RNF115 Inhibits the Post-ER Trafficking of TLRs and TLRs-Mediated Immune Responses by Catalyzing K11-Linked Ubiquitination of RAB1A and RAB13.

The subcellular localization and intracellular trafficking of Toll-like receptors (TLRs) critically regulate TLRs-mediated antimicrobial immunity and autoimmunity. Here, it is demonstrated that the E3 ubiquitin ligase RNF115 inhibits the post-endoplasmic reticulum (ER) trafficking of TLRs and TLRs-mediated immune responses by catalyzing ubiquitination of the small GTPases RAB1A and RAB13. It is shown that the 14-3-3 chaperones bind to AKT1-phosphorylated RNF115 and facilitate RNF115 localizing on the ER and the Golgi apparatus. RNF115 interacts with RAB1A and RAB13 and catalyzes K11-linked ubiquitination on the Lys49 and Lys61 residues of RAB1A and on the Lys46 and Lys58 residues of RAB13, respectively. Such a modification impairs the recruitment of guanosine diphosphate (GDP) dissociation inhibitor 1 (GDI1) to RAB1A and RAB13, a prerequisite for the reactivation of RAB proteins. Consistently, knockdown of RAB1A and RAB13 in Rnf115+/+ and Rnf115-/- cells markedly inhibits the post-ER and the post-Golgi trafficking of TLRs, respectively. In addition, reconstitution of RAB1AK49/61R or RAB13K46/58R into Rnf115+/+ cells but not Rnf115-/- cells promotes the trafficking of TLRs from the ER to the Golgi apparatus and from the Golgi apparatus to the cell surface, respectively. These findings uncover a common and step-wise regulatory mechanism for the post-ER trafficking of TLRs.

Almost periodic solutions for a SVIR epidemic model with relapse.

This paper is devoted to a nonautonomous SVIR epidemic model with relapse, that is, the recurrence rate is considered in the model. The permanent of the system is proved, and the result on the existence and uniqueness of globally attractive almost periodic solution of this system is obtained by constructing a suitable Lyapunov function. Some analysis for the necessity of considering the recurrence rate in the model is also presented. Moreover, some examples and numerical simulations are given to show the feasibility of our main results. Through numerical simulation, we have obtained the influence of vaccination rate and recurrence rate on the spread of the disease. The conclusion is that in order to control the epidemic of infectious diseases, we should increase the vaccination rate while reducing the recurrence rate of the disease.

Unusual Bicyclo[3.2.1]Octanoid Neolignans from Leaves of Piper crocatum and Their Effect on Pyruvate Dehydrogenase Activity.

Three undescribed bicyclo[3.2.1]octanoid neolignan glucosides, along with a known neolignan, were isolated from the leaves of Piper crocatum Ruiz & Pav. Their chemical structures were elucidated using extensive spectroscopic analyses including 1D and 2D NMR experiments and HR-ESI-MS analysis, as well as through comparison with previously reported data. Two compounds were assessed for their inhibitory effect against pyruvate dehydrogenase E1α S300 phosphorylation. The fluorescent image suggested that both compounds (60 µM) revealed a stronger inhibition effect than the positive control (dichloroacetate, DCA 5 mM), with IC50 values of 99.82 µM and 80.25 µM, respectively.

Anti-allergic Inflammatory Components from the Leaves of Piper crocatum Ruiz & Pav.

Piper crocatum Ruiz & Pav. (P. crocatum), a traditional medicinal plant, has been shown to possess various pharmacological activities, including anticancer activity, antioxidant activity, antibacterial activity, anti-hyperglycemic activity, anti-allergic inflammatory activity and others. To identify the potential anti-allergic inflammatory effective constituents of P. crocatum, 13 single compounds were isolated from the methanol extract of P. crocatum leaves, and their structures were identified by contrasting their NMR spectroscopic data and previously published papers. First, the anti-allergic inflammatory activities of these single compounds were examined by accessing immune function related biomarkers such as nitric oxide (NO) and ß-hexosaminidase. We found that the methanol extract and catechaldehyde (compound 1) potently suppressed NO production. Additionally, Western blot analysis showed that P. crocatum methanol extract and compound 1 suppressed the production of NO by reducing inducible nitric oxide synthase (iNOS) expression in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. Consistent with these observations, P. crocatum methanol extract and compound 1 remarkably decreased ß-hexosaminidase release from RBL-2H3 cells stimulated with 2,4-dinitrophenylated bovine serum albumin (DNP-BSA)-specific immunoglobulin E (IgE) antibodies. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay indicated that P. crocatum methanol extract and compound 1 exhibited no cytotoxicity to RAW264.7 and RBL-2H3 cells. Based on these findings, compound 1 is suggested as an active anti-allergic inflammatory component of P. crocatum.

