3.28, Ps<0.01), IL-5 (H=-3.35, Ps<0.01), IL-10 (H=-4.46, Ps<0.01), and IL-28A (H=-2.75, Ps=0.02) than control subjects. Compared with the CID group, the ICD group had significantly more errors in the spatial reference memory task (H=-2.84, Ps=0.01) of the NBMT, and lower levels of IL-5 (H=3.41, Ps<0.01), IL-10 (H=5.30, Ps<0.01), IL-13 (H=3.89, Ps<0.01), and GM-CSF (H=2.72, Ps=0.02). A partial correlation analysis showed that the level of one or more of IL-4, IL-5, IL-10, IL-13, and TGF-ß1 was positively correlated with cognitive function (MoCA-C score and/or performance in spatial memory task) in ICD patients. CONCLUSION: ICD is a distinct condition that can be distinguished from CID based on immune dysfunction and specific types of cognitive dysfunction.

[Design, synthesis and evaluation of 4-pyridinylthiazole-2-amines as acetylcholinesterase inhibitors].

Alzheimer's disease (AD) is a degenerative disease of the nervous system. Compound I reported to have inhibitory activity on AChE was used as a lead compound in this study, and 4-pyridinylthiazole-2-amines were designed by optimizing compound I structure. The new compounds were synthesized from acetylpyridines through five-steps of reaction, and their inhibition activities on AChE were measured in vitro by Ellman method. The new compounds exhibited a clear inhibitory activity on AChE in vitro. The bioactivity of compound 13c was the best among them, and its IC(50) value was 0.15 µmol·L(-1), which was better than that of rivastigmine and compound I in the control. Meanwhile, it exhibited little inhibition on butyrylcholinesterase. So the selective inhibitory activities of 4-pyridinylthiazole-2-amines to acetylcholinesterase were worth of studying furtherly.

[Design, synthesis and evaluation of new L-proline derivatives as acetylcholinesterase inhibitors].

In this paper, fourteen new L-proline derivatives were designed and synthesized, and their acetlcholinesterase (AChE) inhibitory activities were also investigated in vitro. New L-proline derivatives were prepared from substituted 2-bromo-1-acetophenones through four-step reaction; and their bioactivities as AChE inhibitors were measured by Ellman spectrophotometry. The results showed that the target compounds had a certain AChE inhibitory activity to in vitro. The bioactivity of compound 8b was the best of them, and its IC50 value was 5.45 µmol.L-1, which was better than that of rivastigmine. So the acetylcholinesterase inhibitory activities of new L-proline derivatives were worth to be further studied.

[Design, synthesis and evaluation of 5-aminobenzimidazolone derivatives as acetylcholinesterase inhibitors].

The target compounds were prepared from 5-aminobenzimidazolone by two steps reaction, and their AChE inhibitory activities were measured by Ellman method in vitro. The AChE inhibitory activity of compound 4d is the best of them, and its IC50 value is equal to 7.2 µmol·L(-1), which is better than that of rivastigmine; moreover the 4d had no inhibitory activities to BuChE. Therefore, the inhibitory activities of 5-aminobenzimidazolone derivatives to acetylcholinesterase are worth further researching.