Epigenetic profile of the immune system associated with symptom severity and treatment response in schizophrenia.

BACKGROUND: Environmental modification of genetic information (epigenetics) is often invoked to explain interindividual differences in the phenotype of schizophrenia. In clinical practice, such variability is most prominent in the symptom profile and the treatment response. Epigenetic regulation of immune function is of particular interest, given the therapeutic relevance of this mechanism in schizophrenia. METHODS: We analyzed the DNA methylation data of immune-relevant genes in patients with schizophrenia whose disease duration was less than 3 years, with previous lifetime antipsychotic treatment of no more than 2 weeks total. RESULTS: A total of 441 patients met the inclusion criteria. Core symptoms were consistently associated with 206 methylation positions, many of which had previously been implicated in inflammatory responses. Of these, 24 methylation positions were located either in regulatory regions or near the CpG islands of 20 genes, including the SRC gene, which is a key player in glutamatergic signalling. These symptom-associated immune genes were enriched in neuronal development functions, such as neuronal migration and glutamatergic synapse. Compared with using only clinical information (including scores on the Positive and Negative Syndrome Scale), integrating methylation data into the model significantly improved the predictive ability (as indicated by area under the curve) for response to 8 weeks of antipsychotic treatment. LIMITATIONS: We focused on a small number of methylation probes (immune-centred search) and lacked nutritional data and direct brain-based measures. CONCLUSION: Epigenetic modifications of the immune system are associated with symptom severity at onset and subsequent treatment response in schizophrenia.

Holistic energy landscape management in 2D/3D heterojunction via molecular engineering for efficient perovskite solar cells.

Constructing two-dimensional (2D) perovskite atop of 3D with energy landscape management is still a challenge in perovskite photovoltaics. Here, we report a strategy through designing a series of π-conjugated organic cations to construct stable 2D perovskites and to realize delicate energy level tunability at 2D/3D heterojunctions. As a result, the hole transfer energy barriers can be reduced both at heterojunctions and within 2D structures, and the preferable work function shift reduces charge accumulation at interface. Leveraging these insights and also benefitted from the superior interface contact between conjugated cations and poly(triarylamine) (PTAA) hole transporting layer, a solar cell with power conversion efficiency of 24.6% has been achieved, which is the highest among PTAA-based n-i-p devices to the best of our knowledge. The devices exhibit greatly enhanced stability and reproducibility. This approach is generic to several hole transporting materials, offering opportunities to realize high efficiency without using the unstable Spiro-OMeTAD.

Tailoring Molecular-Scale Contact at the Perovskite/Polymeric Hole-Transporting Material Interface for Efficient Solar Cells.

Perovskite solar cells (PSCs) have delivered a power conversion efficiency (PCE) of more than 25% and incorporating polymers as hole-transporting layers (HTLs) can further enhance the stability of devices toward the goal of commercialization. Among the various polymeric hole-transporting materials, poly(triaryl amine) (PTAA) is one of the promising HTL candidates with good stability; however, the hydrophobicity of PTAA causes problematic interfacial contact with the perovskite, limiting the device performance. Using molecular side-chain engineering, a uniform 2D perovskite interlayer with conjugated ligands, between 3D perovskites and PTAA is successfully constructed. Further, employing conjugated ligands as cohesive elements, perovskite/PTAA interfacial adhesion is significantly improved. As a result, the thin and lateral extended 2D/3D heterostructure enables as-fabricated PTAA-based PSCs to achieve a PCE of 23.7%, improved from the 18% of reference devices. Owing to the increased ion-migration energy barrier and conformal 2D coating, unencapsulated devices with the new ligands exhibit both superior thermal stability under 60 °C heating and moisture stability in ambient conditions.

Potential type 2 diabetes mellitus drug HMPA promotes short-chain fatty acid production by improving carbon catabolite repression effect of gut microbiota.