Global behavior of a multi-group SEIR epidemic model with age structure and spatial diffusion.

Different epidemic models with one or two characteristics of multi-group, age structure and spatial diffusion have been proposed, but few models take all three into consideration. In this paper, a novel multi-group SEIR epidemic model with both age structure and spatial diffusion is constructed for the first time ever to study the transmission dynamics of infectious diseases. We first analytically study the positivity, boundedness, existence and uniqueness of solution and the existence of compact global attractor of the associated solution semiflow. Based on some assumptions for parameters, we then show that the disease-free steady state is globally asymptotically stable by utilizing appropriate Lyapunov functionals and the LaSalle's invariance principle. By means of Perron-Frobenius theorem and graph-theoretical results, the existence and global stability of endemic steady state are ensured under appropriate conditions. Finally, feasibility of main theoretical results is showed with the aid of numerical examples for model with two groups which is important from the viewpoint of applications.

Coumarin and Moracin Derivatives from Mulberry Leaves (Morus alba L.) with Soluble Epoxide Hydrolase Inhibitory Activity.

This study identified three coumarins (1-3), and six moracin derivatives (4-9). The structures of these natural compounds were determined by the spectroscopic methods, including 1D and 2D NMR methods, and comparison with previous reported data. All of the isolated compounds were assessed for the effects on the soluble epoxide hydrolase (sEH) inhibitory activity. Among them, compounds 1-7 exhibited significant inhibitory effect with 100% inhibitory, with IC50 values of 6.9, 0.2, 15.9, 1.1, 1.2, 9.9, and 7.7 µM, respectively. A kinetic study revealed that compounds 1-4, and 6 were competitive types of inhibitors, compounds 5 and 7 were mixed types of inhibitors. These results suggest that moracin and coumarin derivatives from mulberry leaves are significant sEH inhibitors.

Anti-Melanogenic Effect of Dendropanax morbiferus and Its Active Components via Protein Kinase A/Cyclic Adenosine Monophosphate-Responsive Binding Protein- and p38 Mitogen-Activated Protein Kinase-Mediated Microphthalmia-Associated Transcription Factor Downregulation.

Dendropanax morbiferus H. Lév has been reported to have some pharmacologic activities and also interested in functional cosmetics. We found that the water extract of D. morbiferus leaves significantly inhibited tyrosinase activity and melanin formation in α-melanocyte stimulating hormone (MSH)-induced B16-F10 cells. D. morbiferus reduced melanogenesis-related protein levels, such as microphthalmia-associated transcription factor (MITF), TRP-1, and TRP-2, without any cytotoxicity. Two active ingredients of D. morbiferus, (10E)-9,16-dihydroxyoctadeca-10,17-dien-12,14-diynoate (DMW-1) and (10E)-(-)-10,17-octadecadiene-12,14-diyne-1,9,16-triol (DMW-2) were identified by testing the anti-melanogenic effects and then by liquid chromatography-tandem mass spectrometry (LC/MS/MS) analysis. DMW-1 and DMW-2 significantly inhibited melanogenesis by the suppression of protein kinase A (PKA)/cyclic AMP (cAMP)-responsive binding protein (CREB) and p38 MAPK phosphorylation. DMW-1 showed a better inhibitory effect than DMW-2 in α-MSH-induced B16-F10 cells. D. morbiferus and its active component DMW-1 inhibited melanogenesis through the downregulation of cAMP, p-PKA/CREB, p-p38, MITF, TRP-1, TRP-2, and tyrosinase. These results indicate that D. morbiferus and DMW-1 may be useful ingredients for cosmetics and therapeutic agents for skin hyperpigmentation disorders.

Identification of potential inflammatory inhibitors from Aster tataricus.

