[Effect of Erxian Decoction-containing serum on H_2O_2-induced proliferation and osteogenic differentiation of MC3T3-E1 cells via BK channels].

This study aimed to investigate the effects of Erxian Decoction(EXD)-containing serum on the proliferation and osteogenic differentiation of MC3T3-E1 cells under oxidative stress through BK channels. The oxidative stress model was induced in MC3T3-E1 cells by H_2O_2, and 3 mmol·L~(-1) tetraethylammonium(TEA) chloride was used to block the BK channels in MC3T3-E1 cells. MC3T3-E1 cells were divided into a control group, a model group, an EXD group, a TEA group, and a TEA+EXD group. After MC3T3-E1 cells were treated with corresponding drugs for 2 days, 700 µmol·L~(-1) H_2O_2 was added for treatment for another 2 hours. CCK-8 assay was used to detect cell proliferation activity. The alkaline phosphatase(ALP) assay kit was used to detect the ALP activity of cells. Western blot and real-time fluorescence-based quantitative PCR(RT-qPCR) were used to detect protein and mRNA expression, respectively. Alizarin red staining was used to detect the mineralization area of osteoblasts. The results showed that compared with the control group, the model group showed significantly blunted cell proliferation activity and ALP activity, reduced expression of BK channel α subunit(BKα), collagen Ⅰ(COL1), bone morphogenetic protein 2(BMP2), osteoprotegerin(OPG), and phosphorylated Akt, decreased mRNA expression levels of Runt-related transcription factor 2(RUNX2), BMP2, and OPG, and declining area of calcium nodules. EXD-containing serum could significantly potentiate the cell proliferation activity and ALP activity, up-regulate the protein expression of BKα, COL1, BMP2, OPG, and phosphorylated Akt, and forkhead box protein O1(FoxO1), promote the mRNA expression of RUNX2, BMP2, and OPG, and enlarge the area of calcium nodules. However, BK channel blockage by TEA reversed the effects of EXD-containing serum in promoting the protein expression of BKα, COL1, BMP2, OPG, and phosphorylated Akt and FoxO1, increasing the mRNA expression of RUNX2, BMP2, and OPG, and enlarging the area of calcium nodules. EXD-containing serum could improve the proliferation activity, osteogenic differentiation, and mineralization ability of MC3T3-E1 cells under oxidative stress, which might be related to the regulation of BK channels and downstream Akt/FoxO1 signaling pathway.

Directional Doping and Cocrystallizing an Open-Shell Ag39 Superatom via Precursor Engineering.

Metal precursors employed in the bottom-up synthesis of metal nanoclusters (NCs) are of great importance in directing their composition and geometrical structure. In this work, a silver nanocluster co-protected by phosphine and thiolate, namely, [Ag39(PFBT)24(TPP)8]2- (Ag39, PFBT = pentafluorobenzenethiol, TPP = triphenylphosphine), was isolated and structurally characterized. It adopts a three-layered Ag13@Ag18@Ag8S24P8 core-shell structure. The Ag13@Ag18 kernel is unusual in multilayer noble metal NCs. By introducing a copper precursor in the synthesis, a bimetallic nanocluster [Ag37Cu2(PFBT)24(TPP)8]2- (Ag37Cu2) with an identical structure to Ag39 apart from two outer Ag atoms being substituted by Cu atoms was obtained. Astoundingly, the Cu precursor used in the synthesis was found to be critical in determining the final structure. The alteration of the Cu precursor led to the cocrystallization of the above alloy nanocluster with a Ag14 nanocluster, namely, [Ag37Cu2(PFBT)24(TPP)8]2-·[Ag14(PFBT)6(TPP)8] (Ag37Cu2·Ag14). The electronic structure analyzed by theoretical calculation reveals that Ag39 is a 17-electron open-shell superatom. The optical absorption of Ag39, Ag37Cu2, and Ag37Cu2·Ag14 was compared and studied in detail. This work not only enriches the family of alloy metallic nanoclusters but also provides a metal NC-based cocrystal platform for in-depth study of its crystal growth and photophysical property.

Ursolic acid reduces Adriamycin resistance of human ovarian cancer cells through promoting the HuR translocation from cytoplasm to nucleus.

