Molecules

Editorial

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4 pages, 158 KiB

Open AccessEditorial

Special Issue: Antibacterial Materials and Coatings

by Krasimir Vasilev, Alex Cavallaro and Peter Zilm

Molecules 2018, 23(3), 585; https://doi.org/10.3390/molecules23030585 - 6 Mar 2018

Cited by 23 | Viewed by 4980

Abstract

n/a Full article

(This article belongs to the Special Issue Antibacterial Materials and Coatings)

Research

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14 pages, 4507 KiB

Open AccessArticle

N-Methylcytisine Ameliorates Dextran-Sulfate-Sodium-Induced Colitis in Mice by Inhibiting the Inflammatory Response

by Yan-Fang Jiao, Min Lu, Yu-Ping Zhao, Ning Liu, Ya-Ting Niu, Yang Niu, Ru Zhou and Jian-Qiang Yu

Molecules 2018, 23(3), 510; https://doi.org/10.3390/molecules23030510 - 25 Feb 2018

Cited by 28 | Viewed by 4698

Abstract

This study aimed to investigate the anti-inflammatory effects of N-methylcytisine (NMC) in a dextran sulfate sodium (DSS)-induced colitis model and explore its possible mechanisms. Experimental colitis was induced by administering the mice with 5% DSS for 7 days. Different doses of NMC [...] Read more.

This study aimed to investigate the anti-inflammatory effects of N-methylcytisine (NMC) in a dextran sulfate sodium (DSS)-induced colitis model and explore its possible mechanisms. Experimental colitis was induced by administering the mice with 5% DSS for 7 days. Different doses of NMC (1, 4 and 16 mg/kg) and 5-aminosalicylic acid (100 mg/kg) were given orally once every day for 7 days. The protective effect of NMC was evaluated using the disease activity index, colon length and results of histopathological examination. The possible mechanisms of NMC were explored by evaluating the expression levels of tumour necrosis factor-α, interleukin-1β and interleukin-6 (IL-6) using ELISA and analysing the protein expression levels of nuclear factor (NF)-κB p65, p-NF-κB p65, p-IκB, IκB, IκB kinase (IKK) and p-IKK using western blots. Results demonstrated that the oral administration of NMC attenuated the DSS-induced clinical symptoms and pathological damage. In addition, NMC treatment significantly reduced myeloperoxidase activity and level of pro-inflammatory cytokines. Further studies revealed that NMC blocked the activation of NF-κB by inhibiting IκB and IKK phosphorylation. These findings suggested that NMC exerts anti-inflammatory effects on DSS-induced colitis, and its mechanism may be related to the suppression of NF-κB activation. Thus, NMC may have potential therapeutic value in the treatment of colitis. Full article

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12 pages, 1011 KiB

Open AccessArticle

Black Tea Samples Origin Discrimination Using Analytical Investigations of Secondary Metabolites, Antiradical Scavenging Activity and Chemometric Approach

by Wojciech Koch, Wirginia Kukula-Koch and Łukasz Komsta

Molecules 2018, 23(3), 513; https://doi.org/10.3390/molecules23030513 - 26 Feb 2018

Cited by 32 | Viewed by 8473 | Correction

Abstract

A comprehensive study on the composition and antioxidant properties of black tea samples with a chemometric approach was performed via LC-ESI-Q-TOF-MS, DPPH radical scavenging assay, and Folin–Ciocalteu assay (TPC). Marked differences between the teas from seven different countries (China, India, Iran, Japan, Kenya, [...] Read more.

A comprehensive study on the composition and antioxidant properties of black tea samples with a chemometric approach was performed via LC-ESI-Q-TOF-MS, DPPH radical scavenging assay, and Folin–Ciocalteu assay (TPC). Marked differences between the teas from seven different countries (China, India, Iran, Japan, Kenya, Nepal, Sri Lanka) were shown. The Indian samples demonstrated the highest total catechin content (184.8 mg/100 mL), the largest TPC and DPPH scavenging potential (58.2 mg/100 mL and 84.5%, respectively). The applied principal component analysis (PCA) and ANOVA revealed several correlations between the level of catechins in tea infusions. EC (epicatechin), ECG (epicatechin gallate), EGC (epigallocatechin), and EGCG (epigallocatechin-3-gallate) content was not correlated with DPPH, gallic acid, and TPC; however, a strong correlation of EC and ECG between themselves and a negative correlation of these two catechins with EGCG and EGC was noted. Interestingly, simple catechins were not found to be responsible for antioxidant properties of the black teas. The samples collected in the higher altitudes were similar. Full article

(This article belongs to the Special Issue Extractable and Non-Extractable Antioxidants)

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9 pages, 953 KiB

Open AccessArticle

Simultaneous Separation of Eight Lignans in Forsythia suspensa by β-Cyclodextrin-Modified Capillary Zone Electrophoresis

by Jun Liang, Feng-Qiu Gong and Hui-Min Sun

Molecules 2018, 23(3), 514; https://doi.org/10.3390/molecules23030514 - 26 Feb 2018

Cited by 7 | Viewed by 3548

Abstract

The aim of the study was to develop an alternative capillary zone electrophoresis (CZE) for simultaneous determination of phillyrin (1), phillygenin (2), epipinoresinol-4-O-β-glucoside (3), pinoresinol-4-O-β-glucoside (4), lariciresinol (5), pinoresinol [...] Read more.

The aim of the study was to develop an alternative capillary zone electrophoresis (CZE) for simultaneous determination of phillyrin (1), phillygenin (2), epipinoresinol-4-O-β-glucoside (3), pinoresinol-4-O-β-glucoside (4), lariciresinol (5), pinoresinol (6), isolariciresinol (7) and vladinol D (8) in Forsythia suspensa. The structural types of lignans 1–8 could be attributed to bisepoxylignans (1–4 and 6), monoepoxylignans (5 and 8) and cyclolignan (7). The major difficulties in the CZE separation of 1–8 could be summarization as the simultaneous presence of free lignans (1, 2 and 5–8) and lignan glucosides (3 and 4) and simultaneous occurrence of two pairs of isomers (3 and 4 as well as 5 and 7). Without the addition of β-CD and methanol, the resolution of these analytes was quite poor. However, in this study, compounds 1–8 were excellently separated from each other within 15 min under optimized conditions with a borax running buffer (40 mM borax, pH 10.30) containing 2 mM β-CD and 5% methanol (v/v) at the voltage of 20 kV, temperature of 35 °C and detection wavelength of 234 nm. Validation of the method included tests of linearity, precision, repeatability, stability and accuracy. In addition, the method offered inherent advantages such as lower analytical cost, no need of specific columns and use of small amounts of organic solvents and reagents. Finally, this green and economic CZE was successfully applied for the determination of these bioactive components 1–8 in F. suspensa fruits and its commercial extracts. Full article

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12 pages, 6682 KiB

Open AccessArticle

Synthesis and Evaluation of Bakuchiol Derivatives as Potential Anticancer Agents

by Cheng-Zhu Wu, Da-Chuan Liu, Xing Guo, Yiqun Dai, Tao Ma, Hong-Mei Li and Qiang Huo

Molecules 2018, 23(3), 515; https://doi.org/10.3390/molecules23030515 - 26 Feb 2018

Cited by 12 | Viewed by 5870

Abstract

A series of bakuchiol derivatives were synthesized and evaluated for their anti-proliferative and the inhibitory activities on SMMC7721 cell line migration using PX-478 as a positive control. The results showed (S,E)-4-(7-methoxy-3,7-dimethyl-3-vinyloct-1-en-1-yl)phenol (10) to have the best activity [...] Read more.

A series of bakuchiol derivatives were synthesized and evaluated for their anti-proliferative and the inhibitory activities on SMMC7721 cell line migration using PX-478 as a positive control. The results showed (S,E)-4-(7-methoxy-3,7-dimethyl-3-vinyloct-1-en-1-yl)phenol (10) to have the best activity among the tested compounds, which included PX-478. In addition, compound 10 showed greater inhibitory activity than that of bakuchiol in the transwell migration and invasion assays at every dose. In western blotting tests, compound 10 showed a promising ability to downregulate the expression of HIF-1α and its associated downstream proteins MMP-2 and MMP-9. Moreover, this effect was dose-dependent and could represent a possible mechanism of action for the anticancer activity of compound 10. Full article

(This article belongs to the Section Medicinal Chemistry)

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13 pages, 4868 KiB

Open AccessArticle

Preparation and Characterization of Quaternized Chitosan Derivatives and Assessment of Their Antioxidant Activity

by Fang Luan, Lijie Wei, Jingjing Zhang, Wenqiang Tan, Yuan Chen, Fang Dong, Qing Li and Zhanyong Guo

Molecules 2018, 23(3), 516; https://doi.org/10.3390/molecules23030516 - 26 Feb 2018

Cited by 64 | Viewed by 6142

Abstract

Chitosan (CS) is an abundant and renewable polysaccharide that is reported to exhibit a great variety of beneficial properties. However, the poor solubility of chitosan in water limits its applications. In this paper, we successfully synthesized single N-quaternized (QCS) and double N [...] Read more.

Chitosan (CS) is an abundant and renewable polysaccharide that is reported to exhibit a great variety of beneficial properties. However, the poor solubility of chitosan in water limits its applications. In this paper, we successfully synthesized single N-quaternized (QCS) and double N-diquaternized (DQCS) chitosan derivatives, and the resulting quaternized materials were water-soluble. The degree of quaternization (DQ) of QCS and DQCS was 0.8 and 1.3, respectively. These derivatives were characterized by FTIR, ¹H NMR, ¹³C NMR, TGA, and SEM. Moreover, the antioxidant activity of the chitosan was evaluated by free radical scavenging ability (against DPPH-radical, hydroxyl-radical, and superoxide-radical) and ferric reducing power. Our results suggested that the antioxidant abilities were in the order of DQCS > QCS > CS, which was consistent with the number of quaternized groups. These data demonstrate that the number of quaternized groups of chitosan derivatives contributes to their antioxidant activity. Therefore, DQCS, with a higher number of quaternized groups and higher positive charge density, is endowed with high antioxidant activity, and can be used as a candidate material in food and pharmaceutical industries. Full article

(This article belongs to the Special Issue Polysaccharide-based Materials)

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13 pages, 3047 KiB

Open AccessArticle

Aloin Suppresses Lipopolysaccharide-Induced Inflammatory Response and Apoptosis by Inhibiting the Activation of NF-κB

by Xuan Luo, Haowei Zhang, Xiduan Wei, Mengjuan Shi, Ping Fan, Weidong Xie, Yaou Zhang and Naihan Xu

Molecules 2018, 23(3), 517; https://doi.org/10.3390/molecules23030517 - 26 Feb 2018

Cited by 31 | Viewed by 8477

Abstract

Numerous herbal-derived natural products are excellent anti-inflammatory agents. Several studies have reported that aloin, the major anthraquinone glycoside obtained from the Aloe species, exhibits anti-inflammatory activity. However, the molecular mechanism of this activity is not well understood. In this report, we found that [...] Read more.

Numerous herbal-derived natural products are excellent anti-inflammatory agents. Several studies have reported that aloin, the major anthraquinone glycoside obtained from the Aloe species, exhibits anti-inflammatory activity. However, the molecular mechanism of this activity is not well understood. In this report, we found that aloin suppresses lipopolysaccharide-induced pro-inflammatory cytokine secretion and nitric oxide production, and downregulates the expression of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Aloin inhibits the phosphorylation and acetylation of the NF-κB p65 subunit by suppressing the upstream kinases p38 and Msk1, preventing LPS-induced p65 translocation to the nucleus. We have also shown that aloin inhibits LPS-induced caspase-3 activation and apoptotic cell death. Collectively, these findings suggest that aloin effectively suppresses the inflammatory response, primarily through the inhibition of NF-κB signaling. Full article

(This article belongs to the Section Natural Products Chemistry)

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14 pages, 1354 KiB

Open AccessFeature PaperCommunication

Convergent Synthesis of N,S-bis Glycosylquinolin-2-ones via a Pd-G3-XantPhos Precatalyst Catalysis

by Wafa Redjdal, Nada Ibrahim, Belkacem Benmerad, Mouad Alami and Samir Messaoudi

Molecules 2018, 23(3), 519; https://doi.org/10.3390/molecules23030519 - 26 Feb 2018

Cited by 8 | Viewed by 5071

Abstract

Buchwald-Hartwig-Migita cross-coupling of 1-thiosugars with α- or β-3-iodo-N-glycosylquinolin-2-ones has been accomplished under mild and operationally simple reaction conditions through the use of a Pd-G3 XantPhos palladacycle precatalyst. This new methodology has been successfully applied to a variety of α- or β-mono-, [...] Read more.

Buchwald-Hartwig-Migita cross-coupling of 1-thiosugars with α- or β-3-iodo-N-glycosylquinolin-2-ones has been accomplished under mild and operationally simple reaction conditions through the use of a Pd-G3 XantPhos palladacycle precatalyst. This new methodology has been successfully applied to a variety of α- or β-mono-, di-, and poly-thiosugar derivatives to efficiently synthesize a series of α- or β-N,S-bis-glycosyl quinolin-2-ones, which are difficult to synthesize by classical methods. Full article

(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)

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22 pages, 2756 KiB

Open AccessArticle

Design of Two Alternative Routes for the Synthesis of Naftifine and Analogues as Potential Antifungal Agents

by Rodrigo Abonia, Alexander Garay, Juan C. Castillo, Braulio Insuasty, Jairo Quiroga, Manuel Nogueras, Justo Cobo, Estefanía Butassi and Susana Zacchino

Molecules 2018, 23(3), 520; https://doi.org/10.3390/molecules23030520 - 26 Feb 2018

Cited by 13 | Viewed by 5310

Abstract

Two practical and efficient approaches have been implemented as alternative procedures for the synthesis of naftifine and novel diversely substituted analogues 16 and 20 in good to excellent yields, mediated by Mannich-type reactions as the key step of the processes. In these approaches, [...] Read more.

Two practical and efficient approaches have been implemented as alternative procedures for the synthesis of naftifine and novel diversely substituted analogues 16 and 20 in good to excellent yields, mediated by Mannich-type reactions as the key step of the processes. In these approaches, the γ-aminoalcohols 15 and 19 were obtained as the key intermediates and their subsequent dehydration catalyzed either by Brønsted acids like H₂SO₄ and HCl or Lewis acid like AlCl₃, respectively, led to naftifine, along with the target allylamines 16 and 20. The antifungal assay results showed that intermediates 18 (bearing both a β-aminoketo- and N-methyl functionalities in their structures) and products 20 were the most active. Particularly, structures 18b, 18c, and the allylamine 20c showed the lowest MIC values, in the 0.5–7.8 µg/mL range, against the dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes. Interesting enough, compound 18b bearing a 4-Br as the substituent of the phenyl ring, also displayed high activity against Candida albicans and Cryptococcus neoformans with MIC₈₀ = 7.8 µg/mL, being fungicide rather than fungistatic with a relevant MFC value = 15.6 µg/mL against C. neoformans. Full article

(This article belongs to the Section Bioorganic Chemistry)

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17 pages, 3395 KiB

Open AccessArticle

Melatonin in Apples and Juice: Inhibition of Browning and Microorganism Growth in Apple Juice

by Haixia Zhang, Xuan Liu, Ting Chen, Yazhen Ji, Kun Shi, Lin Wang, Xiaodong Zheng and Jin Kong

Molecules 2018, 23(3), 521; https://doi.org/10.3390/molecules23030521 - 27 Feb 2018

Cited by 33 | Viewed by 6815

Abstract

Synthetic melatonin (N-acetyl-5-methoxytryptamine, MT) is popular in the US and Asian markets as a health supplement. Here, we identified a naturally occurring melatonin source in apple juice. Melatonin was present in all 18 apple cultivars tested. The highest melatonin level of [...] Read more.

Synthetic melatonin (N-acetyl-5-methoxytryptamine, MT) is popular in the US and Asian markets as a health supplement. Here, we identified a naturally occurring melatonin source in apple juice. Melatonin was present in all 18 apple cultivars tested. The highest melatonin level of the edible part of apple was detected in the apple peel. The melatonin content in ‘Fuji’ apple juice is comparable to the level of its flesh. Melatonin was consumed during the process of juicing due to its interaction with the oxidants. Melatonin addition significantly reduced the juice color change to brown (browning). The mechanism is that melatonin scavenges the free radicals, which was indicated by the ASBT analysis; therefore, inhibiting the conversion of o-diphenolic compounds into quinones. Most importantly, melatonin exhibited powerful anti-microorganism activity in juice. The exact mechanisms of this action are currently unknown. These effects of melatonin can preserve the quality and prolong the shelf life of apple juice. The results provide valuable information regarding commerciall apple juice processing and storage. Full article

(This article belongs to the Special Issue Melatonin as an Antioxidant and a Functionally Pleiotropic Molecule: Synthesis, Metabolism and Activities in Organisms)

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14 pages, 4099 KiB

Open AccessArticle

Inhibiting the NLRP3 Inflammasome Activation with MCC950 Ameliorates Diabetic Encephalopathy in db/db Mice

by Yadong Zhai, Xiangbao Meng, Tianyuan Ye, Weijie Xie, Guibo Sun and Xiaobo Sun

Molecules 2018, 23(3), 522; https://doi.org/10.3390/molecules23030522 - 27 Feb 2018

Cited by 86 | Viewed by 8641

Abstract

Diabetes is associated with a high risk of developing cognitive dysfunction and neuropsychiatric disabilities, and these disease symptomsare termed diabetic encephalopathy (DEP). Inflammation is involved in the development of DEP. The cleavage and maturation of the proinflammatory cytokine interleukin (IL)-1β is regulated by [...] Read more.

Diabetes is associated with a high risk of developing cognitive dysfunction and neuropsychiatric disabilities, and these disease symptomsare termed diabetic encephalopathy (DEP). Inflammation is involved in the development of DEP. The cleavage and maturation of the proinflammatory cytokine interleukin (IL)-1β is regulated by the NLRP3 inflammasome. Obese and type 2 diabetic db/db mice show anxiety- and depression-like behaviors and cognitive disorders associated with hippocampal inflammation. The purpose of this study was to explore the role of NLRP3 inflammasome in DEP. Results showed that expression levels of inflammasome components including NLRP3, apoptosis-associated speck-like protein (ASC), and caspase-1, as well as IL-1β in the hippocampus of diabetic db/db mice were higher than those of non-diabetic db/m mice. Treatment of db/db mice with NLRP3 inflammasome inhibitor MCC950 ameliorated anxiety- and depression-like behaviors as well as cognitive dysfunction, and reversed increased NLRP3, ASC, and IL-1βexpression levels and caspase-1 activity in hippocampus. Moreover, MCC950 treatment significantly improved insulin sensitivity in db/db mice. These results demonstrate that inhibition of NLRP3 inflammasome activation may prove to be a potential therapeutic approach for DEP treatment. Full article

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11 pages, 2602 KiB

Open AccessArticle

Aberrant Glycosylation Augments the Immuno-Stimulatory Activities of Soluble Calreticulin

by Fang-Yuan Gong, Zheng Gong, Cui-Cui Duo, Jun Wang, Chao Hong and Xiao-Ming Gao

Molecules 2018, 23(3), 523; https://doi.org/10.3390/molecules23030523 - 27 Feb 2018

Cited by 4 | Viewed by 3406

Abstract

Calreticulin (CRT), a luminal resident calcium-binding glycoprotein of the cell, is a tumor-associated antigen involved in tumorigenesis and also an autoantigen targeted by autoantibodies found in patients with various autoimmune diseases. We have previously shown that prokaryotically expressed recombinant murine CRT (rCRT) exhibits [...] Read more.

Calreticulin (CRT), a luminal resident calcium-binding glycoprotein of the cell, is a tumor-associated antigen involved in tumorigenesis and also an autoantigen targeted by autoantibodies found in patients with various autoimmune diseases. We have previously shown that prokaryotically expressed recombinant murine CRT (rCRT) exhibits strong stimulatory activities against monocytes/macrophages in vitro and potent immunogenicity in vivo, which is partially attributable to self-oligomerization of soluble rCRT. However, even in oligomerized form native CRT (nCRT) isolated from mouse liver is much less active than rCRT, arguing against the possibility that self-oligomerization alone would license potent pro-inflammatory properties to nCRT. Since rCRT differs from nCRT in its lack of glycosylation, we wondered if aberrant glycosylation of eukaryotically expressed CRT (eCRT) would significantly enhance its immunological activity. In the present study, tunicamycin, an N-glycosyltransferase inhibitor, was employed to treat CHO cells (CHO-CRT) stably expressing full-length recombinant mouse CRT in secreted form for preparation of aberrantly glycosylated eCRT (tun-eCRT). Our biochemical and immunological analysis results indicate that eCRT produced by CHO-CRT cells is similar to nCRT in terms of glycosylation level, lack of self-oligomerization, relatively poor immunogenicity and weak macrophage-stimulatory activity, while tun-eCRT shows reduced glycosylation yet much enhanced ability to elicit specific humoral responses in mice and TNF-α and nitric oxide production by macrophages in vitro. Given that abberant glycosylation of proteins is a hallmark of cancer cells and also related to the development of autoimmune disorders in humans, our data may provide useful clues for better understanding of potentiating roles of dysregulated glycosylation of molecules such as CRT in tumorigenesis and autoimmunity. Full article

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9 pages, 3284 KiB

Open AccessArticle

Virtual Screening of Small Molecular Inhibitors against DprE1

by Gang Zhang, Song Guo, Huaqing Cui and Jianguo Qi

Molecules 2018, 23(3), 524; https://doi.org/10.3390/molecules23030524 - 27 Feb 2018

Cited by 23 | Viewed by 7715

Abstract

Decaprenylphosphoryl-β-d-ribose oxidase (DprE1) is the flavoprotein subunit of decaprenylphosphoryl-d-ribose epimerase involved in cell wall synthesis in Mycobacterium tuberculosis and catalyzes the conversion of decaprenylphosphoryl ribose to decaprenylphosphoryl arabinose. DprE1 is a potential target against tuberculosis, including multidrug-resistant tuberculosis. We [...] Read more.

Decaprenylphosphoryl-β-d-ribose oxidase (DprE1) is the flavoprotein subunit of decaprenylphosphoryl-d-ribose epimerase involved in cell wall synthesis in Mycobacterium tuberculosis and catalyzes the conversion of decaprenylphosphoryl ribose to decaprenylphosphoryl arabinose. DprE1 is a potential target against tuberculosis, including multidrug-resistant tuberculosis. We identified potential DprE1 inhibitors from the ChemDiv dataset through virtual screening based on pharmacophore and molecular docking. Thirty selected compounds were subjected to absorption, distribution, metabolism, excretion, and toxicity prediction with the Discovery Studio software package. Two compounds were obtained as hits for inhibiting DprE1 activity in M. tuberculosis and are suitable for further in vitro and in vivo evaluation. Full article

(This article belongs to the Section Medicinal Chemistry)

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11 pages, 4337 KiB

Open AccessArticle

The Effect of Annealing Treatment and Atom Layer Deposition to Au/Pt Nanoparticles-Decorated TiO₂ Nanorods as Photocatalysts

by Shuang Shuang and Zhengjun Zhang

Molecules 2018, 23(3), 525; https://doi.org/10.3390/molecules23030525 - 9 Feb 2018

Cited by 21 | Viewed by 5416

Abstract

The wide band gap of TiO₂ hinders the utilization of visible light in high-performance photocatalysis. Herein, vertically aligned Ti nanopillar arrays (NPAs) were grown by the glancing angle deposition method (GLAD) and then thermally oxidized into TiO₂ NPAs. The metallic nanoparticles [...] Read more.

The wide band gap of TiO₂ hinders the utilization of visible light in high-performance photocatalysis. Herein, vertically aligned Ti nanopillar arrays (NPAs) were grown by the glancing angle deposition method (GLAD) and then thermally oxidized into TiO₂ NPAs. The metallic nanoparticles (NPs) were fabricated by successive ion layer adsorption and reaction (SILAR) method. And we covered ultrathin TiO₂ layer on Au/Pt NPs decorated NPA using atomic layer deposition (ALD) method and did annealing process in the end. The photoelectrochemical (PEC) performance and dye degradation have been studied. We find the dye degradation efficiency of best combination reaches up to 1.5 times higher than that of original Au/Pt-TiO₂ sample under visible light irradiation. The TiO₂ ALD layer effectively protects the nanostructure from corrosion and helps the transmission of electrons to the electrolyte. By controlling the annealing temperature we could achieve a matched band gap due to change in noble metal particle size. Our work demonstrates that rational design of composite nanostructures enhances the usage of broader wavelength range light and optimizes photocatalytic degradation of organic pollutants in practical applications. Full article

(This article belongs to the Special Issue Chemistry of Aerogels and Their Applications)

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16 pages, 2562 KiB

Open AccessArticle

Mycobacterium tuberculosis H37Rv LpqG Protein Peptides Can Inhibit Mycobacterial Entry through Specific Interactions

by Christian David Sánchez-Barinas, Marisol Ocampo, Magnolia Vanegas, Jeimmy Johana Castañeda-Ramirez, Manuel Alfonso Patarroyo and Manuel Elkin Patarroyo

Molecules 2018, 23(3), 526; https://doi.org/10.3390/molecules23030526 - 27 Feb 2018

Cited by 5 | Viewed by 3924

Abstract

Mycobacterium tuberculosis is the causative agent of tuberculosis, a disease causing major mortality worldwide. As part of a systematic methodology for studying M. tuberculosis surface proteins which might be involved in host-pathogen interactions, our group found that LpqG surface protein (Rv3623) found in [...] Read more.

Mycobacterium tuberculosis is the causative agent of tuberculosis, a disease causing major mortality worldwide. As part of a systematic methodology for studying M. tuberculosis surface proteins which might be involved in host-pathogen interactions, our group found that LpqG surface protein (Rv3623) found in M. tuberculosis complex strains was located on the mycobacterial envelope and that peptide 16661 (²¹SGCDSHNSGSLGADPRQVTVY⁴⁰) had high specific binding to U937 monocyte-derived macrophages and inhibited mycobacterial entry to such cells in a concentration-dependent way. A region having high specific binding to A549 alveolar epithelial cells was found which had low mycobacterial entry inhibition. As suggested in previous studies, relevant sequences in the host-pathogen interaction do not induce an immune response and peptides characterised as HABPs are poorly recognised by sera from individuals regardless of whether they have been in contact with M. tuberculosis. Our approach to designing a synthetic, multi-epitope anti-tuberculosis vaccine has been based on identifying sequences involved in different proteins’ mycobacteria-target cell interaction and modifying their sequence to improve their immunogenic characteristics, meaning that peptide 16661 sequence should be considered in such design. Full article

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12 pages, 3378 KiB

Open AccessArticle

MicroRNA and Transcriptomic Profiling Showed miRNA-Dependent Impairment of Systemic Regulation and Synthesis of Biomolecules in Rag2 KO Mice

by Abu Musa Md Talimur Reza, Yun-Jung Choi and Jin-Hoi Kim

Molecules 2018, 23(3), 527; https://doi.org/10.3390/molecules23030527 - 27 Feb 2018

Cited by 2 | Viewed by 3850

Abstract

The Rag2 knockout (KO) mouse is a well-established immune-compromised animal model for biomedical research. A comparative study identified the deregulated expression of microRNAs (miRNAs) and messenger RNAs (mRNAs) in Rag2 KO mice. However, the interaction between deregulated genes and miRNAs in the alteration [...] Read more.

The Rag2 knockout (KO) mouse is a well-established immune-compromised animal model for biomedical research. A comparative study identified the deregulated expression of microRNAs (miRNAs) and messenger RNAs (mRNAs) in Rag2 KO mice. However, the interaction between deregulated genes and miRNAs in the alteration of systemic (cardiac, renal, hepatic, nervous, and hematopoietic) regulations and the synthesis of biomolecules (such as l-tryptophan, serotonin, melatonin, dopamine, alcohol, noradrenaline, putrescine, and acetate) are unclear. In this study, we analyzed both miRNA and mRNA expression microarray data from Rag2 KO and wild type mice to investigate the possible role of miRNAs in systemic regulation and biomolecule synthesis. A notable finding obtained from this analysis is that the upregulation of several genes which are target molecules of the downregulated miRNAs in Rag2 KO mice, can potentially trigger the degradation of l-tryptophan, thereby leading to the systemic impairment and alteration of biomolecules synthesis as well as changes in behavioral patterns (such as stress and fear responses, and social recognition memory) in Rag2 gene-depleted mice. These findings were either not observed or not explicitly described in other published Rag2 KO transcriptome analyses. In conclusion, we have provided an indication of miRNA-dependent regulations of clinical and pathological conditions in cardiac, renal, hepatic, nervous, and hematopoietic systems in Rag2 KO mice. These results may significantly contribute to the prediction of clinical disease caused by Rag2 deficiency. Full article

(This article belongs to the Section Chemical Biology)

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21 pages, 3568 KiB

Open AccessArticle

Substrate Binding Switches the Conformation at the Lynchpin Site in the Substrate-Binding Domain of Human Hsp70 to Enable Allosteric Interdomain Communication

by Kohei Umehara, Miho Hoshikawa, Naoya Tochio and Shin-ichi Tate

Molecules 2018, 23(3), 528; https://doi.org/10.3390/molecules23030528 - 27 Feb 2018

Cited by 10 | Viewed by 4093

Abstract

The stress-induced 70 kDa heat shock protein (Hsp70) functions as a molecular chaperone to maintain protein homeostasis. Hsp70 contains an N-terminal ATPase domain (NBD) and a C-terminal substrate-binding domain (SBD). The SBD is divided into the β subdomain containing the substrate-binding site (βSBD) [...] Read more.

The stress-induced 70 kDa heat shock protein (Hsp70) functions as a molecular chaperone to maintain protein homeostasis. Hsp70 contains an N-terminal ATPase domain (NBD) and a C-terminal substrate-binding domain (SBD). The SBD is divided into the β subdomain containing the substrate-binding site (βSBD) and the α-helical subdomain (αLid) that covers the βSBD. In this report, the solution structures of two different forms of the SBD from human Hsp70 were solved. One structure shows the αLid bound to the substrate-binding site intramolecularly, whereas this intramolecular binding mode is absent in the other structure solved. Structural comparison of the two SBDs from Hsp70 revealed that client-peptide binding rearranges residues at the interdomain contact site, which impairs interdomain contact between the SBD and the NBD. Peptide binding also disrupted the inter-subdomain interaction connecting the αLid to the βSBD, which allows the binding of the αLid to the NBD. The results provide a mechanism for interdomain communication upon substrate binding from the SBD to the NBD via the lynchpin site in the βSBD of human Hsp70. In comparison to the bacterial ortholog, DnaK, some remarkable differences in the allosteric signal propagation among residues within the Hsp70 SBD exist. Full article

(This article belongs to the Special Issue NMR as a Tool to Investigate Biomolecular Structure, Recognition and Dynamics)

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10 pages, 3076 KiB

Open AccessArticle

Enhanced Hydrolysis of Cellulose in Ionic Liquid Using Mesoporous ZSM-5

by Tianlu Chen, Chunrong Xiong and Yousheng Tao

Molecules 2018, 23(3), 529; https://doi.org/10.3390/molecules23030529 - 27 Feb 2018

Cited by 19 | Viewed by 3869

Abstract

Mesoporous ZSM-5 prepared by alkaline treatment was demonstrated as an efficient catalyst for the cellulose hydrolysis in ionic liquid (IL), affording a high yield of reducing sugar. It was demonstrated that mesoporous ZSM-5 (SiO₂/Al₂O₃ = 38) had 76.2% [...] Read more.

Mesoporous ZSM-5 prepared by alkaline treatment was demonstrated as an efficient catalyst for the cellulose hydrolysis in ionic liquid (IL), affording a high yield of reducing sugar. It was demonstrated that mesoporous ZSM-5 (SiO₂/Al₂O₃ = 38) had 76.2% cellulose conversion and 49.6% yield of total reducing sugar (TRS). In comparison, the conventional ZSM-5 had a mere 41.3% cellulose conversion with 33.2% yield of TRS. The results indicated that the important role of mesopores in zeolites in elevating the TRS yield may be due to the diffusional alleviation of cellulose macromolecules. The effects of reaction time, temperature, and the ratio of catalyst to cellulose were investigated for optimal reaction conditions. It was found that IL could enter the inner channel of mesoporous ZSM-5 to promote the generation of H⁺ from Brönsted acid sites, which facilitated hydrolysis. Moreover, the mesoporous ZSM-5 showed excellent reusability for catalytic cycles by means of calcination of the used one, promising for its practical applications in the hydrolysis of cellulose. Full article

(This article belongs to the Special Issue Zeolites and Related Nanoporous Materials: Synthesis, Characterization and Applications in Catalysis and Green Chemistry)

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12 pages, 1486 KiB

Open AccessArticle

Determination of Propionylbrassinolide and Its Impurities by High-Performance Liquid Chromatography with Evaporative Light Scattering Detection

by Lidong Cao, Hong Zhang, Hongjun Zhang, Li Yang, Miaomiao Wu, Puguo Zhou and Qiliang Huang

Molecules 2018, 23(3), 531; https://doi.org/10.3390/molecules23030531 - 27 Feb 2018

Cited by 4 | Viewed by 4889

Abstract

The discovery of brassinolide in 1979, a milestone in brassinosteroids research, has sparked great interest of brassinolide analogs (BLs) in agricultural applications. Among these BLs, propionylbrassinolide has captured considerable attention because it shows plant growth regulating activity with an excellent durability. Two impurities [...] Read more.

The discovery of brassinolide in 1979, a milestone in brassinosteroids research, has sparked great interest of brassinolide analogs (BLs) in agricultural applications. Among these BLs, propionylbrassinolide has captured considerable attention because it shows plant growth regulating activity with an excellent durability. Two impurities of propionylbrassinolide were isolated and purified by semi-preparative high-performance liquid chromatography (HPLC), and the chemical structures were confirmed. For simultaneous separation and determination of propionylbrassinolide and impurities, an efficient analytical method based on HPLC with evaporative light scattering detector (HPLC-ELSD) was developed. The optimized analysis was performed on a C18 reversed phase column (250 mm × 4.60 mm, 5 μm) with isocratic elution of acetonitrile and water (90:10, v/v) as the mobile phase. The drift tube temperature of the ELSD system was set to 50 °C and the auxiliary gas pressure was 150 kPa. The regression equations demonstrated a good linear relationship (R² = 0.9989–0.9999) within the test ranges. The limits of detection (LODs) and quantification (LOQs) for propionylbrassinolide, impurity 1 and 2 were 1.3, 1.2, 1,3 and 4.3, 4.0, 4.2 mg/L, respectively. The fully validated HPLC-ELSD method was readily applied to quantify the active ingredient and impurities in propionylbrassinolide technical concentrate. Moreover, the optimized separation conditions with ELSD have been successfully transferred to mass spectrometry (MS) detector for LC-MS determination. Full article

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13 pages, 3320 KiB

Open AccessArticle

Radical Chemistry in a Femtosecond Laser Plasma: Photochemical Reduction of Ag⁺ in Liquid Ammonia Solution

by Victoria Kathryn Meader, Mallory G. John, Laysa M. Frias Batista, Syeda Ahsan and Katharine Moore Tibbetts

Molecules 2018, 23(3), 532; https://doi.org/10.3390/molecules23030532 - 27 Feb 2018

Cited by 33 | Viewed by 7154

Abstract

Plasmas with dense concentrations of reactive species such as hydrated electrons and hydroxyl radicals are generated from focusing intense femtosecond laser pulses into aqueous media. These radical species can reduce metal ions such as Au³⁺ to form metal nanoparticles (NPs). However, the [...] Read more.

Plasmas with dense concentrations of reactive species such as hydrated electrons and hydroxyl radicals are generated from focusing intense femtosecond laser pulses into aqueous media. These radical species can reduce metal ions such as Au³⁺ to form metal nanoparticles (NPs). However, the formation of H₂O₂ by the recombination of hydroxyl radicals inhibits the reduction of Ag⁺ through back-oxidation. This work has explored the control of hydroxyl radical chemistry in a femtosecond laser-generated plasma through the addition of liquid ammonia. The irradiation of liquid ammonia solutions resulted in a reaction between NH₃ and OH·, forming peroxynitrite and ONOO⁻, and significantly reducing the amount of H₂O₂ generated. Varying the liquid ammonia concentration controlled the Ag⁺ reduction rate, forming 12.7 ± 4.9 nm silver nanoparticles at the optimal ammonia concentration. The photochemical mechanisms underlying peroxynitrite formation and Ag⁺ reduction are discussed. Full article

(This article belongs to the Special Issue Radical Chemistry)

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15 pages, 2333 KiB

Open AccessArticle

Calycophyllum spruceanum (Benth.), the Amazonian “Tree of Youth” Prolongs Longevity and Enhances Stress Resistance in Caenorhabditis elegans

by Herbenya Peixoto, Mariana Roxo, Hector Koolen, Felipe Da Silva, Emerson Silva, Markus Santhosh Braun, Xiaojuan Wang and Michael Wink

Molecules 2018, 23(3), 534; https://doi.org/10.3390/molecules23030534 - 27 Feb 2018

Cited by 19 | Viewed by 6430

Abstract

The tree popularly known in Brazil as mulateiro or pau-mulato (Calycophyllum spruceanum (Benth.) K. Schum.) is deeply embedded in the herbal medicine of the Amazon region. Different preparations of the bark are claimed to have anti-aging, antioxidant, antimicrobial, emollient, wound healing, hemostatic, [...] Read more.