BACKGROUND AND PURPOSE: Gut microbiota plays an important role in type 2 diabetes mellitus (T2DM) progression. From our previous work N-(4-Hydroxyphenethyl)-3-mercapto-2-methylpropanamide (HMPA) is a potential T2DM drug. We evaluated the effect of HMPA on gut microbiota and studied the molecular mechanism underlying HMPA's regulation of gut microbiota. EXPERIMENTAL APPROACH: The pseudo germ-free (PGF) T2DM model and faecal microbiota transplantation method were used to study whether gut microbiota mediates the actions of HMPA. The composition of gut microbiota was detected by using 16S rRNA sequence. Short-chain fatty acids (SCFAs) content was detected by gas chromatography. The HMPA probe was synthesised for finding and identifying the target protein of HMPA. The effect of HMPA on the utilisation of carbon sources in Bifidobacterium was evaluated. KEY RESULTS: HMPA has a slight effect on the PGF T2DM model. The gut microbiota changed by HMPA can also alleviate the symptoms of T2DM. HMPA can regulate gut microbiota structure, increase SCFAs production and reduce nitrate content in the intestinal tissues. The thickness of the mucus on colon tissues increases after HMPA treatment. The target protein of HMPA in gut microbiota is the nitrogen metabolism global transcriptional regulator (GlnR). HMPA promotes the utilisation of less preferred carbon source in the gut microbiota and increases the fermentation product of SCFAs. CONCLUSION AND IMPLICATIONS: HMPA plays a hypoglycaemic role through the gut microbiota. HMPA improves the carbon catabolite repression effect of gut microbiota and increases SCFAs production by targeting GlnR. GlnR may be a target for gut microbiota regulation.

N2 plasma-activated NiO nanosheet arrays with enhanced water splitting performance.

NiO is a promising electrocatalyst for electrochemical energy conversion due to its rich redox sites, low cost, and ease of synthesis. However, hindered by low electrical conductivity and limited electrocatalytic active sites, bare NiO usually exhibits poor electrochemical performance towards hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). Herein, we develop an N2 plasma activation approach to simultaneously improve both HER and OER activity of NiO by constructing heterostructured Ni/Ni3N/NiO nanosheet arrays on Ni foam. The optimized N2 plasma-activated NiO nanosheet arrays for HER and OER (denoted as P-NiO-HER and P-NiO-OER) only need an overpotential of 46 and 294 mV, respectively, to achieve 10 mA cm-2. Moreover, for overall water splitting, the assembled electrolysis cell with P-NiO-HER and P-NiO-OER as the cathode and anode, respectively, only requires a small voltage of 1.57 V to deliver 10 mA cm-2. Remarkably, the plasma-activated NiO nanosheet arrays exhibit excellent stability for up to 50 h for HER, OER, and full water electrolysis. The strategy developed here to activate the electrocatalytic performance of metal oxides opens a new door for water splitting.

Prim-O-glucosylcimifugin enhances the antitumour effect of PD-1 inhibition by targeting myeloid-derived suppressor cells.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells that play an important role in immune evasion, PD-1/PD-L1 inhibitor tolerance and tumour progression. Therefore, MDSCs are potential targets for cancer immunotherapy. In this study, we screened an effective polymorphonuclear MDSC (PMN-MDSC) inhibitor from the Traditional Chinese Medicine Library and evaluated its synergistic antitumour effects with PD-1 inhibitor. METHODS: In the present study, we found that PMN-MDSCs accumulate heavily in the spleen and bone marrow of melanoma (B16-F10) tumour-bearing mice. Then, we determined the top 10 key proteins in the upregulated KEGG pathways of PMN-MDSCs in tumour-bearing mice through proteomics and Cytoscape analysis. The key proteins were then used as targets for the screening of PMN-MDSC inhibitors from the traditional Chinese Medicine Library (20000 compounds) through molecular docking and weight calculation of the docking score. Finally, the inhibitory effect of the inhibitor was verified through proteomics and metabolomics analysis in vitro and melanoma (B16-F10) and triple-negative breast cancer (4 T1) mouse tumour models in vivo. RESULTS: Traditional Chinese medicine saposhnikovia root extract Prim-O-glucosylcimifugin (POG) could bind well to the target proteins and inhibit the proliferation, metabolism and immunosuppressive ability of PMN-MDSCs by inhibiting arginine metabolism and the tricarboxylic acid cycle (TCA cycle). POG could also increase CD8 T-lymphocyte infiltration in the tumours and enhance the antitumour effect of PD-1 inhibitor in B16-F10 and 4 T1 mouse tumour models. CONCLUSIONS: POG was successfully screened from the traditional Chinese Medicine library as a PMN-MDSC inhibitor. POG exhibited a good synergistic antitumour effect with PD-1 inhibitor. This study provided a potential option for enhancing the efficacy of PD-1 inhibitors in clinical applications.

