The pH-Induced Increase of the Rate Constant for HER at Au(111) in Acid Revealed by Combining Experiments and Kinetic Simulation.

Origins of pH effects on the kinetics of electrocatalytic reactions involving the transfer of both protons and electrons, including the hydrogen evolution reaction (HER) considered in this study, are heatedly debated. By taking the HER at Au(111) in acid solutions of different pHs and ionic concentrations as the model systems, herein, we report how to derive the intrinsic kinetic parameters of such reactions and their pH dependence through the measurement of j-E curves and the corresponding kinetic simulation based on the Frumkin-Butler-Volmer theory and the modified Poisson-Nernst-Planck equation. Our study reveals the following: (i) the same set of kinetic parameters, such as the standard activation Gibbs free energy, charge transfer coefficient, and Gibbs adsorption energy for Had at Au(111), can simulate well all the j-E curves measured in solutions with different pH and temperatures; (ii) on the reversible hydrogen electrode scale, the intrinsic rate constant increases with the increase of pH, which is in contrast with the decrease of the HER current with the increase of pH; and (iii) the ratio of the rate constants for HER at Au(111) in x M HClO4 + (0.1 - x) M NaClO4 (pH ≤ 3) deduced before properly correcting the electric double layer (EDL) effects to the ones estimated with EDL correction is in the range of ca. 10 to 40, and even in a solution of x M HClO4 + (1 - x) M NaClO4 (pH ≤ 2) there is a difference of ca. 5× in the rate constants without and with EDL correction. The importance of proper correction of the EDL effects as well as several other important factors on unveiling the intrinsic pH-dependent reaction kinetics are discussed to help converge our analysis of pH effects in electrocatalysis.

[Shaofu Zhuyu Decoction attenuates fibrosis in endometriosis through regulating PTEN/Akt/mTOR signaling pathway].

The present study aimed to investigate the protective role of Shaofu Zhuyu Decoction(SFZY) against endometriosis fibrosis in mice, and decipher the underlying mechanism through the phosphatase and tensin homolog deleted on chromosome ten(PTEN)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR) pathway. Eighty-five BALB/c female mice were randomly assigned into a blank group, a model group, high-, medium, and low-dose SFZY(SFZY-H, SFZY-M, and SFZY-L, respectively) groups, and a gestrinone suspension(YT) group. The model of endometriosis was induced by intraperitoneal injection of uterine fragments. The mice in different groups were administrated with corresponding groups by gavage 14 days after modeling, and the blank group and model group with equal volume of distilled water by gavage. The treatment lasted for 14 days. The body weight, paw withdrawal latency caused by heat stimuli, and total weight of dissected ectopic focus were compared between different groups. The pathological changes of the ectopic tissue were observed via hematoxylin-eosin(HE) and Masson staining. Real-time PCR was employed to measure the mRNA levels of α-smooth muscle actin(α-SMA) and collagen type Ⅰ(collagen-Ⅰ) in the ectopic tissue. The protein levels of PTEN, Akt, mTOR, p-Akt, and p-mTOR in the ectopic tissue were determined by Western blot. Compared with the blank group, the modeling first decreased and then increased the body weight of mice, increased the total weight of ectopic focus, and shortened the paw withdrawal latency. Compared with the model group, SFZY and YT increased the body weight, prolonged the paw withdrawal latency, and decreased the weight of ectopic focus. Furthermore, the drug administration, especially SFZY-H and YT(P<0.01), recovered the pathological and reduced the area of collagen deposition. Compared with the blank group, the modeling up-regulated the mRNA levels of α-SMA and collagen-Ⅰ in the ectopic focus, and such up-regulation was attenuated after drug intervention, especially in the SFZY-H and YT groups(P<0.05,P<0.01). Compared with the blank group, the modeling down-regulated the protein level of PTEN and up-regulated the protein levels of Akt, mTOR, p-Akt, and p-mTOR(P<0.01, P<0.001). Drug administration, especially SFZY-H and YT, restored such changes(P<0.01). SFZY may significantly attenuate the focal fibrosis in the mouse model of endometriosis by regulating the PTEN/Akt/mTOR signaling pathway.

