In Situ One-Pot Synthesis of C-Decorated and Cl-Doped Sea-Urchin-like Rutile Titanium Dioxide with Highly Efficient Visible-Light Photocatalytic Activity.

Titanium dioxide (TiO2) that offers high light-harvesting capacity and efficient charge separation holds great promise in photocatalysis. In this work, an in situ one-pot hydrothermal synthesis was explored to prepare a C-decorated and Cl-doped sea-urchin-like rutile TiO2 (Cl-TiO2/C). The growth of sea-urchin-like 3D hierarchical nanostructures was governed by a mechanism of nucleation and nuclei growth-dissolution-recrystallization growth from time-dependent morphology evolution. The crystal morphology and the content of Cl and C could be controlled by the volume ratio of HCl to TBOT. Systematic studies indicated that the 0.4Cl-TiO2/C sample (the volume ratio of HCl to TBOT was 0.4) exhibited the highest visible-light photocatalytic activity for the degradation of rhodamine B, with kinetic rate constant (k) of 0.0221 min-1, being 6.5 and 3.75 times higher than that of TiO2 and Cl-TiO2. The enhanced photocatalytic performance could be attributed to the high charge separation and transfer efficiency induced by Cl-doping and C decoration and the excellent light-harvesting capacity caused by its sea-urchin-like nanostructure. Moreover, the 0.4Cl-TiO2/C sample exhibited good reusability and excellent structural stability for five cycles. This facile one-pot approach provides new insight for the preparation of a TiO2-based photocatalyst with excellent photocatalytic performance for potential application in practical wastewater treatment.

[Corrigendum] Beneficial effects of sulfonamide­based gallates on osteoblasts in vitro.

Following the publication of the above article, an interested reader drew to the authors' attention that three figures in their paper (namely Figs. 2, 4 and 5) appeared to feature panels containing overlapping data. The authors re­examined their original data, and realized that they had made inadvertent errors in the compilation of the data in these figures; specifically, the data shown in the panels for Fig. 2G, Fig. 4C, D and I, and Fig. 5E and I had been selected incorrectly. The corrected versions of Figs. 2, 4 and 5 are shown below and on the next page. All the authors approve of this corrigendum, and are grateful of the Editor of Molecular Medicine Reports for granting them the opportunity to publish this corrigendum. Furthermore, they regret that these errors were introduced into the paper, even though they did not substantially alter any of the major conclusions reported in the paper, and apologize to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 15: 1149­1156, 2017; DOI: 10.3892/mmr.2017.6142].

Synthesis of novel caffeic acid derivatives and their protective effect against hydrogen peroxide induced oxidative stress via Nrf2 pathway.

AIM: This study was aimed to synthesize novel caffeic acid derivatives and evaluate their potential applications for the treatment of oxidative stress associated disease. MAIN METHODS: Caffeic acid sulfonamide derivatives were synthesized by coupling sulfonamides to the backbone of caffeic acid and fully characterized by melting point test, FT-IR, MS, NMR, UV-vis and n-octanol-water distribution assay. Their free radical scavenging ability was evaluated using DPPH assay and cytotoxicity against A549 cells were determined by MTT assay. The protective effect of these derivatives against hydrogen peroxide (H2O2) induced oxidative injury was assessed in A549 cells from cell viability, production of reactive oxygen species (ROS) and malondialdehyde (MDA), alternation of antioxidase activities, and expressions of Nrf2 and its target genes. KEY FINDINGS: Six novel caffeic acid sulfonamide derivatives were obtained. The derivatives showed better liphophilicity than the parent caffeic acid. CASMZ, CAST and CASQ exhibited similar DPPH scavenging capability as caffeic acid, while the protection of hydroxyl groups on the benzene ring with acetyl groups caused decrease in radical scavenging activity. No inhibitory effect on the proliferation of A549 cells were observed up to a concentration of 50 µM. Pre-treatment of cells with these derivatives strongly inhibited H2O2 induced decrease of cell viability, reduced the production of ROS and MDA, promoted antioxidase activities, and further upregulated the expression of Nrf2 and its target genes. SIGNIFICANCE: Caffeic acid sulfonamide derivatives were synthesized with simple reactions under mild conditions. They might protect cells from H2O2-induced oxidative injury via Nrf2 pathway.

