Development of a Multi-Target Strategy for the Treatment of Vitiligo via Machine Learning and Network Analysis Methods.

Vitiligo is a complex disorder characterized by the loss of pigment in the skin. The current therapeutic strategies are limited. The identification of novel drug targets and candidates is highly challenging for vitiligo. Here we proposed a systematic framework to discover potential therapeutic targets, and further explore the underlying mechanism of kaempferide, one of major ingredients from Vernonia anthelmintica (L.) willd, for vitiligo. By collecting transcriptome and protein-protein interactome data, the combination of random forest (RF) and greedy articulation points removal (GAPR) methods was used to discover potential therapeutic targets for vitiligo. The results showed that the RF model performed well with AUC (area under the receiver operating characteristic curve) = 0.926, and led to prioritization of 722 important transcriptomic features. Then, network analysis revealed that 44 articulation proteins in vitiligo network were considered as potential therapeutic targets by the GAPR method. Finally, through integrating the above results and proteomic profiling of kaempferide, the multi-target strategy for vitiligo was dissected, including 1) the suppression of the p38 MAPK signaling pathway by inhibiting CDK1 and PBK, and 2) the modulation of cellular redox homeostasis, especially the TXN and GSH antioxidant systems, for the purpose of melanogenesis. Meanwhile, this strategy may offer a novel perspective to discover drug candidates for vitiligo. Thus, the framework would be a useful tool to discover potential therapeutic strategies and drug candidates for complex diseases.

Insights into the mechanism of Arnebia euchroma on leukemia via network pharmacology approach.

BACKGROUND: Arnebia euchroma (A. euchroma) is a traditional Chinese medicine (TCM) used for the treatment of blood diseases including leukemia. In recent years, many studies have been conducted on the anti-tumor effect of shikonin and its derivatives, the major active components of A. euchroma. However, the underlying mechanism of action (MoA) for all the components of A. euchroma on leukemia has not been explored systematically. METHODS: In this study, we analyzed the MoA of A. euchroma on leukemia via network pharmacology approach. Firstly, the chemical components and their concentrations in A. euchroma as well as leukemia-related targets were collected. Next, we predicted compound-target interactions (CTIs) with our balanced substructure-drug-target network-based inference (bSDTNBI) method. The known and predicted targets of A. euchroma and leukemia-related targets were merged together to construct A. euchroma-leukemia protein-protein interactions (PPIs) network. Then, weighted compound-target bipartite network was constructed according to combination of eight central attributes with concentration information through Cytoscape. Additionally, molecular docking simulation was performed to calculate whether the components and predicted targets have interactions or not. RESULTS: A total of 65 components of A. euchroma were obtained and 27 of them with concentration information, which were involved in 157 targets and 779 compound-target interactions (CTIs). Following the calculation of eight central attributes of targets in A. euchroma-leukemia PPI network, 37 targets with all central attributes greater than the median values were selected to construct the weighted compound-target bipartite network and do the KEGG pathway analysis. We found that A. euchroma candidate targets were significantly associated with several apoptosis and inflammation-related biological pathways, such as MAPK signaling, PI3K-Akt signaling, IL-17 signaling, and T cell receptor signaling pathways. Moreover, molecular docking simulation demonstrated that there were eight pairs of predicted CTIs had the strong binding free energy. CONCLUSIONS: This study deciphered that the efficacy of A. euchroma in the treatment of leukemia might be attributed to 10 targets and 14 components, which were associated with inhibiting leukemia cell survival and inducing apoptosis, relieving inflammatory environment and inhibiting angiogenesis.

The Alexipharmic Mechanisms of Five Licorice Ingredients Involved in CYP450 and Nrf2 Pathways in Paraquat-Induced Mice Acute Lung Injury.

Oxidative stress is an important mechanism in acute lung injury (ALI) induced by paraquat (PQ), one of the most widely used herbicides in developing countries. In clinical prophylaxis and treatment, licorice is a widely used herbal medicine in China due to its strong alexipharmic characteristics. However, the corresponding biochemical mechanism of antioxidation and detoxification enzymes induced by licorice's ingredients is still not fully demonstrated. In this study, the detoxification effect of licorice was evaluated in vivo and in vitro. The detoxification and antioxidation effect of its active ingredients involved in the treatment was screened systematically according to Absorption, Distribution, Metabolism, and Excretion (ADME): predictions and evidence-based literature mining methods in silico approach. Data shows that licorice alleviate pulmonary edema and fibrosis, decrease Malondialdehyde (MDA) contents and increase Superoxide Dismutase (SOD) activity in PQ-induced ALI mice, protect the morphologic appearance of lung tissues, induce cytochrome 3A4 (CYA3A4) and Nuclear factor erythroid 2-related factor 2 (Nrf2) expression to active detoxification pathways, reduce the accumulation of PQ in vivo, protect or improve the liver and renal function of mice, and increase the survival rate. The 104 genes of PPI network contained all targets of licorice ingredients and PQ, which displayed the two redox regulatory enzymatic group modules cytochrome P450 (CYP450) and Nrf2 via a score-related graphic theoretic clustering algorithm in silico. According to ADME properties, glycyrol, isolicoflavonol, licochalcone A, 18beta-glycyrrhetinic acid, and licoisoflavone A were employed due to their oral bioavailability (OB) ≥ 30%, drug-likeness (DL) ≥ 0.1, and being highly associated with CYP450 and Nrf2 pathways, as potential activators to halt PQ-induced cells death in vitro. Both 3A4 inhibitor and silenced Nrf2 gene decreased the alexipharmic effects of those ingredients significantly. All these disclosed the detoxification and antioxidation effects of licorice on acute lung injury induced by PQ, and glycyrol, isolicoflavonol, licochalcone A, 18beta-glycyrrhetinic acid, and licoisoflavone A upregulated CYP450 and Nrf2 pathways underlying the alexipharmic mechanisms of licorice.