IrO2 as a promising support to boost oxygen reduction reaction on Pt in acid under high temperature conditions.

Metal oxide nanoparticle (NP) supports of both good conductivity and stability have the potential to enhance both the reaction activity and stability of the loaded electrocatalysts. In this paper, a facile two-step approach to disperse Pt nanoparticles on the surface of an IrO2 NP support (Pt/IrO2) was developed. Physical characterization by x-ray diffraction spectroscopy and transmission/scanning electron microscopy suggests a good dispersion of the Pt NPs. The temperature effect (from 293 to 353 K) of oxygen reduction reaction on Pt/IrO2 was studied by using a rotating ring disk electrode The results show that although the kinetic current density on Pt/IrO2 is close to that on commercial Pt/C at room temperature, the apparent activation energy (Ea,app) in the former case is much lower, suggesting a much higher activity at elevated temperatures. The superiority in Ea,app is attributed to the electron interaction between Pt and the IrO2 support, as supported by the change of surface chemical state given by x-ray photo-electron spectroscopy.

Gene mining and efficient biosynthesis of a fungal peptidyl alkaloid.

Objective: Peptidyl alkaloids, a series of important natural products can be assembled by fungal non-ribosomal peptide synthetases (NRPSs). However, many of the NRPSs associated gene clusters are silent under laboratory conditions, and the traditional chemical separation yields are low. In this study, we aim to discovery and efficiently prepare fungal peptidyl alkaloids assembled by fungal NRPSs. Methods: Bioinformatics analysis of gene cluster containing NRPSs from the genome of Penicillium thymicola, and heterologous expression of the putative gene cluster in Aspergillus nidulans were performed. Isolation, structural identification, and biological evaluation of the product from heterologous expression were carried out. Results: The putative tri-modular NRPS AncA was heterologous-expressed in A. nidulans to give anacine (1) with high yield, which showed moderate and selective cytotoxic activity against A549 cell line. Conclusion: Heterologous expression in A. nidulans is an efficient strategy for mining fungal peptidyl alkaloids.

TRIM31 enhances chemoresistance in glioblastoma through activation of the PI3K/Akt signaling pathway.

Temozolomide (TMZ) resistance is a complication of treatment of glioma, and new strategies are urgently required to overcome chemoresistance in glioma cells. In the present study, it was demonstrated that tripartite motif-containing 31 (TRIM31) was abnormally upregulated in glioma tissues and cell lines compared with normal samples. Furthermore, the role of TRIM31 was assessed by overexpressing and knocking down its expression. Overexpression of TRIM31 increased cell viability, increased TMZ IC50 values and inhibited apoptosis in A172 and U251 cells; whereas overexpression of TRIM31 decreased the expression of the apoptosis-associated protein p53. Knockdown of TRIM31 increased apoptosis in cells treated with TMZ. Additionally, the mechanisms by which TRIM31 affected glioma cells treated with TMZ were determined. Overexpression of TRIM31 increased phosphorylation of AKT and inhibiting the PI3K/AKT signaling pathway abolished the increase in cell viability and decreased phospho-Akt protein expression in TRIM31 overexpressing A172 cells treated with TMZ. Together, the findings suggest that TRIM31 may be a potentially novel target for glioma chemotherapy.