The tree popularly known in Brazil as mulateiro or pau-mulato (Calycophyllum spruceanum (Benth.) K. Schum.) is deeply embedded in the herbal medicine of the Amazon region. Different preparations of the bark are claimed to have anti-aging, antioxidant, antimicrobial, emollient, wound healing, hemostatic, contraceptive, stimulant, and anti-diabetic properties. The current study aims to provide the first step towards a science-based evidence of the beneficial effects of C. spruceanum in the promotion of longevity and in the modulation of age-related markers. For this investigation, we used the model system Caenorhabditis elegans to evaluate in vivo antioxidant and anti-aging activity of a water extract from C. spruceanum. To chemically characterize the extract, HPLC MS (High Performance Liquid Chromatography Mass Spectrometry)/MS analyses were performed. Five secondary metabolites were identified in the extract, namely gardenoside, 5-hydroxymorin, cyanidin, taxifolin, and 5-hydroxy-6-methoxycoumarin-7-glucoside. C. spruceanum extract was able to enhance stress resistance and to extend lifespan along with attenuation of aging-associated markers in C. elegans. The demonstrated bioactivities apparently depend on the DAF-16/FOXO pathway. The data might support the popular claims of mulateiro as the “tree of youth”, however more studies are needed to clarify its putative benefits to human health. Full article

(This article belongs to the Special Issue Plant Derived Natural Products and Age Related Diseases)

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20 pages, 4574 KiB

Open AccessArticle

Tolerance to Stress Combination in Tomato Plants: New Insights in the Protective Role of Melatonin

by Vicente Martinez, Manuel Nieves-Cordones, Maria Lopez-Delacalle, Reyes Rodenas, Teresa C. Mestre, Francisco Garcia-Sanchez, Francisco Rubio, Pedro A. Nortes, Ron Mittler and Rosa M. Rivero

Molecules 2018, 23(3), 535; https://doi.org/10.3390/molecules23030535 - 28 Feb 2018

Cited by 254 | Viewed by 15054

Abstract

Abiotic stresses such as drought, heat or salinity are major causes of yield loss worldwide. Recent studies have revealed that the acclimation of plants to a combination of different environmental stresses is unique and therefore cannot be directly deduced from studying the response [...] Read more.

Abiotic stresses such as drought, heat or salinity are major causes of yield loss worldwide. Recent studies have revealed that the acclimation of plants to a combination of different environmental stresses is unique and therefore cannot be directly deduced from studying the response of plants to each of the different stresses applied individually. The efficient detoxification of reactive oxygen species (ROS) is thought to play a key role in enhancing the tolerance of plants to abiotic stresses. Here, we report on the role of melatonin in the protection of the photosynthetic apparatus through the increase in ROS detoxification in tomato plants grown under the combination of salinity and heat, two of the most common abiotic stresses known to act jointly. Plants treated with exogenous melatonin showed a different modulation in the expression on some antioxidant-related genes and their related enzymes. More specifically, ascorbate peroxidase, glutathione reductase, glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase (APX, GR, GPX and Ph-GPX, resepctively) showed an antagonistic regulation as compared to plants that did not receive melatonin. This translated into a better antioxidant capacity and to a lesser ROS accumulation under stress combination. The performance of the photosynthesis parameters and the photosystems was also increased in plants treated with exogenous melatonin under the combination of salinity and heat. In accordance with these findings, tomato plants treated with melatonin were found to grow better under stress combination that the non-treated ones. Our study highlights the important role that exogenous melatonin plays in the acclimation of plants to a combination of two different abiotic stresses, and how this compound can specifically regulate oxidative stress-related genes and enzymes to increase plant tolerance. Full article

(This article belongs to the Special Issue Melatonin as an Antioxidant and a Functionally Pleiotropic Molecule: Synthesis, Metabolism and Activities in Organisms)

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14 pages, 2797 KiB

Open AccessArticle

Exploring N-acyl-4-azatetracyclo[5.3.2.0^2,6.0^8,10]dodec-11-enes as 11β-HSD1 Inhibitors

by Rosana Leiva, Andrew McBride, Margaret Binnie, Scott P. Webster and Santiago Vázquez

Molecules 2018, 23(3), 536; https://doi.org/10.3390/molecules23030536 - 28 Feb 2018

Cited by 1 | Viewed by 3204

Abstract

We recently found that a cyclohexanecarboxamide derived from 4-azatetracyclo[5.3.2.0^2,6.0^8,10]dodec-11-ene displayed low nanomolar inhibition of 11β-HSD1. In continuation of our efforts to discover potent and selective 11β-HSD1 inhibitors, herein we explored several replacements for the cyclohexane ring. Some derivatives exhibited [...] Read more.

We recently found that a cyclohexanecarboxamide derived from 4-azatetracyclo[5.3.2.0^2,6.0^8,10]dodec-11-ene displayed low nanomolar inhibition of 11β-HSD1. In continuation of our efforts to discover potent and selective 11β-HSD1 inhibitors, herein we explored several replacements for the cyclohexane ring. Some derivatives exhibited potent inhibitory activity against human 11β-HSD1, although with low selectivity over the isoenzyme 11β-HSD2, and poor microsomal stability. Full article

(This article belongs to the Section Medicinal Chemistry)

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10 pages, 3548 KiB

Open AccessArticle

Lignin from Hardwood and Softwood Biomass as a Lubricating Additive to Ethylene Glycol

by Liwen Mu, Jian Wu, Leonidas Matsakas, Minjiao Chen, Alireza Vahidi, Mattias Grahn, Ulrika Rova, Paul Christakopoulos, Jiahua Zhu and Yijun Shi

Molecules 2018, 23(3), 537; https://doi.org/10.3390/molecules23030537 - 28 Feb 2018

Cited by 39 | Viewed by 5540

Abstract

Ethylene glycol (EG)-based lubricant was prepared with dissolved organosolv lignin from birch wood (BL) and softwood (SL) biomass. The effects of different lignin types on the rheological, thermal, and tribological properties of the lignin/EG lubricants were comprehensively investigated by various characterization techniques. Dissolving [...] Read more.

Ethylene glycol (EG)-based lubricant was prepared with dissolved organosolv lignin from birch wood (BL) and softwood (SL) biomass. The effects of different lignin types on the rheological, thermal, and tribological properties of the lignin/EG lubricants were comprehensively investigated by various characterization techniques. Dissolving organosolv lignin in EG results in outstanding lubricating properties. Specifically, the wear volume of the disc by EG-44BL is only 8.9% of that lubricated by pure EG. The enhanced anti-wear property of the EG/lignin system could be attributed to the formation of a robust lubrication film and the strong adhesion of the lubricant on the contacting metal surface due to the presence of a dense hydrogen bonding (H-bonding) network. The lubricating performance of EG-BL outperforms EG-SL, which could be attributed to the denser H-bonding sites in BL and its broader molecular weight distribution. The disc wear loss of EG-44BL is only 45.7% of that lubricated by EG-44SL. Overall, H-bonding is the major contributor to the different tribological properties of BL and SL in EG-based lubricants. Full article

(This article belongs to the Special Issue Lignin for Energy, Chemicals and Materials)

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13 pages, 1455 KiB

Open AccessArticle

Bivariate Correlation Analysis of the Chemometric Profiles of Chinese Wild Salvia miltiorrhiza Based on UPLC-Qqq-MS and Antioxidant Activities

by Xiaodan Zhang, Yange Yu, Yesheng Cen, Dongfeng Yang, Zhechen Qi, Zhuoni Hou, Shuanglai Han, Zengxuan Cai and Kuancheng Liu

Molecules 2018, 23(3), 538; https://doi.org/10.3390/molecules23030538 - 28 Feb 2018

Cited by 28 | Viewed by 4772

Abstract

To better understand the mechanisms underlying the pharmacological actions of Salvia miltiorrhiza, correlation between the chemical profiles and in vitro antioxidant activities in 50 batches of wild S. miltiorrhiza samples was analyzed. Our ultra-performance liquid chromatography–tandem mass spectrometry analysis detected twelve phenolic [...] Read more.

To better understand the mechanisms underlying the pharmacological actions of Salvia miltiorrhiza, correlation between the chemical profiles and in vitro antioxidant activities in 50 batches of wild S. miltiorrhiza samples was analyzed. Our ultra-performance liquid chromatography–tandem mass spectrometry analysis detected twelve phenolic acids and five tanshinones and obtained various chemical profiles from different origins. In a principal component analysis (PCA) and cluster analysis, the tanshinones cryptotanshinone, tanshinone IIA and dihydrotanshinone I exhibited higher weights in PC1, whereas the phenolic acids danshensu, salvianolic acids A and B and lithospermic acid were highly loaded in PC2. All components could be optimized as markers of different locations and might be suitable for S. miltiorrhiza quality analyses. Additionally, the DPPH and ABTS assays used to comprehensively evaluate antioxidant activities indicated large variations, with mean DPPH and ABTS scavenging potencies of 32.24 and 23.39 μg/mL, respectively, among S. miltiorrhiza extract solutions. Notably, samples that exceeded the mean IC₅₀ values had higher phenolic acid contents. A correlation analysis indicated a strong correlation between the antioxidant activities and phenolic acid contents. Caffeic acid, danshensu, rosmarinic acid, lithospermic acid and salvianolic acid B were major contributors to antioxidant activity. In conclusion, phenolic compounds were the predominant antioxidant components in the investigated plant species. These plants may be sources of potent natural antioxidants and beneficial chemopreventive agents. Full article

(This article belongs to the Collection Phytochemicals: Biosynthesis, Metabolism and Biological Activities)

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14 pages, 5751 KiB

Open AccessArticle

Mechanistic Insight into the Degradation of Nitrosamines via Aqueous-Phase UV Photolysis or a UV-Based Advanced Oxidation Process: Quantum Mechanical Calculations

by Daisuke Minakata and Erica Coscarelli

Molecules 2018, 23(3), 539; https://doi.org/10.3390/molecules23030539 - 28 Feb 2018

Cited by 14 | Viewed by 5817

Abstract

Nitrosamines are a group of carcinogenic chemicals that are present in aquatic environments that result from byproducts of industrial processes and disinfection products. As indirect and direct potable reuse increase, the presence of trace nitrosamines presents challenges to water infrastructures that incorporate effluent [...] Read more.

Nitrosamines are a group of carcinogenic chemicals that are present in aquatic environments that result from byproducts of industrial processes and disinfection products. As indirect and direct potable reuse increase, the presence of trace nitrosamines presents challenges to water infrastructures that incorporate effluent from wastewater treatment. Ultraviolet (UV) photolysis or UV-based advanced oxidation processes that produce highly reactive hydroxyl radicals are promising technologies to remove nitrosamines from water. However, complex reaction mechanisms involving radicals limit our understandings of the elementary reaction pathways embedded in the overall reactions identified experimentally. In this study, we perform quantum mechanical calculations to identify the hydroxyl radical-induced initial elementary reactions with N-nitrosodimethylamine (NDMA), N-nitrosomethylethylamine, and N-nitrosomethylbutylamine. We also investigate the UV-induced NDMA degradation mechanisms. Our calculations reveal that the alkyl side chains of nitrosamine affect the reaction mechanism of hydroxyl radicals with each nitrosamine investigated in this study. Nitrosamines with one- or two-carbon alkyl chains caused the delocalization of the electron density, leading to slower subsequent degradation. Additionally, three major initial elementary reactions and the subsequent radical-involved reaction pathways are identified in the UV-induced NDMA degradation process. This study provides mechanistic insight into the elementary reaction pathways, and a future study will combine these results with the kinetic information to predict the time-dependent concentration profiles of nitrosamines and their transformation products. Full article

(This article belongs to the Special Issue Radical Chemistry)

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14 pages, 1149 KiB

Open AccessArticle

RPiRLS: Quantitative Predictions of RNA Interacting with Any Protein of Known Sequence

by Wen-Jun Shen, Wenjuan Cui, Danze Chen, Jieming Zhang and Jianzhen Xu

Molecules 2018, 23(3), 540; https://doi.org/10.3390/molecules23030540 - 28 Feb 2018

Cited by 10 | Viewed by 3757

Abstract

RNA-protein interactions (RPIs) have critical roles in numerous fundamental biological processes, such as post-transcriptional gene regulation, viral assembly, cellular defence and protein synthesis. As the number of available RNA-protein binding experimental data has increased rapidly due to high-throughput sequencing methods, it is now [...] Read more.

RNA-protein interactions (RPIs) have critical roles in numerous fundamental biological processes, such as post-transcriptional gene regulation, viral assembly, cellular defence and protein synthesis. As the number of available RNA-protein binding experimental data has increased rapidly due to high-throughput sequencing methods, it is now possible to measure and understand RNA-protein interactions by computational methods. In this study, we integrate a sequence-based derived kernel with regularized least squares to perform prediction. The derived kernel exploits the contextual information around an amino acid or a nucleic acid as well as the repetitive conserved motif information. We propose a novel machine learning method, called RPiRLS to predict the interaction between any RNA and protein of known sequences. For the RPiRLS classifier, each protein sequence comprises up to 20 diverse amino acids but for the RPiRLS-7G classifier, each protein sequence is represented by using 7-letter reduced alphabets based on their physiochemical properties. We evaluated both methods on a number of benchmark data sets and compared their performances with two newly developed and state-of-the-art methods, RPI-Pred and IPMiner. On the non-redundant benchmark test sets extracted from the PRIDB, the RPiRLS method outperformed RPI-Pred and IPMiner in terms of accuracy, specificity and sensitivity. Further, RPiRLS achieved an accuracy of 92% on the prediction of lncRNA-protein interactions. The proposed method can also be extended to construct RNA-protein interaction networks. The RPiRLS web server is freely available at http://bmc.med.stu.edu.cn/RPiRLS. Full article

(This article belongs to the Special Issue Computational Analysis for Protein Structure and Interaction)

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19 pages, 11827 KiB

Open AccessArticle

Simultaneous Analysis of Saccharides between Fresh and Processed Radix Rehmanniae by HPLC and UHPLC-LTQ-Orbitrap-MS with Multivariate Statistical Analysis

by Shujuan Xue, Lili Wang, Suiqing Chen and Yongxian Cheng

Molecules 2018, 23(3), 541; https://doi.org/10.3390/molecules23030541 - 28 Feb 2018

Cited by 39 | Viewed by 5653

Abstract

Radix Rehmanniae (RR) is a kind of herb which is widely used in the clinical and food processing industry. There are four forms of RR used in traditional Chinese medicine practice, which include fresh RR (FRR), raw RR (RRR), processed RR (PRR), and [...] Read more.

Radix Rehmanniae (RR) is a kind of herb which is widely used in the clinical and food processing industry. There are four forms of RR used in traditional Chinese medicine practice, which include fresh RR (FRR), raw RR (RRR), processed RR (PRR), and another processed RR (APRR), in which the APRR was processed by nine cycles of repeated steaming and drying. There are a large number of saccharides in RR. However, the differences in content were shown by different processing methods. In this study, an effective method using high-performance liquid chromatography (HPLC) and high-performance liquid chromatography-mass spectrometry (LC-MS) coupled with multivariate statistical analysis to rapidly distinguish different RR samples and validate the proposed chemical conversion mechanism. The datasets of the content of saccharides were subjected to principal component analysis (PCA) and one-way analysis of variance. The results showed that there different changes occurred in the contents of saccharides corresponding to the different processing methods, in which the contents of monosaccharides—namely arabinose, glucose, mannose, and galactose—had an increasing trend or remained relatively stable. However, the contents of fructose and oligosaccharides, including manninotriose, melibiose, sucrose, and raffinose, first increased and then reduced, or gradually decreased, yet the content of stachyose gradually decreased. The MSⁿ data indicated that manninotriose, melibiose, and some monosaccharides were produced by the hydrolysis of oligosaccharides. In addition, the fragmentation pathways of 1-phenyl-3-methyl-5-pyrazolone (PMP) derivatization of monosaccharides were also found that its glycosidic bond was first broken and subsequently its inside ring broke, and the characteristic fragment ions were produced at m/z 511.22, 493.20, 373.16, and 175.08 in the PMP derivatization of monosaccharides. In conclusion, this study illustrates the change and chemical conversion mechanism of saccharides by processing in RR samples which might play a key role in further application of RR. Full article

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9 pages, 714 KiB

Open AccessArticle

Six Heterocyclic Metabolites from the Myxobacterium Labilithrix luteola

by Lucky S. Mulwa, Rolf Jansen, Dimas F. Praditya, Kathrin I. Mohr, Joachim Wink, Eike Steinmann and Marc Stadler

Molecules 2018, 23(3), 542; https://doi.org/10.3390/molecules23030542 - 28 Feb 2018

Cited by 25 | Viewed by 5429

Abstract

Two new secondary metabolites, labindole A [2-methyl-3-(2-nitroethyl)-3H-indole] (1) and labindole B [2-methyl-3-(2-nitrovinyl)-3H-indole] (2), were isolated from the myxobacterium Labilithrix luteola (DSM 27648^T). Additionally, four metabolites 3, 4, 5 and 6 already known from other sources [...] Read more.

Two new secondary metabolites, labindole A [2-methyl-3-(2-nitroethyl)-3H-indole] (1) and labindole B [2-methyl-3-(2-nitrovinyl)-3H-indole] (2), were isolated from the myxobacterium Labilithrix luteola (DSM 27648^T). Additionally, four metabolites 3, 4, 5 and 6 already known from other sources were obtained. Their structures were elucidated from high resolution electrospray ionisation mass spectrometry (HRESIMS) and 1D and 2D nuclear magnetic resonance (NMR) spectroscopy data and their relative configuration was assigned based on nuclear Overhauser effect (NOE) and vicinal ¹H-NMR coupling data. The compounds where tested for biological activities; labindoles A (1) and B (2) exhibited significant activity against Hepatitis C Virus, 9H-carbazole (3), 3-chloro-9H-carbazole (4) and 4-hydroxymethyl-quinoline (5) showed antifungal activities. Moreover, compound 3 had weak to moderate antibacterial activities, while labindoles A (1) and B (2) were devoid of significant antifungal and antibacterial effects. Full article

(This article belongs to the Section Natural Products Chemistry)

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14 pages, 2602 KiB

Open AccessArticle

A Sample and Sensitive HPLC-MS/MS Method for Simultaneous Determination of Ziyuglycoside I and Its Metabolite Ziyuglycoside II in Rat Pharmacokinetics

by Zhi-Feng Li, Meng-Ying Zhou, Ting Tan, Chen-Cong Zhong, Qi Wang, Ling-Ling Pan, Ying-Ying Luo, Shi-Lin Yang, Yu-Lin Feng and Hui Ouyang

Molecules 2018, 23(3), 543; https://doi.org/10.3390/molecules23030543 - 28 Feb 2018

Cited by 12 | Viewed by 4218

Abstract

Ziyuglycoside I (ZGS1) is a promising drug candidate for the treatment of leucopenia. Currently, information on ZGS1 and its in vivo metabolite ziyuglycoside II (ZGS2) is limited. The objective of this study was to investigate the pharmacokinetics, tissue distribution, and excretion of ziyuglycoside [...] Read more.

Ziyuglycoside I (ZGS1) is a promising drug candidate for the treatment of leucopenia. Currently, information on ZGS1 and its in vivo metabolite ziyuglycoside II (ZGS2) is limited. The objective of this study was to investigate the pharmacokinetics, tissue distribution, and excretion of ziyuglycoside I (ZGS1) and its metabolite ziyuglycoside II (ZGS2) in rats. In our study, a simple and sensitive high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) method was established for simultaneous determination of ZGS1 and its metabolite for Sprague-Dawley rat pharmacokinetics studies. The method was validated following internationally-approved guidelines. The results presented in this study indicated that subcutaneous administration of ZGS1 prolonged its extension time and increased the area under the curve (AUC_0–t) of ZGS2 during 0 to t minutes. In summary, in this study, the pharmacokinetic characteristics of ZGS1 and its metabolite ZGS2 were defined and its tissue distribution, and excretion in rats were described. Our finding may be beneficial for leucopenia drug that focus on ZGS1. Full article

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17 pages, 3048 KiB

Open AccessArticle

The Multivariate Regression Statistics Strategy to Investigate Content-Effect Correlation of Multiple Components in Traditional Chinese Medicine Based on a Partial Least Squares Method

by Ying Peng, Su-ning Li, Xuexue Pei and Kun Hao

Molecules 2018, 23(3), 545; https://doi.org/10.3390/molecules23030545 - 1 Mar 2018

Cited by 11 | Viewed by 3694

Abstract

Amultivariate regression statisticstrategy was developed to clarify multi-components content-effect correlation ofpanaxginseng saponins extract and predict the pharmacological effect by components content. In example 1, firstly, we compared pharmacological effects between panax ginseng saponins extract and individual saponin combinations. Secondly, we examined the anti-platelet [...] Read more.

Amultivariate regression statisticstrategy was developed to clarify multi-components content-effect correlation ofpanaxginseng saponins extract and predict the pharmacological effect by components content. In example 1, firstly, we compared pharmacological effects between panax ginseng saponins extract and individual saponin combinations. Secondly, we examined the anti-platelet aggregation effect in seven different saponin combinations of ginsenoside Rb1, Rg1, Rh, Rd, Ra3 and notoginsenoside R1. Finally, the correlation between anti-platelet aggregation and the content of multiple components was analyzed by a partial least squares algorithm. In example 2, firstly, 18 common peaks were identified in ten different batches of panax ginseng saponins extracts from different origins. Then, we investigated the anti-myocardial ischemia reperfusion injury effects of the ten different panax ginseng saponins extracts. Finally, the correlation between the fingerprints and the cardioprotective effects was analyzed by a partial least squares algorithm. Both in example 1 and 2, the relationship between the components content and pharmacological effect was modeled well by the partial least squares regression equations. Importantly, the predicted effect curve was close to the observed data of dot marked on the partial least squares regression model. This study has given evidences that themulti-component content is a promising information for predicting the pharmacological effects of traditional Chinese medicine. Full article

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12 pages, 2793 KiB

Open AccessArticle

An Injectable, Dual Responsive, and Self-Healing Hydrogel Based on Oxidized Sodium Alginate and Hydrazide-Modified Poly(ethyleneglycol)

by Lei Wang, Wanfu Zhou, Qingguo Wang, Chao Xu, Quan Tang and Haiyang Yang

Molecules 2018, 23(3), 546; https://doi.org/10.3390/molecules23030546 - 1 Mar 2018

Cited by 50 | Viewed by 9720

Abstract

Oxidized sodium alginate is a handily modifiable polysaccharide owing to the pendant aldehyde groups which can form dynamic covalent bonds with amines, acylhydrazines, etc., providing oxidized sodium alginate-based hydrogels with stimuli-responsive properties. However, due to the stiffness and, in particular, the hydrophobicity of [...] Read more.

Oxidized sodium alginate is a handily modifiable polysaccharide owing to the pendant aldehyde groups which can form dynamic covalent bonds with amines, acylhydrazines, etc., providing oxidized sodium alginate-based hydrogels with stimuli-responsive properties. However, due to the stiffness and, in particular, the hydrophobicity of sodium alginate dialdehyde at low pH, the mechanical performance and pH stimuli responsiveness of oxidized sodium alginate-based hydrogels are still strictly limited. Herein, we report a new strategy to build an injectable, dual responsive, and self-healing hydrogel based on oxidized sodium alginate and hydrazide-modified poly(ethyleneglycol) (PEG). The hydrazide-modified PEG, referred to as PEG-DTP, acts as a macromolecule crosslinker. We found that the presence of PEG-DTP reduces the hydrophobicity of oxidized sodium alginate at low pH so effectively that even a pH-induced reversible sol-gel transitions can be realized. Meanwhile, the disulfide bonds in PEG-DTP endows the hydrogel with the other reversible sol-gel transitions by redox stimuli. In particular, due to the softness of PEG-DTP chains, mechanical performance was also enhanced significantly. Our results indicate we can easily integrate multi-stimuli responsiveness, injectability, and self-healing behavior together into an oxidized sodium alginate-based hydrogel merely by mixing an oxidized sodium alginate solution with PEG-DTP solution in certain proportions. Full article

(This article belongs to the Special Issue Stimuli-Responsive Polymeric Materials)

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11 pages, 4034 KiB

Open AccessArticle

Effects of Styrene-Acrylic Sizing on the Mechanical Properties of Carbon Fiber Thermoplastic Towpregs and Their Composites

by Sean Bowman, Qiuran Jiang, Hafeezullah Memon, Yiping Qiu, Wanshuang Liu and Yi Wei

Molecules 2018, 23(3), 547; https://doi.org/10.3390/molecules23030547 - 1 Mar 2018

Cited by 29 | Viewed by 5578

Abstract

Thermoplastic towpregs are convenient and scalable raw materials for the fabrication of continuous fiber-reinforced thermoplastic matrix composites. In this paper, the potential to employ epoxy and styrene-acrylic sizing agents was evaluated for the making of carbon fiber thermoplastic towpregs via a powder-coating method. [...] Read more.

Thermoplastic towpregs are convenient and scalable raw materials for the fabrication of continuous fiber-reinforced thermoplastic matrix composites. In this paper, the potential to employ epoxy and styrene-acrylic sizing agents was evaluated for the making of carbon fiber thermoplastic towpregs via a powder-coating method. The protective effects and thermal stability of these sizing agents were investigated by single fiber tensile test and differential scanning calorimetry (DSC) measurement. The results indicate that the epoxy sizing agent provides better protection to carbon fibers, but it cannot be used for thermoplastic towpreg processing due to its poor chemical stability at high temperature. The bending rigidity of the tows and towpregs with two styrene-acrylic sizing agents was measured by cantilever and Kawabata methods. The styrene-acrylic sized towpregs show low torque values, and are suitable for further processing, such as weaving, preforming, and winding. Finally, composite panels were fabricated directly from the towpregs by hot compression molding. Both of the composite panels show superior flexural strength (>400 MPa), flexural modulus (>63 GPa), and interlaminar shear strength (>27 MPa), indicating the applicability of these two styrene-acrylic sizing agents for carbon fiber thermoplastic towpregs. Full article

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14 pages, 5651 KiB

Open AccessArticle

iTRAQ-Based Identification of Proteins Related to Lignin Synthesis in the Pear Pollinated with Pollen from Different Varieties

by Shumei Li, Xueqiang Su, Qing Jin, Guohui Li, Yanming Sun, Muhammad Abdullah, Yongping Cai and Yi Lin

Molecules 2018, 23(3), 548; https://doi.org/10.3390/molecules23030548 - 1 Mar 2018

Cited by 17 | Viewed by 3868

Abstract

Most pears in Anhui Province are a kind of self-incompatible fruit whose quality is strongly influenced by the male pollen. The proteomic variation of Dangshan Su pollinated by different varieties was analysed using the isobaric tag for relative and absolute quantitation (iTRAQ) to [...] Read more.

Most pears in Anhui Province are a kind of self-incompatible fruit whose quality is strongly influenced by the male pollen. The proteomic variation of Dangshan Su pollinated by different varieties was analysed using the isobaric tag for relative and absolute quantitation (iTRAQ) to investigate the effect of pollination by different varieties on the pear lignin pathway. Among the 3980 proteins identified from the two samples, 139 proteins were identified as differentially expressed proteins (DEPs). Of these proteins, laccase-4 (LAC4), was found to be related with lignin synthesis, and β-glucosidase 15 (BGLU15) and peroxidase 47 (PER47) were involved in the phenylpropanoid pathway. Moreover, the lignin and stone cell contents were lower in DW (Dangshan Su pollinated by Wonhwang) than those in DJ (Dangshan Su pollinated by Jingbaili). The effect of pollination on the synthesis of lignin through the regulation of the expression of PER47, BGLU15 and LAC4 ultimately affects the formation of stone cells and the fruit quality. We report for the first time that different pollinations influence the protein expression profile in the Dangshan Su pear, and this result provides some new epididymal targets for regulating the synthesis of lignin, regulating the content of stone cells and improving the quality of the pears. Full article

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12 pages, 6786 KiB

Open AccessFeature PaperArticle

Trimethylamine-N-Oxide (TMAO)-Induced Impairment of Cardiomyocyte Function and the Protective Role of Urolithin B-Glucuronide

by Monia Savi, Leonardo Bocchi, Letizia Bresciani, Angela Falco, Federico Quaini, Pedro Mena, Furio Brighenti, Alan Crozier, Donatella Stilli and Daniele Del Rio

Molecules 2018, 23(3), 549; https://doi.org/10.3390/molecules23030549 - 1 Mar 2018

Cited by 76 | Viewed by 6581

Abstract

One of the most recently proposed candidates as a potential trigger for cardiovascular diseases is trimethylamine-N-oxide (TMAO). Possible direct effects of TMAO on myocardial tissue, independent of vascular damage, have been only partially explored so far. In the present study, we [...] Read more.

One of the most recently proposed candidates as a potential trigger for cardiovascular diseases is trimethylamine-N-oxide (TMAO). Possible direct effects of TMAO on myocardial tissue, independent of vascular damage, have been only partially explored so far. In the present study, we assessed the detrimental direct effects of TMAO on cardiomyocyte contractility and intracellular calcium dynamics, and the ability of urolithin B-glucuronide (Uro B-gluc) in counteracting TMAO-induced cell damage. Cell mechanics and calcium transients were measured, and ultrastructural analysis was performed in ventricular cardiomyocytes isolated from the heart of normal adult rats. Cells were either untreated, exposed to TMAO, or to TMAO and Uro B-gluc. TMAO exposure worsened cardiomyocyte mechanics and intracellular calcium handling, as documented by the decrease in the fraction of shortening (FS) and the maximal rate of shortening and re-lengthening, associated with reduced efficiency in the intracellular calcium removal. Ultrastructurally, TMAO-treated cardiomyocytes also exhibited glycogen accumulation, a higher number of mitochondria and lipofuscin-like pigment deposition, suggesting an altered cellular energetic metabolism and a higher rate of protein oxidative damage, respectively. Uro B-gluc led to a complete recovery of cellular contractility and calcium dynamics, and morphologically to a reduced glycogen accumulation. We demonstrated for the first time a direct negative role of TMAO on cardiomyocyte functional properties and the ability of Uro B-gluc in counteracting these detrimental effects. Full article

(This article belongs to the Special Issue Dietary Antioxidants: Evidence of Protective Effects against Chronic Disease)

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10 pages, 851 KiB

Open AccessArticle

Rapid Determination of Active Compounds and Antioxidant Activity of Okra Seeds Using Fourier Transform Near Infrared (FT-NIR) Spectroscopy

by Fangbo Xia, Chenchen Li, Ning Zhao, He Li, Qi Chang, Xinmin Liu, Yonghong Liao and Ruile Pan

Molecules 2018, 23(3), 550; https://doi.org/10.3390/molecules23030550 - 2 Mar 2018

Cited by 20 | Viewed by 4556

Abstract

Okra seeds (OSD) have been proved to possess significantly anti-fatigue activity and due to their high contents of flavonoids and polyphenols. While, the quality of OSD is easily affected by harvest time, region and other factors. In this research, the rapid method based [...] Read more.

Okra seeds (OSD) have been proved to possess significantly anti-fatigue activity and due to their high contents of flavonoids and polyphenols. While, the quality of OSD is easily affected by harvest time, region and other factors. In this research, the rapid method based on Fourier transform near infrared (FT-NIR) spectroscopy was developed for quality assessment of okra seeds. Firstly, 120 samples’ spectra were acquired, and quantification of isoquercitrin, quercetin-3-O-gentiobioside, total phenols (TP) and antioxidant assays including 1-diphenyl-2-picrylhydrazyl (DPPH) scavenging, ferric reducing antioxidant power (FRAP) were conducted. Next, partial least squares (PLS) regression and full cross-validation were applied to develop calibration models for these data, and external validation was used to determine models’ quality. The coefficient of determination for calibration (

R_{c}^{2}

), the root mean square error of cross validation (RMSECV) and the corresponding determination coefficients for cross-validation (

R_{cv}^{2}

) proved all these models have excellent precision. Besides, the residual predictive deviation (RPD) of models (4.07 for isoquercitrin, 4.04 for quercetin-3-O-gentiobioside, 9.79 for TP, 4.58 for DPPH and 4.12 for FRAP) also demonstrated that these models possessed good predicative ability. All these results showed that FT-NIR spectroscopy could be used to rapidly determine active compounds and antioxidant activity of okra seeds. Full article

(This article belongs to the Section Analytical Chemistry)

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10 pages, 2325 KiB

Open AccessArticle

Quantitative ¹H-NMR Spectroscopy for Profiling Primary Metabolites in Mulberry Leaves

by Qianqian Liang, Qiuying Wang, Yuan Wang, Ya-nan Wang, Jia Hao and Miaomiao Jiang

Molecules 2018, 23(3), 554; https://doi.org/10.3390/molecules23030554 - 2 Mar 2018

Cited by 11 | Viewed by 10461

Abstract

The primary metabolites in aqueous extract of mulberry (Morus alba L.) leaves were characterized by using proton nuclear magnetic resonance (¹H-NMR) spectroscopy. With the convenience of resonance assignment, GABA together with the other 10 primary metabolites was simultaneously identified and [...] Read more.

The primary metabolites in aqueous extract of mulberry (Morus alba L.) leaves were characterized by using proton nuclear magnetic resonance (¹H-NMR) spectroscopy. With the convenience of resonance assignment, GABA together with the other 10 primary metabolites was simultaneously identified and quantified in one ¹H-NMR spectrum. In this study, external calibration curves for metabolites were employed to calculate the concentrations of interests. The proposed quantitative approach was demonstrated with good linearity (r² ranged in the interval of 0.9965–0.9999), precision, repeatability, stability (RSD values in the ranges of 0.35–4.89%, 0.77–7.13% and 0.28–2.33%, respectively) and accuracy (recovery rates from 89.2% to 118.5%). The established ¹H-NMR method was then successfully applied to quantify 11 primary metabolites in mulberry leaves from different geographical regions within a rapid analysis time and a simple sample preparation procedure. Full article

(This article belongs to the Collection Phytochemicals: Biosynthesis, Metabolism and Biological Activities)

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16 pages, 2060 KiB

Open AccessArticle

Enzyme Kinetics and Molecular Docking Studies on Cytochrome 2B6, 2C19, 2E1, and 3A4 Activities by Sauchinone

by Eun Chae Gong, Satya Chea, Anand Balupuri, Nam Sook Kang, Young-Won Chin and Young Hee Choi

Molecules 2018, 23(3), 555; https://doi.org/10.3390/molecules23030555 - 2 Mar 2018

Cited by 12 | Viewed by 5167

Abstract

Sauchinone, an active lignan isolated from the aerial parts of Saururus chinensis (Saururaceae), exhibits anti-inflammatory, anti-obesity, anti-hyperglycemic, and anti-hepatic steatosis effects. As herb–drug interaction (HDI) through cytochrome P450s (CYPs)-mediated metabolism limits clinical application of herbs and drugs in combination, this study sought to [...] Read more.

Sauchinone, an active lignan isolated from the aerial parts of Saururus chinensis (Saururaceae), exhibits anti-inflammatory, anti-obesity, anti-hyperglycemic, and anti-hepatic steatosis effects. As herb–drug interaction (HDI) through cytochrome P450s (CYPs)-mediated metabolism limits clinical application of herbs and drugs in combination, this study sought to explore the enzyme kinetics of sauchinone towards CYP inhibition in in vitro human liver microsomes (HLMs) and in vivo mice studies and computational molecular docking analysis. In in vitro HLMs, sauchinone reversibly inhibited CYP2B6, 2C19, 2E1, and 3A4 activities in non-competitive modes, showing inhibition constant (K_i) values of 14.3, 16.8, 41.7, and 6.84 μM, respectively. Also, sauchinone time-dependently inhibited CYP2B6, 2E1 and 3A4 activities in vitro HLMs. Molecular docking study showed that sauchinone could be bound to a few key amino acid residues in the active site of CYP2B6, 2C19, 2E1, and 3A4. When sibutramine, clopidogrel, or chlorzoxazone was co-administered with sauchinone to mice, the systemic exposure of each drug was increased compared to that without sauchinone, because sauchinone reduced the metabolic clearance of each drug. In conclusion, when sauchinone was co-treated with drugs metabolized via CYP2B6, 2C19, 2E1, or 3A4, sauchinone–drug interactions occurred because sauchinone inhibited the CYP-mediated metabolic activities. Full article

(This article belongs to the Section Natural Products Chemistry)

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15 pages, 1301 KiB

Open AccessArticle

Investigation of an ¹⁸F-labelled Imidazopyridotriazine for Molecular Imaging of Cyclic Nucleotide Phosphodiesterase 2A

by Susann Schröder, Barbara Wenzel, Winnie Deuther-Conrad, Rodrigo Teodoro, Mathias Kranz, Matthias Scheunemann, Ute Egerland, Norbert Höfgen, Detlef Briel, Jörg Steinbach and Peter Brust

Molecules 2018, 23(3), 556; https://doi.org/10.3390/molecules23030556 - 2 Mar 2018

Cited by 8 | Viewed by 4419

Abstract

Specific radioligands for in vivo visualization and quantification of cyclic nucleotide phosphodiesterase 2A (PDE2A) by positron emission tomography (PET) are increasingly gaining interest in brain research. Herein we describe the synthesis, the ¹⁸F-labelling as well as the biological evaluation of our latest [...] Read more.