Synthesis of caffeic acid sulfonamide derivatives and their protective effect against H2O2 induced oxidative damage in A549 cells.

Exogenous antioxidants are considered as important therapeutic tools for oxidative stress associated disorders as they can regulate the redox state, which is associated with cell and organ function. Inspired by natural polyphenols, six new caffeic acid sulfonamide derivatives were synthesized by coupling sulfonamides to the backbone of caffeic acid with good yields. Their structure and lipophilicity were characterized by 1H nuclear magnetic resonance (NMR), 13C{1H} NMR, infrared spectroscopy (IR) and oil-water partition coefficient assay. Their free radical scavenging activity and antioxidant activity were assessed by DPPH assay and hydrogen peroxide (H2O2) induced oxidative stress in human lung carcinoma A549 cells. The oil-water partition coefficient results indicate that the conjugation of sulfonamides increases the lipophilicity of caffeic acid. The CASMD, CASDZ and CASN results show higher free radical scavenging effects compared with vitamin C. The derivatives do not show any inhibitory effect on the proliferation of A549 cells up to a concentration of 200 µM, except CASDZ which significantly inhibits the growth of A549 cells at a concentration of 200 µM. In addition, the obtained derivatives markedly attenuate H2O2 induced decrease of cell viability, inhibit the production of ROS and MDA, and promote the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). Besides, treatment of H2O2 stimulated A549 cells with caffeic acid sulfonamide derivatives further increases mRNA expression of NF-E2-related factor 2 (Nrf2) and its target genes, including heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1) and thioredoxin reductase 1 (TXNRD1). These results suggest that these new caffeic acid sulfonamide derivatives have higher lipophilicity and better antioxidant activities than the parent caffeic acid, and they might be able to control the antioxidant response in cells via the Nrf2 pathway.

Correction: A Novel Synthesized Sulfonamido-Based Gallate-JEZ-C as Potential Therapeutic Agents for Osteoarthritis.

[This corrects the article DOI: 10.1371/journal.pone.0125930.].

Design, Synthesis, and Bioactive Screen In Vitro of Cyclohexyl (E)-4-(Hydroxyimino)-4-Phenylbutanoates and Their Ethers for Anti-Hepatitis B Virus Agents.

A series of oxime Cyclohexyl (E)-4-(hydroxyimino)-4-phenylbutanoates and their ethers were designed, synthesized, and evaluated for anti-hepatitis B virus (HBV) activities with HepG 2.2.15 cell line in vitro. Most of these compounds possessed anti-HBV activities, and among them, compound 4B-2 showed significant inhibiting effects on the secretion of HBsAg (IC50 = 63.85 ± 6.26 µM, SI = 13.41) and HBeAg (IC50 = 49.39 ± 4.17 µM, SI = 17.34) comparing to lamivudine (3TC) in HBsAg (IC50 = 234.2 ± 17.17 µM, SI = 2.2) and HBeAg (IC50 = 249.9 ± 21.51 µM, SI = 2.07). Docking study of these compounds binding to a protein residue (PDB ID: 3OX8) from HLA-A2 that with the immunodominant HBcAg18-27 epitope (HLA-A2.1- restricted CTL epitope) active site was carried out by using molecular operation environment (MOE) software. Docking results showed that behaviors of these compounds binding to the active site in HLA-A protein residue partly coincided with their behaviors in vitro anti-HBV active screening.

The Application of a Desktop NMR Spectrometer in Drug Analysis.