6-Gingerol stabilized the p-VEGFR2/VE-cadherin/ß-catenin/actin complex promotes microvessel normalization and suppresses tumor progression.

BACKGROUND: Anti-angiogenic therapies demonstrate anti-tumor effects by decreasing blood supply to tumors and inhibiting tumor growth. However, anti-angiogenic therapy may leads to changes in tumor microenvironment and increased invasiveness of tumor cells, which in turn promotes distant metastasis and increased drug resistance. METHODS: The CO-IP assays, N-STORM and cytoskeleton analysis were used to confirm the mechanism that p-VEGFR2/VE-cadherin/ß-catenin/actin complex regulates vascular remodeling and improves the tumor microenvironment. 6-gingerol (6G), the major bioactive component in ginger, stabilized this complex by enhancing the binding of VEGFa to VEGFR2 with non-pathway dependent. Biacore, pull down and molecular docking were employed to confirm the interaction between 6G and VEGFR2 and enhancement of VEGFa binding to VEGFR2. RESULTS: Here, we report that microvascular structural entropy (MSE) may be a prognostic factor in several tumor types and have potential as a biomarker in the clinic. 6G regulates the structural organization of the microvascular bed to decrease MSE via the p-VEGFR2/VE-cadherin/ß-catenin/actin complex and inhibit tumor progression. 6G promotes the normalization of tumor vessels, improves the tumor microenvironment and decreases MSE, facilitating the delivery of chemotherapeutic agents into the tumor core and thereby reducing tumor growth and metastasis. CONCLUSIONS: This study demonstrated the importance of vascular normalization in tumor therapy and elucidated the mechanism of action of ginger, a medicinal compound that has been used in China since ancient times.

YY1 Complex Promotes Quaking Expression via Super-Enhancer Binding during EMT of Hepatocellular Carcinoma.

Quaking (QKI) is an alternative splicing factor that can regulate circRNA formation in the progression of epithelial-mesenchymal transition, but the mechanism remains unclear. High expression of QKI is correlated with short survival time, metastasis, and high clinical stage and pathology grade in hepatocellular carcinoma (HCC). Here we report that transcription of the QKI gene was activated by the Yin-Yang 1 (YY1)/p65/p300 complex, in which YY1 bound to the super-enhancer and promoter of QKI, p65 combined with the promoter, and p300 served as a mediator to maintain the stability of the complex. This YY1/p65/p300 complex increased QKI expression to promote the malignancy of HCC as well as an increased circRNA formation in vitro and in vivo. Hyperoside is one of several plant-derived flavonol glycoside compounds. Through virtual screening and antitumor activity analysis, we found that hyperoside inhibited QKI expression by targeting the YY1/p65/p300 complex. Overall, our study suggests that the regulatory mechanism of QKI depends on the YY1/p65/p300 complex and that it may serve as a potential target for treatment of HCC. SIGNIFICANCE: These findings identify the YY1/p65/p300 complex as a regulator of QKI expression, identifying several potential therapeutic targets for the treatment of HCC.

Thymidine phosphorylase promotes malignant progression in hepatocellular carcinoma through pentose Warburg effect.