Specific radioligands for in vivo visualization and quantification of cyclic nucleotide phosphodiesterase 2A (PDE2A) by positron emission tomography (PET) are increasingly gaining interest in brain research. Herein we describe the synthesis, the ¹⁸F-labelling as well as the biological evaluation of our latest PDE2A (radio-)ligand 9-(5-Butoxy-2-fluorophenyl)-2-(2-([¹⁸F])fluoroethoxy)-7-methylimidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine (([¹⁸F])TA5). It is the most potent PDE2A ligand out of our series of imidazopyridotriazine-based derivatives so far (IC₅₀ hPDE2A = 3.0 nM; IC₅₀ hPDE10A > 1000 nM). Radiolabelling was performed in a one-step procedure starting from the corresponding tosylate precursor. In vitro autoradiography on rat and pig brain slices displayed a homogenous and non-specific binding of the radioligand. Investigation of stability in vivo by reversed-phase HPLC (RP-HPLC) and micellar liquid chromatography (MLC) analyses of plasma and brain samples obtained from mice revealed a high fraction of one main radiometabolite. Hence, we concluded that [¹⁸F]TA5 is not appropriate for molecular imaging of PDE2A neither in vitro nor in vivo. Our ongoing work is focusing on further structurally modified compounds with enhanced metabolic stability. Full article

(This article belongs to the Special Issue Current Aspects of Radiopharmaceutical Chemistry)

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11 pages, 2417 KiB

Open AccessArticle

Capsaicin and Piperine Can Overcome Multidrug Resistance in Cancer Cells to Doxorubicin

by Hanmei Li, Sonja Krstin, Shihui Wang and Michael Wink

Molecules 2018, 23(3), 557; https://doi.org/10.3390/molecules23030557 - 2 Mar 2018

Cited by 68 | Viewed by 7834

Abstract

Background: Multidrug resistance (MDR) can develop in cancer cells after treatment with anticancer drugs, mainly due to the overexpression of the ATP-binding cassette (ABC) transporters. We analyzed the ability of two pungent-tasting alkaloids—capsaicin and piperine from Capsicum frutescens and Piper nigrum, respectively—to [...] Read more.

Background: Multidrug resistance (MDR) can develop in cancer cells after treatment with anticancer drugs, mainly due to the overexpression of the ATP-binding cassette (ABC) transporters. We analyzed the ability of two pungent-tasting alkaloids—capsaicin and piperine from Capsicum frutescens and Piper nigrum, respectively—to reverse multidrug resistance in the cancer cell lines Caco-2 and CEM/ADR 5000, which overexpress P-glycoprotein (P-gp) and other ABC transporters. Methods: The MTT assay was first used to determine the cytotoxicity of doxorubicin, the alkaloids, and digitonin alone, and then their combinations. Furthermore, rhodamine (Rho) 123 and calcein-AM were used to detect the effects of alkaloids on the activity of P-gp. Results: Capsaicin and piperine synergistically enhanced the cytotoxicity of doxorubicin in Caco-2 and CEM/ADR 5000 cells. Furthermore, capsaicin and piperine increased the intracellular accumulation of the fluorescent P-glycoprotein (P-gp) substrates rhodamine and calcein and inhibited their efflux from the MDR cell lines. Conclusion: Our study has demonstrated that capsaicin and piperine are P-gp substrates and have potential chemosensitizing activity, which might be interesting for the development of novel modulators of multidrug resistance. Full article

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8 pages, 1590 KiB

Open AccessFeature PaperArticle

Calixarenes as High Temperature Matrices for Thermally Activated Delayed Fluorescence: C₇₀ in Dihomooxacalix[4]arene

by Tiago Palmeira, Alexandre S. Miranda, Paula M. Marcos and Mário N. Berberan-Santos

Molecules 2018, 23(3), 558; https://doi.org/10.3390/molecules23030558 - 2 Mar 2018

Cited by 4 | Viewed by 4040

Abstract

Thermally activated delayed fluorescence (TADF) of ¹²C₇₀ and ¹³C₇₀ was observed up to 140 °C in a p-tert-butyldihomooxacalix[4]arene solid matrix, a temperature range significantly higher than that of previous TADF quantitative studies. An effective singlet–triplet energy gap of [...] Read more.

Thermally activated delayed fluorescence (TADF) of ¹²C₇₀ and ¹³C₇₀ was observed up to 140 °C in a p-tert-butyldihomooxacalix[4]arene solid matrix, a temperature range significantly higher than that of previous TADF quantitative studies. An effective singlet–triplet energy gap of 29 kJ/mol and triplet formation quantum yields of 0.97 and 0.99 were measured for ¹²C₇₀ and ¹³C₇₀, respectively. The photophysical properties of the two fullerenes in this new matrix are comparable to those obtained in polystyrene at a lower temperature range. Calixarenes are proposed to be suitable matrices for high temperature TADF studies and applications. Full article

(This article belongs to the Special Issue Calixarenes, Pillararenes, and Cucurbiturils)

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15 pages, 397 KiB

Open AccessArticle

Molecular Reactivity and Absorption Properties of Melanoidin Blue-G1 through Conceptual DFT

by Juan Frau and Daniel Glossman-Mitnik

Molecules 2018, 23(3), 559; https://doi.org/10.3390/molecules23030559 - 2 Mar 2018

Cited by 35 | Viewed by 4617

Abstract

This computational study presents the assessment of eleven density functionals that include CAM-B3LYP, LC-wPBE, M11, M11L, MN12L, MN12SX, N12, N12SX, wB97, wB97X and wB97XD related to the Def2TZVP basis sets together with the Solvation Model Density (SMD) solvation model in calculating the molecular [...] Read more.

This computational study presents the assessment of eleven density functionals that include CAM-B3LYP, LC-wPBE, M11, M11L, MN12L, MN12SX, N12, N12SX, wB97, wB97X and wB97XD related to the Def2TZVP basis sets together with the Solvation Model Density (SMD) solvation model in calculating the molecular properties and structure of the Blue-G1 intermediate melanoidin pigment. The chemical reactivity descriptors for the system are calculated via the conceptual Density Functional Theory (DFT). The choice of the active sites related to the nucleophilic, electrophilic, as well as radical attacks is made by linking them with the Fukui function indices, the electrophilic Parr functions and the condensed dual descriptor

Δ

f

(r)

. The prediction of the maximum absorption wavelength tends to be considerably accurate relative to its experimental value. The study found the MN12SX and N12SX density functionals to be the most appropriate density functionals in predicting the chemical reactivity of the studied molecule. Full article

(This article belongs to the Special Issue The Molecular Electron Density Theory: A Modern View of Molecular Reactivity in Organic Chemistry)

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10 pages, 961 KiB

Open AccessArticle

Isolation and Purification of Two Isoflavones from Hericium erinaceum Mycelium by High-Speed Counter-Current Chromatography

by Jinzhe He, Peng Fan, Simin Feng, Ping Shao and Peilong Sun

Molecules 2018, 23(3), 560; https://doi.org/10.3390/molecules23030560 - 2 Mar 2018

Cited by 20 | Viewed by 4094

Abstract

High-speed counter-current chromatography (HSCCC) was used to separate and purify two isoflavones for the first time from Hericium erinaceum (H. erinaceum) mycelium using a two-phase solvent system composed of chloroform-dichloromethane-methanol-water (4:2:3:2, v/v/v/v). These two [...] Read more.

High-speed counter-current chromatography (HSCCC) was used to separate and purify two isoflavones for the first time from Hericium erinaceum (H. erinaceum) mycelium using a two-phase solvent system composed of chloroform-dichloromethane-methanol-water (4:2:3:2, v/v/v/v). These two isoflavones were identified as genistein (4′,5,7-trihydroxyisoflavone, C₁₅H₁₀O₅) and daidzein (4′,7-dihydroxyisoflavone, C₁₅H₁₀O₄), using infrared spectroscopy (IR), electro-spary ionisation mass (ESI-MS), ¹H-nuclear magnetic resonance (NMR) and ¹³C-NMR spectra. About 23 mg genistein with 95.7% purity and 18 mg daidzein with 97.3% purity were isolated from 150 mg ethanolic extract of H. erinaceum mycelium. The results demonstrated that HSCCC was a feasible method to separate and purify genistein and daidzein from H. erinaceum mycelium. Full article

(This article belongs to the Special Issue Innovative Extraction Techniques and Hyphenated Instrument Configuration for Complex Matrices Analysis)

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11 pages, 7297 KiB

Open AccessArticle

Wedelolactone Enhances Osteoblastogenesis through ERK- and JNK-mediated BMP2 Expression and Smad/1/5/8 Phosphorylation

by Di Zhu, Xue Deng, Xiao-Fei Han, Xiao-Xin Sun, Tao-Wen Pan, Lu-Ping Zheng and Yan-Qiu Liu

Molecules 2018, 23(3), 561; https://doi.org/10.3390/molecules23030561 - 2 Mar 2018

Cited by 26 | Viewed by 6155

Abstract

Our previous study showed that wedelolactone, a compound isolated from Ecliptae herba, has the potential to enhance osteoblastogenesis. However, the molecular mechanisms by which wedelolactone promoted osteoblastogenesis from bone marrow mesenchymal stem cells (BMSCs) remain largely unknown. In this study, treatment with [...] Read more.

Our previous study showed that wedelolactone, a compound isolated from Ecliptae herba, has the potential to enhance osteoblastogenesis. However, the molecular mechanisms by which wedelolactone promoted osteoblastogenesis from bone marrow mesenchymal stem cells (BMSCs) remain largely unknown. In this study, treatment with wedelolactone (2 μg/mL) for 3, 6, and 9 days resulted in an increase in phosphorylation of extracellular signal-regulated kinases (ERKs), c-Jun N-terminal protein kinase (JNK), and p38. Phosphorylation of mitogen-activated protein kinases (MAPKs), ERK and JNK started to increase on day 3 of treatment, and p38 phosphorylation was increased by day 6 of treatment. Expression of bone morphogenetic protein (BMP2) mRNA and phosphorylation of Smad1/5/8 was enhanced after treatment of cells with wedelolactone for 6 and 9 days. The addition of the JNK inhibitor SP600125, ERK inhibitor PD98059, and p38 inhibitor SB203580 suppressed wedelolactone-induced alkaline-phosphatase activity, bone mineralization, and osteoblastogenesis-related marker genes including Runx2, Bglap, and Sp7. Increased expression of BMP2 mRNA and Smad1/5/8 phosphorylation was blocked by SP600125 and PD98059, but not by SB203580. These results suggested that wedelolactone enhanced osteoblastogenesis through induction of JNK- and ERK-mediated BMP2 expression and Smad1/5/8 phosphorylation. Full article

(This article belongs to the Collection Bioactive Compounds)

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10 pages, 3648 KiB

Open AccessArticle

Modification and Characterization of Fe₃O₄ Nanoparticles for Use in Adsorption of Alkaloids

by Linyan Yang, Jing Tian, Jiali Meng, Ruili Zhao, Cun Li, Jifei Ma and Tianming Jin

Molecules 2018, 23(3), 562; https://doi.org/10.3390/molecules23030562 - 2 Mar 2018

Cited by 69 | Viewed by 4737

Abstract

Magnetite (Fe₃O₄) is a ferromagnetic iron oxide of both Fe(II) and Fe(III), prepared by FeCl₂ and FeCl₃. XRD was used for the confirmation of Fe₃O₄. Via the modification of Tetraethyl orthosilicate (TEOS), [...] Read more.

Magnetite (Fe₃O₄) is a ferromagnetic iron oxide of both Fe(II) and Fe(III), prepared by FeCl₂ and FeCl₃. XRD was used for the confirmation of Fe₃O₄. Via the modification of Tetraethyl orthosilicate (TEOS), (3-Aminopropyl)trimethoxysilane (APTMS), and Alginate (AA), Fe₃O₄@SiO₂, Fe₃O₄@SiO₂-NH₂, and Fe₃O₄@SiO₂-NH₂-AA nanoparticles could be obtained, and IR and SEM were used for the characterizations. Alkaloid adsorption experiments exhibited that, as for Palmatine and Berberine, the most adsorption could be obtained at pH 8 when the adsorption time was 6 min. The adsorption percentage of Palmatine was 22.2%, and the adsorption percentage of Berberine was 23.6% at pH 8. Considering the effect of adsorption time on liquid phase system, the adsorption conditions of 8 min has been chosen when pH 7 was used. The adsorption percentage of Palmatine was 8.67%, and the adsorption percentage of Berberine was 7.25%. Considering the above conditions, pH 8 and the adsorption time of 8min could be chosen for further uses. Full article

(This article belongs to the Special Issue Innovative Extraction Techniques and Hyphenated Instrument Configuration for Complex Matrices Analysis)

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13 pages, 4890 KiB

Open AccessArticle

Antiangiogenic Potential of Microbial Metabolite Elaiophylin for Targeting Tumor Angiogenesis

by Haet Nim Lim, Jun-Pil Jang, Jang Mi Han, Jae-Hyuk Jang, Jong Seog Ahn and Hye Jin Jung

Molecules 2018, 23(3), 563; https://doi.org/10.3390/molecules23030563 - 2 Mar 2018

Cited by 25 | Viewed by 4574

Abstract

Angiogenesis plays a very important role in tumor progression through the creation of new blood vessels. Therefore, angiogenesis inhibitors could contribute to cancer treatment. Here, we show that a microbial metabolite, elaiophylin, exhibits potent antiangiogenic activity from in vitro and in vivo angiogenesis [...] Read more.

Angiogenesis plays a very important role in tumor progression through the creation of new blood vessels. Therefore, angiogenesis inhibitors could contribute to cancer treatment. Here, we show that a microbial metabolite, elaiophylin, exhibits potent antiangiogenic activity from in vitro and in vivo angiogenesis assays. Elaiophylin dramatically suppressed in vitro angiogenic characteristics such as proliferation, migration, adhesion, invasion and tube formation of human umbilical vein endothelial cells (HUVECs) stimulated by vascular endothelial growth factor (VEGF) at non-toxic concentrations. In addition, elaiophylin immensely inhibited in vivo angiogenesis of the chorioallantoic membrane (CAM) from growing chick embryos without cytotoxicity. The activation of VEGF receptor 2 (VEGFR2) in HUVECs by VEGF was inhibited by elaiophylin, resulting in the suppression of VEGF-induced activation of downstream signaling molecules, Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, nuclear factor-κB (NFκB), matrix metalloproteinase (MMP)-2 and -9 which are closely associated with VEGF-induced angiogenesis. We also found that elaiophylin blocked tumor cell-induced angiogenesis both in vitro and in vivo. Elaiophylin downregulated the expression of VEGF by inhibiting hypoxia inducible factor-1α (HIF-1α) accumulation in tumor cells. To our knowledge, these results for the first time demonstrate that elaiophylin effectively inhibits angiogenesis and thus may be utilized as a new class of natural antiangiogenic agent for cancer therapy. Full article

(This article belongs to the Collection Natural Products: Anticancer Potential and Beyond)

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16 pages, 5137 KiB

Open AccessArticle

Synergistic Effects of Salvianolic Acid B and Puerarin on Cerebral Ischemia Reperfusion Injury

by Chengli Ling, Jianming Liang, Chun Zhang, Ruixiang Li, Qianqian Mou, Jin Qin, Xiaofang Li and Jianxin Wang

Molecules 2018, 23(3), 564; https://doi.org/10.3390/molecules23030564 - 2 Mar 2018

Cited by 43 | Viewed by 5059

Abstract

Ischemic stroke (IS) is characterized by the sudden loss of blood circulation to an area of the brain, resulting in a corresponding loss of neurologic function. It has been a worldwide critical disease threatening to the health and life of human beings. Despite [...] Read more.

Ischemic stroke (IS) is characterized by the sudden loss of blood circulation to an area of the brain, resulting in a corresponding loss of neurologic function. It has been a worldwide critical disease threatening to the health and life of human beings. Despite significant progresses achieved, effective treatment still remains a formidable challenge due to the complexity of the disease. Salvianolic acid B (Sal-B) and Puerarin (Pue) are two active neuroprotectants isolated from traditional Chinese herbs, Salvia miltiorrhiza and Kudzu root respectively, which have been used for the prevention and treatment of IS for thousands of years in China. The activities of two compounds against cerebral ischemia reperfusion injury have been confirmed via various pathways. However, the therapeutic efficacy of any of the two components is still unsatisfied. In the present study, the effect of the combination of Sal-B and Pue on IS was evaluated and validated in vitro and in vivo. The ratio of two compounds was firstly optimized based on the results of CoCl₂ damaged PC12 cells model. The co-administration exhibited significantly protective effect in CoCl₂ induced PC12 cells injury model by reducing ROS, inhibiting apoptosis and improving mitochondrial membrane potential in vitro. Moreover, Sal-B + Pue significantly relieved neurological deficit scores and infarct area than Sal-B or Pue alone in vivo. The results indicated that neuroprotection mechanism of Sal-B + Pue was related to TLR4/MyD88 and SIRT1 activation signaling pathway to achieve synergistic effect, due to the inhibition of NF-κB transcriptional activity and expression of pro-inflammatory cytokine (TNF-α, IL-1β, IL-6). In conclusion, the combination of Sal-B and Pue exerted much stronger neuroprotective effect than Sal-B or Pue alone, which provides a potential new drug and has great significance for the treatment of IS. Full article

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14 pages, 15130 KiB

Open AccessArticle

New Drug Candidate Targeting the 4A1 Orphan Nuclear Receptor for Medullary Thyroid Cancer Therapy

by Lei Zhang, Wen Liu, Qun Wang, Qinpei Li, Huijuan Wang, Jun Wang, Tieshan Teng, Mingliang Chen, Ailing Ji and Yanzhang Li

Molecules 2018, 23(3), 565; https://doi.org/10.3390/molecules23030565 - 2 Mar 2018

Cited by 22 | Viewed by 5526

Abstract

Medullary thyroid cancer (MTC) is a relatively rare thyroid cancer responsible for a substantial fraction of thyroid cancer mortality. More effective therapeutic drugs with low toxicity for MTC are urgently needed. Orphan nuclear receptor 4A1 (NR4A1) plays a pivotal role in regulating the [...] Read more.

Medullary thyroid cancer (MTC) is a relatively rare thyroid cancer responsible for a substantial fraction of thyroid cancer mortality. More effective therapeutic drugs with low toxicity for MTC are urgently needed. Orphan nuclear receptor 4A1 (NR4A1) plays a pivotal role in regulating the proliferation and apoptosis of a variety of tumor cells. Based on the NR4A1 protein structure, 2-imino-6-methoxy-2H-chromene-3-carbothioamide (IMCA) was identified from the Specs compounds database using the protein structure-guided virtual screening approach. Computationally-based molecular modeling studies suggested that IMCA has a high affinity for the ligand binding pocket of NR4A1. MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide] and apoptosis assays demonstrated that IMCA resulted in significant thyroid cancer cell death. Immunofluorescence assays showed that IMCA induced NR4A1 translocation from the nucleus to the cytoplasm in thyroid cancer cell lines, which may be involved in the cell apoptotic process. In this study, the quantitative polymerase chain reaction results showed that the IMCA-induced upregulation of sestrin1 and sestrin2 was dose-dependent in thyroid cancer cell lines. Western blot showed that IMCA increased phosphorylation of adenosine 5′-monophosphate-activated protein kinase (AMPK) and decreased phosphorylation of ribosomal protein S6 kinase (p70S6K), which is the key enzyme in the mammalian target of rapamycin (mTOR) pathway. The experimental results suggest that IMCA is a drug candidate for MTC therapy and may work by increasing the nuclear export of NR4A1 to the cytoplasm and the tumor protein 53 (p53)-sestrins-AMPK-mTOR signaling pathway. Full article

(This article belongs to the Section Medicinal Chemistry)

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14 pages, 4448 KiB

Open AccessFeature PaperArticle

A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing

by Conrad V. Simoben, Dina Robaa, Alokta Chakrabarti, Karin Schmidtkunz, Martin Marek, Julien Lancelot, Srinivasaraghavan Kannan, Jelena Melesina, Tajith B. Shaik, Raymond J. Pierce, Christophe Romier, Manfred Jung and Wolfgang Sippl

Molecules 2018, 23(3), 566; https://doi.org/10.3390/molecules23030566 - 2 Mar 2018

Cited by 32 | Viewed by 6385

Abstract

A promising means in the search of new small molecules for the treatment of schistosomiasis (amongst other parasitic ailments) is by targeting the parasitic epigenome. In the present study, a docking based virtual screening procedure using the crystal structure of histone deacetylase 8 [...] Read more.

A promising means in the search of new small molecules for the treatment of schistosomiasis (amongst other parasitic ailments) is by targeting the parasitic epigenome. In the present study, a docking based virtual screening procedure using the crystal structure of histone deacetylase 8 from Schistosoma mansoni (smHDAC8) was designed. From the developed screening protocol, we were able to identify eight novel N-(2,5-dioxopyrrolidin-3-yl)-n-alkylhydroxamate derivatives as smHDAC8 inhibitors with IC₅₀ values ranging from 4.4–20.3 µM against smHDAC8. These newly identified inhibitors were further tested against human histone deacetylases (hsHDAC1, 6 and 8), and were found also to be exerting interesting activity against them. In silico prediction of the docking pose of the compounds was confirmed by the resolved crystal structure of one of the identified hits. This confirmed these compounds were able to chelate the catalytic zinc ion in a bidentate fashion, whilst showing an inverted binding mode of the hydroxamate group when compared to the reported smHDAC8/hydroxamates crystal structures. Therefore, they can be considered as new potential scaffold for the development of new smHDAC8 inhibitors by further investigation of their structure–activity relationship. Full article

(This article belongs to the Special Issue Modulators of Histone Acetylation: A Medicinal Chemistry Perspective)

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21 pages, 10912 KiB

Open AccessArticle

Identification and Characterizations of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Scaffold Hopping- and 2D-Molecular Fingerprint-Based Similarity Search

by Hong Ding, Wen Chao Lu, Jun Chi Hu, Yu-Chih Liu, Chen Hua Zhang, Fu Lin Lian, Nai Xia Zhang, Fan Wang Meng, Cheng Luo and Kai Xian Chen

Molecules 2018, 23(3), 567; https://doi.org/10.3390/molecules23030567 - 2 Mar 2018

Cited by 13 | Viewed by 5285

Abstract

SET7, serving as the only histone methyltransferase that monomethylates ‘Lys-4’ of histone H3, has been proved to function as a key regulator in diverse biological processes, such as cell proliferation, transcriptional network regulation in embryonic stem cell, cell cycle control, protein stability, heart [...] Read more.

SET7, serving as the only histone methyltransferase that monomethylates ‘Lys-4’ of histone H3, has been proved to function as a key regulator in diverse biological processes, such as cell proliferation, transcriptional network regulation in embryonic stem cell, cell cycle control, protein stability, heart morphogenesis and development. What′s more, SET7 is involved inthe pathogenesis of alopecia aerate, breast cancer, tumor and cancer progression, atherosclerosis in human carotid plaques, chronic renal diseases, diabetes, obesity, ovarian cancer, prostate cancer, hepatocellular carcinoma, and pulmonary fibrosis. Therefore, there is urgent need to develop novel SET7 inhibitors. In this paper, based on DC-S239 which has been previously reported in our group, we employed scaffold hopping- and 2D fingerprint-based similarity searches and identified DC-S285 as the new hit compound targeting SET7 (IC₅₀ = 9.3 μM). Both radioactive tracing and NMR experiments validated the interactions between DC-S285 and SET7 followed by the second-round similarity search leading to the identification ofDC-S303 with the IC₅₀ value of 1.1 μM. In cellular level, DC-S285 retarded tumor cell proliferation and showed selectivity against MCF7 (IC₅₀ = 21.4 μM), Jurkat (IC₅₀ = 2.2 μM), THP1 (IC₅₀ = 3.5 μM), U937 (IC₅₀ = 3.9 μM) cell lines. Docking calculations suggested that DC-S303 share similar binding mode with the parent compoundDC-S239. What′s more, it presented good selectivity against other epigenetic targets, including SETD1B, SETD8, G9a, SMYD2 and EZH2. DC-S303 can serve as a drug-like scaffold which may need further optimization for drug development, and can be used as chemical probe to help the community to better understand the SET7 biology. Full article

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19 pages, 22984 KiB

Open AccessArticle

Search for Fibrous Aggregates Potentially Useful in Regenerative Medicine Formed under Physiological Conditions by Self-Assembling Short Peptides Containing Two Identical Aromatic Amino Acid Residues

by Justyna Fraczyk, Wojciech Lipinski, Agata Chaberska, Joanna Wasko, Kamil Rozniakowski, Zbigniew J. Kaminski, Maciej Bogun, Zbigniew Draczynski, Elzbieta Menaszek, Ewa Stodolak-Zych, Marta Kaminska and Beata Kolesinska

Molecules 2018, 23(3), 568; https://doi.org/10.3390/molecules23030568 - 2 Mar 2018

Cited by 9 | Viewed by 3894

Abstract

This study investigates the propensity of short peptides to self-organize and the influence of aggregates on cell cultures. The dipeptides were derived from both enantiomers of identical aromatic amino acids and tripeptides were prepared from two identical aromatic amino acids with one cysteine [...] Read more.

This study investigates the propensity of short peptides to self-organize and the influence of aggregates on cell cultures. The dipeptides were derived from both enantiomers of identical aromatic amino acids and tripeptides were prepared from two identical aromatic amino acids with one cysteine or methionine residue in the C-terminal, N-terminal, or central position. The formation or absence of fibrous structures under physiological conditions was established using Congo Red and Thioflavine T assays as well as by microscopic examination using normal and polarized light. The in vitro stability of the aggregates in buffered saline solution was assessed over 30 days. Materials with potential for use in regenerative medicine were selected based on the cytotoxicity of the peptides to the endothelial cell line EA.hy 926 and the wettability of the surfaces of the films, as well as using scanning electron microscopy. The criteria were fulfilled by H-dPhedPhe-OH, H-dCysdPhedPhe-OH, H-CysTyrTyr-OH, H-dPhedPhedCys-OH, H-TyrTyrMet-OH, and H–TyrMetTyr–OH. Our preliminary results suggest that the morphology and cell viability of L919 fibroblast cells do not depend on the stereochemistry of the self-organizing peptides. Full article

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12 pages, 1642 KiB

Open AccessArticle

Physicochemical Properties of Bovine Serum Albumin-Glucose and Bovine Serum Albumin-Mannose Conjugates Prepared by Pulsed Electric Fields Treatment

by Wenjie Jian, Liangyu Wang, Lanlan Wu and Yuan-ming Sun

Molecules 2018, 23(3), 570; https://doi.org/10.3390/molecules23030570 - 3 Mar 2018

Cited by 16 | Viewed by 4319

Abstract

The pulsed electric fields (PEF) treatment is a novel method for obtaining glycated proteins by way of a Maillard reaction between proteins and polysaccharides but its effect on the preparation of protein–monosaccharide conjugate has not been explored. This study aimed to prepare bovine [...] Read more.

The pulsed electric fields (PEF) treatment is a novel method for obtaining glycated proteins by way of a Maillard reaction between proteins and polysaccharides but its effect on the preparation of protein–monosaccharide conjugate has not been explored. This study aimed to prepare bovine serum albumin (BSA)–glucose and BSA–mannose conjugates using PEF in pH 10.0 at an intensity of 10 or 20 kV/cm, frequency of 1 kHz, pulse width of 20 μs and 73.5 pulses. The conjugates were evaluated for physicochemical properties. The results indicated that PEF not only promoted Maillard reaction between BSA and glucose or mannose but also alleviated the undesirable browning. PEF treatment favored the increased surface hydrophobicity and emulsifying activity in BSA but reduced surface hydrophobicity and foaming stability and improved foaming capacity in BSA–glucose and BSA–mannose conjugates. These findings provided useful considerations in the application of PEF treatment as a potential method to prepare BSA–monosaccharide conjugates by Maillard reaction. Full article

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11 pages, 2460 KiB

Open AccessArticle

In Vitro and In Vivo Anti-Osteoarthritis Effects of 2,3,5,4′-Tetrahydroxystilbene-2-O-β-d-Glucoside from Polygonum Multiflorum

by Po-Wei Tsai, Yi-Hui Lee, Lih-Geeng Chen, Chia-Jung Lee and Ching-Chiung Wang

Molecules 2018, 23(3), 571; https://doi.org/10.3390/molecules23030571 - 3 Mar 2018

Cited by 24 | Viewed by 4783

Abstract

Polygonum multiflorum Thunb. is a traditional herbal medicine that is rich in polyphenols. The major compound, 2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucoside (THSG) has many pharmacological activities, such as antioxidative and free radical-scavenging properties, and the abilities to reduce hyperlipidemia, prevent lipid peroxidation, and [...] Read more.

Polygonum multiflorum Thunb. is a traditional herbal medicine that is rich in polyphenols. The major compound, 2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucoside (THSG) has many pharmacological activities, such as antioxidative and free radical-scavenging properties, and the abilities to reduce hyperlipidemia, prevent lipid peroxidation, and protect the cardiovascular system. In this study, the anti-osteoarthritis (OA) effects of THSG were explored using in vitro and in vivo models. THSG inhibited nitric oxide (NO) and prostaglandin E₂ (PGE₂) production and inducible NO synthase (iNOS) and cyclooxygenase-2 expressions by lipopolysaccharide-stimulated RAW 264.7 cells. On the other hand, THSG inhibited PGE₂ production and iNOS and matrix metalloproteinase-13 expressions by interleukin-1β-stimulated primary rat chondrocytes. Through a mono-iodoacetate-induced rat OA model assay, THSG reduced paw edema and improved the weight-bearing distribution. Therefore, THSG has anti-inflammatory activity and could be applied as a lead compound for the development as an OA drug. Full article

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9 pages, 2329 KiB

Open AccessFeature PaperArticle

Network Formation via Anion Coordination: Crystal Structures Based on the Interplay of Non-Covalent Interactions

by Matteo Savastano, Carla Bazzicalupi, Palma Mariani and Antonio Bianchi

Molecules 2018, 23(3), 572; https://doi.org/10.3390/molecules23030572 - 3 Mar 2018

Cited by 11 | Viewed by 3413

Abstract

We describe the synthesis and the structural characterization of new H₂L(CF₃CO₂)₂ (1) and H₂L(Ph₂PO₄)₂ (2) compounds containing the diprotonated form (H₂L²⁺) [...] Read more.

We describe the synthesis and the structural characterization of new H₂L(CF₃CO₂)₂ (1) and H₂L(Ph₂PO₄)₂ (2) compounds containing the diprotonated form (H₂L²⁺) of the tetrazine-based molecule 3,6-di(pyridin-4-yl)-1,2,4,5-tetrazine. X-ray diffraction (XRD) analysis of single crystals of these compounds showed that H₂L²⁺ displays similar binding properties toward both anions when salt bridge interactions are taken into account. Nevertheless, the different shapes, sizes and functionalities of trifluoroacetate and diphenyl phosphate anions define quite different organization patterns leading to the peculiar crystal lattices of 1 and 2. These three-dimensional (3D) architectures are self-assembled by a variety of non-covalent forces, among which prominent roles are played by fluorine–π (in 1) and anion–π (in 2) interactions. Full article

(This article belongs to the Special Issue Noncovalent Interactions: A Useful Tool for Crystal Design)

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14 pages, 629 KiB

Open AccessArticle

Quality Evaluation of Apocyni Veneti Folium from Different Habitats and Commercial Herbs Based on Simultaneous Determination of Multiple Bioactive Constituents Combined with Multivariate Statistical Analysis

by Cuihua Chen, Zixiu Liu, Lisi Zou, Xunhong Liu, Chuan Chai, Hui Zhao, Ying Yan and Chengcheng Wang

Molecules 2018, 23(3), 573; https://doi.org/10.3390/molecules23030573 - 3 Mar 2018

Cited by 19 | Viewed by 4071

Abstract

Apocyni Veneti Folium (AVF) is a kind of staple traditional Chinese medicine with vast clinical consumption because of its positive effects. However, due to the habitats and adulterants, its quality is uneven. To control the quality of this medicinal herb, in this study, [...] Read more.

Apocyni Veneti Folium (AVF) is a kind of staple traditional Chinese medicine with vast clinical consumption because of its positive effects. However, due to the habitats and adulterants, its quality is uneven. To control the quality of this medicinal herb, in this study, the quality of AVF was evaluated based on simultaneous determination of multiple bioactive constituents combined with multivariate statistical analysis. A reliable method based on ultra-fast liquid chromatography tandem triple quadrupole mass spectrometry (UFLC-QTRAP-MS/MS) was developed for the simultaneous determination of a total of 43 constituents, including 15 flavonoids, 6 organic acids, 13 amino acids, and 9 nucleosides in 41 Luobumaye samples from different habitats and commercial herbs. Furthermore, according to the contents of these 43 constituents, principal component analysis (PCA) was employed to classify and distinguish between AVF and its adulterants, leaves of Poacynum hendersonii (PHF), and gray relational analysis (GRA) was performed to evaluate the quality of the samples. The proposed method was successfully applied to the comprehensive quality evaluation of AVF, and all results demonstrated that the quality of AVF was higher than the PHF. This study will provide comprehensive information necessary for the quality control of AVF. Full article

(This article belongs to the Collection Advances in Liquid Separation Techniques for Food and Pharmaceutical Analysis)

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8 pages, 684 KiB

Open AccessArticle

Anti-Cancer Activity of Phenyl and Pyrid-2-yl 1,3-Substituted Benzo[1,2,4]triazin-7-ones and Stable Free Radical Precursors

by Lee-Ann J. Keane, Styliana I. Mirallai, Martin Sweeney, Michael P. Carty, Georgia A. Zissimou, Andrey A. Berezin, Panayiotis A. Koutentis and Fawaz Aldabbagh

Molecules 2018, 23(3), 574; https://doi.org/10.3390/molecules23030574 - 3 Mar 2018

Cited by 9 | Viewed by 5017

Abstract

Cell viability studies for benzo[1,2,4]triazin-7-ones and 1,2,4-benzotriazinyl (Blatter-type) radical precursors are described with comparisons made with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). All of the stable free radicals were several orders of magnitude less cytotoxic than the benzo[1,2,4]triazin-7-ones. The synthesis and evaluation of two new pyrid-2-yl benzo[1,2,4]triazin-7-ones [...] Read more.

Cell viability studies for benzo[1,2,4]triazin-7-ones and 1,2,4-benzotriazinyl (Blatter-type) radical precursors are described with comparisons made with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). All of the stable free radicals were several orders of magnitude less cytotoxic than the benzo[1,2,4]triazin-7-ones. The synthesis and evaluation of two new pyrid-2-yl benzo[1,2,4]triazin-7-ones are described, where altering the 1,3-substitution from phenyl to pyrid-2-yl increased cytotoxicity against most cancer cell lines, as indicated using National Cancer Institute (NCI) one-dose testing. COMPARE analysis of five-dose testing data from the NCI showed very strong correlations to the naturally occurring anti-cancer compound pleurotin. COMPARE is program, which analyzes similarities in cytotoxicity data of compounds, and enables quantitative expression as Pearson correlation coefficients. Compounds were also evaluated using the independent MTT assay, which was compared with SRB assay data generated at the NCI. Full article

(This article belongs to the Section Medicinal Chemistry)

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11 pages, 1799 KiB

Open AccessArticle

GC-MS Analysis of the Composition of the Essential Oil from Dendranthema indicum Var. Aromaticum Using Three Extraction Methods and Two Columns

by Sanpeng Fan, Jin Chang, Yufeng Zong, Gaosheng Hu and Jingming Jia

Molecules 2018, 23(3), 576; https://doi.org/10.3390/molecules23030576 - 4 Mar 2018

Cited by 62 | Viewed by 8771

Abstract

Dendranthema indicum var. aromaticum, which is an aromatic plant with a strong and special fragrance throughout the whole plant, is used for the treatment of colds and headaches, and as a mosquito repellant in Shennongjia, Hubei province, China. To analyze the composition [...] Read more.

Dendranthema indicum var. aromaticum, which is an aromatic plant with a strong and special fragrance throughout the whole plant, is used for the treatment of colds and headaches, and as a mosquito repellant in Shennongjia, Hubei province, China. To analyze the composition of the essential oil from this medicinal herb, we developed a gas chromatography-mass Spectrometry (GC-MS) method including microwave-assisted extraction, hydrodistillation and direct headspace analysis in two different stationary phase columns. In total, 115 volatile compounds were identified, of which 90 compounds were identified using Rxi-5MS and 78 using HP-INNOWAX. Our results revealed that the oil was mainly composed of five categories of compound: oxygenated monoterpenes (28.76–78.10%), oxygenated sesquiterpenes (4.27–38.06%), sesquiterpenes (3.22–11.57%), fatty hydrocarbons (1.65–9.81%) and monoterpenes (0–3.32%). The major constituents are α-thujone, β-thujone, cis-sabinol, sabinyl acetate and (-)-neointermedeol.However, the essential oil composition in the published literature differs significantly. Therefore, a cluster analysis was carried out using the top ten compositions in the reported literature as well as this study, using Minitab software. To provide detailed information on plant origin, the ITS1-5.8s-ITS2 region was amplified and sequenced (Accession No. MF668250). Besides, in order to provide a macroscopic view of the chemical composition, the biosynthetic pathway of the main components was summarized according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) database and the published literatures. Full article

(This article belongs to the Collection Recent Advances in Flavors and Fragrances)

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10 pages, 1872 KiB

Open AccessArticle

Quantum Chemical Design Guidelines for Absorption and Emission Color Tuning of fac-Ir(ppy)₃ Complexes

by Yoshiki Natori, Yasutaka Kitagawa, Shogo Aoki, Rena Teramoto, Hayato Tada, Iori Era and Masayoshi Nakano

Molecules 2018, 23(3), 577; https://doi.org/10.3390/molecules23030577 - 5 Mar 2018

Cited by 7 | Viewed by 5457

Abstract

The fac-Ir(ppy)₃ complex, where ppy denotes 2-phenylpyridine, is one of the well-known luminescent metal complexes having a high quantum yield. However, there have been no specific molecular design guidelines for color tuning. For example, it is still unclear how its optical [...] Read more.