A desktop NMR spectrometer was used to qualitatively analyze samples in drug-related cases in order to enhance the accuracy of the results and identify new drugs. Twelve known drugs and their derivatives were used to establish the parameters, conditions, and procedures for the methods and validate the feasibility and reliability of the methods. First, 1-D and 2-D NMR data for these 12 drugs and their derivatives were obtained in detail using a 600-MHz NMR spectrometer to create a data library. Next, some of these 12 drugs were analyzed using a Picospin 80 MHz desktop NMR spectrometer to set up the analytical procedure and method. With the procedure and method established, real case samples were analyzed and the data were compared to those obtained by a standard method. The results indicate that the desktop NMR spectrometer is a reliable and promising approach that can be used in criminology to quickly identify whether or not samples contain illegal drugs.

Synthesis of a series of benzothiazole amide derivatives and their biological evaluation as potent hemostatic agents.

A series of benzothiazole amide derivatives were synthesized through a facile and efficient method via a nucleophilic acyl substitution reaction between 2-aminobenzothiazole and various cinnamic acid compounds. The obtained products exhibited good thermal stabilities. All compounds were evaluated for their in vitro hemostatic activities using the commercially available standard drug etamsylate as a positive control. The results showed that compound Q2 had a significant partial coagulation activity, reduced capillary permeability at 5, 10 and 50 µmol L-1, activated thrombin activity, and a more potent platelet aggregation activity than the positive control group (etamsylate, up to 1283.9 times in the nanomole range). A molecular modeling study revealed that compound Q2 was a competitive thrombin activator. Therefore, Q2 may be a potential lead for further biological screening and for the generation of drug molecules. Moreover, the structure-activity relationship of the prepared compounds is also discussed herein.

Study on the Anticoagulant or Procoagulant Activities of Type II Phenolic Acid Derivatives.

In this study, three type II phenolic acids (caffeic acid, p-hydroxycinnamic acid, and ferulic acid) were used to synthesize a total of 18 phenolic acid derivatives. With molecular docking for molecule design and target protein (factors) screening, in combination with the confirmation of target proteins (factors) by surface plasmon resonance, and the evaluation of haemostatic and anticoagulant activities with five blood assays (plasma recalcification time, prothrombin time, activated partial thromboplastin time, fibrinogen, and thrombin time), the data indicated that caffeic acid derivatives showed certain anticoagulant or procoagulant activities and that two other series contained compounds with the best anticoagulant activities. Using Materials Studio analysis, particular functional groups that affect anticoagulant or procoagulant activities were revealed, and these conclusions can guide the discovery of compounds with better activities.

Synthesis and biological evaluation of a new series of cinnamic acid amide derivatives as potent haemostatic agents containing a 2-aminothiazole substructure.

Ten new cinnamic acid derivatives containing a 2-aminothiazole substructure were designed and synthesized. This series of compounds exhibited good thermostabilities as demonstrated by thermogravimetric analysis. In coagulation assays (prothrombin time, activated partial thromboplastin time and thrombin time) in vitro, most compounds demonstrated excellent activities to promote blood coagulation. Among the studied series, compounds N1, N4, N5 and W5 exhibited a significant coagulation activity. Further studies indicated that compound N5 (IC50=1.87µmol/L) displayed the most suitable efficacy of promoting platelet aggregation than the clinically used haemostatic drug etamsylate (IC50=46.22µmol/L). Furthermore, the relationship between the functional groups of the compounds and the corresponding blood coagulant activity was explored in this study.

Beneficial effects of sulfonamide­based gallates on osteoblasts in vitro.

