Construction of a novel Eu-MOF material based on different detection mechanisms and its application in sensing pollutants aniline, F- and Hg2.

Aniline is an organic pollutant with carcinogenicity and teratogenicity, while F- and Hg2+ are toxic ions that are easily soluble in water. When they are released to the environment, they will pose a threat to human health. Designing a material that can simultaneously detect three types of pollutants is of great significance. In this paper, a novel rare earth metal organic framework material (Eu-MOF) with three-dimensional structure based on 1-methylimidazole-4,5-dicarboxylic acid was synthesized for the first time through solvent thermal method. It has excellent luminescent performance and can be used as a multifunctional fluorescent probe to detect aniline, F-, and Hg2+ based on photoinduced electron transfer, energy competitive absorption, and ion exchange mechanisms, with detection limits of 1.79 × 10-8, 8.13 × 10-8, and 8.83 × 10-7 M, respectively. It is worth noting that Eu-MOF can detect F- and Hg2+ in real water samples, such as lake water and green tea water, with favorable recovery rates.

Transcriptional Responses for Biosynthesis of Triterpenoids in Exogenous Inducers Treated Inonotus Hispidus Using RNA-Seq.

Inonotus hispidus is a traditional medicinal that grows in Northeast China and produces various economically important compounds, including polysaccharide compounds and terpenoids; triterpenoid saponins is the main bioactive component. Our research group has found that the accumulation of triterpenoid was affected by exogenous inducers. Experimental results showed that treatment with methyl jasmonate (MeJA) and oleic acid significantly increased the triterpenoid content of I. hispidus. However, how exogenous inducers enhance production of secondary metabolites in I. hispidus is not well understood. In this study, metabolite changes were further investigated with UPLC-TOF/MS following exogenous inducer treatment. As a result, a total of eight types of triterpenoids in I. hispidus were identified. The RNA-seq analysis was used to evaluate the effects of exogenous inducers on the expression of triterpenoid-synthesis-related genes in I. hispidus in liquid fermentation. This study is the first exploration to profile the transcriptome of I. hispidus after adding exogenous inducers; the generated data and gene will facilitate further molecular studies on the physiology and metabolism in this fungi. By comparative transcriptomic analysis, a series of candidate genes involved in the biosynthetic pathway of triterpenoids are identified, providing new insights into their biosynthesis at the transcriptome level.

Structural analysis and in vitro antitumor effect of polysaccharides from Pholiota adiposa.

Pholiota adiposa is an edible chestnut mushroom with many health benefits, such as antioxidant and anticancer activity. In this paper, polysaccharides were extracted from Pholidota adiposa using an acid extraction process. The crude polysaccharide was purified using DEAE-cellulose chromatography, and two polysaccharide fractions of SPAP2-1 and SPAP2-2 were obtained. The structure was characterized using UV, GPC, GC, FT-IR, methylation, and NMR analysis. Monosaccharide component analysis indicated that SPAP2-1 (19 kDa) and SPAP2-2 (20 kDa) contained mannose, glucose, and galactose with different molecular ratios. Their antitumor effects were investigated using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium (MTT) assay, Annexin V-fluorescein isothiocyanate (FITC), propidium iodide (PI) staining, and flow cytometry. By analyzing the changes in the cells, SPAP2-1 caused damage and changed the proliferation rate of HeLa cells. SPAP2-1 showed strong interference to the cell cycle of HeLa cells and induced cell apoptosis. Overall, these results suggested that polysaccharides from Pholiota adiposa, especially SPAP2-1, may have the potential to be used as a tumor cell inhibitor, which needs further study.

Downregulation of Erythrocyte miR-210 Induces Endothelial Dysfunction in Type 2 Diabetes.

