High fried food consumption impacts anxiety and depression due to lipid metabolism disturbance and neuroinflammation.

Western dietary patterns have been unfavorably linked with mental health. However, the long-term effects of habitual fried food consumption on anxiety and depression and underlying mechanisms remain unclear. Our population-based study with 140,728 people revealed that frequent fried food consumption, especially fried potato consumption, is strongly associated with 12% and 7% higher risk of anxiety and depression, respectively. The associations were more pronounced among male and younger consumers. Consistently, long-term exposure to acrylamide, a representative food processing contaminant in fried products, exacerbates scototaxis and thigmotaxis, and further impairs exploration ability and sociality of adult zebrafish, showing anxiety- and depressive-like behaviors. Moreover, treatment with acrylamide significantly down-regulates the gene expression of tjp2a related to the permeability of blood-brain barrier. Multiomics analysis showed that chronic exposure to acrylamide induces cerebral lipid metabolism disturbance and neuroinflammation. PPAR signaling pathway mediates acrylamide-induced lipid metabolism disorder in the brain of zebrafish. Especially, chronic exposure to acrylamide dysregulates sphingolipid and phospholipid metabolism, which plays important roles in the development of anxiety and depression symptoms. In addition, acrylamide promotes lipid peroxidation and oxidation stress, which participate in cerebral neuroinflammation. Acrylamide dramatically increases the markers of lipid peroxidation, including (±)5-HETE, 11(S)-HETE, 5-oxoETE, and up-regulates the expression of proinflammatory lipid mediators such as (±)12-HETE and 14(S)-HDHA, indicating elevated cerebral inflammatory status after chronic exposure to acrylamide. Together, these results both epidemiologically and mechanistically provide strong evidence to unravel the mechanism of acrylamide-triggered anxiety and depression, and highlight the significance of reducing fried food consumption for mental health.

Profiling prediction of nuclear receptor modulators with multi-task deep learning methods: toward the virtual screening.

Nuclear receptors (NRs) are ligand-activated transcription factors, which constitute one of the most important targets for drug discovery. Current computational strategies mainly focus on a single target, and the transfer of learned knowledge among NRs was not considered yet. Herein we proposed a novel computational framework named NR-Profiler for prediction of potential NR modulators with high affinity and specificity. First, we built a comprehensive NR data set including 42 684 interactions to connect 42 NRs and 31 033 compounds. Then, we used multi-task deep neural network and multi-task graph convolutional neural network architectures to construct multi-task multi-classification models. To improve the predictive capability and robustness, we built a consensus model with an area under the receiver operating characteristic curve (AUC) = 0.883. Compared with conventional machine learning and structure-based approaches, the consensus model showed better performance in external validation. Using this consensus model, we demonstrated the practical value of NR-Profiler in virtual screening for NRs. In addition, we designed a selectivity score to quantitatively measure the specificity of NR modulators. Finally, we developed a freely available standalone software for users to make profiling predictions for their compounds of interest. In summary, our NR-Profiler provides a useful tool for NR-profiling prediction and is expected to facilitate NR-based drug discovery.

Drug repositioning by prediction of drug's anatomical therapeutic chemical code via network-based inference approaches.

Drug discovery and development is a time-consuming and costly process. Therefore, drug repositioning has become an effective approach to address the issues by identifying new therapeutic or pharmacological actions for existing drugs. The drug's anatomical therapeutic chemical (ATC) code is a hierarchical classification system categorized as five levels according to the organs or systems that drugs act and the pharmacology, therapeutic and chemical properties of drugs. The 2nd-, 3rd- and 4th-level ATC codes reserved the therapeutic and pharmacological information of drugs. With the hypothesis that drugs with similar structures or targets would possess similar ATC codes, we exploited a network-based approach to predict the 2nd-, 3rd- and 4th-level ATC codes by constructing substructure drug-ATC (SD-ATC), target drug-ATC (TD-ATC) and Substructure&Target drug-ATC (STD-ATC) networks. After 10-fold cross validation and two external validations, the STD-ATC models outperformed the SD-ATC and TD-ATC ones. Furthermore, with KR as fingerprint, the STD-ATC model was identified as the optimal model with AUC values at 0.899 ± 0.015, 0.916 and 0.893 for 10-fold cross validation, external validation set 1 and external validation set 2, respectively. To illustrate the predictive capability of the STD-ATC model with KR fingerprint, as a case study, we predicted 25 FDA-approved drugs (22 drugs were actually purchased) to have potential activities on heart failure using that model. Experiments in vitro confirmed that 8 of the 22 old drugs have shown mild to potent cardioprotective activities on both hypoxia model and oxygen-glucose deprivation model, which demonstrated that our STD-ATC prediction model would be an effective tool for drug repositioning.