The fac-Ir(ppy)₃ complex, where ppy denotes 2-phenylpyridine, is one of the well-known luminescent metal complexes having a high quantum yield. However, there have been no specific molecular design guidelines for color tuning. For example, it is still unclear how its optical properties are changed when changing substitution groups of ligands. Therefore, in this study, differences in the electronic structures and optical properties among several substituted fac-Ir(ppy)₃ derivatives are examined in detail by density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations. On the basis of those results, we present rational design guidelines for absorption and emission color tuning by modifying the species of substituents and their substitution positions. Full article

(This article belongs to the Special Issue Advanced Functional Dyes)

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19 pages, 5352 KiB

Open AccessArticle

¹H-NMR Profiling and Chemometric Analysis of Selected Honeys from South Africa, Zambia, and Slovakia

by Emmanuel O. Olawode, Roman Tandlich and Garth Cambray

Molecules 2018, 23(3), 578; https://doi.org/10.3390/molecules23030578 - 5 Mar 2018

Cited by 25 | Viewed by 7118

Abstract

Honey is the natural sweet substance produced by honeybee from nectar or honeydew, exhibiting several nutritional and health benefits. It contains a complex mixture of compounds in different proportions, with sugars being the main component. The physicochemical characteristics of ten honeys were evaluated; [...] Read more.

Honey is the natural sweet substance produced by honeybee from nectar or honeydew, exhibiting several nutritional and health benefits. It contains a complex mixture of compounds in different proportions, with sugars being the main component. The physicochemical characteristics of ten honeys were evaluated; represented by five, three, and two from South Africa, Slovakia, and Zambia, respectively. The range of values for the pH (3.75–4.38), electrical conductivity (99–659 µS/cm), and moisture content (14.2–17.7%) are within the recommended limits for quality honeys. ¹H-NMR (Nuclear Magnetic Resonance) profiling of the honeys in D₂O was determined, and the data were analysed by chemometrics. This method is fast, reproducible, and sample pre-treatment is not necessary. The ¹H-NMR fingerprints of various chemical shift regions showed similarity or dissimilarity across geographical origins that are useful for identification, detection of adulteration, and quality control. The principal component analysis PCA and partial linear square discriminant analysis PLS-DA of the ¹H-NMR profiles successively categorises the honeys into two chemically related groups. The R² values are higher than the corresponding Q² values for all samples, confirming the reliability of the model. Honeys in the same cluster contain similar metabolites and belong to the same botanic or floral origin. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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11 pages, 1853 KiB

Open AccessArticle

Steroidal Saponins from Vernonia amygdalina Del. and Their Biological Activity

by Jing Wang, Hua Song, Xiaoxue Wu, Shuyi Zhang, Xuemin Gao, Funan Li, Xuan Zhu and Qing Chen

Molecules 2018, 23(3), 579; https://doi.org/10.3390/molecules23030579 - 5 Mar 2018

Cited by 29 | Viewed by 6394

Abstract

In the present study, four new steroidal saponins, namely vernoniamyoside A–D (1–4), together with the two known steroidal saponins vernoamyoside D (5) and vernonioside B₂ (6) were isolated from the ethanol extract of leaves [...] Read more.

In the present study, four new steroidal saponins, namely vernoniamyoside A–D (1–4), together with the two known steroidal saponins vernoamyoside D (5) and vernonioside B₂ (6) were isolated from the ethanol extract of leaves of the African medicinal plant Vernonia amygdalina Del. (Asteraceae). Their structures were demonstrated by spectral analyses along with 1D and 2D nuclear magnetic resonance (NMR) techniques and mass spectrometry (MS). The cytotoxicity of the compounds was also tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method on the cell lines Hela, MCF-7, BT-549 and MDA-MB-231. Vernoniamyoside A, vernoniamyoside B, and vernonioside B₂ showed cytotoxicity towards BT-549 cell lines. Vernoniamyoside C, vernoniamyoside D and vernoamyoside D showed different levels of cytotoxic activities. Full article

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10 pages, 1350 KiB

Open AccessArticle

Phenolic Compounds from Belamcanda chinensis Seeds

by Ying-Ying Song, Ying Liu, Yong-Ming Yan, Xi-Feng Lu and Yong-Xian Cheng

Molecules 2018, 23(3), 580; https://doi.org/10.3390/molecules23030580 - 5 Mar 2018

Cited by 9 | Viewed by 3896

Abstract

Two new sucrose derivatives, namely, belamcanosides A (1) and B (2), together with five other known compounds (3−7), were isolated from the seeds of Belamcanda chinensis (L.) DC. Their structures were identified based on spectroscopic [...] Read more.

Two new sucrose derivatives, namely, belamcanosides A (1) and B (2), together with five other known compounds (3−7), were isolated from the seeds of Belamcanda chinensis (L.) DC. Their structures were identified based on spectroscopic data. Especially, the absolute configurations of fructose and glucose residues in 1 and 2 were assigned by acid hydrolysis, followed by derivatization and gas chromatography (GC) analysis. Among the known compounds, (−)-hopeaphenol (3), (+)-syringaresinol (4), and quercetin (5), were isolated from B. chinensis for the first time. In addition, biological evaluation of 1 and 2 against cholesterol synthesis and metabolism at the gene level was carried out. The results showed that compounds 1 and 2 could regulate the expression of cholesterol synthesis and metabolism-associated genes, including 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), squalene epoxidase (SQLE), low density lipoprotein receptor (LDLR), and sortilin (SORT1) genes in HepG2 cells. Full article

(This article belongs to the Section Natural Products Chemistry)

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13 pages, 2130 KiB

Open AccessArticle

A Facile One-Pot Construction of Succinimide-Fused Spiro[Pyrrolidine-2,3′-Oxindoles] via 1,3-Dipolar Cycloaddition Involving 3-Amino Oxindoles and Maleimides

by Lunqiang Jin and Feng Liang

Molecules 2018, 23(3), 582; https://doi.org/10.3390/molecules23030582 - 5 Mar 2018

Cited by 4 | Viewed by 3775

Abstract

Increasing interests have been invested in the development of synthetic strategies toward the construction of spiro[pyrrolidine-2,3′-oxindole], which is the core structural skeleton in some compounds with diverse biological activities. In this work, an efficient diastereoselective 1,3-dipolar cycloaddition reaction of azomethine ylides generated in [...] Read more.

Increasing interests have been invested in the development of synthetic strategies toward the construction of spiro[pyrrolidine-2,3′-oxindole], which is the core structural skeleton in some compounds with diverse biological activities. In this work, an efficient diastereoselective 1,3-dipolar cycloaddition reaction of azomethine ylides generated in situ from 3-amino oxindoles and aldehydes with maleimides has been described. The protocol provides a facile and efficient access to structurally diverse succinimide-fused spiro[pyrrolidine-2,3′-oxindole] compounds in good to high yields (up to 93%) with moderate to excellent diastereoselectivities (up to >95:5). The relative stereochemistry of cycloaddition products has been assigned by X-ray diffraction analysis. Full article

(This article belongs to the Special Issue Advances in Spiro Compounds)

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13 pages, 2836 KiB

Open AccessArticle

Anti-Inflammatory Effect of Lupinalbin A Isolated from Apios americana on Lipopolysaccharide-Treated RAW264.7 Cells

by Hyo-Young Kim, Jang Hoon Kim, YangKang So, Si-Yong Kang, Hye Gwang Jeong and Chang Hyun Jin

Molecules 2018, 23(3), 583; https://doi.org/10.3390/molecules23030583 - 6 Mar 2018

Cited by 10 | Viewed by 4724

Abstract

Apios americana, a leguminous plant, is used as food in some countries. Although the biological activities of Apios extract have been reported, there have been no reports about the anti-inflammatory mechanism of lupinalbin A on the RAW264.7 cells. In this study, we investigated [...] Read more.

Apios americana, a leguminous plant, is used as food in some countries. Although the biological activities of Apios extract have been reported, there have been no reports about the anti-inflammatory mechanism of lupinalbin A on the RAW264.7 cells. In this study, we investigated the anti-inflammatory effect of A. americana lupinalbin A on lipopolysaccharide (LPS)-treated RAW264.7 cells. Lupinalbin A significantly inhibited nitric oxide production and inducible nitric oxide synthase expression in LPS-treated RAW264.7 cells. The expression of cytokines, including interleukin-6, tumor necrosis factor-α, and chemokine of monocyte chemoattractant protein, was reduced under lupinalbin A exposure in LPS-treated RAW264.7 cells. In addition, lupinalbin A significantly decreased LPS-induced interferon (IFN)-β production and STAT1 protein levels in RAW264.7 cells. Taken together, these results suggest that A. americana lupinalbin A exerts anti-inflammatory effects via the inhibition of pro-inflammatory cytokines and blocking of IFN-β/STAT1 pathway activation. Full article

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11 pages, 6073 KiB

Open AccessArticle

Melatonin Improves Heat Tolerance in Kiwifruit Seedlings through Promoting Antioxidant Enzymatic Activity and Glutathione S-Transferase Transcription

by Dong Liang, Fan Gao, Zhiyou Ni, Lijin Lin, Qunxian Deng, Yi Tang, Xun Wang, Xian Luo and Hui Xia

Molecules 2018, 23(3), 584; https://doi.org/10.3390/molecules23030584 - 6 Mar 2018

Cited by 96 | Viewed by 6573

Abstract

Evidence exists to suggest that melatonin (MT) is important to abiotic stress tolerance in plants. Here, we investigated whether exogenous MT reduces heat damage on biological parameters and gene expression in kiwifruit (Actinidia deliciosa) seedlings. Pretreatment with MT alleviates heat-induced oxidative [...] Read more.

Evidence exists to suggest that melatonin (MT) is important to abiotic stress tolerance in plants. Here, we investigated whether exogenous MT reduces heat damage on biological parameters and gene expression in kiwifruit (Actinidia deliciosa) seedlings. Pretreatment with MT alleviates heat-induced oxidative harm through reducing H₂O₂ content and increasing proline content. Moreover, MT application raised ascorbic acid (AsA) levels and the activity of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD). We also observed elevation in the activity of enzymes related to the AsA-GSH cycle, such as ascorbate peroxidase (APX), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR), and glutathione reductase (GR). Furthermore, MT application increased the expression of 28/31 glutathione S-transferase (GST) genes, reducing oxidative stress. These results clearly indicate that in kiwifruit, MT exerts a protective effect against heat-related damage through regulating antioxidant pathways. Full article

(This article belongs to the Special Issue Melatonin as an Antioxidant and a Functionally Pleiotropic Molecule: Synthesis, Metabolism and Activities in Organisms)

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15 pages, 1073 KiB

Open AccessArticle

Characterization of Condensed Tannins from Purple Prairie Clover (Dalea purpurea Vent.) Conserved as either Freeze-Dried Forage, Sun-Cured Hay or Silage

by Kai Peng, Qianqian Huang, Zhongjun Xu, Tim A. McAllister, Surya Acharya, Irene Mueller-Harvey, Christopher Drake, Junming Cao, Yanhua Huang, Yuping Sun, Shunxi Wang and Yuxi Wang

Molecules 2018, 23(3), 586; https://doi.org/10.3390/molecules23030586 - 6 Mar 2018

Cited by 19 | Viewed by 4381

Abstract

Conservation methods have been shown to affect forage nutrient composition and value, but little information is available about the effect of forage conservation on plant condensed tannins (CT). The objective of this study was to assess the effects of conservation method on the [...] Read more.

Conservation methods have been shown to affect forage nutrient composition and value, but little information is available about the effect of forage conservation on plant condensed tannins (CT). The objective of this study was to assess the effects of conservation method on the concentration, chemical composition and biological activity of CT. Whole-plant purple prairie clover (PPC, Dalea purpurea Vent.) was harvested at full flower and conserved as freeze-dried forage (FD), hay (HAY) or silage (SIL). Concentration of CT in conserved PPC was determined by the butanol-HCl-acetone method. Structural composition, protein-precipitation capacity and anti-bacterial activity of CT isolated from conserved forage were determined by in situ thiolytic degradation followed by HPLC-MS analysis, a protein precipitation assay using bovine serum albumin and ribulose 1,5-disphosphate carboxylase as model proteins and by an Escherichia coli (E. coli) growth test, respectively. Conservation method had no effect on concentration of total CT, but ensiling decreased (p < 0.001) extractable CT and increased (p < 0.001) protein- and fiber-bound CT. In contrast, hay-making only increased (p < 0.01) protein-bound CT. Regardless of conservation method, epigallocatechin (EGC), catechin (C) and epicatechin (EC) were the major flavan-3-ol units, and gallocatechin (GC) was absent from both terminal and extension units of PPC CT. The SIL CT had the lowest (p < 0.001) EGC, but the highest (p < 0.01) EC in the extension units. Similarly, SIL CT exhibited a lower (p < 0.001) mean degree of polymerization (mDP), but higher (p < 0.001) procyanidins (PC) than FD or HAY CT. The protein-precipitating capacity of CT in conserved PPC ranked (p < 0.001) as FD > HAY > SIL. E. coli growth n M9 medium was inhibited by 25–100 µg/mL of CT isolated from FD, HAY and SIL (p < 0.05), but preservation method had no effect on the ability of CT to inhibit bacterial growth. The results demonstrated that ensiling decreased the extractability and protein-precipitating capacity of CT by increasing the proportions of PC. Purple prairie clover conserved as hay retained more biologically active CT than if it was conserved as silage. Full article

(This article belongs to the Special Issue Special Issue Dedicated to Late Professor Takuo Okuda, “Tannins and Related Polyphenols Revisited: Chemistry, Biochemistry and Biological Activities”)

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18 pages, 8808 KiB

Open AccessArticle

[¹⁸F]fallypride-PET/CT Analysis of the Dopamine D₂/D₃ Receptor in the Hemiparkinsonian Rat Brain Following Intrastriatal Botulinum Neurotoxin A Injection

by Teresa Mann, Jens Kurth, Alexander Hawlitschka, Jan Stenzel, Tobias Lindner, Stefan Polei, Alexander Hohn, Bernd J. Krause and Andreas Wree

Molecules 2018, 23(3), 587; https://doi.org/10.3390/molecules23030587 - 6 Mar 2018

Cited by 8 | Viewed by 5498

Abstract

Intrastriatal injection of botulinum neurotoxin A (BoNT-A) results in improved motor behavior of hemiparkinsonian (hemi-PD) rats, an animal model for Parkinson’s disease. The caudate–putamen (CPu), as the main input nucleus of the basal ganglia loop, is fundamentally involved in motor function and directly [...] Read more.

Intrastriatal injection of botulinum neurotoxin A (BoNT-A) results in improved motor behavior of hemiparkinsonian (hemi-PD) rats, an animal model for Parkinson’s disease. The caudate–putamen (CPu), as the main input nucleus of the basal ganglia loop, is fundamentally involved in motor function and directly interacts with the dopaminergic system. To determine receptor-mediated explanations for the BoNT-A effect, we analyzed the dopamine D₂/D₃ receptor (D₂/D₃R) in the CPu of 6-hydroxydopamine (6-OHDA)-induced hemi-PD rats by [¹⁸F]fallypride-PET/CT scans one, three, and six months post-BoNT-A or -sham-BoNT-A injection. Male Wistar rats were assigned to three different groups: controls, sham-injected hemi-PD rats, and BoNT-A-injected hemi-PD rats. Disease-specific motor impairment was verified by apomorphine and amphetamine rotation testing. Animal-specific magnetic resonance imaging was performed for co-registration and anatomical reference. PET quantification was achieved using PMOD software with the simplified reference tissue model 2. Hemi-PD rats exhibited a constant increase of 23% in D₂/D₃R availability in the CPu, which was almost normalized by intrastriatal application of BoNT-A. Importantly, the BoNT-A effect on striatal D₂/D₃R significantly correlated with behavioral results in the apomorphine rotation test. Our results suggest a therapeutic effect of BoNT-A on the impaired motor behavior of hemi-PD rats by reducing interhemispheric changes of striatal D₂/D₃R. Full article

(This article belongs to the Special Issue Current Aspects of Radiopharmaceutical Chemistry)

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10 pages, 556 KiB

Open AccessArticle

New Steroidal Saponins from the Rhizomes of Paris vietnamensis and Their Cytotoxicity

by Yang Liu, Minchang Wang, Ke Liu, Pengcheng Qiu, Shan Zhang, Yunyang Lu, Na Tang and Haifeng Tang

Molecules 2018, 23(3), 588; https://doi.org/10.3390/molecules23030588 - 6 Mar 2018

Cited by 16 | Viewed by 3860

Abstract

Four new spirostanol saponins, named pavitnosides A–D (1–4), with six known steroidal saponins 5–10 were isolated from the rhizomes of Paris vietnamensis. Their chemical structures were determined based on extensive spectroscopic studies and chemical methods. The [...] Read more.

Four new spirostanol saponins, named pavitnosides A–D (1–4), with six known steroidal saponins 5–10 were isolated from the rhizomes of Paris vietnamensis. Their chemical structures were determined based on extensive spectroscopic studies and chemical methods. The aglycones of pavitnoside B and pavitnoside C were not reported in previous work. The cytotoxicity of all saponins was evaluated against human glioblastoma U87MG and U251 cell lines. The new spirostanol saponin 1 displayed weak anti-proliferative activity against U87MG cell line and the known saponins 8 and 9 exhibited significant cytotoxicity against the two tumor cell lines, with IC₅₀ values of 2.16 to 3.14 μM, but did not affect the growth of primary cultures of human astrocytes. Full article

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19 pages, 5271 KiB

Open AccessArticle

Enzyme-Assisted Extraction Optimization, Characterization and Antioxidant Activity of Polysaccharides from Sea Cucumber Phyllophorus proteus

by Yujing Qin, Qingxia Yuan, Yuexing Zhang, Jialu Li, Xinjiao Zhu, Lingling Zhao, Jing Wen, Jikai Liu, Longyan Zhao and Jinhua Zhao

Molecules 2018, 23(3), 590; https://doi.org/10.3390/molecules23030590 - 6 Mar 2018

Cited by 44 | Viewed by 5391

Abstract

Enzyme-assisted extraction optimization, characterization and in vitro antioxidant activity of polysaccharides from sea cucumber Phyllophorus proteus (PPP) were investigated in the present study. The optimal extraction conditions with a yield of 6.44 ± 0.06% for PPP were determined as follows: Extraction time of [...] Read more.

Enzyme-assisted extraction optimization, characterization and in vitro antioxidant activity of polysaccharides from sea cucumber Phyllophorus proteus (PPP) were investigated in the present study. The optimal extraction conditions with a yield of 6.44 ± 0.06% for PPP were determined as follows: Extraction time of 2.89 h, ratio of extraction solvent to raw material of 16.26 mL/g, extraction pH of 6.83, exraction temperature of 50 °C and papain concentration of 0.15%. Three purified fractions, PPP-1a, PPP-1b and PPP-2 with molecular weights of 369.60, 41.73 and 57.76 kDa, respectively, were obtained from PPP by chromatography of FPA98Cl and Sepharose CL-6B columns. Analysis of monosaccharide compositions showed that PPP-1a consisted of N-acetyl-galactosamine (GalNAc), galactose (Gal) and fucose (Fuc), PPP-1b of Fuc as the only monosaccharide and PPP-2 of glucuronic acid, GalNAc and Fuc. Sulfate contents of PPP, PPP-1a, PPP-1b and PPP-2 were determined to be 21.9%, 20.6%, 25.2% and 28.0% (w/w), respectively. PPP and PPP-1a had higher molecular weight and intrinsic viscosity than those of the PPP-1b and PPP-2. PPP, PPP-1a, PPP-1b and PPP-2 exhibited obvious activities of scavenging 1,1-diphenyl-2-picrylhydrazyl radical, hydroxyl radical, superoxide radical and ABTS radical in different extent, which suggested that the polysaccharides from Phyllophorus proteus may be novel agents having potential value for antioxidation. Full article

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6 pages, 580 KiB

Open AccessCommunication

Two New Anisic Acid Derivatives from Endophytic Fungus Rhizopycnis vagum Nitaf22 and Their Antibacterial Activity

by Ali Wang, Peng Li, Xuping Zhang, Peipei Han, Daowan Lai and Ligang Zhou

Molecules 2018, 23(3), 591; https://doi.org/10.3390/molecules23030591 - 6 Mar 2018

Cited by 8 | Viewed by 3211

Abstract

Rhizopycnis acids A (1) and B (2), two new anisic acid derivatives, were obtained from the ethyl acetate extract of the fermentation cultures of Rhizopycnis vagum, an endophytic fungus isolated from the healthy tissues of Nicotiana tabacum. [...] Read more.

Rhizopycnis acids A (1) and B (2), two new anisic acid derivatives, were obtained from the ethyl acetate extract of the fermentation cultures of Rhizopycnis vagum, an endophytic fungus isolated from the healthy tissues of Nicotiana tabacum. The structures of the two compounds were determined through a series of 1D and 2D NMR and HRMS spectral analyses. Both compounds were the first anisic acid derivatives containing methylbutanoic/methylbutenoic acid group found in fungi. 1 and 2 displayed antibacterial activity against six tested bacteria with IC₅₀ values in the range 16.1~81.3 μg/mL. Full article

(This article belongs to the Section Natural Products Chemistry)

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16 pages, 1556 KiB

Open AccessArticle

Synthesis of Dihydrooxepino[3,2-c]Pyrazoles via Claisen Rearrangement and Ring-Closing Metathesis from 4-Allyloxy-1H-pyrazoles

by Yoshihide Usami, Aoi Kohno, Hiroki Yoneyama and Shinya Harusawa

Molecules 2018, 23(3), 592; https://doi.org/10.3390/molecules23030592 - 6 Mar 2018

Cited by 9 | Viewed by 3600

Abstract

Synthesis of novel pyrazole-fused heterocycles, i.e., dihydro-1H- or 2H-oxepino[3,2-c]pyrazoles (6 or 7) from 4-allyloxy-1H-pyrazoles (1) via combination of Claisen rearrangement and ring-closing metathesis (RCM) has been achieved. A suitable catalyst for [...] Read more.

Synthesis of novel pyrazole-fused heterocycles, i.e., dihydro-1H- or 2H-oxepino[3,2-c]pyrazoles (6 or 7) from 4-allyloxy-1H-pyrazoles (1) via combination of Claisen rearrangement and ring-closing metathesis (RCM) has been achieved. A suitable catalyst for the RCM of 5-allyl-4-allyloxy-1H-pyrazoles (4) was proved to be the Grubbs second generation catalyst (Grubbs^2nd) to give the predicted RCM product at room temperature in three hours. The same reactions of the regioisomer, 3-allyl-4-allyloxy-1H-pyrazoles (5), also proceeded to give the corresponding RCM products. On the other hand, microwave aided RCM at 140 °C on both of 4 and 5 afforded mixtures of isomeric products with double bond rearrangement from normal RCM products in spite of remarkable reduction of the reaction time to 10 min. Full article

(This article belongs to the Collection Heterocyclic Compounds)

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10 pages, 6363 KiB

Open AccessArticle

Forsythoside A Modulates Zymosan-Induced Peritonitis in Mice

by Xiao-Tian Zhang, Yue Ding, Ping Kang, Xin-Yu Zhang and Tong Zhang

Molecules 2018, 23(3), 593; https://doi.org/10.3390/molecules23030593 - 6 Mar 2018

Cited by 26 | Viewed by 5426

Abstract

Acute inflammation is a protective response of the host to physical injury and invading infection. Timely treatment of acute inflammatory reactions is essential to prevent damage to organisms that can eventually lead to chronic inflammation. Forsythoside A (FTA), an active constituent of Forsythia [...] Read more.

Acute inflammation is a protective response of the host to physical injury and invading infection. Timely treatment of acute inflammatory reactions is essential to prevent damage to organisms that can eventually lead to chronic inflammation. Forsythoside A (FTA), an active constituent of Forsythia suspensa, has been reported to have anti-inflammatory, antioxidant, and antibacterial properties. Despite increasing knowledge of its anti-inflammatory effects, the mechanism and the effects on acute inflammation are poorly understood. This study is aimed at exploring the pro-resolving effects of FTA on zymosan-induced acute peritonitis. FTA significantly alleviated peritonitis as evidenced by the decreased number of neutrophils and levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) in the peritoneal cavity, without interfering with interleukin-10 (IL-10). FTA showed marked regulation of inflammatory cytokines and chemokine levels in zymosan-stimulated RAW 264.7 macrophages. Moreover, FTA could suppress the activation of NF-κB. In conclusion, FTA alleviated zymosan-induced acute peritonitis through inhibition of NF-κB activation. Full article

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13 pages, 5247 KiB

Open AccessArticle

Cyclization Reaction of Acyl Thiourea Chitosan: Enhanced Antifungal Properties via Structural Optimization

by Yukun Qin, Weixiang Liu, Ronge Xing, Song Liu, Kecheng Li and Pengcheng Li

Molecules 2018, 23(3), 594; https://doi.org/10.3390/molecules23030594 - 6 Mar 2018

Cited by 6 | Viewed by 3943

Abstract

In this study, 3-methyl-1,2,4-triazolyl chitosan (MTACS) and 3-chloromethyl-1,2,4-triazolyl chitosan (CMTACS) were prepared via cyclization of acyl thiourea chitosan (TUCS). Their structures were confirmed by FT-IR, ¹H-NMR, elemental analysis, DSC, XRD, and SEM. The conformations were predicted using the Gaussian 09 program. Additionally, [...] Read more.

In this study, 3-methyl-1,2,4-triazolyl chitosan (MTACS) and 3-chloromethyl-1,2,4-triazolyl chitosan (CMTACS) were prepared via cyclization of acyl thiourea chitosan (TUCS). Their structures were confirmed by FT-IR, ¹H-NMR, elemental analysis, DSC, XRD, and SEM. The conformations were predicted using the Gaussian 09 program. Additionally, the antifungal properties of MTACS and CMTACS against Stemphylium solani weber (S. solani), Alternaria porri (A. porri), and Gloeosporium theae-sinensis (G. theae-sinensis) were assayed in vitro and ranged from 250 μg/mL to 1000 μg/mL. The results showed that MTACS and CMTACS exhibited enhanced inhibitory effect on the selected fungi compared to the original chitosan and TUCS. In particular, they displayed better antifungal activities against A. porri and G. theae-sinensis than that of the positive control, Triadimefon. The findings described here may lead to them being used as antifungal agents for crop protection. Full article

(This article belongs to the Special Issue Advances in Natural Polysaccharides Research)

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11 pages, 4357 KiB

Open AccessArticle

Cloning and Functional Characterization of Two 4-Coumarate: CoA Ligase Genes from Selaginella moellendorffii

by Xin-Yan Liu, Ping-Ping Wang, Yi-Feng Wu, Ai-Xia Cheng and Hong-Xiang Lou

Molecules 2018, 23(3), 595; https://doi.org/10.3390/molecules23030595 - 7 Mar 2018

Cited by 22 | Viewed by 5244

Abstract

Selaginella is an extant lycopodiophyte genus, which is representative of an ancient lineage of tracheophytes. The important evolutionary status makes it a valuable resource for the study of metabolic evolution in vascular plants. 4-coumarate: CoA ligase (4CL) is the pivotal enzyme that controls [...] Read more.

Selaginella is an extant lycopodiophyte genus, which is representative of an ancient lineage of tracheophytes. The important evolutionary status makes it a valuable resource for the study of metabolic evolution in vascular plants. 4-coumarate: CoA ligase (4CL) is the pivotal enzyme that controls the flow of carbon through the phenylpropanoid metabolic pathway into the specific lignin, flavonoid, and wall-bound phenolics biosynthesis pathways. Although 4CLs have been extensively characterized in other vascular plants, little is known of their functions in Selaginella. Here, we isolated two 4CL genes (Sm4CL1 and Sm4CL2) from Selaginella moellendorffii. Based on the enzymatic activities of the recombinant proteins, both of these genes encoded bona fide 4CLs. The 4CL isoforms in S. moellendorffii have different activities: Sm4CL2 was more active than Sm4CL1. The enzymatic properties and gene expression patterns indicated that the 4CL genes have been conserved in the evolution of vascular plants. Full article

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12 pages, 4208 KiB

Open AccessArticle

Antibacterial and Antifungal Activities of Poloxamer Micelles Containing Ceragenin CSA-131 on Ciliated Tissues

by Marjan M. Hashemi, Brett S. Holden, Maddison F. Taylor, John Wilson, Jordan Coburn, Brian Hilton, Tania Nance, Shawn Gubler, Carl Genberg, Shenglou Deng and Paul B. Savage

Molecules 2018, 23(3), 596; https://doi.org/10.3390/molecules23030596 - 7 Mar 2018

Cited by 24 | Viewed by 4940

Abstract

Ceragenins were designed as non-peptide mimics of endogenous antimicrobial peptides, and they display broad-spectrum antibacterial and antifungal activities, including the ability to eradicate established biofilms. These features of ceragenins make them attractive potential therapeutics for persistent infections in the lung, including those associated [...] Read more.

Ceragenins were designed as non-peptide mimics of endogenous antimicrobial peptides, and they display broad-spectrum antibacterial and antifungal activities, including the ability to eradicate established biofilms. These features of ceragenins make them attractive potential therapeutics for persistent infections in the lung, including those associated with cystic fibrosis. A characteristic of an optimal therapeutic for use in the lungs and trachea is the exertion of potent antimicrobial activities without damaging the cilia that play a critical role in these tissues. In previous work, potent antimicrobial activities of ceragenin CSA-131 have been reported; however, we found in ex vivo studies that this ceragenin, at concentrations necessary to eradicate established biofilms, also causes loss of cilia function. By formulating CSA-131 in poloxamer micelles, cilia damage was eliminated and antimicrobial activity was unaffected. The ability of CSA-131, formulated with a poloxamer, to reduce the populations of fungal pathogens in tracheal and lung tissue was also observed in ex vivo studies. These findings suggest that CSA-131, formulated in micelles, may act as a potential therapeutic for polymicrobial and biofilm-related infections in the lung and trachea. Full article

(This article belongs to the Special Issue Antimicrobial Peptides and Peptidomimetics)

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15 pages, 2833 KiB

Open AccessArticle

Halo-Substituted Chalcones and Azachalcones Inhibited Lipopolysaccharited-Stimulated Pro-Inflammatory Responses through the TLR4-Mediated Pathway

by Tzenge-Lien Shih, Ming-Hwa Liu, Chia-Wai Li and Chia-Feng Kuo

Molecules 2018, 23(3), 597; https://doi.org/10.3390/molecules23030597 - 7 Mar 2018

Cited by 17 | Viewed by 4935

Abstract

A series of B-ring, halo-substituted chalcones and azachalcones were synthesized to evaluate and compare their anti-inflammatory activity. Mouse BALB/c macrophage RAW 264.7 were pre-treated with 10 μg/mL of each compound for one hour before induction of inflammation by lipopolysaccharide (1 μg/mL) for 6 [...] Read more.

A series of B-ring, halo-substituted chalcones and azachalcones were synthesized to evaluate and compare their anti-inflammatory activity. Mouse BALB/c macrophage RAW 264.7 were pre-treated with 10 μg/mL of each compound for one hour before induction of inflammation by lipopolysaccharide (1 μg/mL) for 6 h. Some halo-chalcones and -azachalcones suppressed expression of pro-inflammatory factors toll-like receptor 4 (TLR4), IκB-α, transcription factor p65, interleukine 1β (IL-1β), IL-6, tumor necrosis factor α (TNF-α), and cyclooxygenase 2 (COX-2). The present results showed that the synthetic halo-azachalcones exhibited more significant inhibition than halo-chalcones. Therefore, the nitrogen atom in this series of azachalcones must play a more crucial role than the corresponding C-2 hydroxyl group of chalcones in biological activity. Our findings will lay the background for the future development of anti-inflammatory nutraceuticals. Full article

(This article belongs to the Section Medicinal Chemistry)

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14 pages, 2234 KiB

Open AccessArticle

Cis–Trans Configuration of Coumaric Acid Acylation Affects the Spectral and Colorimetric Properties of Anthocyanins

by Gregory T. Sigurdson, Peipei Tang and M. Mónica Giusti

Molecules 2018, 23(3), 598; https://doi.org/10.3390/molecules23030598 - 7 Mar 2018

Cited by 26 | Viewed by 6489

Abstract

The color expression of anthocyanins can be affected by a variety of environmental factors and structural characteristics. Anthocyanin acylation (type and number of acids) is known to be key, but the influence of acyl isomers (with unique stereochemistries) remains to be explored. The [...] Read more.

The color expression of anthocyanins can be affected by a variety of environmental factors and structural characteristics. Anthocyanin acylation (type and number of acids) is known to be key, but the influence of acyl isomers (with unique stereochemistries) remains to be explored. The objective of this study was to investigate the effects of cis–trans configuration of the acylating group on the spectral and colorimetric properties of anthocyanins. Petunidin-3-rutinoside-5-glucoside (Pt-3-rut-5-glu) and Delphinidin-3-rutinoside-5-glucoside (Dp-3-rut-5-glu) and their cis and trans coumaroylated derivatives were isolated from black goji and eggplant, diluted in pH 1–9 buffers, and analyzed spectrophotometrically (380–700 nm) and colorimetrically (CIELAB) during 72 h of storage (25 °C, dark). The stereochemistry of the acylating group strongly impacted the spectra, color, and stability of the Dp and Pt anthocyanins. Cis acylated pigments exhibited the greatest λ_max in all pH, as much as 66 nm greater than their trans counterparts, showing bluer hues. Cis acylation seemed to reduce hydration across pH, increasing color intensity, while trans acylation generally improved color retention over time. Dp-3-cis-p-cou-rut-5-glu exhibited blue hues even in pH 5 (C*_ab = 10, h_ab = 256°) where anthocyanins are typically colorless. Cis or trans double bond configurations of the acylating group affected anthocyanin spectral and stability properties. Full article

(This article belongs to the Special Issue Advances in Anthocyanin Research 2018)

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17 pages, 5055 KiB

Open AccessArticle

Synthesis, Molecular Docking, and Antimycotic Evaluation of Some 3-Acyl Imidazo[1,2-a]pyrimidines

by Omar Gómez-García, Dulce Andrade-Pavón, Elena Campos-Aldrete, Ricardo Ballinas-Indilí, Alfonso Méndez-Tenorio, Lourdes Villa-Tanaca and Cecilio Álvarez-Toledano

Molecules 2018, 23(3), 599; https://doi.org/10.3390/molecules23030599 - 7 Mar 2018

Cited by 23 | Viewed by 5843

Abstract

A series of 3-benzoyl imidazo[1,2-a]pyrimidines, obtained from N-heteroarylformamidines in good yields, was tested in silico and in vitro for binding and inhibition of seven Candida species (Candida albicans (ATCC 10231), Candida dubliniensis (CD36), Candida glabrata (CBS138), Candida guilliermondii (ATCC [...] Read more.

A series of 3-benzoyl imidazo[1,2-a]pyrimidines, obtained from N-heteroarylformamidines in good yields, was tested in silico and in vitro for binding and inhibition of seven Candida species (Candida albicans (ATCC 10231), Candida dubliniensis (CD36), Candida glabrata (CBS138), Candida guilliermondii (ATCC 6260), Candida kefyr, Candida krusei (ATCC 6358) and Candida tropicalis (MYA-3404)). To predict binding mode and energy, each compound was docked in the active site of the lanosterol 14α-demethylase enzyme (CYP51), essential for fungal growth of Candida species. Antimycotic activity was evaluated as the 50% minimum inhibitory concentration (MIC50) for the test compounds and two reference drugs, ketoconazole and fluconazole. All test compounds had a better binding energy (range: −6.11 to −9.43 kcal/mol) than that found for the reference drugs (range: 48.93 to −6.16 kcal/mol). In general, the test compounds showed greater inhibitory activity of yeast growth than the reference drugs. Compounds 4j and 4f were the most active, indicating an important role in biological activity for the benzene ring with electron-withdrawing substituents. These compounds show the best MIC50 against C. guilliermondii and C. glabrata, respectively. The current findings suggest that the 3-benzoyl imidazo[1,2-a]pyrimidine derivatives, herein synthesized by an accessible methodology, are potential antifungal drugs. Full article

(This article belongs to the Section Medicinal Chemistry)

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14 pages, 1093 KiB

Open AccessArticle

Novel Trifluoromethylcoumarinyl Urea Derivatives: Synthesis, Characterization, Fluorescence, and Bioactivity

by Lili Qiao and Shuanghong Hao

Molecules 2018, 23(3), 600; https://doi.org/10.3390/molecules23030600 - 7 Mar 2018

Cited by 12 | Viewed by 3833

Abstract

A series of novel trifluoromethylcoumarinyl urea derivatives were designed, synthesized, and characterized by ¹H-NMR, ¹³C-NMR, and HR-ESI-MS. The fluorescence spectra of the target compounds were recorded. The spectra show that most of the title compounds glow green with λ_max^em [...] Read more.

A series of novel trifluoromethylcoumarinyl urea derivatives were designed, synthesized, and characterized by ¹H-NMR, ¹³C-NMR, and HR-ESI-MS. The fluorescence spectra of the target compounds were recorded. The spectra show that most of the title compounds glow green with λ_max^em of 500–517 nm, while compounds 5r, 5s, 5u, and 5l (compounds named by authors) glow violet with λ_max^em of 381–443 nm. Moreover, the herbicidal and antifungal activities of the synthesized compounds were evaluated for their potential use as pesticides. The results indicate that compound 5f against the caulis of Amaranthus retroflexus and compounds 5j and 5l against the taproot of Digitaria sanguinalis are equivalent to the commercial herbicide Acetochlor. Nine of the title compounds are more antifungal than commercial fungicide Carbendazim against Botrytis cinerea. Full article

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12 pages, 2908 KiB

Open AccessArticle

Blood Compatibility of Sulfonated Cladophora Nanocellulose Beads

by Igor Rocha, Jonas Lindh, Jaan Hong, Maria Strømme, Albert Mihranyan and Natalia Ferraz

Molecules 2018, 23(3), 601; https://doi.org/10.3390/molecules23030601 - 7 Mar 2018

Cited by 20 | Viewed by 4881

Abstract

Sulfonated cellulose beads were prepared by oxidation of Cladophora nanocellulose to 2,3-dialdehyde cellulose followed by sulfonation using bisulfite. The physicochemical properties of the sulfonated beads, i.e., high surface area, high degree of oxidation, spherical shape, and the possibility of tailoring the porosity, make [...] Read more.

