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Lung adenocarcinoma (LUAD) is the most prevalent subtype of non-small cell lung cancer (NSCLC) with high lethality, and quercitrin exhibits anticancer characteristics. Here, we attempted to uncover the anticancer activity of quercitrin in LUAD. In this work, quercitrin prohibited the cell viability and clone-formation of LUAD cells in vitro. Meanwhile, quercitrin treatment reduced the aggressive phenotypes in LUAD cells. Further, Gap Junction Protein Beta 2 (GJB2) expression was aberrantly higher in LUAD when compared within control tissue. The higher expression of GJB2 is associated with an inferior overall survival for patients with LUAD. Finally, the reintroduction of GJB2 offset the inhibiting influence of quercitrin in LUAD cells. Altogether, these findings disclosed that quercitrin suppressed the growth and metastatic-related traits of LUAD cells partly via regulating GJB2 expression.

Background: To compare the safety, advantages and disadvantages of thyroidectomy for differentiated thyroid carcinoma (DTC) via the bilateral areolar endoscopic approach (BAA) and the conventional open approach (COA).Methods: Eighty-six female patients who underwent thyroidectomy were enrolled and divided into two groups, 42 in the BAA group and 44 in the COA group, according to aesthetic requirements. The operating time, blood loss during surgery, number of dissected lymph nodes, length of hospital stay, drainage removal time and surgical complications between the two surgical approaches were compared. The pain score and cosmetic results of operative incisions were evaluated with the visual analog scale (VAS).Results: Patients in the BAA group had significantly less intraoperative blood loss and a significantly shorter scar length (P < 0.001) than those in the COA group. However, the operation time of 97.6 minutes in the BAA group was significantly longer than that in the COA group (76.4 minutes; P < 0.001). Comparison of the number of central lymph nodes (CLNs) dissected, drainage removal time and length of hospital stay revealed no significant differences (P>0.05). Patients in the BAA group experienced significantly less pain than those in the COA group (PP Conclusions: These results show that BAA thyroidectomy exhibits superior advantages in clinical outcomes, such as causing less pain and achieving better cosmetic satisfaction, compared with COA thyroidectomy. Therefore, BAA thyroidectomy is a safe and ideal surgical method for DTC.

Levo-tetrahydropalmatine (l-THP), an active ingredient of Corydalis yanhusuo, has been reported to be a partial agonist for dopamine D1 receptors (D1R) and an antagonist for D2R. Although it has been safely used clinically in China for decades as an analgesic with sedative/hypnotic properties, there are few studies that address the mechanisms by which l-THP exerts its beneficial effects in chronic pain-induced sleep disturbance. To investigate the effects and mechanisms of l-THP on sleep disturbance in a neuropathic pain-like condition. A mouse model of chronic neuropathic pain induced by partial sciatic nerve ligation (PSNL) was employed. The antinociceptive and hypnotic effects of l-THP were evaluated by measurement of mechanical allodynia, thermal hyperalgesia, and electroencephalogram (EEG) recordings in PSNL mice. Pharmacological approaches and c-Fos expression were used to clarify the mechanisms of l-THP. Intraperitoneal injection of l-THP at 5 and 10 mg/kg not only significantly increased the mechanical threshold by 134.4% and 174.8%, and prolonged the thermal latency by 49.4% and 69.2%, but also increased non-rapid eye movement sleep by 17.5% and 29.6%, and decreased sleep fragmentation in PSNL mice, compared with the vehicle control. Moreover, the antinociceptive effect of l-THP was prevented by D1R antagonist SCH23390 or D2R agonist quinpirole; meanwhile, the hypnotic effect of l-THP was blocked by quinpirole rather than by SCH23390. Immunohistochemistry demonstrated that l-THP inhibited c-Fos overexpression induced by PSNL in the cingulate cortex and the periaqueductal gray. These findings indicated that l-THP exerted analgesic effects by agonism D1R and antagonism D2R, and the antagonism of D2R mediated the hypnotic effect of l-THP in PSNL mice.

Objective The present work aims to evaluate the significance of sleep disturbance and electroencephalogram (EEG) alteration in the early stage of Alzheimer's disease (AD). Background and Rationale Sleep disturbance is common in patients with AD. It is not known if it can occur at the early stage of AD and if EEG recording may help identify the early sign of the disease. Historical Evolution Sleep disturbance in AD has generally been considered as late consequence of the neurodegenerative process. A growing body of evidence has suggested that the sleep disturbance may occur at the early stage of AD. Updated Hypothesis Based on the previous epidemiologic studies and our recent findings, we propose that sleep disturbance may play an important role in the development of AD. Sleep EEG changes may serve as a valuable early sign for AD in the prepathological stage. Early Experimental Data Our data suggested that AβPPswe/PS1ΔE9 transgenic AD mice at preplaque stage (3 and 4 months of age) exhibited different profile of sleep architecture and sleep EEG, which preceded the cognitive deficit and AD neuropathology. Future Experiments and Validation Studies Future experiments should focus on sleep EEG changes in patients with mild cognitive impairment and early stage of AD. Follow-up studies in high-risk population of the elderly are equally important. In addition, the exact molecular mechanism underlying the sleep disturbance should be thoroughly investigated. Major Challenges for the Hypothesis Studies on human participants with early stage of AD, especially the follow-up studies on the presymptomatic elderly in a large population, are difficult and time-consuming. Linkage to Other Major Theories Our hypothesis may link previous theories to establish a bidirectional relationship between sleep disorders and AD, which may finally form a new schematic mechanism to understand the disease pathogenesis and disease progression.