Effective treatments for osteoporosis remain fairly elusive; however, studies have reported that antioxidants may aid in the maintenance of reactive oxygen species at a favorable level, in order to prevent osteoporosis. Gallic acid (GA) and its derivatives are potent antioxidative and anti­inflammatory agents that affect several biochemical and pharmacological pathways; however, GA is slightly cytotoxic and suppresses cell proliferation. The present study modified GA by the introduction of sulfonamide, in order to obtain a novel compound known as JEZ­C, and investigated its effects on osteoblasts by measuring cell proliferation, viability, morphology, alkaline phosphatase (ALP) activity, and the expression of relevant osteoblast markers. Results indicated that JEZ­C may effectively promote osteoblast growth. JEZ­C increased ALP activity, upregulated the expression of osteogenic­related genes, including runt­related transcription factor 2, bone sialoprotein, osteocalcin and alpha­1 type I collagen, thus indicating that JEZ­C enhances bone matrix production and mineralization. The recommended range of JEZ­C concentration is between 6.25x10­3 and 6.25x10­1 µg/ml, within which cell growth was promoted compared with the control. Specifically, treatment with 6.25x10­2 µg/ml JEZ­C is ideal. These findings may represent a novel approach to cell­based therapy for the treatment of osteoporosis.

Synthesis, Biological Evaluation, and Docking Studies of a Novel Sulfonamido-Based Gallate as Pro-Chondrogenic Agent for the Treatment of Cartilage.

Gallic acid (GA) and its derivatives are anti-inflammatory agents and are reported to have potent effects on Osteoarthritis (OA) treatment. Nonetheless, it is generally accepted that the therapeutic effect and biocompatibility of GA is much weaker than its esters due to the high hydrophilicity. The therapeutic effect of GA on OA could be improved if certain structural modifications were made to increase its hydrophobicity. In this study, a novel sulfonamido-based gallate was synthesized by bonding sulfonamide with GA, and its biological evaluations on OA were investigated. Results show that 5-[4-(Pyrimidin-2-ylsulfamoylphenyl)]-carbamoyl-benzene-1,2,3-triyl triacetate (HAMDC) was able to reverse the effects induced by Interleukin-1 (IL-1) stimulation, and it also had a great effect on chondro-protection via promoting cell proliferation and maintaining the phenotype of articular chondrocytes, as well as enhancing synthesis of cartilage specific markers such as aggrecan, collagen II and Sox9. Furthermore, a docking study showed that HAMDC fits into the core of the active site of a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), which provides an explanation for its activity and selectivity.

Chemical properties and antioxidant activity of a water-soluble polysaccharide from Dendrobium officinale.

In this report, a water-soluble polysaccharide was obtained from the dried stems of Dendrobium officinale Kimura et Migo by hot-water (70-75°C) extraction and 85% ethanol precipitation, and successively purification by DEAE-cellulose anion-exchange chromatography and gel-permeation chromatography. The D. officinale polysaccharide (DOP) has a molecular weight of 8500Da. Monosaccharide composition analysis reveals that DOP is composed of mannose, glucose, and arabinose with a trace of galacturonic acid in a molar ratio of 6.2:2.3:2.1:0.1. Periodate oxidation-smith degradation and 1D and 2D NMR spectroscopy analysis suggest the predominance of mannose and glucose, and it contains a 2-O-acetylglucomannan and (1→4)-linked-ß-d-mannopyranosyl and (1→4)-linked-ß-d-glucopyranosyl residues. Atomic force microscope shows that DOP mainly exists as rod-shaped chains, supporting high degrees of polymerization. The antioxidant activities of the polysaccharide in vitro assay indicate that DOP has good scavenging activity of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, higher scavenging activity of hydroxyl radical, and metal chelating activities.

Chondro-Protective and Antiarthritic Effects of Sulfonamido-Based Gallate-ZXHA-TC in Vitro and in Vivo.