Red blood cells (RBC) act as mediators of vascular injury in type 2 diabetes mellitus (T2DM). miR-210 plays a protective role in cardiovascular homeostasis and is decreased in whole blood of T2DM mice. We hypothesized that downregulation of RBC miR-210 induces endothelial dysfunction in T2DM. RBC were coincubated with arteries and endothelial cells ex vivo and transfused in vivo to identify the role of miR-210 and its target protein tyrosine phosphatase 1B (PTP1B) in endothelial dysfunction. RBC from patients with T2DM and diabetic rodents induced endothelial dysfunction ex vivo and in vivo. miR-210 levels were lower in human RBC from patients with T2DM (T2DM RBC) than in RBC from healthy subjects. Transfection of miR-210 in human T2DM RBC rescued endothelial function, whereas miR-210 inhibition in healthy subjects RBC or RBC from miR-210 knockout mice impaired endothelial function. Human T2DM RBC decreased miR-210 expression in endothelial cells. miR-210 expression in carotid artery plaques was lower in T2DM patients than in patients without diabetes. Endothelial dysfunction induced by downregulated RBC miR-210 involved PTP1B and reactive oxygen species. miR-210 mimic attenuated endothelial dysfunction induced by RBC via downregulating vascular PTP1B and oxidative stress in diabetic mice in vivo. These data reveal that the downregulation of RBC miR-210 is a novel mechanism driving the development of endothelial dysfunction in T2DM.

A novel noble-metal-free Mo2C-In2S3 heterojunction photocatalyst with efficient charge separation for enhanced photocatalytic H2 evolution under visible light.

Currently, designing novel noble-metal-free photocatalysts with efficient carriers migration and catalytically active sites have been a researching hotspot in photocatalytic hydrogen evolution. In this paper, a novel noble-metal-free Mo2C-In2S3 heterojunction was synthesized by a simple hydrothermal method. Morphology characterization revealed In2S3 was attached to Mo2C. Electrochemical results showed Mo2C improved the interface conductivity, and promoted the transportation of photogenerated carriers. Under visible light, the optimal Mo2C-In2S3 composite achieved a H2 generation rate of 535.58 µmol h-1 g-1, which was 175.6 and 25.8 times higher than pristine In2S3 (3.05 µmol h-1 g-1) and In2S3-1% Pt (20.73 µmol h-1 g-1). In addition, a reasonable mechanism of the elevated photocatalytic activity was also discussed. This study demonstrates commercial Mo2C has an important effect of separating carriers and replacing Pt as co-catalyst in heterojunctions. This research also provides a method to design and synthesize new noble-metal-free photocatalysts for excellent hydrogen production activity.

Activation of adenosine A2A but not A2B receptors is involved in uridine adenosine tetraphosphate-induced porcine coronary smooth muscle relaxation.

Activation of both adenosine A2A and A2B receptors (A2BR) contributes to coronary vasodilation. We previously demonstrated that uridine adenosine tetraphosphate (Up4A) is a novel vasodilator in the porcine coronary microcirculation, acting mainly on A2AR in smooth muscle cells (SMC). We further investigated whether activation of A2BR is involved in Up4A-mediated coronary SMC relaxation. Both A2AR and A2BR may stimulate H2O2 production leading to activation of KATP channels in SMCs, we also studied the involvement of H2O2 and KATP channels in Up4A-mediated effect. Coronary small arteries dissected from the apex of porcine hearts were mounted on wire myograph for Up4A concentration responses. Up4A-induced coronary SMC relaxation was attenuated by A2AR but not A2BR antagonism or non-selective P2R antagonism, despite greater endogenous A2BR expression vs. A2AR in both coronary small arteries and primary cultured coronary SMCs. Moreover, Up4A-induced coronary SMC relaxation was blunted by H2O2 catabolism. This effect was not altered by KATP channel blockade. Combination of H2O2 catabolism and A2AR antagonism attenuated Up4A-induced coronary SMC relaxation to the similar extent as A2AR antagonism alone. Collectively, Up4A-induced porcine coronary SMC relaxation is mediated by activation of A2AR-H2O2 pathway. This process does not involve A2BR, P2R or KATP channels.

miR-29b Mediates the Chronic Inflammatory Response in Radiotherapy-Induced Vascular Disease.