Ursolic acid (UA) has been shown to suppress various tumor progression, however, its roles in Adriamycin resistance of human ovarian cancer (OC) cells are still unclear. This work aims to investigate the effects of UA on the Adriamycin resistance of human OC cells. Here, we constructed Adriamycin-resistant OC SKOV3-Adr cells and found that UA attenuated Adriamycin resistance in SKOV3-Adr cells. Additionally, UA enhanced Adriamycin sensitivity in the parental SKOV3 and another OC cell line A2780 cells. Mechanistic studies showed that HuR mRNA level was similar between SKOV3 and SKOV3-Adr cells, but the cytoplasmic expression of HuR protein was increased in SKOV3-Adr cells compared with that in SKOV3 cells, and subsequently enhancing the mRNA stability of multidrug resistance gene 1 (MDR1). Moreover, UA had no effects on HuR expression, but promoted the cytoplasm-nucleus translocation of HuR protein, decreased MDR1 mRNA stability and thus reduced MDR1 expression. Furthermore, overexpression of MDR1 rescued the effects of UA on Adriamycin resistance and sensitivity. This work reveals a novel HuR/MDR1 axis responsible for UA-mediated attenuation on Adriamycin resistance in OC cells.

Association of IL-17 and IL-23 Gene Variants with Plasma Levels and Risk of Vulvovaginal Candidiasis in a Chinese Han Population.

BACKGROUND: Vulvovaginal candidiasis (VVC) is a common vaginal inflammatory disease in females. The interleukin (IL)-23/IL-17 axis was involved in vaginal inflammation. Nevertheless, the relationship between gene polymorphisms in the IL-23/IL-17 axis and VVC risk is still unexplored. METHODS: We enrolled 217 VCC cases and 326 controls in this study. The genotyping of all polymorphisms was implemented by PCR-RFLP methods. RESULTS: Data indicated that IL-17F gene rs763780, IL-17A gene rs2275913, and IL-23R rs11209026 polymorphisms were linked with an elevated risk of VVC in Chinese ethnicity. Subgroup analyses uncovered that IL-23R rs11209026, IL-17A rs10484879 and IL-17F rs763780 polymorphisms increased the risk of VVC among smokers or individuals with BMI ≥25 kg/m2. Additionally, IL-17F rs763780 polymorphism was shown to increase the risk of recurrent VVC (RVVC). Furthermore, IL-23 and IL-17 serum levels were higher among VVC cases than controls. We also observed that IL-23 and IL-17 gene polymorphisms were related to their serum levels. Receiver operating characteristics (ROC) curve analysis found that IL-17 and IL-23 serum levels were associated with the relapse of VVC. CONCLUSION: In conclusion, this study indicates that polymorphisms in the IL-23/IL-17 axis increase the risk of VVC.

Neovascularization and Synaptic Function Regulation with Memantine and Rosuvastatin in a Rat Model of Chronic Cerebral Hypoperfusion.

Cerebral hypoperfusion is an important factor in the pathogenesis of cerebrovascular diseases and neurodegenerative disorders. We investigated the effects of memantine and rosuvastatin on both neovascularization and synaptic function in a rat model of chronic cerebral hypoperfusion, which was established by the bilateral common carotid occlusion (2VO) method. We tested learning and memory ability, synaptic function, circulating endothelial progenitor cell (EPC) number, expression of neurotrophic factors, and markers of neovasculogenesis and cell proliferation after memantine and/or rosuvastatin treatment. Rats treated with memantine and/or rosuvastatin showed significant improvement in Morris water maze task and long-term potentiation (LTP) in the hippocampus, compared with untreated 2VO model rats. Circulating EPCs, expression of brain-derived neurotrophic factor, and vascular endothelial growth factor, markers of microvessel density were increased by each of the three interventions. Rosuvastatin also increased cell proliferation in the hippocampus. Combined treatment with memantine and rosuvastatin showed greater effect on enhancement of LTP and expression of neurotrophic factors than either single medication treatment alone. Both memantine and rosuvastatin improved learning and memory, enhanced neovascularization and synaptic function, and upregulated neurotrophic factors in a rat model of chronic cerebral hypoperfusion.

Efficacy of antidepressive medication for depression in Parkinson disease: a network meta-analysis.