Tumor progression is dependent on metabolic reprogramming. Metastasis and vasculogenic mimicry (VM) are typical characteristics of tumor progression. The relationship among metastasis, VM, and metabolic reprogramming remains unclear. In this study, we identified the novel role of Twist1, a VM regulator, in the transcriptional regulation of thymidine phosphorylase (TP) expression. TP promoted the extracellular metabolism of thymidine into ATP and amino acids through the pentose Warburg effect by coupling the pentose phosphate pathway and glycolysis. Moreover, Twist1 relied on TP-induced metabolic reprogramming to promote hepatocellular carcinoma (HCC) metastasis and VM formation mediated by VE-Cad, VEGFR1, and VEGFR2 in vitro and in vivo. The TP inhibitor tipiracil reduced the effect of TP on promoting HCC VM formation and metastasis. Hence, TP, when transcriptionally activated by Twist1, promotes HCC VM formation and metastasis through the pentose Warburg effect and contributes to tumor progression.

Antimalarial Drug Pyrimethamine Plays a Dual Role in Antitumor Proliferation and Metastasis through Targeting DHFR and TP.

Pyrimethamine (Pyr), an antimalarial drug that targeting plasmodium dihydrofolate reductase (pDHFR), has been proved to have antitumor activity. However, its direct target on cancer cells remains unclear. Methotrexate (MTX) is a widely used anticancer drug that blocks human dihydrofolate reductase (hDHFR). In this work, we examined the anticancer effects of Pyr in vitro and in vivo Our results showed that hDHFR and pDHFR have similar secondary and three-dimensional structures and that Pyr can inhibit the activity of hDHFR in lung cancer cells. Although Pyr and MTX can inhibit the proliferation of lung cancer cells by targeting DHFR, only Pyr can inhibit the epithelial-mesenchymal transition (EMT), metastasis and invasion of lung cancer cells. These results indicated that hDHFR is not the only target of Pyr. We further found that thymidine phosphorylase (TP), an enzyme that is closely associated with the EMT of cancer cells, is also a target protein of Pyr. The data retrieved from the Cancer Genome Atlas (TCGA) database revealed that TP overexpression is associated with poor prognosis of patients with lung cancer. In conclusion, Pyr plays a dual role in antitumor proliferation and metastasis by targeting DHFR and TP. Pyr may have potential clinical applications for the treatment of lung cancer.

Glycyrrhizic Acid-Induced Differentiation Repressed Stemness in Hepatocellular Carcinoma by Targeting c-Jun N-Terminal Kinase 1.

Hepatocellular carcinoma (HCC) is one of the most common malignant cancers with poor prognosis and high incidence. Cancer stem cells play a vital role in tumor initiation and malignancy. The degree of differentiation of HCC is closely related to its stemness. Glycyrrhizic acid (GA) plays a critical role in inhibiting the degree of malignancy of HCC. At present, the effect of GA on the differentiation and stemness of HCC has not been reported, and its pharmacological mechanism remains to be elucidated. This study evaluated the effect of GA on the stemness of HCC and investigated its targets through proteomics and chemical biology. Results showed that GA can repress stemness and induce differentiation in HCC in vitro. GEO analysis revealed that cell differentiation and stem cell pluripotency were up-regulated and down-regulated after GA administration, respectively. Virtual screening was used to predict the c-Jun N-terminal kinase 1 (JNK1) as a direct target of GA. Moreover, chemical biology was used to verify the interaction of JNK1 and GA. Experimental data further indicated that JNK1 inhibits stemness and induces differentiation of HCC. GA exerts its function by targeting JNK1. Clinical data analysis from The Cancer Genome Atlas also revealed that JNK1 can aggravate the degree of malignancy of HCC. The results indicated that, by targeting JNK1, GA can inhibit tumor growth through inducing differentiation and repressing stemness. Furthermore, GA enhanced the anti-tumor effects of sorafenib in HCC treatment. These results broadened our insight into the pharmacological mechanism of GA and the importance of JNK1 as a therapeutic target for HCC treatment.