Bai Le Mian capsule (BLMC), which is composed of fifteen kinds of traditional Chinese Medicine, is a popular traditional Chinese medicine for the treatment of insomnia with anxiety. This study was to investigate the anxiolytic effect of BLMC in mice. BLMC (81, 162, and 325 mg/kg, i.g.) was given once or consecutively for 2 weeks, and anxiety behaviors were tested by the elevated plus maze, open field, and light/dark box, in normal mice and anxious model mice by meta-chlorophenyl-piperazine, a compound with known anxiogenic actions. In normal mice, single administration of BLMC at 325 mg/kg prolonged the time spent in central area by 2.1-fold in open-field test. Repeated administration once a day for 2 weeks, BLMC at 325 mg/kg increased the time spent in central area, open arms and light box by 2.8-, 2.0-, and 1.7-fold, respectively. Similarly, in anxious model mice, single treatment of BLMC at 325 mg/kg increased more time in the open arms by 2.1-fold. Consecutive administration for 2 weeks, BLMC at 325 mg/kg increased the time spent in open arms and light box by 2.3- and 2.1-fold. Immunohistochemical study showed that mCPP increased c-Fos expression in the central nucleus of the amygdala and bed nucleus of stria terminalis by 57% and 60%, and the mCPP-induced c-Fos expression could be reversed by single administration of BLMC. These results indicate that BLMC is an effective treatment for anxiety in mice.

Honokiol (HNK) is a small-molecule lignin extracted from Magnolia Officinalis, demonstrating high potency in promoting nonrapid eye movement (NREM) sleep by modulating the benzodiazepine site of the GABAA receptor. However, the clinical use of HNK in the treatment of insomnia is restricted by its extremely low oral bioavailability. In the present work, enhanced oral bioavailability of HNK was achieved by loading it into poly lactide–glycolide acid microparticles (HNK-MP). After oral administration, HNK-MP demonstrated 15-fold increase of AUC0–12 h in comparison to free HNK. The maximum blood concentration (Cmax) of HNK in HNK-MP-treated rats was 3.6 μg/mL at 2 h after oral administration, which was 6.5-fold of that in free HNK-treated rats. Oral administration of HNK-MP (20 mg/kg) efficiently increased NREM sleep by 60% by enhancing the transition from wakefulness to NREM sleep in rats. The biosafety of HNK-MP was assessed in vivo, and no damage occurred in the gastrointestinal tract. The present study pr...

Although general anesthesia (GA) enables patients to undergo surgery without consciousness, the precise neural mechanisms underlying this phenomenon have yet to be identified. In addition to many studies over the past two decades implicating the thalamus, cortex, brainstem, and conventional sleep-wake circuits in GA-induced loss of consciousness (LOC), some recent studies have begun to highlight the importance of other brain areas as well. Here, we found that population activities of neurons expressing dopamine D1 receptor (D1R) in the nucleus accumbens (NAc), a critical interface between the basal ganglia and limbic system, began to decrease before sevoflurane-induced LOC and gradually returned after recovery of consciousness (ROC). Chemogenetic activation of NAcD1R neurons delayed induction of and accelerated emergence from sevoflurane GA, whereas chemogenetic inhibition of NAcD1R neurons exerted opposite effects. Moreover, transient activation of NAcD1R neurons induced significant cortical activation and behavioral emergence during continuous steady-state GA with sevoflurane or deep anesthesia state with constant and stable burst-suppression oscillations. Taken together, our findings uncover that NAcD1R neurons modulated states of consciousness associated with sevoflurane GA and may represent an area for targeting GA-induced changes in consciousness and ameliorating related adverse effects.

Zao Ren An Shen capsule (ZRASC) which is composed of three kinds of traditional Chinese herbs is a popular Chinese medicine for the treatment of insomnia. This study investigated the hypnotic effect of ZRASC in an anxiety-like mouse model. We determined the role of ZRASC in anxiety and co-morbid insomnia using electroencephalogram and electromyogram recordings. Anxiety-like behaviors were tested by using the open-field, light/dark box, or elevated plus-maze in mice. Immunohistochemical techniques were employed to reveal the mechanism by which ZRASC regulated anxiety and insomnia. ZRASC at 680 mg/kg prolonged the time spent in the central area, open arms area, and light box by 1.9, 2.3, and 1.7-fold respectively, compared with the vehicle control group in immobilization stress (IMS) mice. ZRASC at 680 mg/kg given at 08:00 h increased the amount of non-rapid eye movement sleep by 1.4-fold in a 2-h period after dosing in IMS mice. However, it did not alter the sleep-wake behaviors in normal mice. Immunohistochemistry showed that IMS increased c-Fos expression in the neurons of the stria terminalis and tuberomammillary nucleus by 1.8 and 1.6-fold, respectively. In addition, ZRASC (680 mg/kg) reversed the IMS-induced c-Fos expression. Our results suggest that ZRASC is an effective therapeutic strategy for both anxiety disorder and sleep disturbances in an anxiety-like mouse model.

Despite persistent clinical use for over 170 years, the neuronal mechanisms by which general anesthetics produce hypnosis remain unclear. Previous studies suggest that anesthetics exert hypnotic effects by acting on endogenous arousal circuits. Recently, it has been shown that the medial parabrachial nucleus (MPB) is a novel wake-promoting component in the dorsolateral pons. However, it is not known whether and how the MPB contributes to anesthetic-induced hypnosis. Here, we investigated the action of sevoflurane, a widely used volatile anesthetic agent that best represents the drug class of halogenated ethers, on MPB neurons in mice. Using in vivo fiber photometry, we found that the population activities of MPB neurons were inhibited during sevoflurane-induced loss of consciousness. Using in vitro whole-cell patch-clamp recordings, we revealed that sevoflurane suppressed the firing rate of MPB neurons in concentration-dependent and reversible manners. At a concentration equal to MAC of hypnosis, sevoflurane potentiated synaptic GABA

Major depression is a serious, but common, psychological disorder, which consists of a long-lasting depressive mood, feelings of helplessness, anhedonia, and sleep disturbances. It has been reported that rats with bilateral olfactory bulbectomies (OBXs) exhibit depressive-like behaviors which indicates that the olfactory bulb (OB) plays an important role in the formation of depression. However, which type of OB neurons plays an important role in the formation of depression remains unclear. To determine the role of OB neuronal types in depression and related sleep-wake dysfunction. Firstly, we established and evaluated a conventional physical bilateral OBX depression model. Secondly, we used chemical methods to ablate OB neurons, while maintaining the original shape, and evaluated depressive-like behaviors. Thirdly, we utilized AAV-flex-taCasp3-TEVp and transgenetic mice to specifically ablate the OB GABAergic or glutamatergic neurons, then evaluated depressive-like behaviors. Compared with measured parameters in sham mice, mice with OBXs or ibotenic acid–induced OB lesions exhibited depressive-like behaviors and sleep disturbances, as demonstrated by results of depressive-like behavior tests and sleep recordings. Selective lesioning of OB glutamatergic neurons, but not GABAergic neurons induced depressive-like behaviors and increased rapid eye movement sleep during the light phase of the circadian cycle. These results indicate that OB glutamatergic neurons play a key role in olfactory-related depression and sleep disturbance.