Toxic effects of isofenphos-methyl on zebrafish embryonic development.

Isofenphos-methyl (IFP) is widely used as an organophosphorus for controlling underground insects and nematodes. However, excessive use of IFP may pose potential risks to the environment and humans, but little information is available on its sublethal toxicity to aquatic organisms. To address this knowledge gap, the current study exposed zebrafish embryos to 2, 4, and 8 mg/L IFP within 6-96 h past fertilization (hpf) and measured mortality, hatching, developmental abnormalities, oxidative stress, gene expressions, and locomotor activity. The results showed that IFP exposure reduced the rates of heart and survival rate, hatchability, and body length of embryos and induced uninflated swim bladder and developmental malformations. Reduction in locomotive behavior and inhibition of AChE activity indicated that IFP exposure may induce behavioral defects and neurotoxicity in zebrafish larvae. IFP exposure also led to pericardial edema, longer venous sinus-arterial bulb (SV-BA) distance, and apoptosis of the heart cells. Moreover, IFP exposure increased the accumulation of reactive oxygen species (ROS) and the content of malonaldehyde (MDA), also elevated the levels of antioxidant enzymes of superoxide dismutase (SOD) and catalase (CAT), but decreased glutathione (GSH) levels in zebrafish embryos. The relative expressions of heart development-related genes (nkx2.5, nppa, gata4, and tbx2b), apoptosis-related genes (bcl2, p53, bax, and puma), and swim bladder development-related genes (foxA3, anxa5b, mnx1, and has2) were significantly altered by IFP exposure. Collectively, our results indicated that IFP induced developmental toxicity and neurotoxicity to zebrafish embryos and the mechanisms may be relevant to the activation of oxidative stress and reduction of acetylcholinesterase (AChE) content.

Developmental toxicity, immunotoxicity and cardiotoxicity induced by methidathion in early life stages of zebrafish.

Methidathion is a highly effective organophosphorus pesticide and is extensively utilized for the control of insects in agricultural production. However, there is little information on the adverse effects and underlying mechanisms of methidathion on aquatic organisms. In this work, embryonic zebrafish were exposed to methidathion at concentrations of 4, 10, and 25 mg/L for 96 h, and morphological changes and activities of antioxidant indicators alterations were detected. In addition, the locomotor behavioral abilities of zebrafish exposed to methidathion were also measured. To further explore the mechanism of the toxic effects of methidathion, gene expression levels associated with cardiac development, cell apoptosis, and the immune system were tested through qPCR assays. The findings revealed that methidathion exposure could induce a decrease in survival rate, hatchability, length of body, and increase in abnormality of zebrafish, as well as cardiac developmental toxicity. The LC50 value of methidathion in zebrafish embryos was determined to be about 30.72 mg/L at 96 hpf. Additionally, methidathion exposure triggered oxidative stress in zebrafish by increasing SOD activity, ROS, and MDA content. Acridine orange (AO) staining indicated that methidathion exposure led to apoptosis, which was mainly distributed in the pericardial region. Furthermore, significant impairments of locomotor activity in zebrafish larvae were induced by methidathion exposure. Lastly, the expression of pro-inflammatory factors including IFN-γ, IL-6, IL-8, CXCL-clc, TLR4, and MYD88 significantly up-regulated in exposed zebrafish. Taken together, the results in this work illustrated that methidathion caused developmental toxicity, cardiotoxicity, and immunotoxicity in embryogenetic zebrafish.

The protonation state of Glu202 in acetylcholinesterase.