As a consequence of the success of present-day cancer treatment, radiotherapy-induced vascular disease is emerging. This disease is caused by chronic inflammatory activation and is likely orchestrated in part by microRNAs. In irradiated versus nonirradiated conduit arteries from patients receiving microvascular free tissue transfer reconstructions, irradiation resulted in down-regulation of miR-29b and up-regulation of miR-146b. miR-29b affected inflammation and adverse wound healing through its targets pentraxin-3 and dipeptidyl-peptidase 4. In vitro and in vivo, we showed that miR-29b overexpression therapy, through inhibition of pentraxin-3 and dipeptidyl-peptidase 4, could dampen the vascular inflammatory response.

Germinal Center-Derived Antibodies Promote Atherosclerosis Plaque Size and Stability.

BACKGROUND: Atherosclerosis progression is modulated by interactions with the adaptive immune system. Humoral immunity can help protect against atherosclerosis formation; however, the existence, origin, and function of putative atherogenic antibodies are controversial. How such atherosclerosis-promoting antibodies could affect the specific composition and stability of plaques, as well as the vasculature generally, remains unknown. METHODS: We addressed the overall contribution of antibodies to atherosclerosis plaque formation, composition, and stability in vivo (1) with mice that displayed a general loss of antibodies, (2) with mice that had selectively ablated germinal center-derived IgG production, or (3) through interruption of T-B-cell interactions and further studied the effects of antibody deficiency on the aorta by transcriptomics. RESULTS: Here, we demonstrate that atherosclerosis-prone mice with attenuated plasma cell function manifest reduced plaque burden, indicating that antibodies promote atherosclerotic lesion size. However, the composition of the plaque was altered in antibody-deficient mice, with an increase in lipid content and decreases in smooth muscle cells and macrophages, resulting in an experimentally validated vulnerable plaque phenotype. Furthermore, IgG antibodies enhanced smooth muscle cell proliferation in vitro in an Fc receptor-dependent manner, and antibody-deficient mice had decreased neointimal hyperplasia formation in vivo. These IgG antibodies were shown to be derived from germinal centers, and mice genetically deficient for germinal center formation had strongly reduced atherosclerosis plaque formation. mRNA sequencing of aortas revealed that antibodies are required for the sufficient expression of multiple signal-induced and growth-promoting transcription factors and that aortas undergo large-scale metabolic reprograming in their absence. Using an elastase model, we demonstrated that absence of IgG results in an increased severity of aneurysm formation. CONCLUSIONS: We propose that germinal center-derived IgG antibodies promote the size and stability of atherosclerosis plaques, through promoting arterial smooth muscle cell proliferation and maintaining the molecular identity of the aorta. These results could have implications for therapies that target B cells or B-T-cell interactions because the loss of humoral immunity leads to a smaller but less stable plaque phenotype.

A new fluorescent-colorimetric chemosensor based on a Schiff base for detecting Cr3+, Cu2+, Fe3+ and Al3+ ions.

A new Schiff base derivative fluorescence-colorimetric chemosensor 2-hydroxy-5-[(2-hydroxy-1-naphthyl)methylideneamino]benzoic acid (H3L), has been designed and synthesized. H3L displayed high selectivity and sensitivity for detecting Cr3+, Cu2+, Fe3+ and Al3+ ions in DMF/H2O (v/v = 1/1) solution. When Cr3+, Cu2+ or Fe3+ ions were added, the solution of H3L in DMF/H2O exhibited different color changes. While with the addition of Fe3+ or Al3+ ions, the solution of H3L in DMF/H2O displayed different fluorescence responses. The bonding modes and bonding ratios of H3L and metal ions were explored by the Job's plot, 1H NMR titration, and electrospray ionization mass spectrometry (ESI-MS). The detection limits of H3L with Cr3+, Cu2+, Fe3+and Al3+ ions were 3.37 × 10-7 M, 4.65 × 10-7 M, 3.58 × 10-7 M and 4.89 × 10-7 M, respectively.

Aqueous leaching of lithium from simulated pyrometallurgical slag by sodium sulfate roasting.