Time-resolved fluorescence and chemometrics-assisted excitation-emission fluorescence for qualitative and quantitative analysis of scopoletin and scopolin in Erycibe obtusifolia Benth.

This paper presents a new strategy for qualitative identification of scopoletin and scopolin in Erycibe obtusifolia Benth using time-resolved (lifetimes) fluorescence and quantitative analysis with chemometrics-assisted excitation-emission matrix (EEM) fluorescence. Due to the significant spectral overlapping among analytes and interference, the use of the more selective time-resolved fluorescence is proposed for qualitative identification in quality control of traditional Chinese medicine (TCM) for the first time. Using the strategy of combining EEM fluorescence with second-order calibration method, i.e. parallel factor analysis (PARAFAC), the simultaneous quantification of scopoletin and scopolin in the complex system of Erycibe obtusifolia Benth was achieved successfully. The predicted concentrations were compared with the values obtained using high performance liquid chromatography-coupled to fluorimetric detector (HPLC-FLD), and no significant differences between them were observed. Therefore, the proposed methods using time-resolved fluorescence for qualitative analysis and EEMs coupled with second-order calibration for quantitative analysis in TCM are comparable and provide a suitable alternative to the chromatography-based method.

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.

Effect of acetazolamide and gingko biloba on the human pulmonary vascular response to an acute altitude ascent.

Acetazolamide and gingko biloba are the two most investigated drugs for the prevention of acute mountain sickness (AMS). Evidence suggests that they may also reduce pulmonary artery systolic pressure (PASP). To investigate whether these two drugs for AMS prevention also reduce PASP with rapid airlift ascent to high altitude, a randomized controlled trial was conducted on 28 healthy young men with acetazolamide (125 mg bid), gingko biloba (120 mg bid), or placebo for 3 days prior to airlift ascent (397 m) and for the first 3 days at high altitude (3658 m). PASP, AMS, arterial oxygen saturation (Sao2), mean arterial pressure (MAP), heart rate (HR), forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and peak expiratory flow (PEF) were assessed both at 397 m and 3658 m. HR, PEF, and PASP increased with altitude exposure (p<0.05), and SaO2 decreased (p<0.05). PASP with acetazolamide (mean at 3658 m, 26.2 mm Hg; incremental change, 4.7 mm Hg, 95% CI., 2.6-6.9 mm Hg) was lower than that with ginkgo biloba (mean at 3658 m, 33.7 mm Hg, p=0.001; incremental change, 13.1 mm Hg, 95%CI., 9.6-16.5 mm Hg, p=0.002), and with placebo (mean at 3658 m, 34.7 mm Hg, p<0.001; 14.4 mm Hg, 95% CI., 8.8-20.0 mm Hg, p=0.001). The data show that a low prophylactic dosage of acetazolamide, but not gingko biloba, mitigates the early increase of PASP in a quick ascent profile.

Changes in the synaptic structure of hippocampal neurons and impairment of spatial memory in a rat model caused by chronic arsenite exposure.

Many epidemiological studies and in vitro experiments have found that chronic arsenic exposure may influence memory formation. The goal of this study was to create an animal model of memory impairment induced by chronic arsenite exposure and to study the underlying mechanisms. Sixty male Sprague-Dawley (SD) male rats were randomly divided into a control group, a low-dose sodium arsenite exposure group and a high-dose sodium arsenite exposure group. Sodium arsenite was administered by adding it to drinking water for 3 months. Then, the spatial memory of the rats was examined with Morris water maze and Y maze. The concentration of arsenic in the blood and the brain was determined by an atomic fluorescence absorption spectrometer. The ultra-structure of hippocampal neurons was observed by an electron microscope. Timm staining was used for observing mossy fibers. We found that the concentration of arsenic in the blood and the brain increased in a dose-response manner (P<0.05). The performance of rats in the arsenite exposed group (15 mg/kg) was significantly impaired in the Morris water maze and Y maze tasks than those in the control group (P<0.05). Sodium arsenite exposure resulted in abnormal structural changes in the myelin sheaths of nerve fibers and decreases in the terminals of mossy fibers. Together, chronic sodium arsenite exposure through drinking water results in detrimental changes in the neuronal synapses, which may contribute to the arsenite-induced impairment of spatial memory.