Acetylcholinesterase (AChE) is the crucial enzyme in the central nervous system. It is the target of various organophosphorus nerve agents and pesticides, and the inhibition of AChE is a therapeutic strategy for the treatment of various neurological-related diseases. The Glu202 is a key residue adjacent to the catalytic His447 and plays important role in catalysis. Although the Glu202 has long been considered as negatively charged in many studies, more and more evidences support a protonated Glu202. However, Glu202 is freely accessible by solvent, and thus it seems more reasonable for Glu202 to majorly take the deprotonated state. In the present work, we carried out a series of molecular dynamics simulations with the Glu202 adopting different protonation states. Our results show that the protonated Glu202 is important in maintaining the key hydrogen bond network that supports the catalytic triad, whereas the deprotonated Glu202 results in the collapse of the key hydrogen bond network which consequently destabilizes the catalytic His447. We also notice that different protonation states of Glu202 merely alters the binding mode of ACh. However, since the catalytic His447 is disrupted if Glu202 is deprotonated, His447 cannot facilitate the nucleophilic attack performed by Ser203. Therefore, the catalytic efficiency of ACh hydrolysis should be remarkably decreased if Glu202 is deprotonated. Our findings suggest that, when designing and developing highly active AChE inhibitors or proposing mechanistic hypotheses for AChE-catalyzed reactions, the protonated state of Glu202 should be considered.

QKI regulates adipose tissue metabolism by acting as a brake on thermogenesis and promoting obesity.

Adipose tissue controls numerous physiological processes, and its dysfunction has a causative role in the development of systemic metabolic disorders. The role of posttranscriptional regulation in adipose metabolism has yet to be fully understood. Here, we show that the RNA-binding protein quaking (QKI) plays an important role in controlling metabolic homeostasis of the adipose tissue. QKI-deficient mice are resistant to high-fat-diet (HFD)-induced obesity. Additionally, QKI depletion increased brown fat energy dissipation and browning of subcutaneous white fat. Adipose tissue-specific depletion of QKI in mice enhances cold-induced thermogenesis, thereby preventing hypothermia in response to cold stimulus. Further mechanistic analysis reveals that QKI is transcriptionally induced by the cAMP-cAMP response element-binding protein (CREB) axis and restricts adipose tissue energy consumption by decreasing stability, nuclear export, and translation of mRNAs encoding UCP1 and PGC1α. These findings extend our knowledge of the significance of posttranscriptional regulation in adipose metabolic homeostasis and provide a potential therapeutic target to defend against obesity and its related metabolic diseases.

IDL-PPBopt: A Strategy for Prediction and Optimization of Human Plasma Protein Binding of Compounds via an Interpretable Deep Learning Method.

The prediction and optimization of pharmacokinetic properties are essential in lead optimization. Traditional strategies mainly depend on the empirical chemical rules from medicinal chemists. However, with the rising amount of data, it is getting more difficult to manually extract useful medicinal chemistry knowledge. To this end, we introduced IDL-PPBopt, a computational strategy for predicting and optimizing the plasma protein binding (PPB) property based on an interpretable deep learning method. At first, a curated PPB data set was used to construct an interpretable deep learning model, which showed excellent predictive performance with a root mean squared error of 0.112 for the entire test set. Then, we designed a detection protocol based on the model and Wilcoxon test to identify the PPB-related substructures (named privileged substructures, PSubs) for each molecule. In total, 22 general privileged substructures (GPSubs) were identified, which shared some common features such as nitrogen-containing groups, diamines with two carbon units, and azetidine. Furthermore, a series of second-level chemical rules for each GPSub were derived through a statistical test and then summarized into substructure pairs. We demonstrated that these substructure pairs were equally applicable outside the training set and accordingly customized the structural modification schemes for each GPSub, which provided alternatives for the optimization of the PPB property. Therefore, IDL-PPBopt provides a promising scheme for the prediction and optimization of the PPB property and would be helpful for lead optimization of other pharmacokinetic properties.

Anisodamine affects the pigmentation, mineral density, craniofacial area, and eye development in zebrafish embryos.