In the pyrometallurgical treatment for spent lithium-ion batteries (LIBs), lithium is generally present in slag with Al, Ca and Si and is hard to be further treated. In this study, lithium was recovered from a simulated pyrometallurgical slag (pyro-slag) via sodium roasting and water leaching. The thermodynamic process for the reactions between slag and additives such as NaCl, NaNO3 and Na2SO4 were simulated during roasting by the HSC software, where Na2SO4 possessed stronger chemical reactivity. The optimal conditions for roasting were experimentally determined to be 800 °C for 60 min and an Na2SO4/Li molar ratio of 3 : 1, followed by water leaching at 70 °C for 80 min using a liquid-to-solid (L/S) mass ratio of 30 : 1. This yielded a maximum of 93.62% lithium recovery. The mechanism by which insoluble lithium in slag was transformed into soluble lithium by salt roasting was proposed using the analysis of XRD and EDS spectra, in which ion exchange occurred between Na+ and Li+ at a certain temperature.

Simulation Analysis of Fluid-Structure Interaction of High Velocity Environment Influence on Aircraft Wing Materials under Different Mach Numbers.

Aircraft service process is in a state of the composite load of pressure and temperature for a long period of time, which inevitably affects the inherent characteristics of some components in aircraft accordingly. The flow field of aircraft wing materials under different Mach numbers is simulated by Fluent in order to extract pressure and temperature on the wing in this paper. To determine the effect of coupling stress on the wing’s material and structural properties, the fluid-structure interaction (FSI) method is used in ANSYS-Workbench to calculate the stress that is caused by pressure and temperature. Simulation analysis results show that with the increase of Mach number, the pressure and temperature on the wing’s surface both increase exponentially and thermal stress that is caused by temperature will be the main factor in the coupled stress. When compared with three kinds of materials, titanium alloy, aluminum alloy, and Haynes alloy, carbon fiber composite material has better performance in service at high speed, and natural frequency under coupling pre-stressing will get smaller.

Local Delivery of miR-21 Stabilizes Fibrous Caps in Vulnerable Atherosclerotic Lesions.

miRNAs are potential regulators of carotid artery stenosis and concordant vulnerable atherosclerotic plaques. Hence, we analyzed miRNA expression in laser captured micro-dissected fibrous caps of either ruptured or stable plaques (n = 10 each), discovering that miR-21 was significantly downregulated in unstable lesions. To functionally evaluate miR-21 in plaque vulnerability, miR-21 and miR-21/apolipoprotein-E double-deficient mice (Apoe-/-miR-21-/-) were assessed. miR-21-/- mice lacked sufficient smooth muscle cell proliferation in response to carotid ligation injury. When exposing Apoe-/-miR-21-/- mice to an inducible plaque rupture model, they presented with more atherothrombotic events (93%) compared with miR-21+/+Apoe-/- mice (57%). We discovered that smooth muscle cell fate in experimentally induced advanced lesions is steered via a REST-miR-21-REST feedback signaling pathway. Furthermore, Apoe-/-miR-21-/- mice presented with more pronounced atherosclerotic lesions, greater foam cell formation, and substantially higher levels of arterial macrophage infiltration. Local delivery of a miR-21 mimic using ultrasound-targeted microbubbles into carotid plaques rescued the vulnerable plaque rupture phenotype. In the present study, we identify miR-21 as a key modulator of pathologic processes in advanced atherosclerosis. Targeted, lesion site-specific overexpression of miR-21 can stabilize vulnerable plaques.

The fluorescent property of 3-[(2-hydroxy-1-naphthyl) methylideneamino]benzoic acid and its application as fluorescent chemosensor for Hg2+ and Al3+ ions.

This manuscript studies the fluorescent property of 3-[(2-hydroxy-1-naphthyl)methylideneamino]benzoic acid (H2L). Fluorescent spectra show that in different solvents, H2L displays different fluorescent properties, which can be attributed to the interaction between the solvents and H2L. Further study indicates that H2L exhibits a highly selective and sensitive recognition for Hg2+ ions in dimethylsulfoxide (DMSO), Al3+ ions in methanol and N,N'-dimethylformamide/water (DMF/H2O, 1/1, v/v). The bonding modes and bonding ratio of H2L and metal ions in different solvents are explored by Job's plot, 1H NMR titration, and electrospray ionization mass spectrometry (ESI-MS). The probable mechanisms were discussed.