Natural helicid (4-formylphenyl-O-β-d-allopyranoside), a main active constituent from seeds of the Chinese herb Helicia nilagirica, has been reported to exert a sedative, analgesic and hypnotic effect, and is used clinically to treat neurasthenic syndrome, vascular headaches and trigeminal neuralgia. In the current study, mechanical allodynia tests, electroencephalograms, electromyogram recordings and c-Fos expression in neuropathic pain-like model mice of partial sciatic nerve ligation were used to investigate the effect of helicid on neuropathic pain and co-morbid insomnia. Our results showed that helicid at a dose of 100, 200 or 400 mg kg-1 could increase the mechanical threshold by 2.5-, 2.8- and 3.1-fold for 3 h after administration, respectively. Helicid at 200 and 400 mg kg-1 given at 07:00 hours increased the amount of non-rapid eye movement sleep in a 3-h period by 1.27- and 1.35-fold in partial sciatic nerve ligated mice. However, helicid (400 mg kg-1 ) given at 21:00 hours did not change the sleep pattern in normal mice. Immunohistochemical study showed that helicid (400 mg kg-1 ) administration could reverse the increase of c-Fos expression in the neurons of the rostral anterior cingulate cortex and tuberomammillary nucleus, and the decrease of c-Fos expression in the ventrolateral preoptic area caused by partial sciatic nerve ligation. These results indicate that helicid is an effective agent for both neuropathic pain and sleep disturbances in partial sciatic nerve ligated mice.

Parathyroid hormone (PTH) is a novel cardiovascular biomarker which is particularly useful for detection and assessment of heart failure (HF). However, previous studies examining PTH in heart failure have primarily focused on left HF; thus, the relationship between PTH and right HF remains unclear. The aim of the present study was to evaluate the serum PTH levels in patients with chronic right HF. A total of 154 patients with chronic right HF were enrolled in the present study. A binary logistic regression analysis model was used to assess the independent predictive value of PTH levels in chronic right HF. Partial correlative analysis was used to demonstrate the relevance of PTH levels on the parameters of assessment of right heart function. A multiple linear regression analysis model was used to evaluate the independent factors of PTH levels in patients with right HF. The results showed that the serum PTH levels in the right HF group were significantly higher compared with the control group. After adjusting for predictors of right HF, serum PTH levels were associated with right HF with an odds ratio of 1.066 (95% confidence interval: 1.030-1.102, P

Levo-tetrahydropalmatine (l-THP), an active ingredient of Corydalis yanhusuo, has been reported to be a partial agonist for dopamine DTo investigate the effects and mechanisms of l-THP on sleep disturbance in a neuropathic pain-like condition.A mouse model of chronic neuropathic pain induced by partial sciatic nerve ligation (PSNL) was employed. The antinociceptive and hypnotic effects of l-THP were evaluated by measurement of mechanical allodynia, thermal hyperalgesia, and electroencephalogram (EEG) recordings in PSNL mice. Pharmacological approaches and c-Fos expression were used to clarify the mechanisms of l-THP.Intraperitoneal injection of l-THP at 5 and 10 mg/kg not only significantly increased the mechanical threshold by 134.4% and 174.8%, and prolonged the thermal latency by 49.4% and 69.2%, but also increased non-rapid eye movement sleep by 17.5% and 29.6%, and decreased sleep fragmentation in PSNL mice, compared with the vehicle control. Moreover, the antinociceptive effect of l-THP was prevented by DThese findings indicated that l-THP exerted analgesic effects by agonism D

Ethanol is one of the most highly abused psychoactive compounds worldwide and induces sedation and hypnosis. The histaminergic system is involved in the regulation of sleep/wake function and is a crucial player in promoting wakefulness. To explore the role and mechanism of the histaminergic system in ethanol-induced sedation and hypnosis, we recorded locomotor activity (LMA) and electroencephalography (EEG)/electromyography (EMG) in mice using an infrared ray passive sensor recording system and an EEG/EMG recording system, respectively, after administration of ethanol. In vivo microdialysis coupled with high performance liquid chromatography and fluorometry technology were used to detect histamine release in the mouse frontal cortex (FrCx). The results revealed that ethanol significantly suppressed LMA of histamine receptor 1 (H1R)-knockout (KO) and wild-type (WT) mice in the range of 1.5–2.5 g/kg, but suppression was remarkably stronger in WT mice than in H1R-KO mice. At 2.0 and 2.5 g/kg, ethanol remarkably increased non-rapid eye movement sleep and decreased wakefulness, respectively. Neurochemistry experimental data indicated that ethanol inhibited histamine release in the FrCx in a dose-dependent manner. These findings suggest that ethanol induces sedation and hypnosis via inhibiting histamine release in mice.