BACKGROUND: Parkinson disease (PD) was considered as the 2nd most prevalent neurodegenerative disorder after Alzheimer disease, while depression is a prevailing nonmotor symptom of PD. Typically used antidepression medication includes tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI), serotonin and norepinephrine reuptake inhibitors (SNRI), monoamine-oxidase inhibitors (MAOI), and dopamine agonists (DA). Our study aimed at evaluating the efficacy of antidepressive medications for depression of PD. METHODS: Web of Science, PubMed, Embase, and the Cochrane library were searched for related articles. Traditional meta-analysis and network meta-analysis (NMA) were performed with outcomes including depression score, UPDRS-II, UPDRS-III, and adverse effects. Surface under the cumulative ranking curve (SUCRA) was also performed to illustrate the rank probabilities of different medications on various outcomes. The consistency of direct and indirect evidence was also assessed by node-splitting method. RESULTS: Results of traditional pairwise meta-analysis were performed. Concerning depression score, significant improvement was observed in AD, MAOI, SSRI, and SNRI compared with placebo. NMA was performed and more information could be obtained. DA was illustrated to be effective over placebo concerning UPDRS-III, MAOI, and SNRI. DA demonstrated a better prognosis in UPDRS-II scores compared with placebo and MAOI. However, DA and SSRI demonstrated a significant increase in adverse effects compared with placebo. The SUCRA value was calculated to evaluate the ranking probabilities of all medications on investigated outcomes, and the consistency between direct and indirect evidences was assessed by node-splitting method. CONCLUSION: SSRI had a satisfying efficacy for the depression of PD patients and could improve activities of daily living and motor function of patient but the adverse effects are unneglectable. SNRI are the safest medication with high efficacy for depression as well while other outcomes are relatively poor.

Semantic clustering and sleep in patients with amnestic mild cognitive impairment or with vascular cognitive impairment-no dementia.

BACKGROUND: Cognition and sleep deficits occur in amnestic mild cognitive impairment (aMCI) and vascular cognitive impairment-no dementia (VCIND). However, how memory and sleep deficits differ between aMCI and VCIND remains unclear. METHODS: Fifty aMCI and 50 VCIND patients and 38 sex- and age-matched healthy controls (HCs) were administered the Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test-A/B (TMT-A/B), Wisconsin Card Sorting Test (WCST), Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), Benton Judgment of Line Orientation (JLO) test, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and Insomnia Severity Index (ISI) to quantify cognitive deficits and subjective sleep disturbance. RESULTS: Compared with VCIND patients, aMCI patients had lower HVLT-R scores for total recall (p < 0.001), delayed recall (p < 0.001) and recognition (p = 0.001), and for total-recall (p = 0.002) and delayed-recall (p < 0.001) semantic clustering ratios (SCRs). However, VCIND patients exhibited more obvious executive dysfunction (TMT-A, p < 0.001; TMT-B, p < 0.001; WCST, p < 0.001), lower information processing speed (PASAT, p = 0.003; SDMT, p < 0.001), and more severe sleep disturbance (PSQI, p < 0.001; ESS, p < 0.001; ISI, p < 0.001). Additionally, sleep quality and efficiency were related to total and delayed recall (all r values from -0.31 to -0.60, p < 0.05) in aMCI and VCIND. CONCLUSIONS: aMCI and VCIND differ in cognitive function, memory strategy and sleep impairment; these characteristics are helpful to identify and distinguish patients with very early cognitive impairment. Our results also suggest that memory deficits are associated with sleep disturbance in aMCI and VCIND.

Factors associated with post-stroke depression and emotional incontinence: lesion location and coping styles.

Post-stroke depression (PSD) and post-stroke emotional incontinence (PSEI) have attracted worldwide interest in recent years. These emotional disturbances have a negative impact on the rehabilitation process and the associated worse outcome. Consequently, defining the risk factors for development of PSD and PSEI is important. In this study, we evaluated 368 consecutive patients with acute ischemic stroke at admission and at three months later. PSD was evaluated by using the Beck Depression Inventory, and PSEI was evaluated using Kim's criteria. The Social Support Rating Scale and Medical Coping Modes Questionnaire were also used as measurement tools. Multivariate analyses showed that anterior cortex infarction was associated with PSEI three months after stroke occurrence. The appearance of PSD was not related to lesion location. Both motor and sensory dysfunctions was independently associated with PSD at admission, whereas low degree of social utilization was the independent factor associated with PSD 3 months after stroke. Acceptance-resignation is related to PSD and PSEI both at admission and 3 months after stroke. Avoidance was the independent factor related to PSD at 3 months after stroke onset.

Cortisol Supplement Combined with Psychotherapy and Citalopram Improves Depression Outcomes in Patients with Hypocortisolism after Traumatic Brain Injury.