Salidroside improves the hypoxic tumor microenvironment and reverses the drug resistance of platinum drugs via HIF-1α signaling pathway.

BACKGROUND: Hypoxia commonly occurs in solid tumors. The hypoxia in the center of solid tumors considerably decreases the chemosensitivity of tumor cells and induces epithelial-mesenchymal transition (EMT) as well as drug resistance of antitumor drugs. METHODS: Here, the effects of salidroside (Sal) combined with platinum drugs on human hepatocellular carcinoma were examined in vitro and in vivo. We investigated the antitumor effects of Sal by inhibiting the drug resistance and explained its mechanism in inhibiting tumor growth. FINDINGS: The results showed that Sal co-administration reverses the drug resistance of platinum drugs and suppressed metastasis induced by the hypoxic tumor microenvironment. Sal promoted the degradation of HIF-1α. In conclusion, Sal significantly increased the sensitivity to platinum drugs and inhibited hypoxia-induced EMT in hepatocellular carcinoma (HCC) through inhibiting HIF-1α signaling pathway. INTERPRETATION: Therefore, Sal may be an effective platinum drug sensitizer that can improve the chemotherapeutic efficacy in patients with HCC.

Salvianolic acid A targeting the transgelin-actin complex to enhance vasoconstriction.

BACKGROUND: Salvia miltiorrhiza is used extensively to treat cardiovascular diseases. SAA is a major bioactive component in Salvia miltiorrhiza and mediates myocardial ischemia (MI). However, the industrial production of SAA is limited due to low yields. In addition, the direct targets of SAA are unknown. Here we explore cardioprotective mechanisms and targets of SAA in the cardiovascular system. METHODS: Transgelin and actin were identified as targets of SAA using a chemical biology method and were validated by Biacore analysis, microscale thermophoresis and single-molecule imaging. Studies of transgelin (-/-) knockout mice further verify the target. Cardioprotective mechanisms and targets of SAA were studied in cultured vascular smooth muscle cells and transgenic mice. FINDINGS: In WT mice, SAA targeted transgelin and had a protective effect on myocardium but did not have the same protective effect on transgelin (-/-) mice. SAA stabilizes the transgelin-actin complex, modulates the reorganization of the actin cytoskeleton, facilitates F-actin bundling, further enhances the contractility and blood flows of coronary arteries, and improves outcomes of myocardial ischemia. Based on the target, a more active SAA derivative offering myocardial protection, SAA-30, was obtained. INTERPRETATION: We report on the direct targets of SAA and mechanisms of myocardial ischemia treatment. We also find that transgelin may act as a novel therapeutic target of myocardial ischemia. Furthermore, a more effective derivative of SAA provides the basis for further clinical translational research.

First-principles investigation of transition metal atom M (M = Cu, Ag, Au) adsorption on CeO2(110).

Transition metal atom M (M = Cu, Ag, Au) adsorption on CeO(2)(110), a technologically important catalytic support surface, is investigated with density-functional theory within the DFT+U formalism. A set of model configurations was generated by placing M at three surface sites, viz., on top of an O, an O bridge site, and a Ce bridge site. Prior to DFT optimization, small distortions in selected Ce-O distances were imposed to explore the energetics associated with reduction of Ce(4+) to Ce(3+) due to charge transfer to Ce during M adsorption. Charge redistribution is confirmed with spin density isosurfaces and site projected density of states. We demonstrate that Cu and Au atoms can be oxidized to Cu(2+) and Au(2+), although the adsorption energy, E(ads), of Au(2+) is less favorable and, unlike Cu(2+), it has not been experimentally observed. Oxidation of Ag always results in Ag(+). For M adsorption at an O bridge site, E(ads)(2NN) > E(ads)(3NN) > E(ads)(1NN) where NN denotes the nearest neighbor Ce(3+) site relative to M. Alternatively, for M adsorption at a Ce bridge site, E(ads)(3NN) > E(ads)(2NN) > E(ads)(1NN). The adsorption behavior of M on CeO(2) (110) is compared with M adsorption on CeO(2)(111).