Despite persistent clinical use for over 170 years, the neuronal mechanisms by which general anesthetics produce hypnosis remain unclear. Previous studies suggest that anesthetics exert hypnotic effects by acting on endogenous arousal circuits. Recently, it has been shown that the medial parabrachial nucleus (MPB) is a novel wake-promoting component in the dorsolateral pons. However, it is not known whether and how the MPB contributes to anesthetic-induced hypnosis. Here, we investigated the action of sevoflurane, a widely used volatile anesthetic agent that best represents the drug class of halogenated ethers, on MPB neurons in mice. Using in vivo fiber photometry, we found that the population activities of MPB neurons were inhibited during sevoflurane-induced loss of consciousness. Using in vitro whole-cell patch-clamp recordings, we revealed that sevoflurane suppressed the firing rate of MPB neurons in concentration-dependent and reversible manners. At a concentration equal to MAC of hypnosis, sevoflurane potentiated synaptic GABAA receptors (GABAA-Rs), and the inhibitory effect of sevoflurane on the firing rate of MPB neurons was completely abolished by picrotoxin, which is a selective GABAA-R antagonist. At a concentration equivalent to MAC of immobility, sevoflurane directly hyperpolarized MPB neurons and induced a significant decrease in membrane input resistance by increasing a basal potassium conductance. Moreover, pharmacological blockade of GABAA-Rs in the MPB prolongs induction and shortens emergence under sevoflurane inhalation at MAC of hypnosis. These results indicate that sevoflurane inhibits MPB neurons through postsynaptic GABAA-Rs and background potassium channels, which contributes to sevoflurane-induced hypnosis.

The aim of the present study was to investigate the correlation between serum parathyroid hormone (PTH) levels and coronary artery calcification (CAC) in patients without renal failure, as well as to determine independent risk factors of CAC score (CACS). A total of 157 patients who underwent coronary computed tomography angiographic examination at the 101th Hospital of the People's Liberation Army between December 2013 and February 2015 were retrospectively evaluated. The correlation between PTH levels and CACS was determined using a Pearson correlation analysis. A receiver operating characteristic (ROC) curve was drawn to determine the best cutoff PTH level for prediction of CAC. The independent association between serum PTH levels and CAC was analyzed by using a logistic regression analysis model with the response variable Be binary class. The results revealed that PTH levels in patients in the CAC group were significantly higher than those of patients in the non-calcification group. PTH levels were positively correlated with CACS (r=0.288, P

EDITOR’S PERSPECTIVE What We Already Know about This Topic The parabrachial nucleus is a brainstem region involved in arousal. Brain regions involved in arousal regulate anesthetic induction and emergence. What This Article Tells Us That Is New Using chemogenetic techniques, activation of parabrachial nucleus glutamatergic neurons prolonged anesthetic induction and hastened emergence in mice. Inhibition of these neurons provided opposite effects. Modulating the activity of arousal centers may provide an approach to controlling the duration of general anesthesia. Background The parabrachial nucleus (PBN), which is a brainstem region containing glutamatergic neurons, is a key arousal nucleus. Injuries to the area often prevent patient reanimation. Some studies suggest that brain regions that control arousal and reanimation are a key part of the anesthesia recovery. Therefore, we hypothesize that the PBN may be involved in regulating emergence from anesthesia. Methods We investigated the effects of specific activation or inhibition of PBN glutamatergic neurons on sevoflurane general anesthesia using the chemogenetic “designer receptors exclusively activated by designer drugs” approach. Optogenetic methods combined with polysomnographic recordings were used to explore the effects of transient activation of PBN glutamatergic neuron on sevoflurane anesthesia. Immunohistochemical techniques are employed to reveal the mechanism by which PBN regulated sevoflurane anesthesia. Results Chemogenetic activation of PBN glutamatergic neurons by intraperitoneal injections of clozapine-N-oxide decreased emergence time (mean ± SD, control vs. clozapine-N-oxide, 55 ± 24 vs. 15 ± 9 s, P = 0.0002) caused by sevoflurane inhalation and prolonged induction time (70 ± 15 vs. 109 ± 38 s, n = 9, P = 0.012) as well as the ED50 of sevoflurane (1.48 vs. 1.60%, P = 0.0002), which was characterized by a rightward shift of the loss of righting reflex cumulative curve. In contrast, chemogenetic inhibition of PBN glutamatergic neurons slightly increased emergence time (56 ± 26 vs. 87 ± 26 s, n = 8, P = 0.034). Moreover, instantaneous activation of PBN glutamatergic neurons expressing channelrhodopsin-2 during steady-state general anesthesia with sevoflurane produced electroencephalogram evidence of cortical arousal. Immunohistochemical experiments showed that activation of PBN induced excitation of cortical and subcortical arousal nuclei during sevoflurane anesthesia. Conclusions Activation of PBN glutamatergic neurons is helpful to accelerate the transition from general anesthesia to an arousal state, which may provide a new strategy in shortening the recovery time after sevoflurane anesthesia.

Aim: Gelsemine, an alkaloid from the Chinese herb Gelsemium elegans (Gardn & Champ) Benth., is effective in mitigating chronic pain in rats. In the present study we investigated whether the alkaloid improved sleep disturbance, the most common comorbid symptoms of chronic pain, in a mouse model of neuropathic pain. Methods: Mice were subjected to partial sciatic nerve ligation (PSNL). After the mice were injected with gelsemine or pregabalin (the positive control) intraperitoneally, mechanical allodynia and thermal hyperalgesia were assessed, and electroencephalogram (EEG)/electromyogram (EMG) recording was performed. Motor performance of the mice was assessed using rota-rod test. c-Fos expression in the brain was analyzed with immunohistochemical staining. Results: In PSNL mice, gelsemine (2 and 4 mg/kg) increased the mechanical threshold for 4 h and prolonged the thermal latencies for 3 h. Furthermore, gelsemine (4 mg/kg, administered at 6:30 AM) increased non-rapid eye movement (non-REM, NREM) sleep, decreased wakefulness, but did not affect REM sleep during the first 3 h in PSNL mice. Sleep architecture analysis showed that gelsemine decreased the mean duration of wakefulness and increased the total number of episodes of NREM sleep during the first 3 h after the dosing. Gelsemine (4 mg/kg) did not impair motor coordination in PSNL mice. Immunohistochemical study showed that PSNL increased c-Fos expression in the neurons of the anterior cingulate cortex, and gelsemine (4 mg/kg) decreased c-Fos expression by 58%. Gelsemine (4 mg/kg, administered at either 6:30 AM or 8:30 PM) did not produce hypnotic effect in normal mice. Pregabalin produced similar antinociceptive and hypnotic effects, but impaired motor coordination in PSNL mice. Conclusion: Gelsemine is an effective agent for treatment of both neuropathic pain and sleep disturbance in PSNL mice; anterior cingulate cortex might play a role in the hypnotic effects of gelsemine.