Biological evaluation of 2,3-dioxoindolin-N-phenylacetamide derivatives as potent CDC25B and PTP1B phosphatase inhibitors

A series of 2,3-dioxoindolin-N-phenylacetamide derivatives was evaluated for inhibitory activity against CDC25B and PTP1B enzymes. Most of the derivatives showed inhibitory activity against CDC25B (IC50 = 3.2-23.2 µg/mL) and PTP1B (IC50 = 2.9-21.4 µg/mL). Compound 2h showed the most inhibitory activity in vitro with IC50 values of 3.2 and 2.9 µg/mL against CDC25B and PTP1B, respectively, compared with the reference drugs Na3VO4 (IC50 = 2.7 µg/mL) and oleanolic acid (IC50 = 2.3 µg/mL). The results of selectivity experiments showed that the 2,3-dioxoindolin-N-phenylacetamide derivatives were selective inhibitors against CDC25B and PTP1B. Enzyme kinetic experiments demonstrated that compound 2h was a specific inhibitor with the typical characteristics of a mixed inhibitor. In cytotoxic activity assays compound 2h had potent activity against A549, HeLa, and HCT116 cell lines. In addition, compound 2h showed potent tumor inhibitory activity in a colo205 xenograft model in vivo.

Synthesis and antibacterial activity of a series novel 5,7-diisoprenyloxyflavone derivatives

In the present study, a series of novel 5,7-diisoprenyloxyflavone derivatives were designed, synthesized, and evaluated for their antibacterial activity. Most of these compounds displayed significant antibacterial effects against Gram-positive bacteria, especially against strains of multidrug-resistant clinical isolates. Compounds 4c, 4g, 4i, 4j, 4k, 4l, 4n, 4q and 4t showed high levels of antimicrobial activity against Staphylococcus aureus RN4220 with minimum inhibitory concentrations of 4.0-20 µM. Compound 4k showed the most potent activity among these compounds against all multidrug-resistant clinical isolates tested. Unfortunately, none of the compounds were active against Gram-negative bacteria at the doses of 24-164 µM.

Six new monacolin analogs from red yeast rice.

Six novel monacolin analogs, monacolins V1-V6 (1-6), together with seven known ones (7-13), were isolated from the ethyl acetate extract of red yeast rice. Their structures and absolute configurations were determined by spectroscopic methods, especially 2D NMR (1H-1HCOSY, HSQC, HMBC, and NOESY/ROESY) and CD spectroscopic analyses as well as chemical derivation. Monacolins V2 (2) and V3 (3) represent the first examples of monacolins with 3-hydroxybutyrate substitute. The anti-inflammatory inhibitory activities against the lipopolysaccharide (LPS) induced NO production in BV-2 cells as well as antioxidant activities against rat liver microsomal lipid peroxidation were evaluated.

Diphenyl Ethers from a Marine-Derived Aspergillus sydowii.

Six new diphenyl ethers (1⁻6) along with eleven known analogs were isolated from the ethyl acetate extract of a marine-derived Aspergillus sydowii guided by LC-UV-MS. Their structures were unambiguously characterized by HRESIMS, NMR, as well as chemical derivatization. Compounds 1 and 2 are rare diphenyl ether glycosides containing d-ribose. The absolute configuration of the sugar moieties in compounds 1⁻3 was determined by a LC-MS method. All the compounds were evaluated for their cytotoxicities against eight cancer cell lines, including 4T1, U937, PC3, HL-60, HT-29, A549, NCI-H460, and K562, and compounds 1, 5, 6, and 8⁻11 were found to exhibit selective cytotoxicity against different cancer cell lines.

Antidepressant-like Effect of a Chalcone Compound, DHIPC and Its Possible Mechanism.

DHIPC (2,4-dichloro-2´-hydroxyl-4´,6´-diisoprenyloxychalcone) is a new chalcone compound. In this study, its antidepressant-like activity of compound DHIPC was evaluated by the forced swimming test and the tail suspension test in mice. The results showed that DHIPC significantly reduced the immobility time for 2 h after treatment through the oral administration at dose of 10, 20, and 30 mg/kg in the forced swimming test and the tail suspension test, indicating a significant antidepressant-like effect. The maximal effect was obtained at 30 mg/kg, which is similar to the positive control fluoxetine. The main monoamine neurotransmitters and their metabolites in rat brain were also simultaneously determined. It was found that DHIPC significantly increased the concentrations of the main neurotransmitters serotonin and noradrenalin, and also significantly increased 5-hydroxyindoleacetic acid contents in hippocampus, hypothalamus, and cortex in brain part. So, the probable mechanism of action of DHIPC is thought to be related to increase in serotonin and noradrenalin in the brain.