Sulfonated cellulose beads were prepared by oxidation of Cladophora nanocellulose to 2,3-dialdehyde cellulose followed by sulfonation using bisulfite. The physicochemical properties of the sulfonated beads, i.e., high surface area, high degree of oxidation, spherical shape, and the possibility of tailoring the porosity, make them interesting candidates for the development of immunosorbent platforms, including their application in extracorporeal blood treatments. A desired property for materials used in such applications is blood compatibility; therefore in the present work, we investigate the hemocompatibility of the sulfonated cellulose beads using an in vitro whole blood model. Complement system activation (C3a and sC5b-9 levels), coagulation activation (thrombin-antithrombin (TAT) levels) and hemolysis were evaluated after whole blood contact with the sulfonated beads and the results were compared with the values obtained with the unmodified Cladophora nanocellulose. Results showed that neither of the cellulosic materials presented hemolytic activity. A marked decrease in TAT levels was observed after blood contact with the sulfonated beads, compared with Cladophora nanocellulose. However, the chemical modification did not promote an improvement in Cladophora nanocellulose hemocompatibility in terms of complement system activation. Even though the sulfonated beads presented a significant reduction in pro-coagulant activity compared with the unmodified material, further modification strategies need to be investigated to control the complement activation by the cellulosic materials. Full article

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11 pages, 7721 KiB

Open AccessArticle

The Complete Chloroplast Genomes of Two Lancea Species with Comparative Analysis

by Xiaofeng Chi, Jiuli Wang, Qingbo Gao, Faqi Zhang and Shilong Chen

Molecules 2018, 23(3), 602; https://doi.org/10.3390/molecules23030602 - 7 Mar 2018

Cited by 18 | Viewed by 4489

Abstract

The genus Lancea is native to the Qinghai-Tibetan Plateau and consists of two species, Lancea tibetica Hook. f. et Thoms. and Lancea hirsuta Bonati. Here, we report the complete sequences of the chloroplast genomes of L. tibetica and L. hirsuta, which were [...] Read more.

The genus Lancea is native to the Qinghai-Tibetan Plateau and consists of two species, Lancea tibetica Hook. f. et Thoms. and Lancea hirsuta Bonati. Here, we report the complete sequences of the chloroplast genomes of L. tibetica and L. hirsuta, which were 153,665 and 154,045 bp in length, respectively, and each included a pair of inverted repeated regions (25,624 and 25,838 bp in length, respectively) that were separated by a large single copy region (84,401 and 84,588 bp in length, respectively) and a smaller single copy region (18,016 and 17,781 bp in length, respectively). A total of 106 genes in L. tibetica and 105 in L. hirsuta comprised 79 protein-coding genes, and 4 ribosomal RNA (rRNA) genes, as well as 23 and 22 transfer RNA (tRNA) genes in L. tibetica and L. hirsuta, respectively. The gene order, content, and orientation of the two Lancea chloroplast genomes exhibited high similarity. A large number of informative repetitive sequences, including SSRs, were observed in both genomes. Comparisons of the genomes with those of three other Lamiales species revealed 12 highly divergent regions in the intergenic spacers and in the matK, rpoA, rps19, ndhF, ccsA, ndhD, and ycf1 coding regions. A phylogenomic analysis suggested that Lancea forms a monophyletic group that is closely related to the clade composed of the families Phrymaceae, Paulowniaceae, and Rehmanniaceae. Full article

(This article belongs to the Section Molecular Diversity)

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13 pages, 4293 KiB

Open AccessArticle

One-Step Preparation of Phenyl Boron-Modified Magnetic Mesoporous Silica for Selective Enrichment of cis-Diol-Containing Substances

by Hua Fu, Jing Hu, Min Zhang, Yuerong Wang, Hongyang Zhang and Ping Hu

Molecules 2018, 23(3), 603; https://doi.org/10.3390/molecules23030603 - 7 Mar 2018

Cited by 5 | Viewed by 3736

Abstract

For enrichment and separation of cis-diol-containing compounds from biomatrix, a new type of magnetic nanoparticles named MS-48-PBSC, whichwas facilely prepared in a one-step heterogeneous reaction. The morphology results demonstrated that the MS-48-PBSC was a spherical nanomaterial containing a core of silica-coated magnetic [...] Read more.

For enrichment and separation of cis-diol-containing compounds from biomatrix, a new type of magnetic nanoparticles named MS-48-PBSC, whichwas facilely prepared in a one-step heterogeneous reaction. The morphology results demonstrated that the MS-48-PBSC was a spherical nanomaterial containing a core of silica-coated magnetic particle with a diameter of about 200 nm, and a cover layer of mesoporous silica with a thickness of approximate 50 nm. The characterization results showed that MS-48-PBSC presented a pore size of 4.2 nm, a surface area of 548 m²·g⁻¹, and a pore volume of 0.30 cm³·g⁻¹. The MS-48-PBSC also exhibited magnetism of 42 emu·g⁻¹ that contributed to the easy separation of magnetic nanomaterial within 30 s from the matrix with the aid of the external magnetic field. In addition, the MS-48-PBSC exhibited high adsorption capacity for adenosine, xanthosine, uridine, sialic acid, and teicoplanin with 0.60, 0.51, 0.42, 0.75, and 1.26 mg/g, respectively, and showed a high selectivity for the cis-diol structure compounds, relative to interferences of bovine serum albumin, guanine, uric acid, and xanthine. The recoveries of adenosine, xanthosine, uridine, sialic acid, and teicoplanin were 71.8–114.1% with relative standard deviation (RSD) ≤ 8.6%, and the enrichment factors of them were 8–11. MS-48-PBSC exhibited quick separation capability from matrix, high adsorption capacity and size exclusion for bovine serum albumin, which could meet the requirements of separation and enrichment for substances with a cis-diol structure. Full article

(This article belongs to the Section Analytical Chemistry)

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12 pages, 557 KiB

Open AccessArticle

New Terpenoids from Chamaecyparis formosensis (Cupressaceae) Leaves with Modulatory Activity on Matrix Metalloproteases 2 and 9

by Meng-Lun Chang, Hui-Ching Mei, I-Chih Kuo, George Hsiao, Yueh-Hsiung Kuo and Ching-Kuo Lee

Molecules 2018, 23(3), 604; https://doi.org/10.3390/molecules23030604 - 7 Mar 2018

Cited by 1 | Viewed by 4016

Abstract

Chamaecyparis formosensis is Taiwan’s most representative tree, and has high economic value. To date, only a few active chemical constituents have been reported for C. formosensis. In this study, 37 secondary metabolites, including three new compounds (1–3), were [...] Read more.

Chamaecyparis formosensis is Taiwan’s most representative tree, and has high economic value. To date, only a few active chemical constituents have been reported for C. formosensis. In this study, 37 secondary metabolites, including three new compounds (1–3), were extracted from the leaves of C. formosensis. The compounds isolated from the ethyl acetate layer were used at different concentrations to treat HT-1080 human fibrosarcoma cells and to evaluate their effects on matrix metalloprotease 2 (MMP-2) and 9 (MMP-9) expression. Based on extensive analysis of data from high-resolution mass spectrometry (HR-MS) as well as nuclear magnetic resonance (NMR), infrared (IR), and ultraviolet (UV) spectroscopy, the new compounds were identified as 11,12-dihydroxyisodaucenoic acid (1), 12-hydroxyisodaucenoic acid (2), and 1-oxo-2α,3β-dihydroxytotarol (3). Known compounds 4–37 were identified by comparing their spectroscopic data with data reported in the literature. Biological activity tests by gelatin zymographic analysis revealed that seven compounds, including new compound 2, have no cytotoxic effect on HT-1080 cells and were found to increase MMP-2 or MMP-9 expression by 1.25- to 1.59-fold at lower concentrations of 10–50 µM. These naturally derived regulatory compounds could potentially serve as a novel pharmaceutical basis for medical purposes. Full article

(This article belongs to the Collection Bioactive Compounds)

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14 pages, 2127 KiB

Open AccessArticle

Sensitive Detection of 8-Nitroguanine in DNA by Chemical Derivatization Coupled with Online Solid-Phase Extraction LC-MS/MS

by Chiung-Wen Hu, Yuan-Jhe Chang, Jian-Lian Chen, Yu-Wen Hsu and Mu-Rong Chao

Molecules 2018, 23(3), 605; https://doi.org/10.3390/molecules23030605 - 8 Mar 2018

Cited by 9 | Viewed by 3976

Abstract

8-Nitroguanine (8-nitroG) is a major mutagenic nucleobase lesion generated by peroxynitrite during inflammation and has been used as a potential biomarker to evaluate inflammation-related carcinogenesis. Here, we present an online solid-phase extraction (SPE) LC-MS/MS method with 6-methoxy-2-naphthyl glyoxal hydrate (MTNG) derivatization for a [...] Read more.

8-Nitroguanine (8-nitroG) is a major mutagenic nucleobase lesion generated by peroxynitrite during inflammation and has been used as a potential biomarker to evaluate inflammation-related carcinogenesis. Here, we present an online solid-phase extraction (SPE) LC-MS/MS method with 6-methoxy-2-naphthyl glyoxal hydrate (MTNG) derivatization for a sensitive and precise measurement of 8-nitroG in DNA. Derivatization optimization revealed that an excess of MTNG is required to achieve complete derivatization in DNA hydrolysates (MTNG: 8-nitroG molar ratio of 3740:1). The use of online SPE effectively avoided ion-source contamination from derivatization reagent by washing away all unreacted MTNG before column chromatography and the ionization process in mass spectrometry. With the use of isotope-labeled internal standard, the detection limit was as low as 0.015 nM. Inter- and intraday imprecision was <5.0%. This method was compared to a previous direct LC-MS/MS method without derivatization. The comparison showed an excellent fit and consistency, suggesting that the present method has satisfactory effectiveness and reliability for 8-nitroG analysis. This method was further applied to determine the 8-nitroG in human urine. 8-NitroG was not detectable using LC-MS/MS with derivatization, whereas a significant false-positive signal was detected without derivatization. It highlights the use of MTNG derivatization in 8-nitroG analysis for increasing the method specificity. Full article

(This article belongs to the Special Issue Solid Phase Extraction: State of the Art and Future Perspectives)

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12 pages, 12104 KiB

Open AccessArticle

The Detailed Bactericidal Process of Ferric Oxide Nanoparticles on E. coli

by Yunqiao Li, Dong Yang, Shang Wang, Chenyu Li, Bin Xue, Lin Yang, Zhiqiang Shen, Min Jin, Jingfeng Wang and Zhigang Qiu

Molecules 2018, 23(3), 606; https://doi.org/10.3390/molecules23030606 - 8 Mar 2018

Cited by 38 | Viewed by 5122

Abstract

While nanoparticles exert bactericidal effects through the generation of reactive oxygen species (ROS), the processes of the internalization of and the direct physical damage caused by iron oxide nanoparticles are not completely clear. We hypothesize that direct physical or mechanical damage of the [...] Read more.

While nanoparticles exert bactericidal effects through the generation of reactive oxygen species (ROS), the processes of the internalization of and the direct physical damage caused by iron oxide nanoparticles are not completely clear. We hypothesize that direct physical or mechanical damage of the cell membrane and cytoplasmic integrity by nanoparticles is another major cause of bacterial death besides ROS. The aim of this study is to investigate the process of the internalization of iron oxide nanoparticles, and to evaluate the effect of direct physical or mechanical damage on bacterial cell growth and death. The results demonstrate that iron oxide nanoparticles not only inhibited E. coli cell growth, but also caused bacterial cell death. Iron oxide nanoparticles produced significantly elevated ROS levels in bacteria. Transmission electronic microscopy demonstrated that iron oxide nanoparticles were internalized into and condensed the cytoplasm. Strikingly, we observed that the internalized nanoparticles caused intracellular vacuole formation, instead of simply adsorbing thereon; and formed clusters on the bacterial surface and tore up the outer cell membrane to release cytoplasm. This is the first time that the exact process of the internalization of iron oxide nanoparticles has been observed. We speculate that the intracellular vacuole formation and direct physical or mechanical damage caused by the iron oxide nanoparticles caused the bactericidal effect, along with the effects of ROS. Full article

(This article belongs to the Special Issue Selected Papers from the 6th International Conference on Biotechnology and Bioengineering (6-ICBB 2017))

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13 pages, 3608 KiB

Open AccessArticle

Capturing the Alternative Cleavage and Polyadenylation Sites of 14 NAC Genes in Populus Using a Combination of 3′-RACE and High-Throughput Sequencing

by Haoran Wang, Mingxiu Wang and Qiang Cheng

Molecules 2018, 23(3), 608; https://doi.org/10.3390/molecules23030608 - 8 Mar 2018

Cited by 4 | Viewed by 3714

Abstract

Detection of complex splice sites (SSs) and polyadenylation sites (PASs) of eukaryotic genes is essential for the elucidation of gene regulatory mechanisms. Transcriptome-wide studies using high-throughput sequencing (HTS) have revealed prevalent alternative splicing (AS) and alternative polyadenylation (APA) in plants. However, small-scale and [...] Read more.

Detection of complex splice sites (SSs) and polyadenylation sites (PASs) of eukaryotic genes is essential for the elucidation of gene regulatory mechanisms. Transcriptome-wide studies using high-throughput sequencing (HTS) have revealed prevalent alternative splicing (AS) and alternative polyadenylation (APA) in plants. However, small-scale and high-depth HTS aimed at detecting genes or gene families are very few and limited. We explored a convenient and flexible method for profiling SSs and PASs, which combines rapid amplification of 3′-cDNA ends (3′-RACE) and HTS. Fourteen NAC (NAM, ATAF1/2, CUC2) transcription factor genes of Populus trichocarpa were analyzed by 3′-RACE-seq. Based on experimental reproducibility, boundary sequence analysis and reverse transcription PCR (RT-PCR) verification, only canonical SSs were considered to be authentic. Based on stringent criteria, candidate PASs without any internal priming features were chosen as authentic PASs and assumed to be PAS-rich markers. Thirty-four novel canonical SSs, six intronic/internal exons and thirty 3′-UTR PAS-rich markers were revealed by 3′-RACE-seq. Using 3′-RACE and real-time PCR, we confirmed that three APA transcripts ending in/around PAS-rich markers were differentially regulated in response to plant hormones. Our results indicate that 3′-RACE-seq is a robust and cost-effective method to discover SSs and label active regions subjected to APA for genes or gene families. The method is suitable for small-scale AS and APA research in the initial stage. Full article

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10 pages, 913 KiB

Open AccessCommunication

First Look at the Venom of Naja ashei

by Konrad Kamil Hus, Justyna Buczkowicz, Vladimír Petrilla, Monika Petrillová, Andrzej Łyskowski, Jaroslav Legáth and Aleksandra Bocian

Molecules 2018, 23(3), 609; https://doi.org/10.3390/molecules23030609 - 8 Mar 2018

Cited by 29 | Viewed by 5799

Abstract

Naja ashei is an African spitting cobra species closely related to N. mossambica and N. nigricollis. It is known that the venom of N. ashei, like that of other African spitting cobras, mainly has cytotoxic effects, however data about its specific [...] Read more.

Naja ashei is an African spitting cobra species closely related to N. mossambica and N. nigricollis. It is known that the venom of N. ashei, like that of other African spitting cobras, mainly has cytotoxic effects, however data about its specific protein composition are not yet available. Thus, an attempt was made to determine the venom proteome of N. ashei with the use of 2-D electrophoresis and MALDI ToF/ToF (Matrix-Assisted Laser Desorption/Ionization Time of Flight) mass spectrometry techniques. Our investigation revealed that the main components of analysed venom are 3FTxs (Three-Finger Toxins) and PLA₂s (Phospholipases A₂). Additionally the presence of cysteine-rich venom proteins, 5′-nucleotidase and metalloproteinases has also been confirmed. The most interesting fact derived from this study is that the venom of N. ashei includes proteins not described previously in other African spitting cobras—cobra venom factor and venom nerve growth factor. To our knowledge, there are currently no other reports concerning this venom composition and we believe that our results will significantly increase interest in research of this species. Full article

(This article belongs to the Special Issue Analysis of Peptides and Proteins by Electrophoretic Techniques)

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14 pages, 3744 KiB

Open AccessArticle

An Investigation of Atomic Structures Derived from X-ray Crystallography and Cryo-Electron Microscopy Using Distal Blocks of Side-Chains

by Lin Chen, Jing He, Salim Sazzed and Rayshawn Walker

Molecules 2018, 23(3), 610; https://doi.org/10.3390/molecules23030610 - 8 Mar 2018

Cited by 4 | Viewed by 3729

Abstract

Cryo-electron microscopy (cryo-EM) is a structure determination method for large molecular complexes. As more and more atomic structures are determined using this technique, it is becoming possible to perform statistical characterization of side-chain conformations. Two data sets were involved to characterize block lengths [...] Read more.

Cryo-electron microscopy (cryo-EM) is a structure determination method for large molecular complexes. As more and more atomic structures are determined using this technique, it is becoming possible to perform statistical characterization of side-chain conformations. Two data sets were involved to characterize block lengths for each of the 18 types of amino acids. One set contains 9131 structures resolved using X-ray crystallography from density maps with better than or equal to 1.5 Å resolutions, and the other contains 237 protein structures derived from cryo-EM density maps with 2–4 Å resolutions. The results show that the normalized probability density function of block lengths is similar between the X-ray data set and the cryo-EM data set for most of the residue types, but differences were observed for ARG, GLU, ILE, LYS, PHE, TRP, and TYR for which conformations with certain shorter block lengths are more likely to be observed in the cryo-EM set with 2–4 Å resolutions. Full article

(This article belongs to the Special Issue Selected Papers from the 10th Computational Structural Bioinformatics Workshop (CSBW-2017))

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17 pages, 3998 KiB

Open AccessArticle

Anthocyanin-Rich Grape Pomace Extract (Vitis vinifera L.) from Wine Industry Affects Mitochondrial Bioenergetics and Glucose Metabolism in Human Hepatocarcinoma HepG2 Cells

by Nathalia F. F. De Sales, Leandro Silva da Costa, Talita I. A. Carneiro, Daniela A. Minuzzo, Felipe L. Oliveira, Lourdes M. C. Cabral, Alexandre G. Torres and Tatiana El-Bacha

Molecules 2018, 23(3), 611; https://doi.org/10.3390/molecules23030611 - 8 Mar 2018

Cited by 39 | Viewed by 6444

Abstract

Cancer cells demand high ATP provisions to support proliferation, and targeting of energy metabolism is a good strategy to increase their sensitivity to treatments. In Brazil, wine manufacture is expanding, increasing the amount of pomace that is produced. We determined the phenolic composition [...] Read more.

Cancer cells demand high ATP provisions to support proliferation, and targeting of energy metabolism is a good strategy to increase their sensitivity to treatments. In Brazil, wine manufacture is expanding, increasing the amount of pomace that is produced. We determined the phenolic composition and antioxidant properties of a dark skin Grape Pomace Extract and its effects on metabolism and redox state in human hepatocarcinoma HepG2 cells. The material and the methods used represented the industrial process since pomace derived from white wine production and the extract concentrated by pilot plant scale reverse osmosis. Grape pomace extract was rich in polyphenols, mainly anthocyanins, and presented high antioxidant capacity. Short-term metabolic effects, irrespective of any cytotoxicity, involved increased mitochondrial respiration and antioxidant capacity and decreased glycolytic metabolism. Long-term incubation was cytotoxic and cells died by necrosis and GPE was not toxic to non-cancer human fibroblasts. To the best of our knowledge, this is the first report to characterize pomace extract from white wine production from Brazilian winemaking regarding its effects on energy metabolism, suggesting its potential use for pharmaceutical and nutraceutical purposes. Full article

(This article belongs to the Special Issue The Antioxidant Capacities of Natural Products)

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15 pages, 1548 KiB

Open AccessArticle

Variable Levels of Tolerance to Water Stress (Drought) and Associated Biochemical Markers in Tunisian Barley Landraces

by Sameh Dbira, Mohamad Al Hassan, Pietro Gramazio, Ali Ferchichi, Oscar Vicente, Jaime Prohens and Monica Boscaiu

Molecules 2018, 23(3), 613; https://doi.org/10.3390/molecules23030613 - 8 Mar 2018

Cited by 26 | Viewed by 4563

Abstract

Due to its high tolerance to abiotic stress, barley (Hordeum vulgare) is cultivated in many arid areas of the world. In the present study, we evaluate the tolerance to water stress (drought) in nine accessions of “Ardhaoui” barley landraces from different [...] Read more.

Due to its high tolerance to abiotic stress, barley (Hordeum vulgare) is cultivated in many arid areas of the world. In the present study, we evaluate the tolerance to water stress (drought) in nine accessions of “Ardhaoui” barley landraces from different regions of Tunisia. The genetic diversity of the accessions is evaluated with six SSR markers. Seedlings from the nine accessions are subjected to water stress by completely stopping irrigation for three weeks. A high genetic diversity is detected among the nine accessions, with no relationships between genetic distance and geographical or ecogeographical zone. The analysis of growth parameters and biochemical markers in the water stress-treated plants in comparison to their respective controls indicated great variability among the studied accessions. Accession 2, from El May Island, displayed high tolerance to drought. Increased amounts of proline in water-stressed plants could not be correlated with a better response to drought, as the most tolerant accessions contained lower levels of this osmolyte. A good correlation was established between the reduction of growth and degradation of chlorophylls and increased levels of malondialdehyde and total phenolics. These biochemical markers may be useful for identifying drought tolerant materials in barley. Full article

(This article belongs to the Collection Phytochemicals: Biosynthesis, Metabolism and Biological Activities)

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12 pages, 2684 KiB

Open AccessArticle

Multi-Target Anti-Alzheimer Activities of Four Prenylated Compounds from Psoralea Fructus

by Qing-Xia Xu, Ying Hu, Gui-Yang Li, Wei Xu, Ying-Tao Zhang and Xiu-Wei Yang

Molecules 2018, 23(3), 614; https://doi.org/10.3390/molecules23030614 - 8 Mar 2018

Cited by 38 | Viewed by 5425

Abstract

Alzheimer’s disease (AD) is an age-related neurodegenerative disease that is mediated by multiple signaling pathways. In recent years, the components of Psoralea Fructus (PF) have demonstrated some anti-Alzheimer effects both in vitro and in vivo. To further reveal the active compounds of PF [...] Read more.

Alzheimer’s disease (AD) is an age-related neurodegenerative disease that is mediated by multiple signaling pathways. In recent years, the components of Psoralea Fructus (PF) have demonstrated some anti-Alzheimer effects both in vitro and in vivo. To further reveal the active compounds of PF and their mechanisms regulating key targets of AD, in this study, we identified four prenylated compounds from the 70% ethanolic aqueous extract of PF, namely bavachin, bavachinin, bavachalcone, and isobavachalcone. Multi-target bioactivity analysis showed that these compounds could differentially inhibit neuroinflammation, oxidative damage, and key AD-related protein targets, such as amyloid β-peptide 42, β-secretase, glycogen synthase kinase 3β, and acetylcholinesterase. These compounds may generate beneficial effects in AD prevention and treatment. Full article

(This article belongs to the Collection Bioactive Compounds)

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18 pages, 4606 KiB

Open AccessArticle

The Effects of Aronia melanocarpa ‘Viking’ Extracts in Attenuating RANKL-Induced Osteoclastic Differentiation by Inhibiting ROS Generation and c-FOS/NFATc1 Signaling

by Mithun Ghosh, In Sook Kim, Young Min Lee, Seong Min Hong, Taek Hwan Lee, Ji Hong Lim, Trishna Debnath and Beong Ou Lim

Molecules 2018, 23(3), 615; https://doi.org/10.3390/molecules23030615 - 8 Mar 2018

Cited by 16 | Viewed by 4956

Abstract

This study aimed to determine the anti-osteoclastogenic effects of extracts from Aronia melanocarpa ‘Viking’ (AM) and identify the underlying mechanisms in vitro. Reactive oxygen species (ROS) are signal mediators in osteoclast differentiation. AM extracts inhibited ROS production in RAW 264.7 cells in a [...] Read more.

This study aimed to determine the anti-osteoclastogenic effects of extracts from Aronia melanocarpa ‘Viking’ (AM) and identify the underlying mechanisms in vitro. Reactive oxygen species (ROS) are signal mediators in osteoclast differentiation. AM extracts inhibited ROS production in RAW 264.7 cells in a dose-dependent manner and exhibited strong radical scavenging activity. The extracts also attenuated the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts. To attain molecular insights, the effect of the extracts on the signaling pathways induced by receptor activator of nuclear factor kappa B ligand (RANKL) were also investigated. RANKL triggers many transcription factors through the activation of mitogen-activated protein kinase (MAPK) and ROS, leading to the induction of osteoclast-specific genes. The extracts significantly suppressed RANKL-induced activation of MAPKs, such as extracellular signal-regulated kinase (ERK), c-Jun-N-terminal kinase (JNK) and p38 and consequently led to the downregulation of c-Fos and nuclear factor of activated T cells 1 (NFATc1) protein expression which ultimately suppress the activation of the osteoclast-specific genes, cathepsin K, TRAP, calcitonin receptor and integrin β₃. In conclusion, our findings suggest that AM extracts inhibited RANKL-induced osteoclast differentiation by downregulating ROS generation and inactivating JNK/ERK/p38, nuclear factor kappa B (NF-κB)-mediated c-Fos and NFATc1 signaling pathway. Full article

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14 pages, 1952 KiB

Open AccessArticle

Design, Synthesis and Docking Studies of Flavokawain B Type Chalcones and Their Cytotoxic Effects on MCF-7 and MDA-MB-231 Cell Lines

by Addila Abu Bakar, Muhammad Nadeem Akhtar, Norlaily Mohd Ali, Swee Keong Yeap, Ching Kheng Quah, Wan-Sin Loh, Noorjahan Banu Alitheen, Seema Zareen, Zaheer Ul-Haq and Syed Adnan Ali Shah

Molecules 2018, 23(3), 616; https://doi.org/10.3390/molecules23030616 - 8 Mar 2018

Cited by 27 | Viewed by 5359

Abstract

Flavokawain B (1) is a natural chalcone extracted from the roots of Piper methysticum, and has been proven to be a potential cytotoxic compound. Using the partial structure of flavokawain B (FKB), about 23 analogs have been synthesized. Among them, compounds [...] Read more.

Flavokawain B (1) is a natural chalcone extracted from the roots of Piper methysticum, and has been proven to be a potential cytotoxic compound. Using the partial structure of flavokawain B (FKB), about 23 analogs have been synthesized. Among them, compounds 8, 13 and 23 were found in new FKB derivatives. All compounds were evaluated for their cytotoxic properties against two breast cancer cell lines, MCF-7 and MDA-MB-231, thus establishing the structure–activity relationship. The FKB derivatives 16 (IC₅₀ = 6.50 ± 0.40 and 4.12 ± 0.20 μg/mL), 15 (IC₅₀ = 5.50 ± 0.35 and 6.50 ± 1.40 μg/mL) and 13 (IC₅₀ = 7.12 ± 0.80 and 4.04 ± 0.30 μg/mL) exhibited potential cytotoxic effects on the MCF-7 and MDA-MB-231 cell lines. However, the methoxy group substituted in position three and four in compound 2 (IC₅₀ = 8.90 ± 0.60 and 6.80 ± 0.35 μg/mL) and 22 (IC₅₀ = 8.80 ± 0.35 and 14.16 ± 1.10 μg/mL) exhibited good cytotoxicity. The lead compound FKB (1) showed potential cytotoxicity (IC₅₀ = 7.70 ± 0.30 and 5.90 ± 0.30 μg/mL) against two proposed breast cancer cell lines. It is evident that the FKB skeleton is unique for anticancer agents, additionally, the presence of halogens (Cl and F) in position 2 and 3 also improved the cytotoxicity in FKB series. These findings could help to improve the future drug discovery process to treat breast cancer. A molecular dynamics study of active compounds revealed stable interactions within the active site of Janus kinase. The structures of all compounds were determined by ¹H-NMR, EI-MS, IR and UV and X-ray crystallographic spectroscopy techniques. Full article

(This article belongs to the Section Organic Chemistry)

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10 pages, 917 KiB

Open AccessArticle

Antifeedant Activities of Lignans from Stem Bark of Zanthoxylum armatum DC. against Tribolium castaneum

by Wenjuan Zhang, Yang Wang, Zhufeng Geng, Shanshan Guo, Juqin Cao, Zhe Zhang, Xue Pang, Zhenyang Chen, Shushan Du and Zhiwei Deng

Molecules 2018, 23(3), 617; https://doi.org/10.3390/molecules23030617 - 9 Mar 2018

Cited by 31 | Viewed by 4506

Abstract

The speciation of a methanolic extract of Zanthoxylum armatum stem bark has enabled the isolation and characterization of 11 known lignans. Among them, five compounds (6, 8–11) are reported in this plant for the first time. All of [...] Read more.

The speciation of a methanolic extract of Zanthoxylum armatum stem bark has enabled the isolation and characterization of 11 known lignans. Among them, five compounds (6, 8–11) are reported in this plant for the first time. All of the chemical structures were elucidated on the basis of NMR spectral analysis. Additionally, their antifeedant activities against Tribolium castaneum were evaluated scientifically. Among them, asarinin (1), with an EC₅₀ of 25.64 ppm, exhibited a much stronger antifeedant activity than the positive control, toosendanin (EC₅₀ = 71.69 ppm). Moreover, fargesin (2), horsfieldin (3), and magnolone (10), with EC₅₀ values of 63.24, 68.39, and 78.37 ppm, showed almost the same antifeedant activity as the positive control. From the perspective of structure-effectiveness relationship, compounds with the chemical group of methylenedioxy exhibited higher antifeedant activities and have potential to be developed into novel antifeedants or potential lead compounds to protect food and crops in storage. Full article

(This article belongs to the Collection Herbal Medicine Research)

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11 pages, 370 KiB

Open AccessArticle

Energy-Protein Supplementation and Lactation Affect Fatty Acid Profile of Liver and Adipose Tissue of Dairy Cows

by Anna M. Brzozowska, Marek Lukaszewicz and Jolanta M. Oprzadek

Molecules 2018, 23(3), 618; https://doi.org/10.3390/molecules23030618 - 9 Mar 2018

Cited by 9 | Viewed by 3379

Abstract

This article addresses the hypothesis that lactation stage, parity and energy-protein feed additive affect fatty acid composition of blood, liver and adipose tissue of cows. The experiment was conducted on 24 Polish Holstein-Friesian cows divided into two feeding groups. One group of cows [...] Read more.

This article addresses the hypothesis that lactation stage, parity and energy-protein feed additive affect fatty acid composition of blood, liver and adipose tissue of cows. The experiment was conducted on 24 Polish Holstein-Friesian cows divided into two feeding groups. One group of cows was fed solely a total mixed ration, while the other group was fed a ration with the addition of 2 kg of energy-protein supplement per cow/day. During the experiment, the samples of liver, adipose tissue and blood were taken and their fatty acid compositions were determined. Analysis of variance was applied to fatty acid relative weight percentage to determine the effect of the stage of lactation, parity, and energy-protein supplement on the fatty acid composition of the tissues. Stage of lactation had a significant impact on the content of many fatty acids in all examined tissues. We found that parity had no effect on fatty acid composition of blood, whereas it significantly affected C16:1 c9 in liver, and C16:1 c9 and C18:0 in adipose tissue. Energy-protein supplement significantly affected the content of most fatty acids in blood (e.g., C18:1 t11 and C18:3 n-3) and liver (C18:3 n-3, both isomers of conjugated linolenic acid and n-3 fatty acids derived from fish oil), but it did not affect the profile of the adipose tissue of cows. According to our best knowledge, this is the first study showing the relationship between parity, stage of lactation and the composition of fatty acids in blood, liver and adipose tissue of cows. Full article

(This article belongs to the Special Issue The Multiple Roles of Fatty Acids)

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11 pages, 530 KiB

Open AccessArticle

A Novel Synthesis of Highly Functionalized Pyridines by a One-Pot, Three-Component Tandem Reaction of Aldehydes, Malononitrile and N-Alkyl-2-cyanoacetamides under Microwave Irradiation

by Ramadan Ahmed Mekheimer, Mariam Abdullah Al-Sheikh, Hanadi Yousef Medrasi and Najla Hosain Hassan Alsofyani

Molecules 2018, 23(3), 619; https://doi.org/10.3390/molecules23030619 - 9 Mar 2018

Cited by 17 | Viewed by 5867

Abstract

A convenient, fast and environmentally benign procedure for the synthesis of a new series of highly functionalized N-alkylated pyridines as privileged medicinal scaffolds was developed via a unique three-component reaction of easily available aromatic as well as heteroaromatic aldehydes, N-alkyl-2-cyanoacetamides and [...] Read more.

A convenient, fast and environmentally benign procedure for the synthesis of a new series of highly functionalized N-alkylated pyridines as privileged medicinal scaffolds was developed via a unique three-component reaction of easily available aromatic as well as heteroaromatic aldehydes, N-alkyl-2-cyanoacetamides and malononitrile in EtOH in the presence of K₂CO₃ as a base promoter under microwave irradiation. The presented tandem process is presumed to proceed via Knoevenagel condensation, Michael addition, intramolecular cyclization, autoxidation and subsequent aromatization. Particularly valuable features of this protocol, including high product yields, mild conditions, atom-efficiency, simple execution, short reaction times and easy purification make it a highly efficient and promising synthetic strategy to prepare substituted pyridine nuclei. The proposed mechanism of this novel one-pot reaction and structure elucidation of the products are discussed. Full article

(This article belongs to the Section Organic Chemistry)

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14 pages, 810 KiB

Open AccessArticle

Effects of Exogenous Application of Protocatechuic Acid and Vanillic Acid to Chlorophylls, Phenolics and Antioxidant Enzymes of Rice (Oryza sativa L.) in Submergence

by Tran Dang Xuan and Do Tan Khang

Molecules 2018, 23(3), 620; https://doi.org/10.3390/molecules23030620 - 9 Mar 2018

Cited by 39 | Viewed by 4525

Abstract

In this study, effects from application of protocatechuic acid (PA) and vanillic acid (VA) and their mixture on the submergence tolerance of rice were examined. The treatment of 0.01 mM PA and VA did not show significant increase of rice growth as compared [...] Read more.

In this study, effects from application of protocatechuic acid (PA) and vanillic acid (VA) and their mixture on the submergence tolerance of rice were examined. The treatment of 0.01 mM PA and VA did not show significant increase of rice growth as compared to the controls. However, at higher concentrations (0.1–1.0 mM), rice shoot was elevated in submergence by 20.8–22.4%. The survival percentage of rice seedlings at any dose of PA, VA and their mixture was significantly higher than the controls. In general, the mixture of PA and VA was more active to promote shoot elongation and survival in submergence than sole treatment of either PA or VA. The amount of chlorophyll b by PA was significantly increased, while no change in chlorophyll a content was observed. VA remarkably reduced malondialdehyde quantity at three days of submergence, while no significant difference among treatment was observed in PA, the mixture, and respective controls. The two phenolic acids promoted contents of phenolics and flavonoids in rice leaves and roots, however the quantities of endogenous PA and VA in rice were not markedly differed after PA and VA treated on roots of rice seedlings. The ascorbate peroxidase and superoxide dismutase activities were enhanced, while the expression of genes encoding antioxidant enzymes was favored. VA increased the expression level of ascorbate peroxidase genes in higher levels than PA and their mixture, while no significant difference was observed in the other genes including superoxide dismutase, catalase, glutathione reductase, and peroxidase. Findings of this study showed that PA and VA increased the submergence tolerance of rice by promoting the photosynthetic and anti-oxidative processes in rice seedlings. The treatment of PA and VA mixture on seedling roots was potent to promote the submergence tolerance in rice. Full article

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12 pages, 3123 KiB

Open AccessArticle

Efficient Separation of Four Antibacterial Diterpenes from the Roots of Salvia Prattii Using Non-Aqueous Hydrophilic Solid-Phase Extraction Followed by Preparative High-Performance Liquid Chromatography

by Jun Dang, Yulei Cui, Jinjin Pei, Huilan Yue, Zenggen Liu, Weidong Wang, Lijin Jiao, Lijuan Mei, Qilan Wang, Yanduo Tao and Yun Shao

Molecules 2018, 23(3), 623; https://doi.org/10.3390/molecules23030623 - 9 Mar 2018

Cited by 13 | Viewed by 3806

Abstract

An efficient preparative procedure for the separation of four antibacterial diterpenes from a Salvia prattii crude diterpenes-rich sample was developed. Firstly, the XION hydrophilic stationary phase was chosen to separate the antibacterial crude diterpenes-rich sample (18.0 g) into three fractions with a recovery [...] Read more.