To evaluate the antinociceptive and hypnotic effects of pregabalin, we established a neuropathic pain-like model in mice using partial sciatic nerve ligation (PSNL), and examined thermal hyperalgesia, mechanical allodynia, electroencephalogram, rota-rod testing, and c-Fos expression in the anterior cingulate cortex. Gabapentin was used as a reference drug in the study. Pregabalin administered i.g. at 12.5 and 25mg/kg prolonged the duration of thermal latencies by 1.4- and 1.6-fold and increased the mechanical threshold by 2.2- and 3.1-fold 3h after administration, respectively, but did not affect motor coordination in PSNL mice, compared with vehicle control. Pregabalin (12.5 and 25mg/kg) given at 6:30 increased the amount of non-rapid eye movement sleep in a 4-h period by 1.3- and 1.4-fold, respectively, in PSNL mice. However, pregabalin (25mg/kg) given at 20:30 did not alter the sleep pattern in normal mice. Immunohistochemical study showed that PSNL increased c-Fos expression in the neurons of anterior cingulate cortex by 2.1-fold, which could be reversed by pregabalin. These results indicate that pregabalin is an effective treatment for both neuropathic pain and sleep disturbance in PSNL mice.

Background Thyroid carcinoma (TC) is more likely to occur in young women. The aim of this study was to compare the aesthetic effect of different thyroidectomies. Methods One hundred twenty female patients who underwent thyroidectomy were evenly distributed into three groups: conventional access (CA), aesthetic principles access (APA) and minimally invasive access (MIA). The Patient and Observer Scar Assessment Scale (POSAS) was used as the assessment tool for the linear scar. Results The patients in the MIA group showed significantly less intraoperative blood loss, less drainage, a shorter scar length and a shorter duration of drainage than those in the CA group and the APA group. However, the operation time of 129.0 min in the MIA group was significantly longer than the 79.6 min in the CA group and the 77.0 min in the APA group. The best aesthetic score, as assessed by the Observer Scar Assessment Scale (OSAS), was obtained in the APA group. The Patient Scar Assessment Scale (PSAS) scores were significantly lower in the APA group and CA group than in the MIA group. Significantly lower objective scar ratings were found in the APA group than in the other two groups. Conclusion These results show that APA produced the best surgical outcomes in TC patients, indicating that conventional thyroidectomy can produce an ideal aesthetic result using the principles of aesthetic surgery. Thyroid surgery need not be performed through excessively short incisions for the sake of patient satisfaction with the scar’s appearance. Trial registration This clinical trial was retrospectively registered on ClinicalTrials.gov PRS on August 1st,2017 ( NCT03239769 ).

Signal transducer and activator of transcription 3 (STAT3) is considered to be an oncogene. Blocking STAT3 signaling may induce growth arrest and apoptosis in different types of tumors. Cancer cells utilize the glycolytic pathway to maintain cell growth even when adequate oxygen is present. Glycolysis inhibition is a potential therapeutic modality. In the present study, the effects of Prosapogenin A (PSA) from the traditional Chinese medicine, Veratrum, on apoptosis, the STAT3 signaling pathway and glycometabolism in cancer cells were investigated. The results indicated that PSA induced growth inhibition and apoptosis in HeLa, HepG2 and MCF-7 cells. PSA inhibited the STAT3 signaling pathway and modulated the expression of glycometabolism-related genes. The results indicate that the inhibition of the STAT3 signaling and glycometabolism pathways contributes to the PSA-mediated apoptosis of HeLa, HepG2 and MCF-7 cells.

Parathyroid hormone (PTH) levels are useful as a prognostic factor of chronic heart failure (HF) and can predict hospitalization for HF. It is unknown whether serum PTH levels in hospitalized patients with HF can predict discharge and if admission, discharge, or change from admission to discharge PTH measure is the most important predictor of readmission and/or death.A total of 125 consecutive hospitalized patients with HF were enrolled into this study. The receiver operating characteristic (ROC) curves indicated the predicted values of PTH for readmission due to HF and the optimal cutoff points of PTH levels for discharge. The binary logistic regression model indicated an association between PTH levels and readmission due to HF.The PTH level on admission was positively correlated with the New York Heart Association class and N-terminal pro-B-type natriuretic peptide level. The ROC curves showed that the PTH level at discharge (PTHdis) was of predictive value for readmission within 1 year due to HF. A PTHdis level45.2 pg/mL was the best cutoff point for discharge, with a sensitivity of 72.1%, specificity of 61.5%, and area under the ROC curve of 0.693 (95% confidence interval [CI] 0.598-0.788). The results of logistic regression analysis showed that PTHdis had an odds ratio of 1.035 for readmission due to HF (95% CI 1.005-1.067).Serum PTH levels in hospitalized patients with HF were shown to be an independent predictor of discharge and PTHdis was the best predictor of readmission and/or death within 1 year due to HF.