Depression is one of the most prevalent psychiatric disorders in people with Traumatic brain injury (TBI). Depression after TBI is closely related with social and psychological factors and hypothalamic-pituitary -adrenal (HPA) axis dysfunction. However, there is a lack of evidence regarding effective treatment approaches for depression. A total of 68 patients with depression following closed TBI were recruited. Glasgow Coma Scale score (GCS) was employed to demonstrate the severity of neurological deficits and Glasgow Outcome Scale (GOS) was employed to measure functional outcome after TBI. The severity of depression was quantified using the Beck Depression Inventory-II (BDI-II) in line with DSM-IV. Citalopram and Prednisone were administered to subjects with normal cortisol levels or hypocortisolism separately, based on psychotherapeutic interventions. We investigated the relationship between degree of depression of TBI patients and the severity and progression of TBI with the therapeutic effects of Citalopram in combination with psychotherapeutic and Prednisone in depressed patients. There was no relationship between the severity of depression and the severity and progression of TBI. The basic treatment of psychotherapeutic interventions could partially relieve depressive symptoms. Combination of psychotherapeutic support and Citalopram significantly improved depressive symptoms in patients with normal cortisol levels, but not in hypocortisolic patients. Combination of Prednisone administration with psychotherapeutic treatment and Citalopram significantly improved depression outcome in hypocortisolic patients after TBI. Hypocortisolism after TBI may regulate depression. Combination of Prednisone with psychotherapeutic treatment and Citalopram may provide better therapeutic effects in depression patients with hypocortisolism after TBI.

Facile and controllable synthesis of hydroxyapatite/graphene hybrid materials with enhanced sensing performance towards ammonia.

In this work, needle-like and micro-spherical agglomerates of nanocrystalline hydroxyapatite (HA) were successfully assembled on the surface of graphene sheets with the aid of dopamine having two roles, as a template and a reductant for graphite oxide during the process of self-polymerization. The crystalline structure and micromorphology of HA can be conveniently regulated by controlling the mineralization route either with a precipitation (cHA/GR) or biomimetic methodology (bHA/GR). Both the composites exhibit improvements of ∼150% and ∼250% in sensitivity towards the sensing of ammonia at room temperature, compared with that of bare graphene. The combination of the multi-adsorption capability of HA and the electric conductivity of graphene is proposed to be the major reason for the observed enhancements. Gas sensing tests demonstrated that the HA/GR composites exhibit excellent selectivity, high sensitivity and repeatable stability towards the analytical sensing of ammonia.

The incidence of critical-illness-related-corticosteroid-insufficiency is associated with severity of traumatic brain injury in adult rats.

Traumatic brain injury (TBI) causes deleterious critical-illness-related-corticosteroid-insufficiency (CIRCI), leading to high mortality and morbidity. However, the incidence of CIRCI following different TBI severities is not fully defined. This study was designed to investigate mechanistically the effects of injury severity on corticosteroid response and the development of CIRCI in a rat model of experimentally controlled TBI. Adult male Wistar rats were randomly assigned to sham, mild injury, moderate injury or severe injury groups. TBI was induced using a fluid percussion device at magnitudes of 1.2-1.4 atm (mild injury), 2.0-2.2 atm (moderate injury), and 3.2-3.5 atm (severe injury). We first assessed the effects of injury severity on the mortality and CIRCI occurrence using electrical stimulation test to assess corticosteroid response. We also investigated a series of pathological changes in the hypothalamus, especially in the paraventricular nuclei (PVN), among different injury group including: apoptosis detected by a TUNEL assay, blood-brain-barrier (BBB) permeability assessed by brain water content and Evans Blue extravasation into the cerebral parenchyma, and BBB integrity evaluated by CD31 and Claudin-5 expression and transmission electron microscopy. We made the following observations. First, 6.7% of mild-injured, 13.3% of moderate-injured, and 68.8% of severe-injured rats developed CIRCI, with a peak incidence on post-injury day 7. Second, TBI-induced CIRCI is closely correlated with injury severity. As the injury severity rises both the incidence of CIRCI and mortality surge; Third, increased level of injury severity reduces the expression of endothelial tight junction protein, aggravate BBB permeability and exacerbate the ensuing neural apoptosis in the PVN of hypothalamus. These findings indicate that increased severity of TBI aggravate the incidence of CIRCI by causing damage to tight junctions of vascular endothelial cells and increasing neuronal apoptosis in the PVN of hypothalamus.

Stress-dose hydrocortisone reduces critical illness-related corticosteroid insufficiency associated with severe traumatic brain injury in rats.