Divergent coronary flow responses to uridine adenosine tetraphosphate in atherosclerotic ApoE knockout mice.

Uridine adenosine tetraphosphate (Up4A) exerts potent relaxation in porcine coronary arteries that is reduced following myocardial infarction, suggesting a crucial role for Up4A in the regulation of coronary flow (CF) in cardiovascular disorders. We evaluated the vasoactive effects of Up4A on CF in atherosclerosis using ApoE knockout (KO) mice ex vivo and in vivo. Functional studies were conducted in isolated mouse hearts using the Langendorff technique. Immunofluorescence was performed to assess purinergic P2X1 receptor (P2X1R) expression in isolated mouse coronary arteries. In vivo effects of Up4A on coronary blood flow (CBF) were assessed using ultrasound. Infusion of Up4A (10-9-10-5 M) into isolated mouse hearts resulted in a concentration-dependent reduction in CF in WT and ApoE KO mice to a similar extent; this effect was exacerbated in ApoE KO mice fed a high-fat diet (HFD). The P2X1R antagonist MRS2159 restored Up4A-mediated decreases in CF more so in ApoE KO + HFD than ApoE KO mice. The smooth muscle to endothelial cell ratio of coronary P2X1R expression was greater in ApoE KO + HFD than ApoE KO or WT mice, suggesting a net vasoconstrictor potential of P2X1R in ApoE KO + HFD mice. In contrast, Up4A (1.6 mg/kg) increased CBF to a similar extent among the three groups. In conclusion, Up4A decreases CF more in ApoE KO + HFD mice, likely through a net upregulation of vasoconstrictor P2X1R. In contrast, Up4A increases CBF in vivo regardless of the atherosclerotic model.

Impaired Aortic Contractility to Uridine Adenosine Tetraphosphate in Angiotensin II-Induced Hypertensive Mice: Receptor Desensitization?

OBJECTIVE: We previously showed that uridine adenosine tetraphosphate (Up4A)-mediated aortic contraction is partly mediated through purinergic P2X1 receptors (P2X1R). It has been reported that the plasma level of Up4A is elevated in hypertensive patients, implying a potential role for Up4A-P2X1R signaling in hypertension. This study investigated the vasoactive effect of Up4A in aortas isolated from angiotensin (Ang) II-infused (21 days) hypertensive mice. METHODS: Blood pressure was measured by tail cuff plethysmography. Aortas were isolated for isometric tension measurements, and protein expression was analyzed by western blot. RESULTS: Mean and systolic arterial pressures were elevated by ~50% in Ang II-infused mice. Protein levels of both AT1R and P2X1R were upregulated in Ang II-infused aortas. Surprisingly, Up4A (10-9-10-5 M)-induced concentration-dependent contraction was significantly impaired in Ang II-infused mice. Studies in control mice revealed that both P2X1R (MRS2159) and AT1R (losartan) antagonists significantly attenuated Up4A-induced aortic contraction. In addition, desensitization of AT1R by prior Ang II (100 nM) exposure had no effect on Up4A-induced aortic contraction. However, subsequent serial exposure responses to Up4A-induced aortic contraction were markedly reduced, suggesting a desensitization of purinergic receptors. This desensitization was further confirmed in control mice by prior exposure of aortas to the P2X1R desensitizer α, ß-methylene ATP (10 µM). CONCLUSION: Despite upregulation of AT1R and P2X1R in hypertension, Up4A-mediated aortic contraction was impaired in Ang II-infused mice, likely through the desensitization of P2X1R but not AT1R. This implies that vascular P2X1R activity, rather than plasma Up4A level, may determine the role of Up4A in hypertension.

MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions.