Aster tataricus L.f. is a traditional Eastern Asian herbal medicine used for the relief of cough-related illnesses. In this study, 32 known compounds and two novel monoterpene glycosides were isolated from the roots of A. tataricus. With the aid of reported data, elucidation of the root-extract components was carried out using a multitude of spectroscopic techniques. All isolates were investigated for their ability to inhibit nitric oxide (NO) secretion in lipopolysaccharide-activated RAW264.7 cells. Compound 7 remarkably suppressed NO production with an IC50 value of 8.5 µM. In addition, compound 7 exhibited significant inhibitory activity against the production of inflammatory cytokines (prostaglandin E2, interleukin-6, and interleukin-1 beta) and the expression of inflammatory enzymes (inducible nitric oxide synthase and cyclooxygenase-2) via inhibition of nuclear factor-kappa B activation. Moreover, compound 7 effectively prevented the downstream activation of the mitogen-activated protein kinase signaling pathway by inhibiting phosphorylation of c-Jun N-terminal kinases, extracellular signal-regulated kinases, and p38. These results outline compound 7 as a potential inhibitor for the broad treatment of inflammatory diseases, such as atopic dermatitis, asthma, and various allergies.

Isolation of Two New Compounds and Other Constituents from Leaves of Piper crocatum and Study of Their Soluble Epoxide Hydrolase Activities.

Two new phenolic glucosides, pipercroside A and B (1 and 2), along with 10 known compounds were isolated from the leaves of Piper crocatum Ruiz & Pav. Their chemical structures were elucidated through extensive spectroscopic analyses, including 1D and 2D NMR experiments and HR-ESI-MS analysis and comparison with previously reported data. All the isolated compounds were assessed for soluble epoxide hydrolase (sEH) inhibitory activity. Among them, erigeside II (5) showed inhibitory activity with an IC50 value of 58.5 µM.

Identification of Anti-Melanogenesis Constituents from Morus alba L. Leaves.

The individual parts of Morus alba L. including root bark, branches, leaves, and fruits are used as a cosmetic ingredient in many Asian countries. This study identified several anti-melanogenesis constituents in a 70% ethanol extract of M. alba leaves. The ethyl acetate fraction of the initial ethanol extract decreased the activity of tyrosinase, a key enzyme in the synthetic pathway of melanin. Twelve compounds were isolated from this fraction and their structures were identified based on spectroscopic spectra. Then, the authors investigated the anti-melanogenesis effects of the isolated compounds in B16-F10 mouse melanoma cells. Compounds 3 and 8 significantly inhibited not only melanin production but also intracellular tyrosinase activity in alpha-melanocyte-stimulating-hormone (α-MSH)-induced B16-F10 cells in a dose-dependent manner. These same compounds also inhibited melanogenesis-related protein expression such as microphthalmia-associated transcription factor (MITF), tyrosinase, and tyrosinase-related protein-1 (TRP-1). Compound 3 modulated the cAMP-responsive element-binding protein (CREB) and p38 signaling pathways in α-MSH-activated B16-F10 melanoma cells, which resulted in the anti-melanogenesis effects. These results suggest that compound 3, isolated from M. alba leaves, could be used to inhibit melanin production via the regulation of melanogenesis-related protein expression.

[Effects of balanced fertilization on growth and fruit quality of 'Huang-guan' pear on desert area.] / å¹³è¡¡æ–½è‚¥å¯¹è’æ¼ åŒºé»„å† æ¢¨ç”Ÿé•¿ä¸Žå“è´¨çš„å½±å“.

A field experiment was carried out to study the effects of balanced fertilization on growth and development, yield, fruit quality and mineral content in 'Huang-guan' pear to provide a theoretical basis for the reasonable level of fertilization in pear orchards. Four treatments were arranged with 12-year old 'Huang-guan' pear trees from the same orchard: conventional fertilization (CK), low levels of N, P2O5 and high level of S (T1), medium levels of N, P2O5 and S (T2), high levels of N, P2O5 and low level of S (T3). The results showed that different treatments had little effect on the growth and development of current-year branch and leaves in the first year. However, in the se-cond year, T1 treatment promoted the length and diameter of current-year branch by 16.2% and 11.4%, respectively. Continuous fertilization could increase the leaf mineral contents in different degrees. The contents of Cu, Fe, and Zn in leaves under T1 treatment, Mg and B in leaves under T2 treatment, and P and Mn in leaves under T3 treatment were highest. Different fertilization levels had no significant effect on yield but on fruit quality. The contents of soluble sugars and vitamin C (Vc) were significantly increased by T2 treatment, which was 4.2% and 7.1% higher than those in CK. However, T1 significantly decreased contents of total soluble solid, soluble sugars and Vc, while highest organic acid content presented in T3. Fruit Fe content was positively correlated with soluble sugar content and fruit shape index, but was negatively correlated with single fruit mass, organic acids and Vc. Fruit P content was positively correlated with fruit shape index and firmness, but was negatively correlated with contents of soluble sugars, organic acids and Vc. Accordingly, T2 could improve fruit quality and maintain the productivity, and thus should be the suitable fertilization strategy for the 'Huang-guan' pear management in desert area.