[Trace phenolic compounds from Red Yeast Rice].

Trace chemical constituents from the ethyl acetate extract of Red Yeast Rice were investigated. Four phenolic compounds were isolated by various column chromatographies, and their structures were identified on the basis of spectroscopic analysis including UV, MS, IR and NMR. The four compounds were identified as 2-methyl-5-(2'R-methyl-4'-hydroxy-butyl)-cinnamic acid(1), 5-(2'-hydroxy-6'-methyl phenyl)-3-methylfuran-2-carboxylic acid(2), daidzein(3), and genistein(4). Compound 1 was new and 2 was firstly discovered from the genus Monascus, while 3-4 were obtained from Red Yeast Rice for the first time.

Anti-Inflammatory Prenylated Phenylpropenols and Coumarin Derivatives from Murraya exotica.

Three new prenylated phenylpropenols, exotiacetals A-C (1-3), 10 new coumarin derivatives, exotimarins A-I (4-13), and 35 known analogues (14-48) were isolated from the roots of Murraya exotica. The absolute configurations of the new compounds were assigned via comparison of their specific rotations, single-crystal X-ray diffraction data, Mosher's method, the ECD exciton coupling method, comparison of experimental and calculated ECD data, and the ECD data of the in situ formed transition metal complexes. Compounds 1-3, which possess an unprecedented hexahydro-1H-isochromen-1-ol system, are presumably biosynthesized from two prenylated p-coumaryl alcohol moieties via Diels-Alder [4+2] cycloaddition and cyclic hemiacetal formation reactions. Compounds 1, 28, 33, and 35 demonstrated inhibition against LPS-induced NO production in BV-2 microglial cells with IC50 values of 8.6 ± 0.3, 11.8 ± 0.9, 15.5 ± 0.9, and 16.9 ± 1.0 µM, respectively.

Antiviral activity of arbidol hydrochloride against herpes simplex virus I in vitro and in vivo.

Herpes simplex virus type 1 (HSV-1) causes significant human diseases ranging from skin lesions to encephalitis, especially in neonates and immunocompromised hosts. The discovery of novel anti-HSV-1 drugs with low toxicity is required for public health. Arbidol hydrochloride (ARB) is an indole derivative molecule with broad-spectrum antiviral activity. In this study, the antiviral effects of ARB against HSV-1 infection were evaluated in vitro and in vivo. The results showed that ARB presents significant inhibitory effect on HSV-1 plaque formation and generation of progeny virus, with EC50 values (50% effective concentration) of 5.39 µg/mL (10.49 µM) and 2.26 µg/mL (4.40 µM), respectively. Moreover, time-of-addition and time-of-removal assays further suggested that ARB has viral inhibitory effects when added up to 12 h post-infection (p.i.), which could be further corroborated by determining the expression of viral immediate-early (ICP4, ICP22 and ICP27), early (ICP8 and UL42) and late (gB, gD, gH, VP1/2 and VP16) genes by real-time quantitative PCR as well as the expression of viral protein ICP4 and ICP8 at 6 h and 12 h p.i. Results of the in vivo study showed that ARB could reduce guinea pig skin lesions caused by HSV-1 infection. Conclusively, this report offers new perspectives in the search for therapeutic measures in the treatment of HSV-1 infection.

Phylogenetic analysis based on mitochondrial DNA sequences of wild rats, and the relationship with Seoul virus infection in Hubei, China.

