A Serum Pharmacochemistry and Network Pharmacology-based Approach to Study the Anti-depressant Effect of Chaihu-Shugan San.

AIMS: The aim of this study is to explore the anti-depressant mechanism of Chaihu- Shugan San based on serum medicinal chemistry and network pharmacology methods. BACKGROUND: Depression lacks effective treatments, with current anti-depressants ineffective in 40% of patients. Chaihu-Shugan San (CHSGS) is a well-known traditional Chinese medicine compound to treat depression. However, the chemical components and the underlying mechanisms targeting the liver and brain in the anti-depressant effects of CHSGS need to be elucidated. METHODS: The chemical components of CHSGS in most current network pharmacology studies are screened from TCMSP and TCMID databases. In this study, we investigated the mechanism and material basis of soothing the liver and relieving depression in the treatment of depression by CHSGS based on serum pharmacochemistry. The anti-depressant mechanism of CHSGS was further verified by proteomics and high-throughput data. RESULTS: Through serum medicinal chemistry, we obtained 9 bioactive substances of CHSGS. These ingredients have good human oral bioavailability and are non-toxic. Based on liver ChIPseq data, CHSGS acts on 8 targets specifically localized in the liver, such as FGA, FGB, and FGG. The main contributors to CHSGS soothing the liver qi targets are hesperetin, nobiletin, ferulic acid, naringin and albiflorin. In addition, network pharmacology analysis identified 9 blood components of CHSGS that corresponded to 63 anti-depressant targets in the brain. Among them, nobiletin has the largest number of anti-depressant targets, followed by glycyrrhizic acid, ferulic acid, albiflorin and hesperetin. We also validated the anti-depressant mechanism of CHSGS based on hippocampal proteomics. CHSGS exerts anti-depressant effects on synaptic structure and neuronal function by targeting multiple synapse related proteins. CONCLUSION: This study not only provides a theoretical basis for further expanding the clinical application of CHSGS, but also provides a series of potential lead compounds for the development of depression drugs.

Identification of Hub Genes and Pathways of Middle Cerebral Artery Occlusion in Aged Rats Using the Gene Expression Omnibus Database.

Stroke remained the leading cause of disability in the world, and the most important non-modifiable risk factor was age. The treatment of stroke for elder patients faced multiple difficulties due to its complicated pathogenesis and mechanism. Therefore, we aimed to identify the potential differentially expressed genes (DEGs) and singnalling pathways for aged people of stroke. To compare the DEGs in the aged rats with or without middle cerebral artery occlusion (MCAO) and to analyse the important genes and the key signaling pathways involved in the development of cerebral ischaemia in aged rats. The Gene Expression Omnibus (GEO) analysis tool was used to analyse the DEGs in the GSE166162 dataset of aged MCAO rats compared with aged sham rats. Differential expression analysis was performed in aged MCAO rats and sham rats using limma. In addition, the 74 DEGs (such as Fam111a, Lcn2, Spp1, Lgals3 and Gpnmb were up-regulated; Egr2, Nr4a3, Arc, Klf4 and Nr4a1 were down-regulated) and potential compounds corresponding to the top 20 core genes in the Protein-Protein Interaction (PPI) network was constructed using the STRING database (version 12.0). Among these 30 compounds, resveratrol, cannabidiol, honokiol, fucoxanthin, oleandrin and tyrosol were significantly enriched. These DEGs were subjected to Gene Ontology (GO) function analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to determine the most significantly enriched pathway in aged MCAO rats. Moreover, innate immune response, the complement and coagulation cascades signaling pathway, the IL-17 and other signaling pathways were significantly correlated with the aged MCAO rats. Our study indicates that multiple genes and pathological processes involved in the aged people of stroke. The immune response might be the key pathway in the intervention of cerebral infarction in aged people.

Clinical Features and Management of Suboptimal Ovarian Response During in vitro Fertilization and Embryo Transfer: Analysis Based on a Retrospective Cohort Study.