RATIONALE: In the search for markers and modulators of vascular disease, microRNAs (miRNAs) have emerged as potent therapeutic targets. OBJECTIVE: To investigate miRNAs of clinical interest in patients with unstable carotid stenosis at risk of stroke. METHODS AND RESULTS: Using patient material from the BiKE (Biobank of Karolinska Endarterectomies), we profiled miRNA expression in patients with stable versus unstable carotid plaque. A polymerase chain reaction-based miRNA array of plasma, sampled at the carotid lesion site, identified 8 deregulated miRNAs (miR-15b, miR-29c, miR-30c/d, miR-150, miR-191, miR-210, and miR-500). miR-210 was the most significantly downregulated miRNA in local plasma material. Laser capture microdissection and in situ hybridization revealed a distinct localization of miR-210 in fibrous caps. We confirmed that miR-210 directly targets the tumor suppressor gene APC (adenomatous polyposis coli), thereby affecting Wnt (Wingless-related integration site) signaling and regulating smooth muscle cell survival, as well as differentiation in advanced atherosclerotic lesions. Substantial changes in arterial miR-210 were detectable in 2 rodent models of vascular remodeling and plaque rupture. Modulating miR-210 in vitro and in vivo improved fibrous cap stability with implications for vascular disease. CONCLUSIONS: An unstable carotid plaque at risk of stroke is characterized by low expression of miR-210. miR-210 contributes to stabilizing carotid plaques through inhibition of APC, ensuring smooth muscle cell survival. We present local delivery of miR-210 as a therapeutic approach for prevention of atherothrombotic vascular events.

Effect of Cobalt Concentration and Oxygen Vacancy on Magnetism of Co Doped ZnO Nanorods.

Zn(1-x)Co(x)O (x = 0-0.07) single-crystalline nanorods were prepared by a modified microemulsion route. The crystalline structure, morphology, optical, and hysteresis loop at low and room temperature of as-prepared materials were characterized by XRD, TEM, PL spectra, and magnetic measurement respectively. The nanorods are 80-250 nm in diameter and about 3 µm in length. X-ray diffraction data, TEM images confirm that the materials synthesized in optimal conditions are ZnO:Co single crystalline solid solution without any impurities related to Co. The PL spectra show that the ferromagnetic samples exhibit strong Zn interstitials and oxygen vacancy emission indicating defects may stabilize ferromagnetic order in the obtained diluted magnetic semiconductors. Magnetic measurements show that the Zn(1-x)Co(x)O nanorods exist obvious ferromagnetic characteristics with T(c) above 300 K. M(s) and coercivities first increase and then decrease with dopant concentration increasing, reaching the highest for 3% doping level. The structural and magnetic properties of these samples support the hypothesis that the FM of DMS nanorods is due to a defect mediated mechanism instead of cobalt nanoclusters and carrier mediated.

Mechanisms underlying uridine adenosine tetraphosphate-induced vascular contraction in mouse aorta: Role of thromboxane and purinergic receptors.

Uridine adenosine tetraphosphate (Up4A), a novel endothelium-derived vasoactive agent, is proposed to play a role in cardiovascular disorders and induces aortic contraction through activation of cyclooxygenases (COXs). We and others demonstrated that activation of A1 or A3 adenosine receptors (ARs) results in vascular contraction via thromboxane (TX) A2 production. However, the mechanisms of Up4A-induced vascular contraction in mouse aorta are not understood. We hypothesize that Up4A-induced aortic contraction is through COX-derived TXA2 production, which requires activation of A1 and/or A3AR. Concentration responses to Up4A were conducted in isolated aorta. The TXB2 production, a metabolite of TXA2, was also measured. Up4A (10(-9)-10(-5)M) produced a concentration-dependent contraction >70%, which was markedly attenuated by COX and COX1 but not by COX2 inhibition. Notably, Up4A-induced aortic contraction was blunted by both TX synthase inhibitor ozagrel and TXA2 receptor (TP) antagonist SQ29548. Surprisingly, A3AR deletion had no effect on Up4A-induced contraction. Moreover, A1AR deletion or antagonism as well as A1/A3AR deletion potentiated Up4A-induced aortic contraction, suggesting a vasodilator influence of A1AR. In contrast, non-selective purinergic P2 receptor antagonist PPADS significantly blunted Up4A-induced aortic contraction to a similar extent as selective P2X1R antagonist MRS2159, the latter of which was further reduced by addition of ozagrel. Endothelial denudation almost fully attenuated Up4A-induced contraction. Furthermore, Up4A (3µM) increased TXB2 formation, which was inhibited by either MRS2159 or ozagrel. In conclusion, Up4A-induced aortic contraction depends on activation of TX synthase and TP, which partially requires the activation of P2X1R but not A1 or A3AR through an endothelium-dependent mechanism.