The effects of gallic acid (GA) on arthritis are limited by weak antioxidant effects and inferior biological properties of GA. We recently described a new series of synthesized GA derivatives by coupling with sulfonamides. Among these analogs, a novel compound synthesized from GA and sulfadimoxine (SDM) named ZXHA-TC exhibited the most robust anti-inflammatory potential. In this current study, the chondro-protective and antiarthritic effects of ZXHA-TC were investigated both in vitro and in vivo. In the in vitro study, ZXHA-TC exerted chondro-protective effects as evidenced by promoting cell proliferation and the maintaining of the phenotype of articular chondrocytes treated with interleukin-1-beta (IL-1ß). The potential of ZXHA-TC to slow the progress of osteoarthritis (OA) was suggested by a reduction in matrix metalloproteinases (MMPs) and the up-regulation of the tissue inhibitor of metalloproteinase-1 (TIMP-1). In a rabbit anterior cruciate ligament transaction (ACLT) model of OA, ZXHA-TC exerted a protective effect on arthritis as assessed by macroscopic scores, histological, qRT-PCR, and immunohistochemical analyses. The effects of ZXHA-TC on inhibiting the production of inflammatory mediators in OA may be mediated partly by the suppression of the PI3K/AKT pathway or MAPK cascades, leading to NF-κB inactivation. Thus, this study indicates that ZXHA-TC may be developed as a potential therapeutic agent for OA.

[Simultaneous qualitative and quantitative determination of seven anticoagulant rodenticides in whole blood and urine samples using on-line solid phase extraction with liquid chromatography-linear ion trap mass spectrometry].

A new and sensitive analytical method has been developed for the simultaneous determination of seven anticoagulant rodenticides in whole blood and urine samples by liquid chromatography-linear ion trap mass spectrometry (LC-LIT/MS) with on-line solid phase extraction (on-line SPE). The samples were treated with acetonitrile, followed by dilution, centrifugation, and filtration. The resulting solution was injected into the LC system directly and processed by on-line SPE column for enrichment and purification. Separation was performed on a C18 column with mixed mobile phases of methanol and 0.02 mol/L ammonium acetate aqueous solution for gradient elution. The analytes were detected by the mass spectrometer with electrospray ionization (ESI) in negative mode. MS2 full scan signals of the target parent ions within the locked retention time window were recorded. Self-built database searching was performed for qualitative confirmation, and MS2 fragment ions with high sensitivity and specificity were selected for quantification. Simultaneous qualitative and quantitative analyses of the seven rodenticides were achieved in this way. Good linearities were obtained within the investigated mass concentration ranges of the seven rodenticides, with r2 ≥ 0.9958 in blood and r2 ≥ 0.9946 in urine. The LODs varied from 0.02 ng/mL to 1.00 ng/mL, and the LOQs varied from 0.10 ng/mL to 4.00 ng/mL. The recoveries at three spiked levels in blood and urine samples ranged from 81.0% to 113.9%, with RSDs of 0.1%-6.2% (n = 6). The developed method is simple, sensitive, and can be used for the rapid detection and accurate quantification of the seven anticoagulant rodenticides in whole blood and urine samples.

Stimulating effect of a newly synthesized sulfonamido-based gallate on articular chondrocytes in vitro.

BACKGROUND: The phenotype of chondrocyte is easy to be lost when expanded in vitro by a process defined "dedifferentiation". Traditional growth factors such as transforming growth factor (TGF-ß1) are effective in preventing of dedifferentiation, but high costs and loss of activity limited their use. It is of significance to find substitutes which can reduce dedifferentiation and preserve chondrocytes phenotype to ensure sufficient differentiated cells for further study. METHODS: We synthesized new type of sulfonamido-based gallates named ZXHA-C and investigated its effect on primary articular chondrocytes of rats. After preliminary screening by cytotoxicity test, ZXHA-C of 1.06 × 10-8, 1.06 × 10-7 and 1.06 × 10-6M were chosen for further studies. Cell proliferation, morphology, viability, GAG synthesis and cartilage specific gene expression were detected. Also the effects of ZXHA-C on Wnt/ß-catenin signaling pathway were investigated. RESULTS: ZXHA-C could significantly promote chondrocytes growth. And it could enhance ECM synthesis by up-regulating expression levels of cartilage specific markers like aggrecan, collagen II and Sox9. Expression of collagen I which marked chondrocytes dedifferentiation was also significantly down-regulated after treated by ZXHA-C. Further exploration of the molecular mechanism indicated that ZXHA-C activated the Wnt/ß-catenin signal pathway in chondrocytes, as evidenced by up-regulated gene expression of ß-catenin, Wnt-4, cyclin D1 and Frizzled-2 and decreased glycogen synthase kinase 3ß (GSK-3ß). Among the various concentrations, ZXHA-C of 1.06 × 10-7 M showed the best performance, which was close to positive control (group with TGF-ß1). CONCLUSION: ZXHA-C might be potential a novel agent for the maintenances of chondrocytes phenotype.