Anisodamine is one of the major components of the tropine alkaloid family and is widely used in the treatment of pain, motion sickness, pupil dilatation, and detoxification of organophosphorus poisoning. As a muscarinic receptor antagonist, the low toxicity and moderate drug effect of anisodamine often result in high doses for clinical use, making it important to fully investigate its toxicity. In this study, zebrafish embryos were exposed to 1.3-, 2.6-, and 5.2-mM anisodamine for 7 days to study the toxic effects of drug exposure on pigmentation, mineral density, craniofacial area, and eye development. The results showed that exposure to anisodamine at 1.3 mM resulted in cranial malformations and abnormal pigmentation in zebrafish embryos; 2.6- and 5.2-mM anisodamine resulted in significant eye development defects and reduced bone density in zebrafish embryos. The associated toxicities were correlated with functional development of neural crest cells through gene expression (col1a2, ddb1, dicer1, mab21l1, mab21l2, sox10, tyrp1b, and mitfa) in the dose of 5.2-mM exposed group. In conclusion, this study provides new evidence of the developmental toxicity of high doses of anisodamine in aqueous solutions to organisms and provides a warning for the safe use of this drug.

Pathway-Based Drug Repurposing with DPNetinfer: A Method to Predict Drug-Pathway Associations via Network-Based Approaches.

Identification of drug-pathway associations plays an important role in pathway-based drug repurposing. However, it is time-consuming and costly to uncover new drug-pathway associations experimentally. The drug-induced transcriptomics data provide a global view of cellular pathways and tell how these pathways change under different treatments. These data enable computational approaches for large-scale prediction of drug-pathway associations. Here we introduced DPNetinfer, a novel computational method to predict potential drug-pathway associations based on substructure-drug-pathway networks via network-based approaches. The results demonstrated that DPNetinfer performed well in a pan-cancer network with an AUC (area under curve) = 0.9358. Meanwhile, DPNetinfer was shown to have a good capability of generalization on two external validation sets (AUC = 0.8519 and 0.7494, respectively). As a case study, DPNetinfer was used in pathway-based drug repurposing for cancer therapy. Unexpected anticancer activities of some nononcology drugs were then identified on the PI3K-Akt pathway. Considering tumor heterogeneity, seven primary site-based models were constructed by DPNetinfer in different drug-pathway networks. In a word, DPNetinfer provides a powerful tool for large-scale prediction of drug-pathway associations in pathway-based drug repurposing. A web tool for DPNetinfer is freely available at http://lmmd.ecust.edu.cn/netinfer/.

Discovery of Natural Products Targeting NQO1 via an Approach Combining Network-Based Inference and Identification of Privileged Substructures.

NAD(P)H:quinone oxidoreductase 1 (NQO1) has been shown to be a potential therapeutic target for various human diseases, such as cancer and neurodegenerative disorders. Recent advances in computational methods, especially network-based methods, have made it possible to identify novel compounds for a target with high efficiency and low cost. In this study, we designed a workflow combining network-based methods and identification of privileged substructures to discover new compounds targeting NQO1 from a natural product library. According to the prediction results, we purchased 56 compounds for experimental validation. Without the assistance of privileged substructures, 31 compounds (31/56 = 55.4%) showed IC50 < 100 µM, and 11 compounds (11/56 = 19.6%) showed IC50 < 10 µM. With the assistance of privileged substructures, the two success rates were increased to 61.8 and 26.5%, respectively. Seven natural products further showed inhibitory activity on NQO1 at the cellular level, which may serve as lead compounds for further development. Moreover, network analysis revealed that osthole may exert anticancer effects against multiple cancer types by inhibiting not only carbonic anhydrases IX and XII but also NQO1. Our workflow and computational methods can be easily applied in other targets and become useful tools in drug discovery and development.

Computational Design and Crystal Structure of a Highly Efficient Benzoylecgonine Hydrolase.

Benzoylecgonine (BZE) is the major toxic metabolite of cocaine and is responsible for the long-term cocaine-induced toxicity owing to its long residence time in humans. BZE is also the main contaminant following cocaine consumption. Here, we identified the bacterial cocaine esterase (CocE) as a BZE-metabolizing enzyme (BZEase), which can degrade BZE into biological inactive metabolites (ecgonine and benzoic acid). CocE was redesigned by a reactant-state-based enzyme design theory. An encouraging mutant denoted as BZEase2, presented a >400-fold improved catalytic efficiency against BZE compared with wild-type (WT) CocE. In vivo, a single dose of BZEase2 (1 mg kg-1 , IV) could eliminate nearly all BZE within only two minutes, suggesting the enzyme has the potential for cocaine overdose treatment and BZE elimination in the environment by accelerating BZE clearance. The crystal structure of a designed BZEase was also determined.