The basal forebrain (BF) cholinergic neurons have long been thought to be involved in behavioral wakefulness and cortical activation. However, owing to the heterogeneity of BF neurons and poor selectivity of traditional methods, the precise role of BF cholinergic neurons in regulating the sleep-wake cycle remains unclear. We investigated the effects of cell-selective manipulation of BF cholinergic neurons on the sleep-wake behavior and electroencephalogram (EEG) power spectrum using the pharmacogenetic technique, the 'designer receptors exclusively activated by designer drugs (DREADD)' approach, and ChAT-IRES-Cre mice. Our results showed that activation of BF cholinergic neurons expressing hM3Dq receptors significantly and lastingly decreased the EEG delta power spectrum, produced low-delta non-rapid eye movement sleep, and slightly increased wakefulness in both light and dark phases, whereas inhibition of BF cholinergic neurons expressing hM4Di receptors significantly increased EEG delta power spectrum and slightly decreased wakefulness. Next, the projections of BF cholinergic neurons were traced by humanized Renilla green fluorescent protein (hrGFP). Abundant and highly dense hrGFP-positive fibers were observed in the secondary motor cortex and cingulate cortex, and sparse hrGFP-positive fibers were observed in the ventrolateral preoptic nucleus, a known sleep-related structure. Finally, we found that activation of BF cholinergic neurons significantly increased c-Fos expression in the secondary motor cortex and cingulate cortex, but decreased c-Fos expression in the ventrolateral preoptic nucleus. Taken together, these findings reveal that the primary function of BF cholinergic neurons is to inhibit EEG delta activity through the activation of cerebral cortex, rather than to induce behavioral wakefulness.

The cellular uptake and localization of photosensitizer-loaded nanoparticles have significant impact on photodynamic therapy (PDT) efficacy due to short lifetime and limited action radius of singlet oxygen. Herein, we develop poly(ethylene glycol) (PEG)- and polyethylenimine (PEI)-functionalized zinc(II) phthalocyanine (ZnPc)-loaded mesoporous silica nanoparticles (MSNs), which are able to distribute in the cytosol by endolysosomal escape. In this photosensitizer-carrier system (PEG-PEI-MSNs/ZnPc), ZnPc is a PDT agent; MSNs are the nanocarrier for encapsulating ZnPc; PEI facilitates endosomal escape; and PEG enhances biocompatibility. The as-synthesized PEG-PEI-MSNs/ZnPc have a high escape efficiency from the lysosome to the cytosol due to the "proton sponge" effect of PEI. Compared with the ZnPc-loaded MSNs, the phototoxicity of the PEG-PEI-MSNs/ZnPc is greatly enhanced in vitro. By measuring the mitochondrial membrane potential, a significant loss of >80% Δψm after treatment with PEG-PEI-MSNs/ZnPc-PDT is observed. It is further demonstrated that the ultra-efficient passive tumor targeting and excellent PDT efficacy are achieved in tumor-bearing mice upon intravenous injection of PEG-PEI-MSNs/ZnPc and the followed light exposure. We present here a strategy for enhancement of PDT efficacy by endolysosomal escape and highlight the promise of using multifunctional MSNs for cancer therapy.

Novel hybrid biomaterial of Tat peptide modified gelatin-siloxane nanoparticles (Tat-GS NPs), with positive surface potential was synthesised through a two-step sol-gel process. The particles were subsequently tested in vitro with HeLa cells by fluorescent activitated cell sorter analysis, confocal laser scanning microscopy, and transmission electron microscopy to determine whether the functionalisation with Tat peptide allowed particles to transfer across the cell membrane and locate in the nucleus. Our current results indicated that the internalisation of Tat-GS NPs in HeLa cells is time- and concentration- dependent. Moreover, Tat-GS NPs could penetrate the nucleus membrane and enter into nucleus. The Tat-GS/pDNA nanocomplexes were formulated with higher encapsulation efficiency, and exhibited efficient transfection in vitro. Tat-GS NPs are thus considered as novel non-viral vectors will be widely used in further study.

The nonviral gene delivery system is an attractive alternative to cancer therapy. A new kind of gelatin-silica nanoparticles (GSNPs) was developed through a two-step sol-gel procedure. To improve the transfection efficacy, GSNPs modified with different fusion peptides (Tat, HA2, R8, Tat/HA2, and Tat/R8) were prepared for particle size, zeta potential, cellular uptake, hemolysis activity at physiological pH (7.0) or acidic pH (5.0), and condensation of plasmid DNA. The results suggest that the sizes and zeta potentials of GS-peptide conjugates were 147 - 161 nm and 19 - 33 mV, respectively; GS-peptide conjugates exhibited low cytotoxicity; the plasmid DNA was readily entrapped at a GS-peptide/pDNA weight ratio of 50 - 200. The in vitro and in vivo studies demonstrated that the synergistic effects of cell-penetrating peptide Tat and fusogenic peptide HA2 could promote the efficient cellular internalization, endosome escape, and nucleus targeting, hence delivering the therapeutic nucleic acid efficiently.

This paper is devoted to the unique solvability of backward stochastic Volterra integral equations (BSVIEs, for short), in terms of both M-solution and the adapted solutions. We prove the existence and uniqueness of M-solutions of BSVIEs in Lp (1 1) is also considered, which also generalizes the results in the existing literature.

Speed signal is an important monitoring signal in Steam Turbine Condition Monitoring And Fault Diagnosis(TDM) system. A review on the existing speed measurement methods of rotary machine was proposed to find out the defects of each method. A new approach was introduced to fulfill steam turbine speed accurate measuring. The periods of phase signal pulse generated by the key groove and speed signal pulse generated by the velocimetry gear, were measured respectively by the two independent 16-bit timer/counters, and the "counter overflow" problem was resolved by calling a byte memory unit. According to the record number of the counter, the value of steam turbine speed was calculated accurately. The method of steam turbine speed measurement proposed in this paper can not only simplify the structure of a TDM system, but also reduce its cost.

A sequential thermal and acid activation method was used to improve phosphorus (P) adsorption capability on ferric and alum water treatment residuals (FARs). The optimal conditions were determined as thermal activation at 600 °C for 4 h followed by hydrochloric acid activation at 2 mol/L with a 1:1 solid to liquid ratio. The structure of the FARs after activation was similar to that before activation; however, the pore volume and surface area were reduced due to the loss of activated carbon during heating. The amount of heavy metal extraction from the activated FARs partially increased but was below the standards for hazardous waste identification. After activation, the P-binding ability of the FARs was enhanced, and the maximum P adsorption capacity increased from 28.37 to 53.23 mg/g (pH = 7), as indicated by the Two-site Langmuir model. The activated FARs maintained a high P adsorption capability under different redox conditions; even in anaerobic conditions for 64 d. Low pH was beneficial to P adsorption. Fractionation of the absorbed P from the FARs demonstrated that the activation method was particularly efficient for alum-rich water treatment residuals rather than for ferric-rich water treatment residuals.