Protocatechuic acid benefits proliferation and phenotypic maintenance of rabbit articular chondrocytes: An in vitro study.

Numerous antioxidants exhibit antiarthritic effects due to their inhibitory effect on inflammatory factors. Certain antioxidants, such as protocatechuic acid (PCA) and its analogs, have been reported to be effective in the treatment of arthritis. However, the effect of PCA on chondro-protection may be alleviated due to the induction of apoptosis, as has been demonstrated in stomatocytes. To clearly determine the effect of PCA on the biological and cellular metabolism of rabbit articular chondrocytes in vitro, examinations of cytotoxicity, proliferation and morphology were performed, in addition to analyses of glycosaminoglycan (GAG) synthesis and the expression of cartilage-specific genes. The results revealed that PCA effectively promoted chondrocyte growth, the synthesis of the extracellular matrix and the mRNA expression of aggrecan, collagen II and Sox9, while downregulating the expression of the collagen I gene, a marker of chondrocyte dedifferentiation. In addition, hypertrophy, which may result in chondrocyte ossification, was not detected in the groups. Among the doses (range, 0.05-0.3 mmol/l) of PCA that promoted the proliferation of chondrocytes, a concentration of 0.125 mmol/l produced the optimum performance. The results indicated that PCA, particularly at a dose of 0.125 mmol/l, accelerated the proliferation of rabbit articular chondrocytes in vitro and maintained their phenotype. This study may provide a basis for further research concerning the treatment of cartilage defects.

A Novel Synthesized Sulfonamido-Based Gallate-JEZ-C as Potential Therapeutic Agents for Osteoarthritis.

Gallic acid (GA) and its derivatives are anti-inflammatory agents reported to have an effect on osteoarthritis (OA). However, GA has much weaker anti-oxidant effects and inferior bioactivity compared with its derivatives. We modified GA with the introduction of sulfonamide to synthesize a novel compound named JEZ-C and analyzed its anti-arthritis and chondro-protective effects. Comparison of JEZ-C with its sources i.e. GA and Sulfamethoxazole (SMZ) was also performed. Results showed that JEZ-C could effectively inhibit the IL-1-mediated induction of MMP-1 and MMP-13 and could induce the expression of TIMP-1, which demonstrated its ability to reduce the progression of OA. JEZ-C can also exert chondro-protective effects by promoting cell proliferation and maintaining the phenotype of articular chondrocytes, as evidenced by improved cell growth, enhanced synthesis of cartilage specific markers such as aggrecan, collagen II and Sox9. Meanwhile, expression of the collagen I gene was effectively downregulated, revealing the inhibition of chondrocytes dedifferentiation by JEZ-C. Hypertrophy that may lead to chondrocyte ossification was also undetectable in JEZ-C groups. The recommended dose of JEZ-C ranges from 6.25×10-7 µg/ml to 6.25×10-5 µg/ml, among which the most profound response was observed with 6.25×10-6 µg/ml. In contrast, its source products of GA and SMZ have a weak effect not only in the inhibition of OA but also in the bioactivity of chondrocytes, which indicated the significance of this modification. This study revealed JEZ-C as a promising novel agent in the treatment of chondral and osteochondral lesions.