Anti-allergic inflammatory components from Sanguisorba officinalis L.

Sanguisorba officinalis L. was well known as a traditional herbal medicine to treat inflammation and allergic skin diseases. The aim of this research was to indentify compounds with anti-allergic inflammatory property. Twenty-five compounds (1-25) were isolated from S. officinalis including two new compounds (1 and 8), and their chemical structures were identified by NMR and ESIMS analysis. Consequently, the anti-allergic inflammatory activities of these isolates were investigated by inhibiting ß-hexosaminidase and IL-4 production in PMA/A23187-stimulated RBL-2H3 cells. Compounds 6, 8, 13, 17-18 and 25 significantly inhibited ß-hexosaminidase release and IL-4 production. Additionally, compounds 8, 17 and 25 effectively suppressed the activation of NF-κB and NF-κB p65 translocation into the nucleus. Anti-inflammatory effects of isolated compounds were evaluated in LPS-stimulated RAW264.7 macrophages, and they showed dramatic inhibition on LPS-induced overproduction of nitric oxide (NO) and TNF-α. Consistently, the protein levels of iNOS and COX-2 were remarkably decreased by the single compounds 8, 13 and 25. These results showed that compounds 8, 13 and 25 from S. officinalis may have a therapeutic potential for allergic inflammatory diseases.

Lipolytic effect of compounds isolated from leaves of mulberry (Morus alba L.) in 3T3-L1 adipocytes.

In this study, 19 known compounds were isolated from mulberry (Morus alba L.) leaves. The lipid accumulation inhibitory activity of the isolated compounds was investigated. Compounds 4 and 12 showed good anti-adipogenic activity based on 3T3-L1 adipocytes with values of 36.6 ± 9.0 and 34.7 ± 4.0%, respectively. In addition, compounds 3, 6 and 15 showed significant inhibitory activity with values from 15.4 to 21.2% and compounds 2, 8-9 and 17-18 exhibited weak activity with values ranging from 2.1 to 10.7% at a concentration of 40.0 µM. These results show the potentiality that mulberry leaf is an excellent inhibitory phytochemical source against lipid accumulation.

Standardization of extract mixture of Chaenomeles sinensis and Phyllostachys bambusoides for anti-obesity by HPLC-UV.

JM-101 is a developed functional food formula using water extract of Chaenomeles sinensis and Phyllostachys bambusoides for anti-obesity. Standardization and quality control of herb mixture is more difficult than those of single herb. Additionally, the estimation of mixing ratio is an essential requirement for standardization. This study aimed to develop an efficient analytical method for the standardization of JM-101 based on C. sinensis and P. bambusoides. Protocatechuic acid and p-coumaric acid were selected as marker compounds of JM-101. A mixture of the two medicinal materials (1:1 w/w) was extracted by water and then liquid-liquid extracted (LLE) by ethyl acetate. The supernatant was evaporated to dryness and dissolved in methanol for analysis. The extraction time, material-to-water ratio and ethyl acetate-to-water ratio were optimized by multi-response optimization based on response surface methodology (RSM). The established methods were validated in terms of linearity, precision, accuracy, repeatability, stability and recovery. The novel method based on LLE and RSM provides a sensitive, accurate analysis and excellent extraction efficiency of marker compounds in JM-101, without interruption of other compounds in JM-101. In conclusion, the developed simultaneous analytical method contributes to the standardization of two materials (C. sinensis and P. bambusoides) and JM-101.

Molecular mechanism of interaction and electron transfer between dihydric phenols and L-cysteine.

The mechanism and electron transfer for pollutant dihydric phenol and biomolecule L-Cysteine (L-Cys) interaction in aqueous solution were studied by means of electrochemistry and UV-VIS spectrophotometry. Two forms of L-Cys, fixed on Au-electrode and free dissolved in the solution, were examined. The results showed that L-Cys of an ordered monolayer fixed on an Au electrode facilitated electron transfer and electrocatalytic redox of three isomers of dihydric phenol. However, free L-Cys does not show such facility. Furthermore, neither cleavage of the original chemical bond nor formation of a new chemical bond was observed in the molecules investigated, suggesting that L-Cys molecules may associate tightly with dihydric phenol molecules to form L-Cys . C(6)H(6)O(2)or (L-Cys) (2) . C(6)H(6)O(2) complex molecule via hydrogen-bonding. Different coordination numbers influence the electrochemical activity and behavior of associated complexes; thus, the function of biomolecules could be affected.