An efficient preparative procedure for the separation of four antibacterial diterpenes from a Salvia prattii crude diterpenes-rich sample was developed. Firstly, the XION hydrophilic stationary phase was chosen to separate the antibacterial crude diterpenes-rich sample (18.0 g) into three fractions with a recovery of 46.1%. Then, the antibacterial fractions I (200 mg), II (200 mg), and III (150 g) were separated by the Megress C18 preparative column, and compounds tanshinone IIA (80.0 mg), salvinolone (62.0 mg), cryptotanshinone (70.0 mg), and ferruginol (68.0 mg) were produced with purities greater than 98%. The procedure achieved large-scale preparation of the four diterpenes with high purity, and it could act as a reference for the efficient preparation of active diterpenes from other plant extracts. Full article

(This article belongs to the Special Issue Solid Phase Extraction: State of the Art and Future Perspectives)

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16 pages, 4257 KiB

Open AccessFeature PaperArticle

Preparation of Well-Dispersed Chitosan/Alginate Hollow Multilayered Microcapsules for Enhanced Cellular Internalization

by Carla Ribeiro, João Borges, Ana M. S. Costa, Vítor M. Gaspar, Verónica De Zea Bermudez and João F. Mano

Molecules 2018, 23(3), 625; https://doi.org/10.3390/molecules23030625 - 10 Mar 2018

Cited by 33 | Viewed by 6333

Abstract

Hollow multilayered capsules have shown massive potential for being used in the biomedical and biotechnology fields, in applications such as cellular internalization, intracellular trafficking, drug delivery, or tissue engineering. In particular, hollow microcapsules, developed by resorting to porous calcium carbonate sacrificial templates, natural-origin [...] Read more.

Hollow multilayered capsules have shown massive potential for being used in the biomedical and biotechnology fields, in applications such as cellular internalization, intracellular trafficking, drug delivery, or tissue engineering. In particular, hollow microcapsules, developed by resorting to porous calcium carbonate sacrificial templates, natural-origin building blocks and the prominent Layer-by-Layer (LbL) technology, have attracted increasing attention owing to their key features. However, these microcapsules revealed a great tendency to aggregate, which represents a major hurdle when aiming for cellular internalization and intracellular therapeutics delivery. Herein, we report the preparation of well-dispersed polysaccharide-based hollow multilayered microcapsules by combining the LbL technique with an optimized purification process. Cationic chitosan (CHT) and anionic alginate (ALG) were chosen as the marine origin polysaccharides due to their biocompatibility and structural similarity to the extracellular matrices of living tissues. Moreover, the inexpensive and highly versatile LbL technology was used to fabricate core-shell microparticles and hollow multilayered microcapsules, with precise control over their composition and physicochemical properties, by repeating the alternate deposition of both materials. The microcapsules’ synthesis procedure was optimized to extensively reduce their natural aggregation tendency, as shown by the morphological analysis monitored by advanced microscopy techniques. The well-dispersed microcapsules showed an enhanced uptake by fibroblasts, opening new perspectives for cellular internalization. Full article

(This article belongs to the Special Issue Chitin and Chitosan Derivatives: Biological Activities and Application)

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20 pages, 2528 KiB

Open AccessFeature PaperArticle

Chiral Thioxanthones as Modulators of P-glycoprotein: Synthesis and Enantioselectivity Studies

by Ana Lopes, Eva Martins, Renata Silva, Madalena M. M. Pinto, Fernando Remião, Emília Sousa and Carla Fernandes

Molecules 2018, 23(3), 626; https://doi.org/10.3390/molecules23030626 - 10 Mar 2018

Cited by 19 | Viewed by 4141

Abstract

Recently, thioxanthone derivatives were found to protect cells against toxic P-glycoprotein (P-gp) substrates, acting as potent inducers/activators of this efflux pump. The study of new P-gp chiral modulators produced from thioxanthone derivatives could clarify the enantioselectivity of this ABC transporter towards this new [...] Read more.

Recently, thioxanthone derivatives were found to protect cells against toxic P-glycoprotein (P-gp) substrates, acting as potent inducers/activators of this efflux pump. The study of new P-gp chiral modulators produced from thioxanthone derivatives could clarify the enantioselectivity of this ABC transporter towards this new class of modulators. The aim of this study was to evaluate the P-gp modulatory ability of four enantiomeric pairs of new synthesized chiral aminated thioxanthones (ATxs) 1–8, studying the influence of the stereochemistry on P-gp induction/ activation in cultured Caco-2 cells. The data displayed that all the tested compounds (at 20 μM) significantly decreased the intracellular accumulation of a P-gp fluorescent substrate (rhodamine 123) when incubated simultaneously for 60 min, demonstrating an increased activity of the efflux, when compared to control cells. Additionally, all of them except ATx 3 (+), caused similar results when the accumulation of the P-gp fluorescent substrate was evaluated after pre-incubating cells with the test compounds for 24 h, significantly reducing the rhodamine 123 intracellular accumulation as a result of a significant increase in P-gp activity. However, ATx 2 (−) was the only derivative that, after 24 h of incubation, significantly increased P-gp expression. These results demonstrated a significantly increased P-gp activity, even without an increase in P-gp expression. Therefore, ATxs 1–8 were shown to behave as P-gp activators. Furthermore, no significant differences were detected in the activity of the protein when comparing the enantiomeric pairs. Nevertheless, ATx 2 (−) modulates P-gp expression differently from its enantiomer, ATx 1 (+). These results disclosed new activators and inducers of P-gp and highlight the existence of enantioselectivity in the induction mechanism. Full article

(This article belongs to the Special Issue Chirality in Health and Environment: Recent developments)

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13 pages, 1990 KiB

Open AccessArticle

Microbes a Tool for the Remediation of Organotin Pollution Determined by Static Headspace Gas Chromatography-Mass Spectrometry

by Christopher Finnegan, David Ryan, Anne-Marie Enright and Guiomar Garcia-Cabellos

Molecules 2018, 23(3), 627; https://doi.org/10.3390/molecules23030627 - 10 Mar 2018

Cited by 5 | Viewed by 6638

Abstract

Tributyltin (TBT) is one of the most toxic anthropogenic compounds introduced into the marine environment. Despite its global ban in 2008, TBT is still a problem of great concern due to its high affinity for particulate matter, providing a direct and potentially persistent [...] Read more.

Tributyltin (TBT) is one of the most toxic anthropogenic compounds introduced into the marine environment. Despite its global ban in 2008, TBT is still a problem of great concern due to its high affinity for particulate matter, providing a direct and potentially persistent route of entry into benthic sediments. Bioremediation strategies may constitute an alternative approach to conventional physicochemical methods, benefiting from the microorganism’s potential to metabolize anthropogenic compounds. In this work, a simple, precise and accurate static headspace gas chromatography method was developed to investigate the ability of TBT degrading microbes in sedimentary microcosms over a period of 120 days. The proposed method was validated for linearity, repeatability, accuracy, specificity, limit of detection and limit of quantification. The method was subsequently successfully applied for the detection and quantification of TBT and degradation compounds in sediment samples on day 0, 30, 60, 90 and 120 of the experiment employing the principles of green chemistry. On day 120 the concentration of TBT remaining in the microcosms ranged between 91.91 ng/g wet wt for the least effective microbial inoculant to 52.73 ng/g wet wt for the most effective microbial inoculant from a starting concentration of 100 ng/g wet wt. Full article

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11 pages, 1534 KiB

Open AccessArticle

Gold-Catalyzed Addition of β-Ketoesters to Alkenes: Influence of Electronic and Steric Effects in the Reaction Outcome

by Agustina La-Venia, Mirta P. Mischne and Ernesto G. Mata

Molecules 2018, 23(3), 629; https://doi.org/10.3390/molecules23030629 - 10 Mar 2018

Viewed by 3249

Abstract

The gold-catalyzed intermolecular hydroalkylation of olefins with β-ketoesters represents a conceptually attractive and useful synthetic tool; however, it has been scarcely applied, remaining a challenge for chemists. The aim of the current study was to investigate the addition of these 1,3-diketo-compounds to alkenes [...] Read more.

The gold-catalyzed intermolecular hydroalkylation of olefins with β-ketoesters represents a conceptually attractive and useful synthetic tool; however, it has been scarcely applied, remaining a challenge for chemists. The aim of the current study was to investigate the addition of these 1,3-diketo-compounds to alkenes under gold catalysis conditions, in order to establish the electronic and steric effects of the alkenyl substrates in the reaction outcome. The screening of different catalyst systems and diverse olefins enabled defining the alkenyl requirements and the best reaction conditions to efficiently achieve the coupled products. Full article

(This article belongs to the Special Issue Organometallic Catalysis in Organic Synthesis)

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15 pages, 1849 KiB

Open AccessArticle

In Vitro ADME Properties of Two Novel Antimicrobial Peptoid-Based Compounds as Potential Agents against Canine Pyoderma

by Ines Greco, Bernard D. Hummel, Jaspreet Vasir, Jeffrey L. Watts, Jason Koch, Johannes E. Hansen, Hanne Mørck Nielsen, Peter Damborg and Paul R. Hansen

Molecules 2018, 23(3), 630; https://doi.org/10.3390/molecules23030630 - 10 Mar 2018

Cited by 9 | Viewed by 5924

Abstract

Antimicrobial peptides (AMPs) hold promise as the next generation of antimicrobial agents, but often suffer from rapid degradation in vivo. Modifying AMPs with non-proteinogenic residues such as peptoids (oligomers of N-alkylglycines) provides the potential to improve stability. We have identified two novel [...] Read more.

Antimicrobial peptides (AMPs) hold promise as the next generation of antimicrobial agents, but often suffer from rapid degradation in vivo. Modifying AMPs with non-proteinogenic residues such as peptoids (oligomers of N-alkylglycines) provides the potential to improve stability. We have identified two novel peptoid-based compounds, B1 and D2, which are effective against the canine skin pathogen Staphylococcus pseudintermedius, the main cause of antibiotic use in companion animals. We report on their potential to treat infections topically by characterizing their release from formulation and in vitro ADME properties. In vitro ADME assays included skin penetration profiles, stability to proteases and liver microsomes, and plasma protein binding. Both B1 and D2 were resistant to proteases and >98% bound to plasma proteins. While half-lives in liver microsomes for both were >2 h, peptoid D2 showed higher stability to plasma proteases than the peptide-peptoid hybrid B1 (>2 versus 0.5 h). Both compounds were suitable for administration in an oil-in-water cream formulation (50% release in 8 h), and displayed no skin permeation, in the absence or presence of skin permeability modifiers. Our results indicate that these peptoid-based drugs may be suitable as antimicrobials for local treatment of canine superficial pyoderma and that they can overcome the inherent limitations of stability encountered in peptides. Full article

(This article belongs to the Special Issue Antimicrobial Peptides and Peptidomimetics)

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13 pages, 2596 KiB

Open AccessArticle

Preliminary Characterization and Bioactivities of Some Impatiens L. Water-Soluble Polysaccharides

by Katarzyna Szewczyk, Esther Marie Heise and Jakub P. Piwowarski

Molecules 2018, 23(3), 631; https://doi.org/10.3390/molecules23030631 - 11 Mar 2018

Cited by 16 | Viewed by 3622

Abstract

Preliminary characterization and bioactivity of water-soluble polysaccharides from four Impatiens species—I. glandulifera Royle, I. parviflora DC., I. balsamina L., and I. noli-tangere L.—were investigated. The yields of polysaccharides range widely from 1.97% for I. parviflora roots to 18.63% for I. balsamina aerial [...] Read more.

Preliminary characterization and bioactivity of water-soluble polysaccharides from four Impatiens species—I. glandulifera Royle, I. parviflora DC., I. balsamina L., and I. noli-tangere L.—were investigated. The yields of polysaccharides range widely from 1.97% for I. parviflora roots to 18.63% for I. balsamina aerial parts. SEC (Size exclusion chromatography) chromatograms show that all samples contained a low molecular weight part that consisted of components of similar molecular weight. The aerial parts and roots of I. balsamina, and I. glandulifera aerial parts had considerable amounts of high molecular weight components up to 2.3 MDa. The sugar composition analysis revealed that Impatiens polysaccharides consisted primarily of galactose, arabinose, rhamnose, mannose, xylose, and glucose. All polysaccharide fractions, except for I. parviflora roots, also contain galacturonic acid. Moreover, in vitro bioactivity of obtained polysaccharides were evaluated. The antioxidant activity was evaluated on the basis of 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2-azino-bis-(3-ethyl-benzthia-6-sulfonic acid) (ABTS) radical scavenging assays. The highest antioxidant activity was obtained for I. balsamina aerial parts and I. parviflora roots. Among the tested fractions, only the polysaccharides from I. glandulifera aerial parts were able to significantly decrease the production of IL-8 by 32.7 ± 10.5%. The results suggest that Impatiens species can be considered as a new source of antioxidants. Full article

(This article belongs to the Section Natural Products Chemistry)

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14 pages, 5203 KiB

Open AccessArticle

Production of Micro- and Nanoscale Lignin from Wheat Straw Using Different Precipitation Setups

by Stefan Beisl, Petra Loidolt, Angela Miltner, Michael Harasek and Anton Friedl

Molecules 2018, 23(3), 633; https://doi.org/10.3390/molecules23030633 - 11 Mar 2018

Cited by 32 | Viewed by 5546

Abstract

Micro- and nanosize lignin has recently gained interest due to its improved properties compared to standard lignin available today. As the second most abundant biopolymer after cellulose, lignin is readily available but used for rather low-value applications. Applications for lignin in micro- to [...] Read more.

Micro- and nanosize lignin has recently gained interest due to its improved properties compared to standard lignin available today. As the second most abundant biopolymer after cellulose, lignin is readily available but used for rather low-value applications. Applications for lignin in micro- to nanoscale however, ranging from improvement of mechanical properties of polymer nanocomposites, have bactericidal and antioxidant properties and impregnations to hollow lignin drug carriers for hydrophobic and hydrophilic substances. This research represents a whole biorefinery process chain and compares different precipitation setups to produce submicron lignin particles from lignin containing an organosolv pretreatment extract from wheat straw. A batch precipitation in a stirred vessel was compared with continuous mixing of extract and antisolvent in a T-fitting and mixing in a T-fitting followed by a static mixer. The precipitation in the combination of T-fitting and static mixer with improved precipitation parameters yields the smallest particle size of around 100 nm. Furthermore, drying of particles did not influence the particle sizes negatively by showing decreased particle diameters after the separation process. Full article

(This article belongs to the Special Issue Lignin for Energy, Chemicals and Materials)

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19 pages, 3953 KiB

Open AccessFeature PaperArticle

Increasing Polarity in Tacrine and Huprine Derivatives: Potent Anticholinesterase Agents for the Treatment of Myasthenia Gravis

by Carles Galdeano, Nicolas Coquelle, Monika Cieslikiewicz-Bouet, Manuela Bartolini, Belén Pérez, M. Victòria Clos, Israel Silman, Ludovic Jean, Jacques-Philippe Colletier, Pierre-Yves Renard and Diego Muñoz-Torrero

Molecules 2018, 23(3), 634; https://doi.org/10.3390/molecules23030634 - 11 Mar 2018

Cited by 31 | Viewed by 5556

Abstract

Symptomatic treatment of myasthenia gravis is based on the use of peripherally-acting acetylcholinesterase (AChE) inhibitors that, in some cases, must be discontinued due to the occurrence of a number of side-effects. Thus, new AChE inhibitors are being developed and investigated for their potential [...] Read more.

Symptomatic treatment of myasthenia gravis is based on the use of peripherally-acting acetylcholinesterase (AChE) inhibitors that, in some cases, must be discontinued due to the occurrence of a number of side-effects. Thus, new AChE inhibitors are being developed and investigated for their potential use against this disease. Here, we have explored two alternative approaches to get access to peripherally-acting AChE inhibitors as new agents against myasthenia gravis, by structural modification of the brain permeable anti-Alzheimer AChE inhibitors tacrine, 6-chlorotacrine, and huprine Y. Both quaternization upon methylation of the quinoline nitrogen atom, and tethering of a triazole ring, with, in some cases, the additional incorporation of a polyphenol-like moiety, result in more polar compounds with higher inhibitory activity against human AChE (up to 190-fold) and butyrylcholinesterase (up to 40-fold) than pyridostigmine, the standard drug for symptomatic treatment of myasthenia gravis. The novel compounds are furthermore devoid of brain permeability, thereby emerging as interesting leads against myasthenia gravis. Full article

(This article belongs to the Special Issue The Cholinesterases—Structure, Mechanism, Function and Drug Design: The 25th Anniversary of the Solution of the Crystal Structure of Acetylcholinesterase by Joel L. Sussman and Israel Silman)

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12 pages, 2443 KiB

Open AccessArticle

Lung Cancer Chemopreventive Activity of Patulin Isolated from Penicillium vulpinum

by Aymeric Monteillier, Pierre-Marie Allard, Katia Gindro, Jean-Luc Wolfender and Muriel Cuendet

Molecules 2018, 23(3), 636; https://doi.org/10.3390/molecules23030636 - 12 Mar 2018

Cited by 11 | Viewed by 4557

Abstract

Lung cancer is the most lethal form of cancer in the world. Its development often involves an overactivation of the nuclear factor kappa B (NF-κB) pathway, leading to increased cell proliferation, survival, mobility, and a decrease in apoptosis. Therefore, NF-κB inhibitors are actively [...] Read more.

Lung cancer is the most lethal form of cancer in the world. Its development often involves an overactivation of the nuclear factor kappa B (NF-κB) pathway, leading to increased cell proliferation, survival, mobility, and a decrease in apoptosis. Therefore, NF-κB inhibitors are actively sought after for both cancer chemoprevention and therapy, and fungi represent an interesting unexplored reservoir for such molecules. The aim of the present work was to find naturally occurring lung cancer chemopreventive compounds by investigating the metabolites of Penicillium vulpinum, a fungus that grows naturally on dung. Penicillium vulpinum was cultivated in Potato Dextrose Broth and extracted with ethyl acetate. Bioassay-guided fractionation of this extract was performed by measuring NF-κB activity using a HEK293 cell line transfected with an NF-κB-driven luciferase reporter gene. The mycotoxin patulin was identified as a nanomolar inhibitor of TNF-α-induced NF-κB activity. Immunocytochemistry and Western blot analyses revealed that its mechanism of action involved an inhibition of p65 nuclear translocation and was independent from the NF-κB inhibitor α (IκBα) degradation process. Enhancing its interest in lung cancer chemoprevention, patulin also exhibited antiproliferative, proapoptotic, and antimigration effects on human lung adenocarcinoma cells through inhibition of the Wnt pathway. Full article

(This article belongs to the Special Issue Plant Derived Natural Products and Age Related Diseases)

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16 pages, 2855 KiB

Open AccessArticle

Discovery of Oxime Ethers as Hepatitis B Virus (HBV) Inhibitors by Docking, Screening and In Vitro Investigation

by Jie Tan, Min Zhou, Xinhua Cui, Zhuocai Wei and Wanxing Wei

Molecules 2018, 23(3), 637; https://doi.org/10.3390/molecules23030637 - 12 Mar 2018

Cited by 9 | Viewed by 3817

Abstract

A series of oxime ethers with C₆-C₄ fragment was designed and virtually bioactively screened by docking with a target, then provided by a Friedel–Crafts reaction, esterification (or amidation), and oximation from p-substituted phenyl derivatives (Methylbenzene, Methoxybenzene, Chlorobenzene). Anti-hepatitis B [...] Read more.

A series of oxime ethers with C₆-C₄ fragment was designed and virtually bioactively screened by docking with a target, then provided by a Friedel–Crafts reaction, esterification (or amidation), and oximation from p-substituted phenyl derivatives (Methylbenzene, Methoxybenzene, Chlorobenzene). Anti-hepatitis B virus (HBV) activities of all synthesized compounds were evaluated with HepG2.2.15 cells in vitro. Results showed that most of compounds exhibited low cytotoxicity on HepG2.2.15 cells and significant inhibition on the secretion of HBsAg and HBeAg. Among them, compound 5c-1 showed the most potent activity on inhibiting HBsAg secretion (IC₅₀ = 39.93 μM, SI = 28.51). Results of the bioactive screening showed that stronger the compounds bound to target human leukocyte antigen A protein in docking, the more active they were in anti-HBV activities in vitro. Full article

(This article belongs to the Section Medicinal Chemistry)

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7 pages, 1315 KiB

Open AccessCommunication

Prenylated Polyphenols from Broussonetia kazinoki as Inhibitors of Nitric Oxide Production

by Da Yeon Lee, Hwa Jin Lee and Jae-Ha Ryu

Molecules 2018, 23(3), 639; https://doi.org/10.3390/molecules23030639 - 12 Mar 2018

Cited by 6 | Viewed by 4003

Abstract

Excessive nitric oxide (NO) production by macrophages has been involved in inflammatory diseases. Seven polyphenols (1–7) were isolated from Broussonetia kazinoki (B. kazinoki) and investigated as potential inhibitors of NO overproduction in lipopolysaccharide (LPS)-activated RAW 264.7 cells. Among them, [...] Read more.

Excessive nitric oxide (NO) production by macrophages has been involved in inflammatory diseases. Seven polyphenols (1–7) were isolated from Broussonetia kazinoki (B. kazinoki) and investigated as potential inhibitors of NO overproduction in lipopolysaccharide (LPS)-activated RAW 264.7 cells. Among them, four prenylated polyphenols (2–4 and 6) with a catechol moiety efficiently suppressed the LPS-induced high level of NO with IC₅₀ values of less than 6 µM. The compounds 2–4 and 6 also attenuated protein and mRNA levels of inducible nitric oxide synthase (iNOS). Moreover, they suppressed the nuclear factor κB (NF-κB) activity by inhibiting the degradation of inhibitory-κB-α (I-κB-α) and the translocation of NF-κB into the nucleus in LPS-activated macrophages. Taken together, these findings suggest that polyphenols from B. kazinoki might be beneficial for treatment of inflammatory diseases. Full article

(This article belongs to the Collection Bioactive Compounds)

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10 pages, 1132 KiB

Open AccessArticle

An Efficient Chemoenzymatic Approach towards the Synthesis of Rugulactone

by Theodore Tyrikos-Ergas, Vasileios Giannopoulos and Ioulia Smonou

Molecules 2018, 23(3), 640; https://doi.org/10.3390/molecules23030640 - 12 Mar 2018

Cited by 4 | Viewed by 3216

Abstract

Rugulactone is a natural product isolated from the plant Cryptocarya rugulosa. It has shown very important biological activity as an inhibitor of the nuclear factor κB (NF-κB) activation pathway. A new chemoenzymatic approach towards the synthesis of rugulactone is presented here. The [...] Read more.

Rugulactone is a natural product isolated from the plant Cryptocarya rugulosa. It has shown very important biological activity as an inhibitor of the nuclear factor κB (NF-κB) activation pathway. A new chemoenzymatic approach towards the synthesis of rugulactone is presented here. The chirality, induced to the key intermediate by a stereoselective enzymatic reduction utilizing NADPH-dependent ketoreductase, is described in detail. Full article

(This article belongs to the Section Bioorganic Chemistry)

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12 pages, 2071 KiB

Open AccessArticle

Eudesmane-Type Sesquiterpene Glycosides from Dictamnus dasycarpus Turcz.

by Shengcai Yang, Zheng Li, Jianli Wang, Jingya Ruan, Chang Zheng, Peijian Huang, Lifeng Han, Yi Zhang and Tao Wang

Molecules 2018, 23(3), 642; https://doi.org/10.3390/molecules23030642 - 13 Mar 2018

Cited by 10 | Viewed by 4900

Abstract

Eudesmane-type sesquiterpenes have been reported to exhibit varieties of biological activities. During the process of investigating this kind of natural product from the root bark of Dictamnus dasycarpus Turcz., 13 eudesmane-type sesquiterpene glycosides including six new isolates, named as dictameudesmnosides A₁ ( [...] Read more.

Eudesmane-type sesquiterpenes have been reported to exhibit varieties of biological activities. During the process of investigating this kind of natural product from the root bark of Dictamnus dasycarpus Turcz., 13 eudesmane-type sesquiterpene glycosides including six new isolates, named as dictameudesmnosides A₁ (1), A₂ (2), B (3), C (4), D (5), and E (6), together with seven known ones (7–13), were obtained. Herein, their structures were determined by the analysis of physical data, spectroscopic analysis, and chemical methods. The existence of α-configuration glucose units in their structures (1–5, 8) is not very common in natural glycosidic components. Meanwhile, compounds 3–5, 7, and 9–13 displayed TG accumulation inhibitory effects on HepG2 cells. Full article

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11 pages, 1241 KiB

Open AccessArticle

Comparison of Multiple Bioactive Constituents in Different Parts of Eucommia ulmoides Based on UFLC-QTRAP-MS/MS Combined with PCA

by Ying Yan, Hui Zhao, Cuihua Chen, Lisi Zou, Xunhong Liu, Chuan Chai, Chengcheng Wang, Jingjing Shi and Shuyu Chen

Molecules 2018, 23(3), 643; https://doi.org/10.3390/molecules23030643 - 13 Mar 2018

Cited by 46 | Viewed by 5057

Abstract

Eucommia ulmoides Oilv. (EU), also called Du-zhong, is a classical traditional Chinese medicine. Its bark, leaf, and male flower are all used for medicinal purposes, called Eucommiae Cortex (EC), Eucommiae Folium (EF), and Eucommiae Flos Male (EFM). In order to study the difference [...] Read more.

Eucommia ulmoides Oilv. (EU), also called Du-zhong, is a classical traditional Chinese medicine. Its bark, leaf, and male flower are all used for medicinal purposes, called Eucommiae Cortex (EC), Eucommiae Folium (EF), and Eucommiae Flos Male (EFM). In order to study the difference in synthesis and the accumulation of metabolites in different parts of EU, a reliable method based on ultra-fast liquid chromatography tandem triple quadrupole mass spectrometry (UFLC-QTRAP-MS/MS) was developed for the simultaneous determination of a total of 21 constituents, including two lignans, 6 iridoids, 6 penylpropanoids, 6 flavonoids, and one phenol in the samples (EC, EF, and EFM). Furthermore, principal component analysis (PCA) was performed to evaluate and classify the samples according to the contents of these 21 constituents. All of the results demonstrated that the chemical compositions in EC, EF, and EFM were significantly different and the differential constituents (i.e., aucubin, geniposidic acid, chlorogenic acid, pinoresinol-di-O-β-d-glucopyranoside, geniposide, cryptochlorogenic acid, rutin, and quercetin) were remarkably associated with sample classifications. The research will provide the basic information for revealing the laws of metabolite accumulation in EC, EF, and EFM from the same origin. Full article

(This article belongs to the Collection Advances in Liquid Separation Techniques for Food and Pharmaceutical Analysis)

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13 pages, 4029 KiB

Open AccessArticle

The Effect of Tomatine on Gene Expression and Cell Monolayer Integrity in Caco-2

by Mattia P. Arena, Coen Govers, Concetta Lotti, Luigi Ricciardi, Harry J. Wichers and Jurriaan J. Mes

Molecules 2018, 23(3), 644; https://doi.org/10.3390/molecules23030644 - 13 Mar 2018

Cited by 10 | Viewed by 5205

Abstract

More understanding of the risk-benefit effect of the glycoalkaloid tomatine is required to be able to estimate the role it might play in our diet. In this work, we focused on effects towards intestinal epithelial cells based on a Caco-2 model in order [...] Read more.

More understanding of the risk-benefit effect of the glycoalkaloid tomatine is required to be able to estimate the role it might play in our diet. In this work, we focused on effects towards intestinal epithelial cells based on a Caco-2 model in order to analyze the influence on the cell monolayer integrity and on the expression levels of genes involved in cholesterol/sterol biosynthesis (LDLR), lipid metabolism (NR2F2), glucose and amino acid uptake (SGLT1, PAT1), cell cycle (PCNA, CDKN1A), apoptosis (CASP-3, BMF, KLF6), tight junctions (CLDN4, OCLN2) and cytokine-mediated signaling (IL-8, IL1β, TSLP, TNF-α). Furthermore, since the bioactivity of the compound might vary in the presence of a food matrix and following digestion, the influence of both pure tomatine and in vitro digested tomatine with and without tomato fruit matrix was studied. The obtained results suggested that concentrations <20 µg/mL of tomatine, either undigested or in vitro digested, do not compromise the viability of Caco-2 cells and stimulate cytokine expression. This effect of tomatine, in vitro digested tomatine or in vitro digested tomatine with tomato matrix differs slightly, probably due to variations of bioactivity or bioavailability of the tomatine. The results lead to the hypothesis that tomatine acts as hormetic compound that can induce beneficial or risk toxic effects whether used in low or high dose. Full article

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11 pages, 4638 KiB

Open AccessArticle

Anti-Inflammatory and Tissue Regenerative Effects of Topical Treatment with Ozonated Olive Oil/Vitamin E Acetate in Balanitis Xerotica Obliterans

by Monica Currò, Tiziana Russo, Nadia Ferlazzo, Daniela Caccamo, Pietro Antonuccio, Salvatore Arena, Saveria Parisi, Patrizia Perrone, Riccardo Ientile, Carmelo Romeo and Pietro Impellizzeri

Molecules 2018, 23(3), 645; https://doi.org/10.3390/molecules23030645 - 13 Mar 2018

Cited by 30 | Viewed by 8799

Abstract

Balanitis xerotica obliterans (BXO) is a chronic inflammatory skin disorder, considered the male genital variant of lichen sclerosus. Anti-inflammatory drugs are commonly used in BXO. We evaluated the effects of an innovative formulation of ozonated olive oil with vitamin E acetate (OZOILE^® [...] Read more.

Balanitis xerotica obliterans (BXO) is a chronic inflammatory skin disorder, considered the male genital variant of lichen sclerosus. Anti-inflammatory drugs are commonly used in BXO. We evaluated the effects of an innovative formulation of ozonated olive oil with vitamin E acetate (OZOILE^®) on the inflammatory status and tissue remodeling in male children with BXO. The mRNA transcripts of proteins involved either in inflammation or in dynamics of tissue regeneration were analyzed by quantitative real-time PCR, in foreskins affected by BXO removed from patients untreated or treated with OZOILE^® cream for 7 days before circumcision. We found a significant reduction in mRNA levels of IL-1β, TNF-α, INF–γ, transglutaminase 2 and NOS2 in foreskins treated with OZOILE^® in comparison to untreated ones (p < 0.001). No significant differences were observed in NF-κB activation in the specimens obtained from treated and untreated patients. Hence, OZOILE^® treatment up-regulated hypoxia-inducible factor (HIF)-1alpha, vascular endothelial growth factor (VEGF) and E-cadherin gene expression (p < 0.001). The treatment with OZOILE^® showed effective results in children affected by BXO by reducing the inflammatory process and stimulating mechanisms for tissue regeneration of the foreskin. A randomized clinical trial on a large number of children affected by BXO might be useful to verify the efficacy of topical treatment with OZOILE^®. Full article

(This article belongs to the Section Medicinal Chemistry)

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14 pages, 2591 KiB

Open AccessArticle

Ruthenium(η⁶,η¹-arene-CH₂-NHC) Catalysts for Direct Arylation of 2-Phenylpyridine with (Hetero)Aryl Chlorides in Water

by Nazan Kaloğlu, İsmail Özdemir, Nevin Gürbüz, Hakan Arslan and Pierre H. Dixneuf

Molecules 2018, 23(3), 647; https://doi.org/10.3390/molecules23030647 - 13 Mar 2018

Cited by 24 | Viewed by 4326

Abstract

A series of new benzimidazolium halides were synthesized in good yields as unsymmetrical N-heterocyclic carbene (NHC) precursors containing the N–CH₂–arene group. The benzimidazolium halides were readily converted into ruthenium(II)–NHC complexes with the general formula [RuCl₂(η⁶,η¹ [...] Read more.

A series of new benzimidazolium halides were synthesized in good yields as unsymmetrical N-heterocyclic carbene (NHC) precursors containing the N–CH₂–arene group. The benzimidazolium halides were readily converted into ruthenium(II)–NHC complexes with the general formula [RuCl₂(η⁶,η¹–arene–CH₂–NHC)]. The structures of all new compounds were characterized by ¹H NMR (Nuclear Magnetic Resonance), ¹³C NMR, FT-IR (Fourier Transform Infrared) spectroscopy and elemental analysis techniques. The single crystal structure of one benzimidazole ruthenium complex, 2b, was determined. The complex is best thought of as containing an octahedrally coordinated Ru center with the arene residue occupying three sites, the remaining sites being occupied by a (carbene)C–Ru bond and two Ru–Cl bonds. The catalytic activity of [RuCl₂(η⁶,η¹–arene–CH₂–NHC)] complexes was evaluated in the direct (hetero)arylation of 2-phenylpyridine with (hetero)aryl chlorides in water as the nontoxic reaction medium. These results show that catalysts 2a and 2b were the best for monoarylation with simple phenyl and tolyl chlorides. For functional aryl chlorides, 2d, 2e, and 2c appeared to be the most efficient. Full article

(This article belongs to the Special Issue Organometallic Catalysis in Organic Synthesis)

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11 pages, 1804 KiB

Open AccessArticle

Vinylation of a Secondary Amine Core with Calcium Carbide for Efficient Post-Modification and Access to Polymeric Materials

by Konstantin S. Rodygin, Alexander S. Bogachenkov and Valentine P. Ananikov

Molecules 2018, 23(3), 648; https://doi.org/10.3390/molecules23030648 - 13 Mar 2018

Cited by 34 | Viewed by 7553

Abstract

We developed a simple and efficient strategy to access N-vinyl secondary amines of various naturally occurring materials using readily available solid acetylene reagents (calcium carbide, KF, and KOH). Pyrrole, pyrazole, indoles, carbazoles, and diarylamines were successfully vinylated in good yields. Cross-linked and [...] Read more.

We developed a simple and efficient strategy to access N-vinyl secondary amines of various naturally occurring materials using readily available solid acetylene reagents (calcium carbide, KF, and KOH). Pyrrole, pyrazole, indoles, carbazoles, and diarylamines were successfully vinylated in good yields. Cross-linked and linear polymers were synthesized from N-vinyl carbazoles through free radical and cationic polymerization. Post-modification of olanzapine (an antipsychotic drug substance) was successfully performed. Full article

(This article belongs to the Special Issue Alkynes: From Reaction Design to Applications in Organic Synthesis)

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11 pages, 1185 KiB

Open AccessCommunication

Development and Validation of a HPLC-UV Method for Extraction Optimization and Biological Evaluation of Hot-Water and Ethanolic Extracts of Dendropanax morbifera Leaves

by Hyung-Jae Choi, Dae-Hun Park, Seung-Hui Song, In-Soo Yoon and Seung-Sik Cho

Molecules 2018, 23(3), 650; https://doi.org/10.3390/molecules23030650 - 13 Mar 2018

Cited by 22 | Viewed by 5445

Abstract

Dendropanax morbifera Leveille (Araliaceae) has been used in traditional oriental remedies for cancer, inflammation, diabetes, and thrombosis. However, a validated analytical method, standardization, and optimization of extraction conditions with respect to biological activity have not been reported. In this study, a simple and [...] Read more.

Dendropanax morbifera Leveille (Araliaceae) has been used in traditional oriental remedies for cancer, inflammation, diabetes, and thrombosis. However, a validated analytical method, standardization, and optimization of extraction conditions with respect to biological activity have not been reported. In this study, a simple and validated HPLC method for identifying and quantifying active substances in D. morbifera was developed. Hot water and ethanolic D. morbifera leaf extracts from different production regions were prepared and evaluated with regard to their chemical compositions and biological activities. The contents of active compounds such as rutin and chlorogenic acid were determined in four samples collected from different regions. The 80% ethanolic extract showed the best antioxidant activity, phenolic content, reducing power, and xanthine oxidase (XO) inhibitory activity. The validated HPLC method confirmed the presence of chlorogenic acid and rutin in D. morbifera leaf extracts. The antioxidant and XO inhibitory activity of D. morbifera extract could be attributed to the marker compounds. Collectively, these results suggest that D. morbifera leaves could be beneficial for the treatment or prevention of hyperuricemia-related disease, and the validated HPLC method could be a useful tool for the quality control of food or drug formulations containing D. morbifera. Full article

(This article belongs to the Collection Advances in Liquid Separation Techniques for Food and Pharmaceutical Analysis)

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12 pages, 2057 KiB

Open AccessArticle

A Green Protocol for Microwave-Assisted Extraction of Volatile Oil Terpenes from Pterodon emarginatus Vogel. (Fabaceae)

by Giuliana M. Vila Verde, Diogo A. Barros, Marilene Silva Oliveira, Gilberto L.B. Aquino, Danilo M. Santos, José Realino De Paula, Lucas D. Dias, Marta Piñeiro and Mariette M. Pereira

Molecules 2018, 23(3), 651; https://doi.org/10.3390/molecules23030651 - 13 Mar 2018

Cited by 10 | Viewed by 4276

Abstract

Microwave-assisted extraction of volatile oils (MAE) potentially offers a more efficient and bio-sustainable method than conventional extraction by Clevenger apparatus (CE). This study aimed to optimise the MAE of the volatile oil from Pterodon emarginatus fruits and characterise the volatile compounds. A 2 [...] Read more.