This article introduced the four-terminal network method, Riccati transfer matrix method and finite element method respectively, and the applications of three methods in inherent characteristics analysis of turbine generator units’ torsional vibration. Considering an actual case of 600 MW units in one power, the natural frequencies and normal vibration mode of units’ torsional vibration were worked out through the three methods, and compared with the testing natural frequencies, the results showed that the calculation precisions of three methods are very high, and the three methods can be used to analyze actual units. Comparatively, the results obtained by four-terminal network method are closer to testing natural frequencies with a higher calculation precision.

National Natural Science Foundation of China [30970733, 30901175]; National Basic Research Program of China [2007CB935603, 2010CB732402]; Program for New Century Excellent Talents in Fujian Province University.

Head trauma and acute disorders often instantly compress the cerebral cortex and lead to functional abnormalities. Here we used rat epidural bead implantation model and investigated the immediate changes following acute compression. The dendritic arbors of affected cortical pyramidal neurons were filled with intracellular dye and reconstructed 3-dimensionally for analysis. Compression was found to shorten the apical, but not basal, dendrites of underlying layer III and V cortical pyramidal neurons and reduced dendritic spines on the entire dendritic arbor immediately. Dendrogram analysis showed that in addition to distal, proximal apical dendrites also quickly reconfigured. We then focused on apical dendritic trunks and explored how proximal dendrites were rapidly altered. Compression instantly twisted the microtubules and deformed the membrane contour of dendritic trunks likely a result of the elastic nature of dendrites as immediate decompression restored it and stabilization of microtubules failed to block it. Subsequent adaptive remodeling restored plasmalemma and microtubules to normal appearance in 3 days likely via active mechanisms as taxol blocked the restoration of microtubules and in addition partly affected plasmalemmal reorganization which presumably engaged recycling of excess membrane. In short, the structural dynamics and the associated mechanisms that we revealed demonstrate how compression quickly altered the morphology of cortical output neurons and hence cortical functions consequently.

National Natural Science Foundation of China [30670559]; National Basic Research Program of China (973 Program) [2007CB935603]; Program for New Century Excellent Talents in Fujian Province University

We studied the cytoarchitecture and dendritic arbors of the output neurons of the sensorimotor cortex of aged rats and found that although individual cortical layer became thinner, the overall cytoarchitecture and neuron densities remained comparable to those of young adults. To find out whether aging affects cortical outputs we studied the soma-dendritic arbors of layers III and V pyramidal neurons, main output neurons of the cerebral cortex, using brain slice intracellular dye injection technique. With a fluorescence microscope, selected neurons were filled with fluorescence dye under visual guidance. Injected slices were resectioned into thinner sections for converting the injected dye into non-fading material immunohistochemically. The long apical dendritic trunk and branches could be routinely revealed. This allowed us to reconstruct and study the dendritic arbors of these neurons in isolation in 300-microm-thick dimension. Analysis shows that their cell bodies did not shrink, but the densities of spines on dendrites and the total dendritic length significantly reduced. Among spines, those with long thin stalks thought to be involved in memory acquisition appeared to be reduced. These could underlie the compromise of sensorimotor functions following aging.

To study the chemical constituents of Veratrum dahuricum (Turcz.) Loes. f., a new aurone glycoside named as (Z)-7, 4'-dimethoxy-6-hydroxyl-aurone-4-O-β-glucopyranoside was isolated from the 95% ethanol extracts of the rhizomes and roots of Veratrum dahuricum (Turcz.) Loes. f. by repeated column chromatography on silica gel and recrystallization. Its structure was established by extensive spectroscopic analyses, and its cytotoxicities against HepG-2, MCF7 and A549 cell lines were measured in vitro.

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. The present study evaluated effects of paeoniflorin on neuropathic pain and associated insomnia and the mechanisms involved. 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. 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. 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.

To achieve an efficiency of intracellular photosensitizers (PSs) delivery and efficacy of photodynamic therapy, we have developed a novel class of PS formulation for encapsulating sulfonated aluminum phthalocyanine (AlPcS4) by taking advantage of the membrane-disruptive peptides Tat/HA2 and the photothermally triggered delivery system using AuNR@pNIPAAm. The coordinated effects of cell penetrating peptide Tat and fusogenic peptide HA2 could enhance the efficient cellular internalization and endo/lysosome escape of PSs delivery systems. Singlet oxygen generation was inhibited due to the reaction between loaded AlPcS4 and Au nanorods, which indicated that the AlPcS4-loaded, AuNR@pNIPAAm delivery system might be nonphototoxic in the circulatory system. However, this PSs-loaded nanosystem became highly phototoxic as it underwent the near-infrared irradiation by using the combined lights of 808 and 680 nm. Upon irradiation, the Tat/HA2 conjugated AuNR@pNIPAAm-Pc elicited an active photodynamic response against the cancer cells, leading to effective cells killing via mitochondria-associated apoptotic pathway. This study also demonstrated improved PDT therapeutic efficacy after intravenous administration of Tat/HA2-AuNR@pNIPAAm-Pc and the subsequent lights irradiations in tumor-bearing mice. We describe here a strategy for enhanced photodynamic eradication of solid tumors by endo/lysosomal escape and highlight the great promise of peptide-based nanocarriers used for cancer therapy.