Background: Based on dynamic changes of indicators during controlled ovarian hyperstimulation and of clinical outcomes of suboptimal ovarian response with different protocols, this study aimed to summarize the clinical characteristics of SOR and provide clinical recommendations. Methods: Data of 125 patients with SOR and 125 controls who had undergone appropriate protocols for in vitro fertilization-embryo transfer were collected from a single medical center from January 2017 to January 2019. Basic clinical indexes, including age, BMI, antral-follicle count, infertility time, basic follicle-stimulating hormone, luteinizing hormone, LH/FSH ratio, estradiol, progesterone, testosterone, androstenedione, prolactin, anti-Mullerian hormone, and thyroid stimulating hormone levels, were analyzed using T-test. Dynamic indexes during COH, including amount and days of gonadotropin, sex hormone levels, and number of large/medium/small follicles at specified time periods, were analyzed using T-test and joint diagnosis analysis with ROC curves. Indexes of laboratory and clinical indicators were analyzed using the chi-square test. Results: For the SOR group, BMI, duration time, and dosage of gonadotropin used for SOR were significantly higher. In the ultra-long/long group, ROC curve analysis showed that the LH/FSH ratio and BMI yielded cutoff values of 0.61 and 21.35 kg/m2, respectively. A combined diagnosis of the two indexes showed higher sensitivity (90%) and specificity (59%). In the GnRH-ant group, ROC curve analysis showed an LH level, an LH/FSH ratio on COH day 2, and BMI yielded cutoff values of 2.47 IU/L, 0.57, and 23.95 kg/m2, respectively. Combining the two indexes with BMI, both showed increased sensitivity (77%) and specificity (72% and 74%). The estradiol level and progesterone level during the late follicular stage in SOR patients were significantly lower than those in control patients for both protocol groups. At each monitoring time, delayed follicular development was observed. The live-birth rate in fresh cycles of the ultra-long/long group and the live-birth rate in cumulative cycles of the antagonist group in the SOR group were lower than those in the control group. Conclusion: SOR had adverse effects on clinical outcome. We provide some threshold values of basic LH/FSH ratio, BMI, COH day 2 LH, counts of follicles, and levels of estradiol/progesterone to be taken as reference to assist the early recognition of SOR.

Analysis of the proportion and clinical characteristics of obstructive sleep apnea in women with polycystic ovary syndrome.

PURPOSE: To investigate the proportion and clinical characteristics of obstructive sleep apnea (OSA) in Chinese patients with polycystic ovarian syndrome (PCOS) through home sleep apnea test (HSAT) and to evaluate the reproductive endocrine and metabolic characteristics in these patients. METHODS: The study was a cross-sectional analysis of infertile PCOS patients who underwent sleep respiratory monitoring between January and December 2019 at Peking University Third Hospital Reproductive Medical Center and respiratory and critical care medicine department. The prevalence of OSA, body mass index (BMI), menstruation, reproductive endocrine, and metabolic characteristics were collected in patients with PCOS. Logistic regression was performed to identify significant relationships among these factors and OSA. RESULTS: Amont 328 patients with PCOS, the prevalence of OSA was 40% (131/328), and six cases (5%) were severe. Univariate analysis showed that BMI and blood pressure were significantly higher in patients with OSA than in those without OSA (P < 0.05), whereas the anti-Mullerian hormone was lower than that in patients without OSA. In terms of glucose and lipid metabolism, the glycosylated hemoglobin (HbA1c), fasting plasma glucose, and fasting insulin levels were significantly higher in patients with PCOS and comorbid OSA than in those without OSA (all P < 0.05). Patients with OSA also had higher triglyceride, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein levels and lower high-density lipoprotein cholesterol levels (P < 0.05). Logistic regression analysis revealed that higher BMI, elevated serum testosterone, and decreased high-density lipoprotein cholesterol (HDL-C) are correlated with occurrence of OSA (P < 0.05). CONCLUSION: OSA in patients with PCOS was associated with multiple alterations in indexes of reproductive endocrine and metabolic disorders.

Curcumin inhibits adverse psychological stress-induced proliferation and invasion of glioma cells via down-regulating the ERK/MAPK pathway.

Curcumin is a natural polyphenol extracted from the rhizome of Curcuma that has an important antitumour effect, but its effect on adverse psychological stress-induced tumour proliferation and invasion has not been reported to date. Here, we found that curcumin not only inhibited the growth of xenografts in chronically stressed nude mice, but also decreased the expression of matrix metalloproteinase (MMP)-2/9 and CD147 in tumour tissues. Exogenous norepinephrine (NE) was used to stimulate glioma cells to simulate the stress environment in vitro, and it was found that curcumin inhibited the NE-induced proliferation and invasion of glioma cells in a dose-dependent manner. Further research found that the effects of NE on glioma cells could lead to the activation of the mitogen-activated protein kinase (MAPK) signalling pathway through ß-adrenergic receptor, while curcumin suppressed the level of extracellular signal-regulated kinase (ERK)1/2 phosphorylation. In addition, blocking ERK1/2 expression with U0126 resulted in the down-regulated expression of CD147, which further led to the decreased expression of MMP-2 and MMP-9. Curcumin could also inhibit the expression of cyclin D1/CDK4/6 and anti-apoptotic protein Bcl-2/Bcl-XL induced by NE, and induced cell cycle changes and increased apoptosis. Therefore, curcumin may be a potential candidate drug for preventing and treating the progression of glioma induced by adverse psychological stress.