Microwave-assisted extraction of volatile oils (MAE) potentially offers a more efficient and bio-sustainable method than conventional extraction by Clevenger apparatus (CE). This study aimed to optimise the MAE of the volatile oil from Pterodon emarginatus fruits and characterise the volatile compounds. A 2³ full-factorial central composite design and response surface methodology were used to evaluate the effects of time (min), moisture (%) and microwave power (W) on the extraction yield. The process optimisation was based on the desirability function approach. The reaction time and moisture conditions were standardised in these analyses. The volatile oil composition was analysed by Gas Chromatography/Mass Spectrometry (GC/MS) in order to compare techniques extractions influences. Microwave irradiation showed excellent performance for extraction of the volatile oil from Pterodon emarginatus and there were some advantages in compare to conventional method with respect to the time (14 times), energy (6 times), reagents amounts and waste formation. About chemical composition presents significant differences with the type of extraction. Caryophyllene (25.65%) and trans-α-bisabolol (6.24%) were identified as major components in MAE sample while caryophyllene (6.75%) and γ-elemene (7.02%) are the components with higher relative percentage in CE samples. The microwaves assisted process shown an increase of economic interested compounds present in volatile oil. Full article

(This article belongs to the Section Natural Products Chemistry)

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12 pages, 1627 KiB

Open AccessArticle

Identification of the NADPH Oxidase 4 Inhibiting Principle of Lycopus europaeus

by Silvia Revoltella, Giorgia Baraldo, Birgit Waltenberger, Stefan Schwaiger, Philipp Kofler, Julia Moesslacher, Astrid Huber-Seidel, Konrad Pagitz, Roland Kohl, Pidder Jansen-Duerr and Hermann Stuppner

Molecules 2018, 23(3), 653; https://doi.org/10.3390/molecules23030653 - 14 Mar 2018

Cited by 11 | Viewed by 4394

Abstract

NADPH oxidase 4 (Nox4) has recently been implicated as driving force in cellular senescence. Thus, there is growing interest to develop Nox4 inhibitors, which might be valuable agents for cosmeceutical applications. Alpine plants represent a valuable source for the identification of novel bioactive [...] Read more.

NADPH oxidase 4 (Nox4) has recently been implicated as driving force in cellular senescence. Thus, there is growing interest to develop Nox4 inhibitors, which might be valuable agents for cosmeceutical applications. Alpine plants represent a valuable source for the identification of novel bioactive natural products with anti-ageing effects, especially substances that protect plants against UV radiation, which is also known to contribute to the ageing of human skin. Therefore, the aim of this study was to identify novel Nox4 inhibitors from alpine plants. Within an initial screening of extracts of alpine plants on their ability to inhibit Nox4 activity in HEK cells, the methanolic extract of the subaerial parts of Lycopus europaeus showed a strong inhibition of Nox4 (81% chemiluminescence quenching) and a simultaneously high cell viability (91% vitality). Rosmarinic acid was isolated and identified as the major compound in this bioactive extract. It showed a dose dependent inhibitory activity on Nox4 with an IC₅₀ of 1 µM. Moreover, it also showed a significant inhibitory activity on Nox2 in the low micromolar range, whereas no inhibition of Nox5 was detected. Further investigations confirmed that the observed effects of rosmarinic acid on Nox2 and Nox4 are real inhibitory activities, and not due to ROS scavenging effects. Therefore, L. europaeus, which we demonstrated to be a good source of rosmarinic acid, has great potential for usage in cosmeceutical products with anti-ageing activity. Full article

(This article belongs to the Special Issue Plant Derived Natural Products and Age Related Diseases)

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18 pages, 4556 KiB

Open AccessArticle

Silver Nanoparticles Synthesized Using Wild Mushroom Show Potential Antimicrobial Activities against Food Borne Pathogens

by Yugal Kishore Mohanta, Debasis Nayak, Kunal Biswas, Sameer Kumar Singdevsachan, Elsayed Fathi Abd_Allah, Abeer Hashem, Abdulaziz A. Alqarawi, Dhananjay Yadav and Tapan Kumar Mohanta

Molecules 2018, 23(3), 655; https://doi.org/10.3390/molecules23030655 - 14 Mar 2018

Cited by 101 | Viewed by 7804

Abstract

The present study demonstrates an economical and eco-friendly method for the synthesis of silver nanoparticles (AgNPs) using the wild mushroom Ganoderma sessiliforme. The synthesis of AgNPs was confirmed and the products characterized by UV-visible spectroscopy, dynamic light scattering spectroscopy and X-ray diffraction [...] Read more.

The present study demonstrates an economical and eco-friendly method for the synthesis of silver nanoparticles (AgNPs) using the wild mushroom Ganoderma sessiliforme. The synthesis of AgNPs was confirmed and the products characterized by UV-visible spectroscopy, dynamic light scattering spectroscopy and X-ray diffraction analysis. Furthermore, Fourier transform infrared spectroscopy (ATR-FTIR) analysis was performed to identify the viable biomolecules involved in the capping and active stabilization of AgNPs. Moreover, the average sizes and morphologies of AgNPs were analyzed by field emission scanning electron microscopy (FE-SEM). The potential impacts of AgNPs on food safety and control were evaluated by the antimicrobial activity of the synthesized AgNPs against common food-borne bacteria, namely, Escherichia coli, Bacillus subtilis, Streptococcus faecalis, Listeria innocua and Micrococcus luteus. The results of this study revealed that the synthesized AgNPs can be used to control the growth of food-borne pathogens and have potential application in the food packaging industry. Moreover, the AgNPs were evaluated for antioxidant activity (DPPH), for biocompatibility (L-929, normal fibroblast cells), and for cytotoxic effects on human breast adenosarcoma cells (MCF-7 & MDA-MB231) to highlight their potential for use in a variety of bio-applications. Full article

(This article belongs to the Section Green Chemistry)

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11 pages, 2631 KiB

Open AccessArticle

Preliminary Quality Evaluation and Characterization of Phenolic Constituents in Cynanchi Wilfordii Radix

by Takashi Uchikura, Hiroaki Tanaka, Hidemi Sugiwaki, Morio Yoshimura, Naoko Sato-Masumoto, Takashi Tsujimoto, Nahoko Uchiyama, Takashi Hakamatsuka and Yoshiaki Amakura

Molecules 2018, 23(3), 656; https://doi.org/10.3390/molecules23030656 - 14 Mar 2018

Cited by 8 | Viewed by 4150

Abstract

A new phenolic compound, 2-O-β-laminaribiosyl-4-hydroxyacetophenone (1), was isolated from Cynanchi Wilfordii Radix (CWR, the root of Cynanchum wilfordii Hemsley), along with 10 known aromatic compounds, including cynandione A (2), bungeisides-C (7) and –D (8 [...] Read more.

A new phenolic compound, 2-O-β-laminaribiosyl-4-hydroxyacetophenone (1), was isolated from Cynanchi Wilfordii Radix (CWR, the root of Cynanchum wilfordii Hemsley), along with 10 known aromatic compounds, including cynandione A (2), bungeisides-C (7) and –D (8), p-hydroxyacetophenone (9), 2′,5′-dihydroxyacetophenone (10), and 2′,4′-dihydroxyacetophenone (11). The structure of the new compound (1) was elucidated using spectroscopic methods and chemical methods. The structure of cynandione A (2), including a linkage mode of the biphenyl parts that remained uncertain, was unambiguously confirmed using the 2D ¹³C–¹³C incredible natural abundance double quantum transfer experiment (INADEQUATE) spectrum. Additionally, health issues related to the use of Cynanchi Auriculati Radix (CAR, the root of Cynanchum auriculatum Royle ex Wight) instead of CWR have emerged. Therefore, constituents present in methanolic extracts of commercially available CWRs and CARs were examined using UV-sensitive high-performance liquid chromatography (HPLC), resulting in common detection of three major peaks ascribed to cynandione A (2), p-hydroxyacetophenone (9), and 2′,4′-dihydroxyacetophenone (11). Thus, to distinguish between these ingredients, a thin-layer chromatography (TLC) method, combined with only UV irradiation detection, focusing on wilfosides C1N (12) and K1N (13) as marker compounds characteristic of CAR, was performed. Furthermore, we propose this method as a simple and convenient strategy for the preliminary distinction of CWR and CAR to ensure the quality and safety of their crude drugs. Full article

(This article belongs to the Special Issue Special Issue Dedicated to Late Professor Takuo Okuda, “Tannins and Related Polyphenols Revisited: Chemistry, Biochemistry and Biological Activities”)

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10 pages, 3097 KiB

Open AccessArticle

Anti-Cancer Activity of Lobaric Acid and Lobarstin Extracted from the Antarctic Lichen Stereocaulon alpnum

by Ju-Mi Hong, Sung-Suk Suh, Tai Kyoung Kim, Jung Eun Kim, Se Jong Han, Ui Joung Youn, Joung Han Yim and Il-Chan Kim

Molecules 2018, 23(3), 658; https://doi.org/10.3390/molecules23030658 - 14 Mar 2018

Cited by 29 | Viewed by 4253

Abstract

Lobaric acid and lobarstin, secondary metabolites derived from the antarctic lichen Stereocaulon alpnum, exert various biological activities, including antitumor, anti-proliferation, anti-inflammation, and antioxidant activities. However, the underlying mechanisms of these effects have not yet been elucidated in human cervix adenocarcinoma and human [...] Read more.

Lobaric acid and lobarstin, secondary metabolites derived from the antarctic lichen Stereocaulon alpnum, exert various biological activities, including antitumor, anti-proliferation, anti-inflammation, and antioxidant activities. However, the underlying mechanisms of these effects have not yet been elucidated in human cervix adenocarcinoma and human colon carcinoma. In the present study, we evaluated the anticancer effects of lobaric acid and lobarstin on human cervix adenocarcinoma HeLa cells and colon carcinoma HCT116 cells. We show that the proliferation of Hela and HCT116 cells treated with lobaric acid and lobarstin significantly decreased in a dose- and time-dependent manner. Using flow cytometry analysis, we observed that the treatment with these compounds resulted in significant apoptosis in both cell lines, following cell cycle perturbation and arrest in G2/M phase. Furthermore, using immunoblot analysis, we investigated the expression of cell cycle and apoptosis-related marker genes and found a significant downregulation of the apoptosis regulator B-cell lymphoma 2 (Bcl-2) and upregulation of the cleaved form of the poly (ADP-ribose) polymerase (PARP), a DNA repair and apoptosis regulator. These results suggest that lobaric acid and lobarstin could significantly inhibit cell proliferation through cell cycle arrest and induction of apoptosis via the mitochondrial apoptotic pathway in cervix adenocarcinoma and colon carcinoma cells. Taken together, our data suggests that lobaric acid and lobarstin might be novel agents for clinical treatment of cervix adenocarcinoma and colon carcinoma. Full article

(This article belongs to the Section Medicinal Chemistry)

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10 pages, 784 KiB

Open AccessArticle

A Novel Approach for Microbial Synthesis of Enantiomerically Pure Whisky Lactones Based on Solid-State Fermentation

by Filip Boratyński, Ewa Szczepańska, Aleksandra Grudniewska, Bartłomiej Skalny and Teresa Olejniczak

Molecules 2018, 23(3), 659; https://doi.org/10.3390/molecules23030659 - 14 Mar 2018

Cited by 6 | Viewed by 4651

Abstract

In this study, solid-state fermentation (SSF) was proposed as an alternative approach to obtain optically pure forms of one of the most common aroma compounds, whisky lactone. Filamentous fungi were used for enantioselective hydrolysis of a racemate of trans and cis whisky lactones, [...] Read more.

In this study, solid-state fermentation (SSF) was proposed as an alternative approach to obtain optically pure forms of one of the most common aroma compounds, whisky lactone. Filamentous fungi were used for enantioselective hydrolysis of a racemate of trans and cis whisky lactones, utilizing rapeseed cake as a growth medium. Among the tested fungi, Fusarium oxysporum AM13 and Papularia rosea AM17 were chosen for further studies. Various process parameters, including temperature, moisture content of solid media, and substrate concentration were optimized to maximize the efficiency of the kinetic resolution process. After optimization of the culture conditions (33 °C temperature, 60% moisture content, and substrate concentration of 3 mg/g oilseed cake), F. oxysporum AM13 resolved a mixture of trans-(+)-(4S,5R) and cis-(+)-(4R,5R) whisky lactones with enantiomeric excess (ee), ee > 99% and ee = 98%, respectively. This study presents an inexpensive and environmentally friendly method for the production of enantiomerically pure aroma lactones via the solid-state fermentation of oilseed cake. The results revealed that SSF is an effective method for acquiring highly valued and industrially demanded compounds with negligible economic cost. Full article

(This article belongs to the Collection Recent Advances in Flavors and Fragrances)

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8 pages, 1136 KiB

Open AccessArticle

Influence of Storage Temperature on Radiochemical Purity of ^99mTc-Radiopharmaceuticals

by Licia Uccelli, Alessandra Boschi, Petra Martini, Corrado Cittanti, Stefania Bertelli, Doretta Bortolotti, Elena Govoni, Luca Lodi, Simona Romani, Samanta Zaccaria, Elisa Zappaterra, Donatella Farina, Carlotta Rizzo, Melchiore Giganti and Mirco Bartolomei

Molecules 2018, 23(3), 661; https://doi.org/10.3390/molecules23030661 - 15 Mar 2018

Cited by 4 | Viewed by 4039

Abstract

The influence of effective room temperature on the radiochemical purity of ^99mTc-radiopharmaceuticals was reported. This study was born from the observation that in the isolators used for the preparation of the ^99mTc-radiopharmaceuticals the temperatures can be higher than those reported in [...] Read more.

The influence of effective room temperature on the radiochemical purity of ^99mTc-radiopharmaceuticals was reported. This study was born from the observation that in the isolators used for the preparation of the ^99mTc-radiopharmaceuticals the temperatures can be higher than those reported in the commercial illustrative leaflets of the kits. This is due, in particular, to the small size of the work area, the presence of instruments for heating, the continuous activation of air filtration, in addition to the fact that the environment of the isolator used for the ^99mTc-radiopharmaceuticals preparation and storage is completely isolated and not conditioned. A total of 244 ^99mTc-radiopharmaceutical preparations (seven different types) have been tested and the radiochemical purity was checked at the end of preparation and until the expiry time. Moreover, we found that the mean temperature into the isolator was significantly higher than 25 °C, the temperature, in general, required for the preparation and storage of ^99mTc-radiopharmaceuticals. Results confirmed the radiochemical stability of radiopharmaceutical products. However, as required in the field of quality assurance, the impact that different conditions than those required by the manufacturer on the radiopharmaceuticals quality have to be verified before human administration. Full article

(This article belongs to the Special Issue Current Aspects of Radiopharmaceutical Chemistry)

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18 pages, 3902 KiB

Open AccessArticle

The Ubiquitin-Conjugating Enzyme Gene Family in Longan (Dimocarpus longan Lour.): Genome-Wide Identification and Gene Expression during Flower Induction and Abiotic Stress Responses

by Dengwei Jue, Xuelian Sang, Liqin Liu, Bo Shu, Yicheng Wang, Jianghui Xie, Chengming Liu and Shengyou Shi

Molecules 2018, 23(3), 662; https://doi.org/10.3390/molecules23030662 - 15 Mar 2018

Cited by 18 | Viewed by 4256

Abstract

Ubiquitin-conjugating enzymes (E2s or UBC enzymes) play vital roles in plant development and combat various biotic and abiotic stresses. Longan (Dimocarpus longan Lour.) is an important fruit tree in the subtropical region of Southeast Asia and Australia; however the characteristics of the [...] Read more.

Ubiquitin-conjugating enzymes (E2s or UBC enzymes) play vital roles in plant development and combat various biotic and abiotic stresses. Longan (Dimocarpus longan Lour.) is an important fruit tree in the subtropical region of Southeast Asia and Australia; however the characteristics of the UBC gene family in longan remain unknown. In this study, 40 D. longan UBC genes (DlUBCs), which were classified into 15 groups, were identified in the longan genome. An RNA-seq based analysis showed that DlUBCs showed distinct expression in nine longan tissues. Genome-wide RNA-seq and qRT-PCR based gene expression analysis revealed that 11 DlUBCs were up- or down-regualted in the cultivar “Sijimi” (SJ), suggesting that these genes may be important for flower induction. Finally, qRT-PCR analysis showed that the mRNA levels of 13 DlUBCs under SA (salicylic acid) treatment, seven under methyl jasmonate (MeJA) treatment, 27 under heat treatment, and 16 under cold treatment were up- or down-regulated, respectively. These results indicated that the DlUBCs may play important roles in responses to abiotic stresses. Taken together, our results provide a comprehensive insight into the organization, phylogeny, and expression patterns of the longan UBC genes, and therefore contribute to the greater understanding of their biological roles in longan. Full article

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11 pages, 2580 KiB

Open AccessArticle

Theoretical Calculation and Experimental Verification Demonstrated the Impossibility of Finding Haptens Identifying Triphenylmethane Dyes and Their Leuco Metabolites Simultaneously

by De-Xin Kong, Fang Lv, Ben Hu and Li-Min Cao

Molecules 2018, 23(3), 663; https://doi.org/10.3390/molecules23030663 - 15 Mar 2018

Viewed by 3660

Abstract

Detection of triphenylmethane dyes (TDs), especially the widely used malachite green (MG) and crystal violet (CV), plays an important role in safety control of aquatic products. There are two chromatic forms of TDs: oxidized or reduced. Usually, only one form can be detected [...] Read more.

Detection of triphenylmethane dyes (TDs), especially the widely used malachite green (MG) and crystal violet (CV), plays an important role in safety control of aquatic products. There are two chromatic forms of TDs: oxidized or reduced. Usually, only one form can be detected by reported ELISA antibodies. In this article, molecular shape superimposing and quantum mechanics calculation were employed to elucidate the differences between MG, CV, and their reduced chromatic forms (leucomalachite green, LMG and leucocrystal violet, LCV). A potential hapten was rationally designed and synthesized. Polyclonal antibodies were raised through immunizing New Zealand white rabbits and BALB/C mice. We tested the cross-reactivity ratios between the hapten and TDs. The cross-reactivity ratios were correlated with the difference in surface electrostatic potential. The determination coefficients (r²) of the correlations are 0.901 and 0.813 for the rabbit and mouse antibody, respectively. According to this linear model, the significant difference in the atomic charge seemed to make it impossible to find a hapten that can produce antibodies with good cross-reactivities with both reduced and oxidized TDs. Full article

(This article belongs to the Section Computational and Theoretical Chemistry)

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16 pages, 683 KiB

Open AccessArticle

Moringa oleifera Leaf Extracts as Multifunctional Ingredients for “Natural and Organic” Sunscreens and Photoprotective Preparations

by Anna Baldisserotto, Piergiacomo Buso, Matteo Radice, Valeria Dissette, Ilaria Lampronti, Roberto Gambari, Stefano Manfredini and Silvia Vertuani

Molecules 2018, 23(3), 664; https://doi.org/10.3390/molecules23030664 - 15 Mar 2018

Cited by 67 | Viewed by 12494

Abstract

Moringa oleifera has gained increasing popularity as a food supplement but not in the pharmaceutical and cosmetic area. The aim of this study was the preparation, characterization, and evaluation of extracts from the leaves of Moringa oleifera as a herbal sun care phytocomplex. [...] Read more.

Moringa oleifera has gained increasing popularity as a food supplement but not in the pharmaceutical and cosmetic area. The aim of this study was the preparation, characterization, and evaluation of extracts from the leaves of Moringa oleifera as a herbal sun care phytocomplex. Three different extracts of Moringa oleifera leaves, from Senegal, have been prepared and chemically characterized in the phenolic fraction by HPLC-DAD and Folin–Ciocalteu test. To explore photoprotective properties, an extensive evaluation of UV filtering, antioxidant (DPPH, FRAP, ORAC, PCL), and anti-hyperproliferative (human melanoma Colo38 cells) capacities have been conducted. Furthermore, a formulation study regarding cosmetic prototypes has been carried out in order to determine the Sun Protection Factor (SPF), which was assessed in vitro. The extracts were demonstrated to confer significant values of protection, with an SPF 2, that corresponds to a 50% protection against UV-B rays, at concentrations as low as 2% to 4%. Finally, the evaluation on potential irritation of the finished formulations was conducted by Patch Test and no significant irritant potential was observed. These evidence enlarged the already significant number of activities and potential uses of this plant, which is well-known for its importance in the medicinal and nutritional fields. Full article

(This article belongs to the Section Natural Products Chemistry)

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19 pages, 3151 KiB

Open AccessArticle

Silyl Ketene Acetals/B(C₆F₅)₃ Lewis Pair-Catalyzed Living Group Transfer Polymerization of Renewable Cyclic Acrylic Monomers

by Lu Hu, Wuchao Zhao, Jianghua He and Yuetao Zhang

Molecules 2018, 23(3), 665; https://doi.org/10.3390/molecules23030665 - 15 Mar 2018

Cited by 25 | Viewed by 7220

Abstract

This work reveals the silyl ketene acetal (SKA)/B(C₆F₅)₃ Lewis pair-catalyzed room-temperature group transfer polymerization (GTP) of polar acrylic monomers, including methyl linear methacrylate (MMA), and the biorenewable cyclic monomers γ-methyl-α-methylene-γ-butyrolactone (MMBL) and α-methylene-γ-butyrolactone (MBL) as well. The in [...] Read more.

This work reveals the silyl ketene acetal (SKA)/B(C₆F₅)₃ Lewis pair-catalyzed room-temperature group transfer polymerization (GTP) of polar acrylic monomers, including methyl linear methacrylate (MMA), and the biorenewable cyclic monomers γ-methyl-α-methylene-γ-butyrolactone (MMBL) and α-methylene-γ-butyrolactone (MBL) as well. The in situ NMR monitored reaction of SKA with B(C₆F₅)₃ indicated the formation of Frustrated Lewis Pairs (FLPs), although it is sluggish for MMA polymerization, such a FLP system exhibits highly activity and living GTP of MMBL and MBL. Detailed investigations, including the characterization of key reaction intermediates, polymerization kinetics and polymer structures have led to a polymerization mechanism, in which the polymerization is initiated with an intermolecular Michael addition of the ester enolate group of SKA to the vinyl group of B(C₆F₅)₃-activated monomer, while the silyl group is transferred to the carbonyl group of the B(C₆F₅)₃-activated monomer to generate the single-monomer-addition species or the active propagating species; the coordinated B(C₆F₅)₃ is released to the incoming monomer, followed by repeated intermolecular Michael additions in the subsequent propagation cycle. Such neutral SKA analogues are the real active species for the polymerization and are retained in the whole process as confirmed by experimental data and the chain-end analysis by matrix-assisted laser desorption/ionization time of flight mass spectroscopy (MALDI-TOF MS). Moreover, using this method, we have successfully synthesized well-defined PMMBL-b-PMBL, PMMBL-b-PMBL-b-PMMBL and random copolymers with the predicated molecular weights (M_n) and narrow molecular weight distribution (MWD). Full article

(This article belongs to the Special Issue Lewis Pair Polymerization for New Reactivity and Structure in Polymer Synthesis)

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17 pages, 6665 KiB

Open AccessFeature PaperArticle

Synthesis of New C- and N-β-d-Glucopyranosyl Derivatives of Imidazole, 1,2,3-Triazole and Tetrazole, and Their Evaluation as Inhibitors of Glycogen Phosphorylase

by Sándor Kun, Éva Bokor, Ádám Sipos, Tibor Docsa and László Somsák

Molecules 2018, 23(3), 666; https://doi.org/10.3390/molecules23030666 - 15 Mar 2018

Cited by 14 | Viewed by 4361

Abstract

The aim of the present study was to broaden the structure-activity relationships of C- and N-β-d-glucopyranosyl azole type inhibitors of glycogen phosphorylase. 1-Aryl-4-β-d-gluco-pyranosyl-1,2,3-triazoles were prepared by copper catalyzed azide-alkyne cycloadditions between O-perbenzylated or O-peracetylated β- [...] Read more.

The aim of the present study was to broaden the structure-activity relationships of C- and N-β-d-glucopyranosyl azole type inhibitors of glycogen phosphorylase. 1-Aryl-4-β-d-gluco-pyranosyl-1,2,3-triazoles were prepared by copper catalyzed azide-alkyne cycloadditions between O-perbenzylated or O-peracetylated β-d-glucopyranosyl ethynes and aryl azides. 1-β-d-Gluco-pyranosyl-4-phenyl imidazole was obtained in a glycosylation of 4(5)-phenylimidazole with O-peracetylated α-d-glucopyranosyl bromide. C-β-d-Glucopyranosyl-N-substituted-tetrazoles were synthesized by alkylation/arylation of O-perbenzoylated 5-β-d-glucopyranosyl-tetrazole or from a 2,6-anhydroheptose tosylhydrazone and arenediazonium salts. 5-Substituted tetrazoles were glycosylated by O-peracetylated α-d-glucopyranosyl bromide to give N-β-d-glucopyranosyl-C-substituted-tetrazoles. Standard deprotections gave test compounds which were assayed against rabbit muscle glycogen phosphorylase b. Most of the compounds proved inactive, the best inhibitor was 2-β-d-glucopyranosyl-5-phenyltetrazole (IC₅₀ 600 μM). These studies extended the structure-activity relationships of β-d-glucopyranosyl azole type inhibitors and revealed the extreme sensitivity of such type of inhibitors towards the structure of the azole moiety. Full article

(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)

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10 pages, 1020 KiB

Open AccessCommunication

Asymmetric Total Synthesis of Four Stereoisomers of the Sex Pheromone of the Western Corn Rootworm

by Zhi-Feng Sun, Tao Zhang, Jinyang Liu, Zhen-Ting Du and Huaiji Zheng

Molecules 2018, 23(3), 667; https://doi.org/10.3390/molecules23030667 - 15 Mar 2018

Cited by 7 | Viewed by 4612

Abstract

A convergent synthesis of four stereoisomers of the sex pheromone of the western corn rootworm (8-methyldecan-2-yl propionate, 1) from commercially available chiral starting materials is reported. The key step was Julia–Kocienski olefination between chiral BT-sulfone and chiral aldehyde. This synthetic route provided [...] Read more.

A convergent synthesis of four stereoisomers of the sex pheromone of the western corn rootworm (8-methyldecan-2-yl propionate, 1) from commercially available chiral starting materials is reported. The key step was Julia–Kocienski olefination between chiral BT-sulfone and chiral aldehyde. This synthetic route provided the four stereoisomers of 1 in 24–29% total yield via a six-step sequence. The simple scale-up strategy provides a new way to achieve the asymmetric synthesis of the sex pheromone. Full article

(This article belongs to the Section Organic Chemistry)

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16 pages, 4085 KiB

Open AccessFeature PaperArticle

Anomaly in the Chain Length Dependence of n-Alkane Diffusion in ZIF-4 Metal-Organic Frameworks

by Seungtaik Hwang, Arun Gopalan, Maximilian Hovestadt, Frank Piepenbreier, Christian Chmelik, Martin Hartmann, Randall Q. Snurr and Jörg Kärger

Molecules 2018, 23(3), 668; https://doi.org/10.3390/molecules23030668 - 15 Mar 2018

Cited by 17 | Viewed by 5361

Abstract

Molecular diffusion is commonly found to slow down with increasing molecular size. Deviations from this pattern occur in some host materials with pore sizes approaching the diameters of the guest molecules. A variety of theoretical models have been suggested to explain deviations from [...] Read more.

Molecular diffusion is commonly found to slow down with increasing molecular size. Deviations from this pattern occur in some host materials with pore sizes approaching the diameters of the guest molecules. A variety of theoretical models have been suggested to explain deviations from this pattern, but robust experimental data are scarcely available. Here, we present such data, obtained by monitoring the chain length dependence of the uptake of n-alkanes in the zeolitic imidazolate framework ZIF-4. A monotonic decrease in diffusivity from ethane to n-butane was observed, followed by an increase for n-pentane, and another decrease for n-hexane. This observation was confirmed by uptake measurements with n-butane/n-pentane mixtures, which yield faster uptake of n-pentane. Further evidence is provided by the observation of overshooting effects, i.e., by transient n-pentane concentrations exceeding the (eventually attained) equilibrium value. Accompanying grand canonical Monte Carlo simulations reveal, for the larger n-alkanes, significant differences between the adsorbed and gas phase molecular configurations, indicating strong confinement effects within ZIF-4, which, with increasing chain length, may be expected to give rise to configurational shifts facilitating molecular propagation at particular chain lengths. Full article

(This article belongs to the Special Issue Zeolites and Related Nanoporous Materials: Synthesis, Characterization and Applications in Catalysis and Green Chemistry)

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16 pages, 11738 KiB

Open AccessArticle

Antioxidant and Neuroprotective Effects of N-((3,4-Dihydro-2H-benzo[h]chromen-2-yl)methyl)-4-methoxyaniline in Primary Cultured Rat Cortical Cells: Involvement of ERK-CREB Signaling

by Kyeongjun Lee, Chowee Park, Yeonsoo Oh, Heesoon Lee and Jungsook Cho

Molecules 2018, 23(3), 669; https://doi.org/10.3390/molecules23030669 - 15 Mar 2018

Cited by 12 | Viewed by 2858

Abstract

Excitotoxicity and oxidative stress play vital roles in the development of neurodegenerative disorders including Alzheimer’s disease (AD). In the present study, we investigated the effect of N-((3,4-dihydro-2H-benzo[h]chromen-2-yl)methyl)-4-methoxyaniline (BL-M) on excitotoxic neuronal cell damage in primary cultured rat cortical cells, and compared to [...] Read more.

Excitotoxicity and oxidative stress play vital roles in the development of neurodegenerative disorders including Alzheimer’s disease (AD). In the present study, we investigated the effect of N-((3,4-dihydro-2H-benzo[h]chromen-2-yl)methyl)-4-methoxyaniline (BL-M) on excitotoxic neuronal cell damage in primary cultured rat cortical cells, and compared to that of memantine, a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist clinically used to treat AD. We found that BL-M inhibited glutamate- or N-methyl-d-aspartate (NMDA)-induced excitotoxic cell damage. The IC₅₀ value of BL-M against NMDA toxicity was comparable to that of memantine. BL-M potently inhibited intracellular reactive oxygen species generated by glutamate or NMDA. Additionally, it inhibited the formation of 1,1-diphenyl-2-picryl-hydrazyl radicals in vitro and lipid peroxidation in rat brain homogenates. In contrast, memantine showed minimal or negligible antioxidant activity. Western blotting and immunocytochemical analyses showed that BL-M, not memantine, increased the ERK1/2 phosphorylation and subsequent phosphorylation of cAMP response element-binding protein (CREB). The inhibition of NMDA toxicity by BL-M was dramatically reversed by U0126, a well-known MEK inhibitor, suggesting that ERK1/2-mediated CREB phosphorylation is required for the neuroprotective action. Collectively, in this study, we demonstrated the neuroprotective effect of a newly synthesized chromene derivative BL-M and its underlying action mechanism(s). In contrast to memantine, BL-M exhibited marked antioxidant activity. Furthermore, it enhanced the ERK-mediated phosphorylation of CREB, which plays a crucial neuroprotective role. Our findings suggest that BL-M may be beneficial for AD and other neurodegenerative disorders associated with excitotoxicity as well as oxidative stress. Full article

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16 pages, 5205 KiB

Open AccessArticle

A Reconstruction Method for the Estimation of Temperatures of Multiple Sources Applied for Nanoparticle-Mediated Hyperthermia

by Idan Steinberg, Gil Tamir and Israel Gannot

Molecules 2018, 23(3), 670; https://doi.org/10.3390/molecules23030670 - 16 Mar 2018

Cited by 4 | Viewed by 2925

Abstract

Solid malignant tumors are one of the leading causes of death worldwide. Many times complete removal is not possible and alternative methods such as focused hyperthermia are used. Precise control of the hyperthermia process is imperative for the successful application of such treatment. [...] Read more.

Solid malignant tumors are one of the leading causes of death worldwide. Many times complete removal is not possible and alternative methods such as focused hyperthermia are used. Precise control of the hyperthermia process is imperative for the successful application of such treatment. To that end, this research presents a fast method that enables the estimation of deep tissue heat distribution by capturing and processing the transient temperature at the boundary based on a bio-heat transfer model. The theoretical model is rigorously developed and thoroughly validated by a series of experiments. A 10-fold improvement is demonstrated in resolution and visibility on tissue mimicking phantoms. The inverse problem is demonstrated as well with a successful application of the model for imaging deep-tissue embedded heat sources. Thereby, allowing the physician then ability to dynamically evaluate the hyperthermia treatment efficiency in real time. Full article

(This article belongs to the Special Issue Applications of Magnetic Nanoparticles in Biomedicine)

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13 pages, 4581 KiB

Open AccessArticle

β-Asarone Inhibits Invasion and EMT in Human Glioma U251 Cells by Suppressing Splicing Factor HnRNP A2/B1

by Li Li, Mingxia Wu, Chengqiang Wang, Zanyang Yu, Hongmei Wang, Hongyi Qi and Xiaoyu Xu

Molecules 2018, 23(3), 671; https://doi.org/10.3390/molecules23030671 - 16 Mar 2018

Cited by 24 | Viewed by 3800

Abstract

β-asarone, the main component in the volatile oil of Acori tatarinowii Rhizoma, has been found to possess antitumor activity. However, its effect and mechanisms against tumor invasion and epithelial–mesenchymal transition (EMT) are still unclear. In this study, no or less cytotoxicity was caused [...] Read more.

β-asarone, the main component in the volatile oil of Acori tatarinowii Rhizoma, has been found to possess antitumor activity. However, its effect and mechanisms against tumor invasion and epithelial–mesenchymal transition (EMT) are still unclear. In this study, no or less cytotoxicity was caused by β-asarone within 0–120 μM in human glioma U251 cells for 48 h. β-asarone (30 and 60 μM) inhibited the migration of U251 cells in the wound healing assay, suppressed the invasion of U251 cells in the Boyden chamber invasion assay, and inhibited the adhesion of U251 cells onto the Matrigel. Moreover, β-asarone suppressed EMT with the up-regulation of E-cadherin and the down-regulation of vimentin. HnRNP A2/B1, a well-characterized oncogenic protein, was shown at a high basal level in U251 cells and β-asarone reduced hnRNP A2/B1 expression in a concentration and time-dependent way. Importantly, hnRNP A2/B1 overexpression significantly counteracted the inhibition of β-asarone on the migration, invasion, and adhesion of U251 cells and reversed the modulation of EMT markers by β-asarone. Additionally, β-asarone decreased the MMP-9 and p-STAT3 in U251 cells, which was also reversed by hnRNP A2/B1 overexpression. Together, our results suggest that hnRNP A2/B1 may be a potential molecular target underlying the inhibitory effect of β-asarone on invasion and EMT in glioma cells. Full article

(This article belongs to the Section Natural Products Chemistry)

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11 pages, 982 KiB

Open AccessCommunication

Antiviral Activity of Novel Quinoline Derivatives against Dengue Virus Serotype 2

by Carolina De la Guardia, David E. Stephens, Hang T. Dang, Mario Quijada, Oleg V. Larionov and Ricardo Lleonart

Molecules 2018, 23(3), 672; https://doi.org/10.3390/molecules23030672 - 16 Mar 2018

Cited by 78 | Viewed by 6288

Abstract

Dengue virus causes dengue fever, a debilitating disease with an increasing incidence in many tropical and subtropical territories. So far, there are no effective antivirals licensed to treat this virus. Here we describe the synthesis and antiviral activity evaluation of two compounds based [...] Read more.

Dengue virus causes dengue fever, a debilitating disease with an increasing incidence in many tropical and subtropical territories. So far, there are no effective antivirals licensed to treat this virus. Here we describe the synthesis and antiviral activity evaluation of two compounds based on the quinoline scaffold, which has shown potential for the development of molecules with various biological activities. Two of the tested compounds showed dose-dependent inhibition of dengue virus serotype 2 in the low and sub micromolar range. The compounds 1 and 2 were also able to impair the accumulation of the viral envelope glycoprotein in infected cells, while showing no sign of direct virucidal activity and acting possibly through a mechanism involving the early stages of the infection. The results are congruent with previously reported data showing the potential of quinoline derivatives as a promising scaffold for the development of new antivirals against this important virus. Full article

(This article belongs to the Section Chemical Biology)

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11 pages, 2247 KiB

Open AccessArticle

Sunscreen-Based Photocages for Topical Drugs: A Photophysical and Photochemical Study of A Diclofenac-Avobenzone Dyad

by Isabel Aparici-Espert, Miguel A. Miranda and Virginie Lhiaubet-Vallet

Molecules 2018, 23(3), 673; https://doi.org/10.3390/molecules23030673 - 16 Mar 2018

Cited by 10 | Viewed by 4678

Abstract

Photosensitization by drugs is a problem of increasing importance in modern life. This phenomenon occurs when a chemical substance in the skin is exposed to sunlight. Photosensitizing drugs are reported to cause severe skin dermatitis, and indeed, it is generally advised to avoid [...] Read more.

Photosensitization by drugs is a problem of increasing importance in modern life. This phenomenon occurs when a chemical substance in the skin is exposed to sunlight. Photosensitizing drugs are reported to cause severe skin dermatitis, and indeed, it is generally advised to avoid sunbathing and to apply sunscreen. In this context, the nonsteroidal anti-inflammatory drug (NSAID) diclofenac is a photosensitive drug, especially when administered in topical form. In this work, efforts have been made to design and study an innovative pro-drug/pro-filter system containing diclofenac and the UVA filter avobenzone in order to develop a safer use of this topical drug. The design is based on the presence of a well-established photoremovable phenacyl group in the avobenzone structure. Steady-state photolysis of the dyad in hydrogen-donor solvents, monitored by UV-Vis spectrophotometry and HPLC, confirms the simultaneous photorelease of diclofenac and avobenzone. Laser flash photolysis and phosphorescence emission experiments allow us to gain insight into the photoactive triplet excited-state properties of the dyad. Finally, it is shown that avobenzone provides partial photoprotection to diclofenac from photocyclization to carbazole derivatives. Full article

(This article belongs to the Section Photochemistry)

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13 pages, 1481 KiB

Open AccessFeature PaperArticle

Syntheses of 1-Aryl-5-nitro-1H-indazoles and a General One-Pot Route to 1-Aryl-1H-indazoles

by Joel K. Annor-Gyamfi, Krishna Kumar Gnanasekaran and Richard A. Bunce

Molecules 2018, 23(3), 674; https://doi.org/10.3390/molecules23030674 - 16 Mar 2018

Cited by 7 | Viewed by 5420

Abstract

An efficient route to substituted 1-aryl-1H-indazoles has been developed and optimized. The method involved the preparation of arylhydrazones from acetophenone or benzaldehyde substituted by fluorine at C2 and nitro at C5, followed by deprotonation and nucleophilic aromatic substitution (S_NAr) [...] Read more.