Background Obesity is regarded as a risk factor for cardiovascular disease. Bone morphogenetic protein 4 (BMP4) is a proinflammatory and profibrotic factor, and the reduced expression of this molecule in obese mice seems to be inconsistent with the known proinflammatory effects of obesity. Therefore, we studied BMP4 expression and inflammation in the myocardial tissue and aortas of obese mice. Methods and Results Four-week-old ob/ob mice were used as the experimental group, and C57BL/6 mice comprised the control group. Animals were sacrificed after a 12-week full diet, and then the blood, heart, abdominal aorta, and inguinal adipose tissue were collected. The expression of BMP4 mRNA and protein in the heart and aorta was significantly higher in the experimental group than in the control group, but expression was lower in adipose tissue. Inflammation measured by the expression of IL-1β and IL-9 mRNA and protein and Smad1 and phosphorylated Smad1/5/8 protein in the heart and aorta was higher in the experimental group than in the control group. In addition, the expression of BMP4 in the serum was significantly higher in the experimental group than in the control group. Conclusion BMP4 is significantly overexpressed in the myocardial tissue and aortas of obese mice, and mediates local inflammatory responses.

National Natural Science Foundation of China [30970733, 81171448, 81172394]; National Basic Research Program of China [2010CB732402]

The epidermal growth factor receptor (EGFR) is involved in the proliferation of human tumors and is an effective target for the treatment of cancer. In the present study, a novel quinolone-indolone conjugate, QIC1 [9-Fluoro-3,7-dihydro-3-methyl-10-(4-methyl -1-piperazinyl) -6-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl) -7-oxo-2H-(1,4) oxazino(2,3,4-ij)quinoline], which targeted EGFR, was synthesized in order to investigate the anticancer activity and the potential mechanisms underlying the effect of this compound in human cancer cells. Using MTT assays it was observed that QIC1 inhibited the growth of HepG2 human hepatoma cells, MCF7 human breast cancer cells, HeLa human cervical cancer cells and A549 human lung adenocarcinoma cells. QIC1 arrested cell cycle progression at the G2/M phase in HepG2 cells. QIC1 inhibited the synthesis of DNA in A549 cells. In addition, it resulted in cell apoptosis, in association with increased expression of Bax and reduced expression of Bcl-2. Further analyses demonstrated that QIC1 attenuated the activity of EGFR, and the downstream signal transducer and activator of transcription 3 (STAT3)-mediated hexokinase II (HK2) signaling pathways. Furthermore, QIC1 exhibited antiproliferative effects in MCF7/DOX human doxorubicin-resistant breast cancer cells and also enhanced the anticancer activity of doxorubicin in these cells. In conclusion, the inhibition of proliferation and the induction of apoptosis was associated with reduced expression of phospho-EGFR-phospho-STAT3-HK2. The present results suggest a potential role for QIC1 in the treatment of human cancer.

This study is to investigate the inhibitory effect and mechanism of prosapogenin A (PSA) on MCF7. MTT assay was performed to determine the inhibitory effect of PSA on MCF7 cells. PI/Hoechst 33342 double staining was used to detect cell apoptosis. RT-PCR was used to test the mRNA levels of STAT3, GLUT1, HK and PFKL. Western blotting was performed to determine the expression of STAT3 and pSTAT3 protein in MCF7 cells. The results showed that PSA could dose-dependently inhibit cell growth of MCF7 followed by IC50 of 9.65 micrmol x L(-1) and promote cell apoptosis of MCF7. Reduced mRNA levels of STAT3, HK and PFKL were observed in MCF7 cells treated with 5 micromol x L(-1) of PSA. PSA also decreased the level of pSTAT3 protein. STAT3 siRNA caused decrease of mRNA of GLUT1, HK and PFKL which indicated STAT3 could regulate the expressions of GLUT1, HK and PFKL. The results suggested that PSA could inhibit cell growth and promote cell apoptosis of MCF7 via inhibition of STAT3 and glycometabolism-related gene.

OBJECTIVE: To evaluate the changes of plasma B-type natriuretic peptide(BNP) levels after high-pressure post-dilation following coronary stent deployment. METHODS: A total of 173 patients undergoing percutaneous coronary intervention for the left anterior descending artery were enrolled into the study. All patients were divided into two groups: the conventional group and the post-dilation group. The plasma BNP, troponin I(TnI), myocardial band isoenzyme of creatine kinase(CK-MB) levels and the serum high sensitive C-reactive protein(hs-CRP) levels immediately before and 24 hours after the interventional procedures were compared between the two groups. RESULTS: There were no significant differences between the two groups in terms of clinical features, clinical and biochemical parameters, stent parameters, pre-procedural plasma BNP and TnI levels, pre-procedural serum hs-CRP levels, as well as pre- and post-procedural CK-MB levels (all P>0.05). In the conventional group, post-procedural plasma BNP levels were significantly reduced when compared with the pre-procedural levels, median(25th,75th) were 32.5 ng/L(15.0,52.4) vs. 37.7 ng/L(18.2,67.3), P = 0.001. In the post-dilation group, post-procedural plasma BNP levels were significantly increased when compared with the pre-procedural levels, median(25th,75th) were 53.5 ng/L(29.6,82.8) vs. 44.2 ng/L(17.15,70.7), P

Twelve compounds were isolated from Psoralea corylifolia and their structures were identified as isopsoralen (1), psoralen (2), 8-methoxypsoralen (3), psoralidin (4), corylin (5), bavachin (6), daidzein (7), corylifolinin (8), bavachinin (9), neobavaisoflavone (10), daidzin (11) and astragalin (12). The results showed that psoralidin had the activity of scavenging DPPH free radicals activity (IC50 43.85 mg x L(-1)). Psoralidin (IC50 1.32 mg x L(-1))c, oryfolin (IC50 4.97 mg x L(-1)), daidzin (IC50 10.47 mg x S(-1)), daidzein (IC50 34.22 mg) x L(-1)) and astragalin (IC50 31.27 mg x L(-1)) had the activity of scavenging ABTS free radical. Psoralidin (IC50 40.74 mg x L(-1)), coryfolin (IC50 45.73 mg x L(-1)) and daidzein (IC50 49.44 mg x L(-1)) had alpha-glucosidase inhibitory activity. Corylifolinin and neobavaisoflavone had significantly effect of inhibiting SA, MRSA and ESBLs-SA (MIC 0. 781 3, 1.562, 5, 0.781 25 microg x disc(-1) and 6.25, 6.25, 6.25 microg x disc(-1).