INTRODUCTION: The spectrum of critical illness-related corticosteroid insufficiency (CIRCI) in severe traumatic brain injury (TBI) is not fully defined and no effective treatments for TBI-induced CIRCI are available to date. Despite growing interest in the use of stress-dose hydrocortisone as a potential therapy for CIRCI, there remains a paucity of data regarding its benefits following severe TBI. This study was designed to investigate the effects of stress-dose hydrocortisone on CIRCI development and neurological outcomes in a rat model of severe traumatic brain injury. METHODS: Rats were subjected to lateral fluid percussion injury of 3.2-3.5 atmosphere. These rats were then treated with either a stress-dose hydrocortisone (HC, 3 mg/kg/d for 5 days, 1.5 mg/kg on day 6, and 0.75 mg on day 7), a low-dose methylprednisolone (MP, 1 mg/kg/d for 5 days, 0.5 mg/kg on day 6, and 0.25 mg on day 7) or control saline solution intraperitoneally daily for 7 days after injury. RESULTS: We investigated the effects of stress-dose HC on the mortality, CIRCI occurrence, and neurological deficits using an electrical stimulation test to assess corticosteroid response and modified neurological severity score (mNSS). We also studied pathological changes in the hypothalamus, especially in the paraventricular nuclei (PVN), after stress-dose HC or a low dose of MP was administered, including apoptosis detected by a TUNEL assay, blood-brain barrier (BBB) permeability assessed by brain water content and Evans Blue extravasation into the cerebral parenchyma, and BBB integrity evaluated by CD31 and claudin-5 expression. We made the following observations. First, 70% injured rats developed CIRCI, with a peak incidence on post-injury day 7. The TBI-associated CIRCI was closely correlated with an increased mortality and delayed neurological recovery. Second, post-injury administration of stress-dose HC, but not MP or saline increased corticosteroid response, prevented CIRCI, reduced mortality, and improved neurological function during the first 14 days post injury dosing. Thirdly, these beneficial effects were closely related to improved vascular function by the preservation of tight junctions in surviving endothelial cells, and reduced neural apoptosis in the PVN of hypothalamus. CONCLUSIONS: Our findings indicate that post-injury administration of stress-dose HC, but not MP reduces CIRCI and improves neurological recovery. These improvements are associated with reducing the damage to the tight junction of vascular endothelial cells and blocking neuronal apoptosis in the PVN of the hypothalamus.

A distinct pattern of memory and attention deficiency in patients with depression.

BACKGROUND: Depression related cognitive deficits are frequently considered as simple epiphenomena of the disorder. However, whether or not the depression might directly bring about cognitive deficits is still under investigation. This study was to investigate the distinct pattern of cognitive deficits in patients with depression by comparing the cognitive function before and after anti-depressive drug therapy. METHODS: Sixty cases of patients, first-time diagnosed with depression, were assessed by 17-item Hamilton Rating Scale for Depression (HAMD17scale). The memory ability was tested by quantitatively clinical memory scale, while the attention ability by modified Ruff 2&7 Selective Attention Test. Forty-two healthy volunteers were recruited as controls. The depressive patients were treated with Venlafaxine (75 - 300 mg/d), Fluoxetine (20 - 40 mg/d), Paroxetine (20 - 40 mg/d), and Sertraline (50 - 150 mg/d). After 12 weeks treatment, patients were tested again by HAMD17scale, quantitatively clinical memory scale, and modified Ruff 2&7 selective attention test to assess the effect of anti-depressive drugs on cognitive deficits. RESULTS: The memory quotient (MQ) was significantly lowered in depressive patients. The selection speed was also significantly decreased and the number of missing and error hits increased in the depression group as compared to control. However, there was no significant difference in clinical memory scale and Ruff 2&7 selective attention test between mild-to-moderate and severe depression group. Importantly, after anti-depressive drug therapy, the HAMD17 scale scores in depressive patients were significantly decreased, but the MQ, directional memory (DM), free recall (FR), associative learning (AL), and face recognition were comparable with those before the treatment. Furthermore, the selection speed and the number of missing and error hits were also not significantly different after anti-depressive drugs treatment. CONCLUSIONS: Depressive patients suffer from short-term memory deficits, and attention extent, stability and rearrangement deficiency. Even though anti-depressive drugs sufficiently relieve the cardinal presentation of depression, they could not successfully alleviate the accompanying cognitive deficits. This might indicate a distinct pattern of cognitive deficits in patients with depression.