Seoul virus (SEOV), which is predominantly carried by Rattus norvegicus, is one of the major causes of hemorrhagic fever with renal syndrome (HFRS) in China. Hubei province, located in the central south of China, has experienced some of the most severe epidemics of HFRS. To investigate the mitochondrial DNA (mtDNA)-based phylogenetics of wild rats in Hubei, and the relationship with SEOV infection, 664 wild rats were captured from five trapping sites in Hubei from 2000-2009 and 2014-2015. Using reverse-transcription (RT)-PCR, 41 (6.17%) rats were found to be positive for SEOV infection. The SEOV-positive percentage in Yichang was significantly lower than that in other areas. The mtDNA D-loop and cytochrome b (cyt-b) genes of 103 rats were sequenced. Among these animals, 37 were SEOV-positive. The reconstruction of the phylogenetic relationship (based on the complete D-loop and cyt-b sequences) allowed the rats to be categorized into two lineages, R. norvegicus and Rattus nitidus, with the former including the majority of the rats. For both the D-loop and cyt-b genes, 18 haplotypes were identified. The geographic distributions of the different haplotypes were significantly different. There were no significant differences in the SEOVpositive percentages between different haplotypes. There were three sub-lineages for the D-loop, and two for cyt-b. The SEOV-positive percentages for each of the sub-lineages did not significantly differ. This indicates that the SEOV-positive percentage is not related to the mtDNA D-loop or cyt-b haplotype or the sub-lineage of rats from Hubei.

Synthesis, potential anti-inflammatory and analgesic activities study of (S)-N-substituted-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamides.

A series of (S)-N-substitued-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide derivatives were designed, synthesized and evaluated for their anti-inflammatory and analgesic effects in vivo. Among the synthesized compounds 2a and 2n showed the best anti-inflammatory activity (inhibition rate: 95% and 92.7%, respectively) and analgesic effect (inhibition rate: 100% and 100%, respectively), which was greater than that or nearly equivalent to that of indomethacin. Compounds 2a and 2n were selected to test their inhibitory effects against ovine COX-1 and COX-2 using the cyclooxygenase inhibition assay in vitro. Compounds 2a and 2n are weak inhibitors of COX-1 isozyme but displayed moderate COX-2 isozyme inhibitory effects (IC50=0.47µM and 1.63µM, respectively) and COX-2 selectivity indexes (SI=11.5 and 4.8). Furthermore, compound 2a was more inhibitors of COX-2 isozyme active than the reference drug celecoxib.

Antidepressant-like effects and mechanisms of flavonoids and related analogues.

Flavonoids, possessing a basic phenylbenzopyrone core, are important components of the human diet, and are found in many medicinal plants. Flavonoids include chalcones, flavanones and their derivatives. Synthetic and natural isolated flavonoids display an enormous number of biological activities such as antitumor, antiplatelet, anti-malarial, anti-inflammatory, antidepressant and anticonvulsant properties. This review article focuses on the antidepressant-like effect, structure-activity relationship and mechanism of action of total flavonoid extracts isolation from natural sources, flavonoid compounds and their related analogues.

Specific interference shRNA-expressing plasmids inhibit Hantaan virus infection in vitro and in vivo.

AIM: To investigate the antiviral effects of vectors expressing specific short hairpin RNAs (shRNAs) against Hantaan virus (HTNV) infection in vitro and in vivo. METHODS: Based on the effects of 4 shRNAs targeting different regions of HTNV genomic RNA on viral replication, the most effective RNA interference fragments of the S and M genes were constructed in pSilencer-3.0-H1 vectors, and designated pSilencer-S and pSilencer-M, respectively. The antiviral effect of pSilencer-S/M against HTNV was evaluated in both HTNV-infected Vero-E6 cells and mice. RESULTS: In HTNV-infected Vero-E6 cells, pSilencer-S and pSilencer-M targeted the viral nucleocapsid proteins and envelope glycoproteins, respectively, as revealed in the immunofluorescence assay. Transfection with pSilencer-S or pSilencer-M (1, 2, 4 µg) markedly inhibited the viral antigen expression in dose- and time-dependent manners. Transfection with either plasmid (2 µg) significantly decreased HTNV-RNA level at 3 day postinfectin (dpi) and the progeny virus titer at 5 dpi. In mice infected with lethal doses of HTNV, intraperitoneal injection of pSilencer-S or pSilencer-M (30 µg) considerably increased the survival rates and mean time to death, and significantly reduced the mean virus yields and viral RNA level, and alleviated virus-induced pathological lesions in lungs, brains and kidneys. CONCLUSION: Plasmid-based shRNAs potently inhibit HTNV replication in vitro and in vivo. Our results provide a basis for development of shRNA as therapeutics for HTNV infections in humans.