Psychological Stress Up-Regulates CD147 Expression Through Beta-Arrestin1/ERK to Promote Proliferation and Invasiveness of Glioma Cells.

Psychological stress is closely related to the occurrence and prognosis of various malignant tumors, but the underlying mechanisms are not well studied. CD147 has been reported to be expressed in glioma and other malignant tumors. CD147 not only participates in lactic acid transport, but it also plays an important role in the invasion and metastasis of malignant tumor cells by stimulating the production of numerous matrix metalloproteinases (MMPs) and vascular endothelial growth factor by fibroblasts, and could also act as an autocrine factor stimulating MMPs production in metastatic tumor cells. Here, we found that silencing CD147 in chronically stressed nude mice not only inhibited the proliferation of xenografts but also decreased matrix metalloproteinase-2, 9 expression and lactic acid content in tumor tissues. Furthermore, norepinephrine (NE) was significantly increased in the serum of nude mice in glioma stress model. To determine the underlying cellular mechanism, we added exogenous NE into LN229 and U87 cells to simulate the stress environment in vitro. The invasiveness of the glioma cells was subsequently examined using a Matrigel invasion assay. We demonstrated that knockdown of CD147 inhibited glioma invasiveness and metastasis with norepinephrine stimulation. Luciferase reporter gene experiments further demonstrated that the expression of CD147 is up-regulated primarily by norepinephrine via the ß-Adrenalin receptor (ßAR)-ß-arrestin1-ERK1/2-Sp1 pathway. High expression of CD147 promoted the secretion of MMP-2 and the increment of lactic acid, which accelerated the augmented invasion and metastasis of glioma induced by psychological stress. Taken together, these results suggest that psychological stress promotes glioma proliferation and invasiveness by up-regulating CD147 expression. Thus, CD147 might be a potential target site in the treatment of glioma progression induced by chronic psychological stress.

Degradation of Silicone Rubbers as Sealing Materials for Proton Exchange Membrane Fuel Cells under Temperature Cycling.

Gaskets are compressed in proton exchange membrane fuel cells (PEMFCs) to keep fuel, oxidant and coolant within their respective regions and are very important for sealing and maintaining electrochemical performance of fuel cells during their long-term operation. It has been proved that the gas leakage caused by the failure of the gaskets following long-term operation is one of the main reasons for PEMFC performance degradation. In this work, degradation of silicone rubbers, the potential gasket materials for PEMFCs, were investigated in the simulated PEMFC environment solution, weak acid solution, de-ionized water and air, respectively, under alternating temperature cycling from -20 °C to 90 °C. The changes in hardness, weight, chemical properties, mechanical behavior and surface morphology of the samples of silicone rubbers were studied after a certain number of temperature cycles. The results show that with the increase in temperature cycles, the hardness of the samples increases and the weight of the samples decreases gradually. Scanning electron microscopy reveals that cracks and caves constantly appear on the surface of the samples. Attenuated total reflection Fourier transform infrared spectra (ATR-FTIR) results demonstrate that the surface chemistry changes via de-crosslinking and chain scission in the backbone due to the exposure of samples to the environments over time under alternating temperature cycles.

Self-assembly synthesis of a unique stable cocoon-like hematite @C nanoparticle and its application in lithium ion batteries.

A novel cocoon-like Fe2O3@C nanoparticle was fabricated via a facile hydrothermally molecular self-assembly procedure. Compared to bare Fe2O3 nanoparticles, the carbon coated Fe2O3 nanoparticles exhibit higher specific capacity, excellent rate capacity and cyclic stability as the anode in lithium ion batteries. These cocoon-like Fe2O3@C nanoparticles carry enhanced lithium storage properties with a reversible capacity of 358mAhg-1 after 150 cycles under the current density of 1000mAg-1, while the carbon-free bare Fe2O3 can only deliver a much lower capacity of 127.6mAhg-1 with a continuously decreasing trend. The excellent performance of Fe2O3@C is attributed to the coated carbon layers, which not only enhance the electronic conductivity but also reduce the stress upon the Fe2O3 nanoparticles caused by the volume change during the charge/discharge process.