IL-37 ameliorates the inflammatory process in psoriasis by suppressing proinflammatory cytokine production.

IL-37 is a potent inhibitor of innate immunity by shifting the cytokine equilibrium away from excessive inflammation. Psoriasis is thought to be initiated by abnormal interactions between the cutaneous keratinocytes and systemic immune cells, triggering keratinocyte hyperproliferation. In the current study, we assessed IL-37 in two well-known psoriasis models: a human keratinocyte cell line (HaCaT) and the keratin 14 VEGF-A-transgenic mouse model. First, we used the HaCaT cell line, which was transiently transfected with an overexpressing IL-37 vector, and tested the effect of IL-37 on these cells using a mixture of five proinflammatory cytokines. IL-37 was effective in suppressing the production of CXCL8, IL-6, and S100A7, which were highly upregulated by the mixture of five proinflammatory cytokines. Keratin 14 VEGF-A-transgenic mice were treated with plasmid coding human IL-37 sequence-formulated cationic liposomes, and we observed potent immunosuppressive effects over the 18-d period. In this model, we observed reduced systemic IL-10 levels, local IFN-γ gene transcripts, as well as mild mast cell infiltration into the psoriatic lesions of the mice. Immunohistochemical analysis indicated that IL-37 was expressed by effector memory T cells, as well as macrophages, in human psoriatic plaques. In conclusion, our studies strongly indicate that IL-37 plays a potent immunosuppressive role in the pathogenesis of both experimental psoriasis models in vitro and in vivo by downregulating proinflammatory cytokines. Importantly, our findings highlight new therapeutic strategies that can be designed to use this immunosuppressive anti-inflammatory cytokine in psoriasis and other inflammatory cutaneous diseases.

Histone deacetylases regulate gonadotropin-releasing hormone I gene expression via modulating Otx2-driven transcriptional activity.

BACKGROUND: Precise coordination of the hypothalamic-pituitary-gonadal axis orchestrates the normal reproductive function. As a central regulator, the appropriate synthesis and secretion of gonadotropin-releasing hormone I (GnRH-I) from the hypothalamus is essential for the coordination. Recently, emerging evidence indicates that histone deacetylases (HDACs) play an important role in maintaining normal reproductive function. In this study, we identify the potential effects of HDACs on Gnrh1 gene transcription. METHODOLOGY/PRINCIPAL FINDINGS: Inhibition of HDACs activities by trichostatin A (TSA) and valproic acid (VPA) promptly and dramatically repressed transcription of Gnrh1 gene in the mouse immortalized mature GnRH neuronal cells GT1-7. The suppression was connected with a specific region of Gnrh1 gene promoter, which contains two consensus Otx2 binding sites. Otx2 has been known to activate the basal and also enhancer-driven transcription of Gnrh1 gene. The transcriptional activity of Otx2 is negatively modulated by Grg4, a member of the Groucho-related-gene (Grg) family. In the present study, the expression of Otx2 was downregulated by TSA and VPA in GT1-7 cells, accompanied with the opposite changes of Grg4 expression. Chromatin immunoprecipitation and electrophoretic mobility shift assays demonstrated that the DNA-binding activity of Otx2 to Gnrh1 gene was suppressed by TSA and VPA. Overexpression of Otx2 partly abolished the TSA- and VPA-induced downregulation of Gnrh1 gene expression. CONCLUSIONS/SIGNIFICANCE: Our data indicate that HDAC inhibitors downregulate Gnrh1 gene expression via repressing Otx2-driven transcriptional activity. This study should provide an insight for our understanding on the effects of HDACs in the reproductive system and suggests that HDACs could be potential novel targets for the therapy of GnRH-related diseases.