Synthesis and Evaluation of Phenyliminoindolin-Containing Phenylacetamide Derivatives with the Antidepressant and Anticonvulsant Effects.

BACKGROUND: To discover a novel antidepressant-like effect and anticonvulsant compound, seventeen new 2-oxo-3-phenyliminoindolin-1-Nphenylacetamide compounds were synthesized and screened for the antidepressant activity and anticonvulsant effects. METHOD: 2-oxo-3-phenyliminoindolin-1-N-phenylacetamide derivatives were synthesized with indoline-2, 3-dione as the starting material, through a nucleophilic substitution reaction and a nucleophilic addition-elimination reaction. The target derivatives 2a-2q were evaluated the antidepressant-like activity using the FST, TST, and evaluated anticonvulsant effect by MES test. The main monoamine neurotransmitters and their metabolites in mouse brain regions were also simultaneously determined by HPLC-ECD. RESULTS: It was observed that 13 compounds showed significant reductions in the immobility time in the FST at a concentration of 50 mg/kg. Compound 2b was found to have the most potent antidepressant activity in the FST and the TST for 30 min after treatment. Compound 2b significantly increased the concentrations of the main neurotransmitters 5-HT, NE and the metabolite (5-HIAA, suggesting that the effects of compound 2b may be mediated through these neurotransmitters. As assessed using maximal electroshock, 13 compounds showed the anticonvulsant effects administered at the concentration levels of 100 or 300 mg/kg. Compound 2b showed anticonvulsant effect. Compound 2b could potentially be used as adjuncts of the antidepressants to treat depression in patients with epilepsy. CONCLUSION: In conclusion, compound 2b produced significant antidepressant-like activity and the mechanism of action may be due to increased 5-HT and NE in the mouse. Compound 2b showed more anticonvulsant effect. Compound 2b could potentially be used as adjuncts of the antidepressants to treat depression in patients with epilepsy.

Nitric Oxide Inhibitory Dimeric Sesquiterpenoids from Artemisia rupestris.

Twelve new dimeric sesquiterpenoids (1-12) were isolated from the dried whole plants of Artemisia rupestris. Their structures were determined using MS and NMR data, and the absolute configurations were elucidated on the basis of experimental and calculated ECD spectra. Compounds 1-9 are presumably formed via biocatalyzed [2+2] or [4+2] cycloaddition reactions. Stereoselectivity of the [4+2] Diels-Alder reaction dictated the formation of endo-products. The dimeric sesquiterpenoids exhibited moderate inhibition on NO production stimulated by lipopolysaccharide in BV-2 microglial cells, with IC50 values in the range 17.0-71.8 µM.

New sesquiterpene and thiophene derivatives from Artemisia rupestris.

A new sesquiterpene, rupestrisin A (1), and three new thiophene derivatives, rupestrienes A-C (2-4), were isolated from Artemisia rupestris. Their structures were determined by analyses of MS and NMR spectroscopic data, and the absolute configuration of 1 was established by calculated ECD spectra using time-dependent density functional theory. In in vitro bioassays, compounds 1-4 showed inhibitory effects on LPS-stimulated NO production in BV-2 microglial cells with IC50 values of 24.3, 20.3, 8.5, and 5.3 µM, respectively.