Combined fractional anisotropy and subcortical volumetric abnormalities in healthy immigrants to high altitude: A longitudinal study.

The study of individuals at high-altitude (HA) exposure provides an important opportunity for unraveling physiological and psychological mechanism of brain underlying hypoxia condition. However, this has rarely been assessed longitudinally. We aim to explore the cognitive and cerebral microstructural alterations after chronic HA exposure. We recruited 49 college freshmen who immigrated to Tibet and followed up for 2 years. Control group consisted of 49 gender and age-matched subjects from sea level. Neuropsychological tests were also conducted to determine whether the subjects' cognitive function had changed in response to chronic HA exposure. Surface-based cortical and subcortical volumes were calculated from structural magnetic resonance imaging data, and tract-based spatial statistics (TBSS) analysis of white matter (WM) fractional anisotropy (FA) based on diffusion weighted images were performed. Compared to healthy controls, the high-altitude exposed individuals showed significantly lower accuracy and longer reaction times in memory tests. Significantly decreased gray matter volume in the caudate region and significant FA changes in multiple WM tracts were observed for HA immigrants. Furthermore, differences in subcortical volume and WM integration were found to be significantly correlated with the cognitive changes after 2 years' HA exposure. Cognitive functions such as working memory and psychomotor function were found to be impaired during chronic HA. Differences of brain subcortical volumes and WM integration between HA and sea-level participants indicated potential impairments in the brain structural modifications and microstructural integrity of WM tracts after HA exposure.

Critical fracture properties of puckered and buckled arsenenes by molecular dynamics simulations.

The pioneering prediction and successful synthesis of monolayer arsenene in recent years have promoted intensive studies on this novel two-dimensional (2D) material. Strain-engineered arsenene monolayer can change its geometric structures with tuned charge distribution, which paves the way for achieving novel electronic properties. The practical applications of the strain-driven topological state in arsenene strongly depend on its critical strain value. In this work, mechanical properties such as fracture strain, fracture strength and Young's modulus of two arsenene structures, i.e. buckled arsenene (b-arsenene) and puckered arsenene (p-arsenene), are comprehensively investigated under different modulators such as system dimension, chirality, temperature, strain rate and random surface defect. A maximum fracture strain reduction of 41.7% from 0.24 to 0.14 is observed in armchair b-arsenene when the temperature increases from 100 to 500 K. The most significant impact factor on the mechanical properties of arseneneis found to be surface defects. A maximum fracture strength reduction of 85.7% is predicted in the armchair b-arsenene when the defect ratio increases from 0 to 5%. On the other hand, the strain rate has a negligible effect on the mechanical properties. Our results provide fundamental knowledge on the critical fracture properties of arsenene.

A surface plasmon resonance immunoassay for the rapid analysis of methamphetamine in forensic oral fluid.

BACKGROUND: Current chromatographic methods applied for the forensic analysis of methamphetamine are costly, time-consuming, and require complicated pretreatment procedures. Thus, the rapid detection of methamphetamine is a critical and unmet need. In this study, a surface plasmon resonance (SPR) system based on indirect inhibitive immunoassay was designed for the analysis of methamphetamine in forensic oral fluid samples. METHODS: For the inhibition immunoassay, the diluted oral fluid was mixed with methamphetamine antibody and then injected into the SPR sensor chip. The biosensor chip was constructed by covalently immobilizing of methamphetamine-bovine serum albumin conjugate onto a carboxymethyl dextran surface at an optimized pH. The concentration of antibody was also optimized. RESULTS: The SPR biosensor showed good sensitivity with a limit of detection of 0.44 ng/mL and was comparable or lower than the pre-existing methods. The method was finally tested using oral fluid samples from 20 suspected drug abusers in forensic cases, and it provided an acceptable recovery of 113.2%, indicating good anti-interference capability of the SPR sensor. CONCLUSION: The SPR biosensor was rapid, reproducible, and had a great potential approach for the forensic detection of methamphetamine.

Mitochondrial-Derived Peptide MOTS-c Increases Adipose Thermogenic Activation to Promote Cold Adaptation.

Cold exposure stress causes hypothermia, cognitive impairment, liver injury, and cardiovascular diseases, thereby increasing morbidity and mortality. Paradoxically, cold acclimation is believed to confer metabolic improvement to allow individuals to adapt to cold, harsh conditions and to protect them from cold stress-induced diseases. However, the therapeutic strategy to enhance cold acclimation remains less studied. Here, we demonstrate that the mitochondrial-derived peptide MOTS-c efficiently promotes cold adaptation. Following cold exposure, the improvement of adipose non-shivering thermogenesis facilitated cold adaptation. MOTS-c, a newly identified peptide, is secreted by mitochondria. In this study, we observed that the level of MOTS-c in serum decreased after cold stress. MOTS-c treatment enhanced cold tolerance and reduced lipid trafficking to the liver. In addition, MOTS-c dramatically upregulated brown adipose tissue (BAT) thermogenic gene expression and increased white fat "browning". This effect might have been mediated by MOTS-c-activated phosphorylation of the ERK signaling pathway. The inhibition of ERK signaling disturbed the up-regulatory effect of MOTS-c on thermogenesis. In summary, our results indicate that MOTS-c treatment is a potential therapeutic strategy for defending against cold stress by increasing the adipose thermogenesis via the ERK pathway.

Toll-Like Receptor 4 (TLR4)/Cyclooxygenase-2 (COX-2) Regulates Prostate Cancer Cell Proliferation, Migration, and Invasion by NF-κB Activation.

BACKGROUND Toll-like receptor 4 (TLR4)-mediated signaling has been implicated in invasion, metastasis, and survival of various cancers. Activation of TLR4 can promote cyclooxygenase-2 (COX-2) and nuclear factor-κB (NF-κB). However, little is known about the effects of TLR4/COX-2 in prostate cancer (PCa). MATERIAL AND METHODS In our study, TLR4 and COX-2 expressions were detected by quantitative real-time reverse transcription PCR (qRT-PCR) in PCa tissues (n=34). Cell proliferation was measured by Cell Counting Kit-8 (CCK-8) and carboxyfluorescein succinimidyl ester (CFSE) assays. The migration and invasion abilities were detected by wound healing and Transwell assays. qRT-PCR and western blot assays were performed to detect TLR4, COX-2, matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of matrix metalloproteinases (TIMP)-1, epithelial-cadherin (E-cadherin), vimentin, NF-κB (p65), and p-p65 expressions. RESULTS The results revealed that TLR4 and COX-2 were upregulated in PCa tissues; Silencing of TLR4 or COX-2 inhibited PCa cell proliferation, migration, and invasion, and TLR4 siRNAs combined with COX-2 siRNAs synergistically suppressed PCa cell proliferation, migration, and invasion. Silencing of TLR4 or COX-2 also downregulated MMP-2, MMP-9, and E-cadherin expressions, and upregulated TIMP-1 and vimentin expressions. In addition, silencing of TLR4 or COX-2 inhibited p65 phosphorylation and had a synergistic effect. CONCLUSIONS We demonstrated that TLR4/COX-2 inhibits PCa cell proliferation, migration, and invasion by regulating NF-κB.

Trans-Ferulic Acid-4-ß-Glucoside Alleviates Cold-Induced Oxidative Stress and Promotes Cold Tolerance.

Trans-ferulic acid-4-ß-glucoside (C16H20O9, TFA-4ß-G) is a monomer extracted from the Chinese medicine called radix aconiti carmichaeli (Fuzi). To date, research on this substance is lacking. Here, we found that trans-ferulic acid-4-ß-glucoside effectively promoted cold acclimatization in mice via increased heat production and alleviation of oxidative stress in a cold environment. Thus, our work indicates that ferulic acid-4-ß-glucoside is a potential therapeutic candidate for prevention and treatment of cold stress injury.

[The network pharmacological mechanisms of four anti-vitiligo Uyghur medicines based on Phlegmatic temperament theory].

To explore the network pharmacological mechanisms of four anti-vitiligo Uyghur medicines based on the Phlegmatic temperament theory. First, The anti-vitiligo Uyghur medicine formulas based on Phlegmatic temperament theory were collected. The pharmacokinetic characteristic of main compounds in four anti-vitiligo Uyghur medicines were obtained by using admetSAR. The targets of active compounds were predicted via bSDTNBI (balanced substructure-drug-target network-based inference model) method. Then, biological process (BP) and molecular function (MF) enrichment analysis of targets were analysed via DAVID database. Constructing anti-vitiligo Uyghur medicine formula-Uyghur medicines network model (FMI network) and Uyghur medicines-active compounds-targets-BP-Hilit network model (MCTBHI network), we utilized closeness centrality to analyse key Uyghur medicines, active compounds, key targets as well as Hilit. Finally, the in vitro melanin production model of C57BL/6 mice was used to verify the ability of the active compounds to improve melanogenesis. The results showed that Psoralea corylifolia, Vernonia anthelmintica, Syzygium aromaticum and Anacyclus pyrethrum were the key Uyghur medicines in the FMI network. There were 22 active compounds with a relatively higher bioavailability interacted with 58 therapeutic targets. These active compounds were mainly composed of coumarins and flavonoids. In the MCTBHI network, the MF of 58 therapeutic targets was related to steroid hormone receptor activity, heme binding and enzyme binding functhon. Classification of the Hilit according to the BP of 58 therapeutic targets, the first place was the blood, followed by the lymph, the cerebrospinal fluid and digestive juice. It was found that the expression of some targets located in the skin was closed to the heart muscle, lymph node, spleen, cerebral cortex and so on, which were the main places for Hilit. In particular, ESR1, PTGS2, PPARA, PPARG, PTGS1 and CA2 were regulated by the flavonoids (kaempferide and isorhamnetin). The in vitro melanin production model showed that kaempferide and isorhamnetin could promote the melanin production in C57BL/6 mice ear skin. Based on admetSAR and bSDTNBI, we used network pharmacological method to construct a systematic means of studying anti-vitiligo Uyghur medicines, providing clues for the further study of the modern molecular mechanisms of Phlegmatic temperament.

Cognitive and neuroimaging changes in healthy immigrants upon relocation to a high altitude: A panel study.

BACKGROUND: Cognitive and neuroimaging changes under chronic high-altitude exposure have never been followed up and dynamically assessed. OBJECTIVES: To investigate the cognitive and brain structural/functional alterations associated with chronic high-altitude exposure. METHODS: Sixty-nine college freshmen that were immigrating to Tibet were enrolled and followed up for two years. Neuropsychological tests, including verbal/visual memory and simple/recognition reaction time, were utilized to determine whether the subjects' cognitive function had changed in response to chronic high-altitude exposure. Structural magnetic resonance imaging (MRI) and resting-state functional MRI (rs-fMRI) were used to quantify brain gray matter (GM) volumes, regional homogeneity (ReHo) and functional connectivity (FC) alterations before and after exposure. Areas with changes in both GM and ReHo were used as seeds in the inter-regional FC analysis. RESULTS: The subjects showed significantly lower accuracy in memory tests and longer reaction times after exposure, and neuroimaging analysis showed markedly decreased GM volumes and ReHo in the left putamen. FC analysis seeding of the left putamen showed significantly weakened FC with the superior temporal gyrus, anterior/middle cingulate gyrus and other brain regions. In addition, decreased ReHo was found in the superior temporal gyrus, superior parietal lobule, anterior cingulate gyrus and medial frontal gyrus, while increased ReHo was found in the hippocampus. Differences in ReHo/FC before and after high-altitude exposure in multiple regions were significantly correlated with the cognitive changes. CONCLUSION: Cognitive functions such as working memory and psychomotor function are impaired during chronic high-altitude exposure. The putamen may play an important role in chronic hypoxia-induced cognitive impairment. Hum Brain Mapp 38:3865-3877, 2017. © 2017 Wiley Periodicals, Inc.