An efficient route to substituted 1-aryl-1H-indazoles has been developed and optimized. The method involved the preparation of arylhydrazones from acetophenone or benzaldehyde substituted by fluorine at C2 and nitro at C5, followed by deprotonation and nucleophilic aromatic substitution (S_NAr) ring closure in 45–90%. Modification of this procedure to a one-pot domino process was successful in the acetophenone series (73–96%), while the benzaldehyde series (63–73%) required a step-wise addition of reagents. A general one-pot protocol for 1-aryl-1H-indazole formation without the limiting substitution patterns required for the S_NAr cyclization has also been achieved in 62–78% yields. A selection of 1-aryl-1H-indazoles was prepared in high yield by a procedure that requires only a single laboratory operation. Full article

(This article belongs to the Collection Heterocyclic Compounds)

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20 pages, 6455 KiB

Open AccessArticle

Melatonin Balance the Autophagy and Apoptosis by Regulating UCP2 in the LPS-Induced Cardiomyopathy

by Pan Pan, Hongmin Zhang, Longxiang Su, Xiaoting Wang and Dawei Liu

Molecules 2018, 23(3), 675; https://doi.org/10.3390/molecules23030675 - 16 Mar 2018

Cited by 68 | Viewed by 6741

Abstract

To explore the mechanism of mitochondrial uncoupling protein 2 (UCP2) mediating the protective of melatonin when septic cardiomyopathy. UCP2 knocked out mice and cardiomyocytes were used to study the effect of melatonin in response to LPS. Indicators of myocardial and mitochondria injury including [...] Read more.

To explore the mechanism of mitochondrial uncoupling protein 2 (UCP2) mediating the protective of melatonin when septic cardiomyopathy. UCP2 knocked out mice and cardiomyocytes were used to study the effect of melatonin in response to LPS. Indicators of myocardial and mitochondria injury including mitochondrial membrane potential, mitochondrial permeability transition pore, calcium loading, ROS, and ATP detection were assessed. In addition cell viability and apoptosis as well as autophagy-associated proteins were evaluated. Melatonin was able to protect heart function from LPS, which weakened in the UCP2-knockout mice. Consistently, genipin, a pharmacologic inhibitor of UCP2, augmented LPS-induced damage of AC16 cells. In contrast, melatonin upregulated UCP2 expression and protected the cells from the changes in morphology, mitochondrial membrane potential loss, mitochondrial Ca²⁺ overload, the opening of mitochondrial permeability transition pore, and subsequent increased ROS generation as well as ATP reduction. Mitophagy proteins (Beclin-1 and LC-3β) were increased while apoptosis-associated proteins (cytochrome C and caspase-3) were decreased when UCP2 was up-regulated. In conclusion, UCP2 may play a protecting role against LPS by regulating the balance between autophagy and apoptosis of cardiomyocytes, and by which mechanisms, it may contribute to homeostasis of cardiac function and cardiomyocytes activity. Melatonin may protect cardiomyocytes through modulating UCP2. Full article

(This article belongs to the Special Issue Melatonin as an Antioxidant and a Functionally Pleiotropic Molecule: Synthesis, Metabolism and Activities in Organisms)

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13 pages, 1146 KiB

Open AccessCommunication

Anti-Amyloid Aggregation Activity of Black Sesame Pigment: Toward a Novel Alzheimer’s Disease Preventive Agent

by Lucia Panzella, Thomas Eidenberger and Alessandra Napolitano

Molecules 2018, 23(3), 676; https://doi.org/10.3390/molecules23030676 - 16 Mar 2018

Cited by 16 | Viewed by 4735

Abstract

Black sesame pigment (BSP) represents a low cost, easily accessible material of plant origin exhibiting marked antioxidant and heavy metal-binding properties with potential as a food supplement. We report herein the inhibitory properties of the potentially bioaccessible fraction of BSP following simulated gastrointestinal [...] Read more.

Black sesame pigment (BSP) represents a low cost, easily accessible material of plant origin exhibiting marked antioxidant and heavy metal-binding properties with potential as a food supplement. We report herein the inhibitory properties of the potentially bioaccessible fraction of BSP following simulated gastrointestinal digestion against key enzymes involved in Alzheimer’s disease (AD). HPLC analysis indicated that BSP is transformed under the pH conditions mimicking the intestinal environment and the most abundant of the released compounds was identified as vanillic acid. More than 80% inhibition of acetylcholinesterase-induced aggregation of the β-amyloid Aβ1-40 was observed in the presence of the potentially bioaccessible fraction of BSP, which also efficiently inhibited self-induced Aβ1-42 aggregation and β-secretase (BACE-1) activity, even at high dilution. These properties open new perspectives toward the use of BSP as an ingredient of functional food or as a food supplement for the prevention of AD. Full article

(This article belongs to the Special Issue Dietary Antioxidants: Evidence of Protective Effects against Chronic Disease)

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11 pages, 1728 KiB

Open AccessArticle

Synthesis and Structure-Activity Relationships of LP1 Derivatives: N-Methyl-N-phenylethylamino Analogues as Novel MOR Agonists

by Rita Turnaturi, Carmela Parenti, Orazio Prezzavento, Agostino Marrazzo, Paschalina Pallaki, Zafiroula Georgoussi, Emanuele Amata and Lorella Pasquinucci

Molecules 2018, 23(3), 677; https://doi.org/10.3390/molecules23030677 - 16 Mar 2018

Cited by 12 | Viewed by 3621

Abstract

The opioid pharmacological profile of cis-(−)-N-normetazocine derivatives is deeply affected by the nature of their N-substituents. Here, our efforts were focused on the synthesis and pharmacological evaluation of novel derivatives of the lead LP1, a multitarget opioid analgesic compound [...] Read more.

The opioid pharmacological profile of cis-(−)-N-normetazocine derivatives is deeply affected by the nature of their N-substituents. Here, our efforts were focused on the synthesis and pharmacological evaluation of novel derivatives of the lead LP1, a multitarget opioid analgesic compound featuring an N-phenylpropanamido substituent. LP1 derivatives 5a–d and 6a–d were characterized by flexible groups at the N-substituent that allow them to reposition themselves relative to cis-(−)-N-normetazocine nucleus, thus producing different pharmacological profiles at the mu, delta and kappa opioid receptors (MOR, DOR and KOR) in in vitro and in vivo assays. Among the series, compound 5c, with the best in vitro and in vivo profile, resulted a MOR agonist which displays a K_i^MOR of 6.1 nM in a competitive binding assay, and an IC₅₀ value of 11.5 nM and an I_max of 72% in measurement of cAMP accumulation in HEK293 cells stably expressing MOR, with a slight lower efficacy than LP1. Moreover, in a mouse model of acute thermal nociception, compound 5c, intraperitoneally administered, exhibits naloxone-reversed antinociceptive properties with an ED₅₀ of 4.33 mg/kg. These results expand our understanding of the importance of N-substituent structural variations in the opioid receptor profile of cis-(−)-N-normetazocine derivatives and identify a new MOR agonist useful for the development of novel opioid analgesics for pain treatment. Full article

(This article belongs to the Section Medicinal Chemistry)

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12 pages, 6721 KiB

Open AccessArticle

Discovery of N-(Naphtho[1,2-b]Furan-5-Yl) Benzenesulfonamides as Novel Selective Inhibitors of Triple-Negative Breast Cancer (TNBC)

by Ya Chen, Yong Tang, Beibei Mao, Wenchao Li, Hongwei Jin, Liangren Zhang and Zhenming Liu

Molecules 2018, 23(3), 678; https://doi.org/10.3390/molecules23030678 - 16 Mar 2018

Cited by 4 | Viewed by 3316

Abstract

Any type of breast cancer not expressing genes of the estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) is referred to as triple-negative breast cancer (TNBC). Accordingly, TNBCs do not respond to hormonal therapies or medicines targeting [...] Read more.

Any type of breast cancer not expressing genes of the estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) is referred to as triple-negative breast cancer (TNBC). Accordingly, TNBCs do not respond to hormonal therapies or medicines targeting the ER, PR, or HER2. Systemic chemotherapy is therefore the only treatment option available today and prognoses remain poor. We report the discovery and characterization of N-(naphtho[1,2-b]furan-5-yl)benzenesulfonamides as selective inhibitors of TNBCs. These inhibitors were identified by virtual screening and inhibited different TNBC cell lines with IC₅₀ values of 2–3 μM. The compounds did not inhibit normal (i.e. MCF-7 and MCF-10A) cells in vitro, indicating their selectivity against TNBC cells. Considering the selectivity of these inhibitors for TNBC, these compounds and analogs can serve as a promising starting point for further research on effective TNBC inhibitors. Full article

(This article belongs to the Section Medicinal Chemistry)

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19 pages, 1335 KiB

Open AccessFeature PaperArticle

Novel Semisynthetic Derivatives of Bile Acids as Effective Tyrosyl-DNA Phosphodiesterase 1 Inhibitors

by Oksana V. Salomatina, Irina I. Popadyuk, Alexandra L. Zakharenko, Olga D. Zakharova, Dmitriy S. Fadeev, Nina I. Komarova, Jóhannes Reynisson, H. John Arabshahi, Raina Chand, Konstantin P. Volcho, Nariman F. Salakhutdinov and Olga I. Lavrik

Molecules 2018, 23(3), 679; https://doi.org/10.3390/molecules23030679 - 17 Mar 2018

Cited by 24 | Viewed by 5038

Abstract

An Important task in the treatment of oncological and neurodegenerative diseases is the search for new inhibitors of DNA repair system enzymes. Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is one of the DNA repair system enzymes involved in the removal of DNA damages caused by [...] Read more.

An Important task in the treatment of oncological and neurodegenerative diseases is the search for new inhibitors of DNA repair system enzymes. Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is one of the DNA repair system enzymes involved in the removal of DNA damages caused by topoisomerase I inhibitors. Thus, reducing the activity of Tdp1 can increase the effectiveness of currently used anticancer drugs. We describe here a new class of semisynthetic small molecule Tdp1 inhibitors based on the bile acid scaffold that were originally identified by virtual screening. The influence of functional groups of bile acids (hydroxy and acetoxy groups in the steroid framework and amide fragment in the side chain) on inhibitory activity was investigated. In vitro studies demonstrate the ability of the semisynthetic derivatives to effectively inhibit Tdp1 with IC₅₀ up to 0.29 µM. Furthermore, an excellent fit is realized for the ligands when docked into the active site of the Tdp1 enzyme. Full article

(This article belongs to the Special Issue Hit Generation and Verification for Novel Lead Compounds)

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6 pages, 1186 KiB

Open AccessArticle

Anticancer Phenolics from Dryopteris fragrans (L.) Schott

by Zhen-Dong Liu, Dan-Dan Zhao, Shuai Jiang, Bei Xue, Yan-Long Zhang and Xiu-Feng Yan

Molecules 2018, 23(3), 680; https://doi.org/10.3390/molecules23030680 - 17 Mar 2018

Cited by 11 | Viewed by 4507

Abstract

Cancer is one of the most major diseases that threatens human health and life. The aim of this work was to obtain novel anticancer molecules from D. fragrans, a kind of medicinal plant. The structure of the new compound was identified using [...] Read more.

Cancer is one of the most major diseases that threatens human health and life. The aim of this work was to obtain novel anticancer molecules from D. fragrans, a kind of medicinal plant. The structure of the new compound was identified using spectroscopic data (¹H-NMR, ¹³C-NMR and two dimensions NMR). Its anticancer properties were evaluated using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay against four human cells including lung cancer cells (A549), breast cancer cells (MCF-7), gastric cancer cells (SGC7901) and noncancerous human umbilical vein endothelial cells (HUVEC). A new phenylpropanoid—(E)-caffeic acid-9-O-β-d-xylpyranosyl-(1→2)-β-d-glucopyranosyl ester (1), with seven known compounds (2–8)—was isolated. The IC₅₀ value of compound 1 against MCF-7 cells was 2.65 ± 0.14 µM, and the IC₅₀ values of compound 8 against three cancer cells were below 20 µM. Full article

(This article belongs to the Collection Natural Products: Anticancer Potential and Beyond)

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18 pages, 4960 KiB

Open AccessArticle

Synthesis of Nanometer Sized Bis- and Tris-trityl Model Compounds with Different Extent of Spin–Spin Coupling

by J. Jacques Jassoy, Andreas Meyer, Sebastian Spicher, Christine Wuebben and Olav Schiemann

Molecules 2018, 23(3), 682; https://doi.org/10.3390/molecules23030682 - 17 Mar 2018

Cited by 19 | Viewed by 6005

Abstract

Tris(2,3,5,6-tetrathiaaryl)methyl radicals, so-called trityl radicals, are emerging as spin labels for distance measurements in biological systems based on Electron Paramagnetic Resonance (EPR). Here, the synthesis and characterization of rigid model systems carrying either two or three trityl moieties is reported. The monofunctionalized trityl [...] Read more.

Tris(2,3,5,6-tetrathiaaryl)methyl radicals, so-called trityl radicals, are emerging as spin labels for distance measurements in biological systems based on Electron Paramagnetic Resonance (EPR). Here, the synthesis and characterization of rigid model systems carrying either two or three trityl moieties is reported. The monofunctionalized trityl radicals are connected to the molecular bridging scaffold via an esterification reaction employing the Mukaiyama reagent 2-chloro-methylpyridinium iodide. The bis- and tris-trityl compounds exhibit different inter-spin distances, strength of electron–electron exchange and dipolar coupling and can give rise to multi-spin effects. They are to serve as benchmark systems in comparing EPR distance measurement methods. Full article

(This article belongs to the Special Issue Radical Chemistry)

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8 pages, 1228 KiB

Open AccessArticle

Hyperjaponol H, A New Bioactive Filicinic Acid-Based Meroterpenoid from Hypericum japonicum Thunb. ex Murray

by Rongrong Wu, Zijun Le, Zhenzhen Wang, Shuying Tian, Yongbo Xue, Yong Chen, Linzhen Hu and Yonghui Zhang

Molecules 2018, 23(3), 683; https://doi.org/10.3390/molecules23030683 - 18 Mar 2018

Cited by 14 | Viewed by 4950

Abstract

Hyperjaponol H (1), a new filicinic acid-based meroterpenoid, with a 6/6/10 ring system trans-fused by hetero-Diels–Alder cycloaddition between a germacrane sesquiterpenoid and a filicinic acid moiety, was isolated from aerial parts of Hypericum japonicum. The elucidation of its structure [...] Read more.

Hyperjaponol H (1), a new filicinic acid-based meroterpenoid, with a 6/6/10 ring system trans-fused by hetero-Diels–Alder cycloaddition between a germacrane sesquiterpenoid and a filicinic acid moiety, was isolated from aerial parts of Hypericum japonicum. The elucidation of its structure and absolute configuration were accomplished by the analyses of extensive spectroscopic data and the comparison of Cotton effects of electron circular dichroism (ECD) with previously reported ones. The bioactivity assay showed that hyperjaponol H exhibited a moderate inhibitory efficacy on lytic Epstein-Barr virus (EBV) DNA replication in B95-8 cells. Full article

(This article belongs to the Collection Bioactive Compounds)

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15 pages, 5163 KiB

Open AccessArticle

A Greener and Efficient Method for Nucleophilic Aromatic Substitution of Nitrogen-Containing Fused Heterocycles

by Joana F. Campos, Mohammed Loubidi, Marie-Christine Scherrmann and Sabine Berteina-Raboin

Molecules 2018, 23(3), 684; https://doi.org/10.3390/molecules23030684 - 18 Mar 2018

Cited by 15 | Viewed by 6303

Abstract

A simple and efficient methodology for the nucleophilic aromatic substitution of nitrogen-containing fused heterocycles with interesting biological activities has been developed in an environmentally sound manner using polyethylene glycol (PEG-400) as the solvent, leading to the expected compounds in excellent yields in only [...] Read more.

A simple and efficient methodology for the nucleophilic aromatic substitution of nitrogen-containing fused heterocycles with interesting biological activities has been developed in an environmentally sound manner using polyethylene glycol (PEG-400) as the solvent, leading to the expected compounds in excellent yields in only five minutes. Full article

(This article belongs to the Special Issue Focusing on Sulfur in Medicinal Chemistry)

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20 pages, 10809 KiB

Open AccessArticle

Diabetes Drug Discovery: hIAPP_1–37 Polymorphic Amyloid Structures as Novel Therapeutic Targets

by Isaac Fernández-Gómez, Marquiza Sablón-Carrazana, Alberto Bencomo-Martínez, Guadalupe Domínguez, Reyna Lara-Martínez, Nelly F. Altamirano-Bustamante, Luis Felipe Jiménez-García, Karina Pasten-Hidalgo, Rosa Angélica Castillo-Rodríguez, Perla Altamirano, Suchitil Rivera Marrero, Cristina Revilla-Monsalve, Peter Valdés-Sosa, Fabio Salamanca-Gómez, Eulalia Garrido-Magaña, Chryslaine Rodríguez-Tanty and Myriam M. Altamirano-Bustamante

Molecules 2018, 23(3), 686; https://doi.org/10.3390/molecules23030686 - 19 Mar 2018

Cited by 17 | Viewed by 5456

Abstract

Human islet amyloid peptide (hIAPP_1–37) aggregation is an early step in Diabetes Mellitus. We aimed to evaluate a family of pharmaco-chaperones to act as modulators that provide dynamic interventions and the multi-target capacity (native state, cytotoxic oligomers, protofilaments and fibrils of [...] Read more.

Human islet amyloid peptide (hIAPP_1–37) aggregation is an early step in Diabetes Mellitus. We aimed to evaluate a family of pharmaco-chaperones to act as modulators that provide dynamic interventions and the multi-target capacity (native state, cytotoxic oligomers, protofilaments and fibrils of hIAPP_1–37) required to meet the treatment challenges of diabetes. We used a cross-functional approach that combines in silico and in vitro biochemical and biophysical methods to study the hIAPP_1–37 aggregation-oligomerization process as to reveal novel potential anti-diabetic drugs. The family of pharmaco-chaperones are modulators of the oligomerization and fibre formation of hIAPP_1–37. When they interact with the amino acid in the amyloid-like steric zipper zone, they inhibit and/or delay the aggregation-oligomerization pathway by binding and stabilizing several amyloid structures of hIAPP_1–37. Moreover, they can protect cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP_1–37 oligomers. The modulation of proteostasis by the family of pharmaco-chaperones A–F is a promising potential approach to limit the onset and progression of diabetes and its comorbidities. Full article

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14 pages, 5097 KiB

Open AccessArticle

Miro1 Enhances Mitochondria Transfer from Multipotent Mesenchymal Stem Cells (MMSC) to Neural Cells and Improves the Efficacy of Cell Recovery

by Valentina A. Babenko, Denis N. Silachev, Vasily A. Popkov, Ljubava D. Zorova, Irina B. Pevzner, Egor Y. Plotnikov, Gennady T. Sukhikh and Dmitry B. Zorov

Molecules 2018, 23(3), 687; https://doi.org/10.3390/molecules23030687 - 19 Mar 2018

Cited by 133 | Viewed by 10388

Abstract

A recently discovered key role of reactive oxygen species (ROS) in mitochondrial traffic has opened a wide alley for studying the interactions between cells, including stem cells. Since its discovery in 2006, intercellular mitochondria transport has been intensively studied in different cellular models [...] Read more.

A recently discovered key role of reactive oxygen species (ROS) in mitochondrial traffic has opened a wide alley for studying the interactions between cells, including stem cells. Since its discovery in 2006, intercellular mitochondria transport has been intensively studied in different cellular models as a basis for cell therapy, since the potential of replacing malfunctioning organelles appears to be very promising. In this study, we explored the transfer of mitochondria from multipotent mesenchymal stem cells (MMSC) to neural cells and analyzed its efficacy under normal conditions and upon induction of mitochondrial damage. We found that mitochondria were transferred from the MMSC to astrocytes in a more efficient manner when the astrocytes were exposed to ischemic damage associated with elevated ROS levels. Such transport of mitochondria restored the bioenergetics of the recipient cells and stimulated their proliferation. The introduction of MMSC with overexpressed Miro1 in animals that had undergone an experimental stroke led to significantly improved recovery of neurological functions. Our data suggest that mitochondrial impairment in differentiated cells can be compensated by receiving healthy mitochondria from MMSC. We demonstrate a key role of Miro1, which promotes the mitochondrial transfer from MMSC and suggest that the genetic modification of stem cells can improve the therapies for the injured brain. Full article

(This article belongs to the Special Issue Biology of Reactive Oxygen and Nitrogen Species: Redox Signaling, Metabolic Effects, Cellular Functions and Oxidative Damage)

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15 pages, 2458 KiB

Open AccessArticle

Atypical Kinetics and Albumin Effect of Glucuronidation of 5-n-Butyl-4-{4-[2-(1H-tetrazole-5- yl)-1H-pyrrol-1-yl]phenylmethyl}-2,4-dihydro-2-(2,6- dichlorophenyl)-3H-1,2,4-triazol-3-one, a Novel Nonpeptide Angiotensin Type 1 Receptor Antagonist, in Liver Microsomes and UDP-Glucuronosyl-transferase

by Ying Peng, Xueyuan Zhang, Yinci Zhu, Hui Wu, Shiyin Gu, Qingqing Chang, Yi Zhou, Guangji Wang and Jianguo Sun

Molecules 2018, 23(3), 688; https://doi.org/10.3390/molecules23030688 - 19 Mar 2018

Cited by 3 | Viewed by 3775

Abstract

Ib is a new nonpeptide AT1 receptor antagonist, which plays an active role in cardiovascular protection. Ib monoglucuronide has been identified as its main metabolite. A detailed study of Ib glucuronidation is important for predicting potential DDI. Besides, the elucidation of the “BSA [...] Read more.

Ib is a new nonpeptide AT1 receptor antagonist, which plays an active role in cardiovascular protection. Ib monoglucuronide has been identified as its main metabolite. A detailed study of Ib glucuronidation is important for predicting potential DDI. Besides, the elucidation of the “BSA effect” in Ib glucuronidation would make obtained kinetic parameters more predictive in IVIVE. “BSA effect” means that there is a significant change in in vitro kinetic parameters when generated from incubations performed in the presence of bovine serum albumin (BSA). Five UGTs (UGT1A3, UGT2B4, UGT2B7, UGT1A9 and UGT1A8) were identified that produced abundant Ib monoglucuronide, especially UGT1A3. We investigated Ib glucuronidation in liver microsomes from different species (rat, dog, human) and in five identified major human UGTs. Ib glucuronidation in liver microsomes and recombinant human UGTs all showed substrate inhibition kinetics. DLM showed the strongest affinity and activity, HLM showed the lowest affinity, and RLM showed the weakest activity. The addition of BSA did not alter the enzyme kinetics, but significantly altered enzyme kinetic parameters resulting in a reduction in K_m value and an increase in CL_int value. However, high concentrations of BSA could significantly attenuate this positive effect on enzyme affinity and activity, and the effect of BSA on the V_max of Ib glucuronidation was opposite in different enzyme sources. In conclusion, this study demonstrated the substrate inhibition kinetics of Ib glucuronidation in the liver metabolism and the effect of BSA on its kinetic parameters, in order to provide more accurate in vitro data for in vivo prediction. Full article

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19 pages, 4150 KiB

Open AccessArticle

Screening of Genes Related to Early and Late Flowering in Tree Peony Based on Bulked Segregant RNA Sequencing and Verification by Quantitative Real-Time PCR

by Xiaogai Hou, Qi Guo, Weiqiang Wei, Lili Guo, Dalong Guo and Lin Zhang

Molecules 2018, 23(3), 689; https://doi.org/10.3390/molecules23030689 - 19 Mar 2018

Cited by 32 | Viewed by 5125

Abstract

Tree peony (Paeonia suffruticosa Andrews) is a perennial woody shrub bearing large and colorful flowers. However, the flowering period is short and relatively uniform, which to an important extent hinders the cultivation and exploitation of ornamental peonies. In this study, the segregation [...] Read more.

Tree peony (Paeonia suffruticosa Andrews) is a perennial woody shrub bearing large and colorful flowers. However, the flowering period is short and relatively uniform, which to an important extent hinders the cultivation and exploitation of ornamental peonies. In this study, the segregation of an F₁ population derived from P. ostti ‘Feng Dan’ (an early-flowering cultivar) × P. suffruticosa ‘Xin Riyuejin’ (a late-flowering cultivar) was used to screen and analyze candidate genes associated with flowering period of the two parents. Extreme early- and late-flowering genotypes of the F₁ population at full-bloom stage were sampled to establish an early-flowering mixed pool (T03), a late-flowering mixed pool (T04), a late-flowering male pool (T01), and an early-flowering female pool (T02), using the Sequencing By Synthesis (SBS) technology on the Illumina HiSeq TM2500 platform. A total of 56.51 Gb of clean reads data, comprising at least 87.62% of Quality30 (Q30), was generated, which was then combined into 173,960 transcripts (N50 = 1781) and 78,645 (N50 = 1282) unigenes, with a mean length of 1106.76 and 732.27 base pairs (bp), respectively. Altogether, 58,084 genes were annotated by comparison with public databases, based on an E-value parameter of less than 10⁻⁵ and 10⁻¹⁰ for BLAST and HMMER, respectively. In total, 291 unigene sequences were finally screened out by BSR-seq (bulked segregant RNA-seq) association analysis. To validate these unigenes, we finally confirmed seven unigenes that were related to early and late flowering, which were then verified by quantitative real-time PCR (qRT-PCR). This is the first reported study to screen genes associated with early and late flowering of tree peony by the BSA (bulked sample analysis) method of transcriptome sequencing, and to construct a high-quality transcriptome database. A set of candidate functional genes related to flowering time was successfully obtained, providing an important genetic resource for further studies of flowering in peony and the mechanism of regulation of flowering time in tree peony. Full article

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19 pages, 352 KiB

Open AccessArticle

Representation Learning for Class C G Protein-Coupled Receptors Classification

by Raúl Cruz-Barbosa, Erik-German Ramos-Pérez and Jesús Giraldo

Molecules 2018, 23(3), 690; https://doi.org/10.3390/molecules23030690 - 19 Mar 2018

Cited by 3 | Viewed by 3795

Abstract

G protein-coupled receptors (GPCRs) are integral cell membrane proteins of relevance for pharmacology. The complete tertiary structure including both extracellular and transmembrane domains has not been determined for any member of class C GPCRs. An alternative way to work on GPCR structural models [...] Read more.

G protein-coupled receptors (GPCRs) are integral cell membrane proteins of relevance for pharmacology. The complete tertiary structure including both extracellular and transmembrane domains has not been determined for any member of class C GPCRs. An alternative way to work on GPCR structural models is the investigation of their functionality through the analysis of their primary structure. For this, sequence representation is a key factor for the GPCRs’ classification context, where usually, feature engineering is carried out. In this paper, we propose the use of representation learning to acquire the features that best represent the class C GPCR sequences and at the same time to obtain a model for classification automatically. Deep learning methods in conjunction with amino acid physicochemical property indices are then used for this purpose. Experimental results assessed by the classification accuracy, Matthews’ correlation coefficient and the balanced error rate show that using a hydrophobicity index and a restricted Boltzmann machine (RBM) can achieve performance results (accuracy of 92.9%) similar to those reported in the literature. As a second proposal, we combine two or more physicochemical property indices instead of only one as the input for a deep architecture in order to add information from the sequences. Experimental results show that using three hydrophobicity-related index combinations helps to improve the classification performance (accuracy of 94.1%) of an RBM better than those reported in the literature for class C GPCRs without using feature selection methods. Full article

(This article belongs to the Special Issue Computational Analysis for Protein Structure and Interaction)

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15 pages, 4016 KiB

Open AccessArticle

Efficient (3S)-Acetoin and (2S,3S)-2,3-Butanediol Production from meso-2,3-Butanediol Using Whole-Cell Biocatalysis

by Yuanzhi He, Feixue Chen, Meijing Sun, Huifang Gao, Zewang Guo, Hui Lin, Jiebo Chen, Wensong Jin, Yunlong Yang, Liaoyuan Zhang and Jun Yuan

Molecules 2018, 23(3), 691; https://doi.org/10.3390/molecules23030691 - 19 Mar 2018

Cited by 29 | Viewed by 5367

Abstract

(3S)-Acetoin and (2S,3S)-2,3-butanediol are important platform chemicals widely applied in the asymmetric synthesis of valuable chiral chemicals. However, their production by fermentative methods is difficult to perform. This study aimed to develop a whole-cell biocatalysis strategy for [...] Read more.

(3S)-Acetoin and (2S,3S)-2,3-butanediol are important platform chemicals widely applied in the asymmetric synthesis of valuable chiral chemicals. However, their production by fermentative methods is difficult to perform. This study aimed to develop a whole-cell biocatalysis strategy for the production of (3S)-acetoin and (2S,3S)-2,3-butanediol from meso-2,3-butanediol. First, E. coli co-expressing (2R,3R)-2,3-butanediol dehydrogenase, NADH oxidase and Vitreoscilla hemoglobin was developed for (3S)-acetoin production from meso-2,3-butanediol. Maximum (3S)-acetoin concentration of 72.38 g/L with the stereoisomeric purity of 94.65% was achieved at 24 h under optimal conditions. Subsequently, we developed another biocatalyst co-expressing (2S,3S)-2,3-butanediol dehydrogenase and formate dehydrogenase for (2S,3S)-2,3-butanediol production from (3S)-acetoin. Synchronous catalysis together with two biocatalysts afforded 38.41 g/L of (2S,3S)-butanediol with stereoisomeric purity of 98.03% from 40 g/L meso-2,3-butanediol. These results exhibited the potential for (3S)-acetoin and (2S,3S)-butanediol production from meso-2,3-butanediol as a substrate via whole-cell biocatalysis. Full article

(This article belongs to the Special Issue Frontier in Biocatalysis for Organic Synthesis)

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24 pages, 4066 KiB

Open AccessArticle

Synthesis of Some Novel Fused Pyrimido[4″,5″:5′,6′]-[1,2,4]triazino[3′,4′:3,4] [1,2,4]triazino[5,6-b]indoles with Expected Anticancer Activity

by Rania S. Ali and Hosam A. Saad

Molecules 2018, 23(3), 693; https://doi.org/10.3390/molecules23030693 - 19 Mar 2018

Cited by 11 | Viewed by 4771

Abstract

Our current goal is the synthesis of polyheterocyclic compounds starting from 3-amino-[1,2,4]triazino[5,6-b]indole 1 and studying their anticancer activity to determine whether increasing of the size of the molecules increases the anticancer activity or not. 1-Amino[1,2,4]triazino[3′,4′:3,4]-[1,2,4]triazino[5,6-b]indole-2-carbonitrile (4) was [...] Read more.

Our current goal is the synthesis of polyheterocyclic compounds starting from 3-amino-[1,2,4]triazino[5,6-b]indole 1 and studying their anticancer activity to determine whether increasing of the size of the molecules increases the anticancer activity or not. 1-Amino[1,2,4]triazino[3′,4′:3,4]-[1,2,4]triazino[5,6-b]indole-2-carbonitrile (4) was prepared by the diazotization of 3-amino[1,2,4]-triazino[5,6-b]indole 1 followed by coupling with malononitrile in basic medium then cyclization under reflux to get 4. Also, new fused pyrimido[4″,5″:5′,6′][1,2,4]triazino-[3′,4′:3,4][1,2,4]triazino[5,6-b]indole derivative 6 was prepared and used to obtain polycyclic heterocyclic systems. Confirmation of the synthesized compounds’ structures was carried out using elemental analyses and spectral data (IR, ¹H-NMR and ¹³C-NMR and mass spectra). The anticancer activity of some of the synthesized compounds was tested against HepG2, HCT-116 and MCF-7 cell lines. The anticancer screening results showed that some derivatives display good activity which was more potent than that of the reference drug used. Molecular docking was used to predict the binding between some of the synthesized compounds and the prostate cancer 2q7k hormone and breast ‎cancer 3hb5 receptors. Full article

(This article belongs to the Collection Heterocyclic Compounds)

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10 pages, 2898 KiB

Open AccessCommunication

π-π Conjugation Enhances Oligostilbene’s Antioxidant Capacity: Evidence from α-Viniferin and Caraphenol A

by Xican Li, Yulu Xie, Hong Xie, Jian Yang and Dongfeng Chen

Molecules 2018, 23(3), 694; https://doi.org/10.3390/molecules23030694 - 19 Mar 2018

Cited by 21 | Viewed by 4470

Abstract

α-Viniferin and caraphenol A, the two oligostilbenes, have the sole difference of the presence or absence of an exocyclic double bond at the π-π conjugative site. In this study, the antioxidant capacity and relevant mechanisms for α-viniferin and caraphenol A were comparatively explored [...] Read more.

α-Viniferin and caraphenol A, the two oligostilbenes, have the sole difference of the presence or absence of an exocyclic double bond at the π-π conjugative site. In this study, the antioxidant capacity and relevant mechanisms for α-viniferin and caraphenol A were comparatively explored using spectrophotometry, UV-visible spectral analysis, and electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC–ESI–Q–TOF–MS/MS) analysis. The spectrophotometric results suggested that caraphenol A always gave lower IC₅₀ values than α-viniferin in cupric ion-reducing antioxidant capacity assay, ferric-reducing antioxidant power assay, 1,1-diphenyl-2-picryl-hydrazl radical (DPPH•)-scavenging, and 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide radical-scavenging assays. In UV-visible spectra analysis, caraphenol A was observed to show enhanced peaks at 250–350 nm when mixed with Fe²⁺, but α-viniferin exhibited no similar effects. UPLC–ESI–Q–TOF–MS/MS analysis revealed that α-viniferin mixed with DPPH• produced radical adduct formation (RAF) peak (m/z = 1070–1072). We conclude that the antioxidant action of α-viniferin and caraphenol A may involve both redox-mediated mechanisms (especially electron transfer and H⁺-transfer) and non-redox-mediated mechanisms (including Fe²⁺-chelating or RAF). The π-π conjugation of the exocyclic double bond in caraphenol A can greatly enhance the redox-mediated antioxidant mechanisms and partially promote the Fe²⁺-chelating mechanism. This makes caraphenol A far superior to α-viniferin in total antioxidant levels. Full article

(This article belongs to the Special Issue The Antioxidant Capacities of Natural Products)

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15 pages, 1971 KiB

Open AccessArticle

Gallic Acid Content and an Antioxidant Mechanism Are Responsible for the Antiproliferative Activity of ‘Ataulfo’ Mango Peel on LS180 Cells

by Gustavo. R. Velderrain-Rodríguez, Heriberto Torres-Moreno, Mónica A. Villegas-Ochoa, J. Fernando Ayala-Zavala, Ramón E. Robles-Zepeda, Abraham Wall-Medrano and Gustavo A. González-Aguilar

Molecules 2018, 23(3), 695; https://doi.org/10.3390/molecules23030695 - 19 Mar 2018

Cited by 95 | Viewed by 8476

Abstract

Mango “Ataulfo” peel is a rich source of polyphenols (PP), with antioxidant and anti-cancer properties; however, it is unknown whether such antiproliferative activity is related to PP’s antioxidant activity. The content (HPLC-DAD), antioxidant (DPPH, FRAP, ORAC), and antiproliferative activities (MTT) of free (FP) [...] Read more.

Mango “Ataulfo” peel is a rich source of polyphenols (PP), with antioxidant and anti-cancer properties; however, it is unknown whether such antiproliferative activity is related to PP’s antioxidant activity. The content (HPLC-DAD), antioxidant (DPPH, FRAP, ORAC), and antiproliferative activities (MTT) of free (FP) and chemically-released PP from mango ‘Ataulfo’ peel after alkaline (AKP) and acid (AP) hydrolysis, were evaluated. AKP fraction was higher (µg/g DW) in gallic acid (GA; 23,816 ± 284) than AP (5610 ± 8) of FR (not detected) fractions. AKP fraction and GA showed the highest antioxidant activity (DPPH/FRAP/ORAC) and GA’s antioxidant activity follows a single electron transfer (SET) mechanism. AKP and GA also showed the best antiproliferative activity against human colon adenocarcinoma cells (LS180; IC₅₀ (µg/mL) 138.2 ± 2.5 and 45.7 ± 5.2) and mouse connective cells (L929; 93.5 ± 7.7 and 65.3 ± 1.2); Cheminformatics confirmed the hydrophilic nature (LogP, 0.6) and a good absorption capacity (75%) for GA. Data suggests that GA’s antiproliferative activity appears to be related to its antioxidant mechanism, although other mechanisms after its absorption could also be involved. Full article

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15 pages, 4037 KiB

Open AccessArticle

Molecular Modeling and Structural Stability of Wild-Type and Mutant CYP51 from Leishmania major: In Vitro and In Silico Analysis of a Laboratory Strain

by Masoud Keighobadi, Saeed Emami, Milad Lagzian, Mahdi Fakhar, Alireza Rafiei and Reza Valadan

Molecules 2018, 23(3), 696; https://doi.org/10.3390/molecules23030696 - 19 Mar 2018

Cited by 12 | Viewed by 4984

Abstract

Cutaneous leishmaniasis is a neglected tropical disease and a major public health in the most countries. Leishmania major is the most common cause of cutaneous leishmaniasis. In the Leishmania parasites, sterol 14α-demethylase (CYP51), which is involved in the biosynthesis of sterols, has been [...] Read more.

Cutaneous leishmaniasis is a neglected tropical disease and a major public health in the most countries. Leishmania major is the most common cause of cutaneous leishmaniasis. In the Leishmania parasites, sterol 14α-demethylase (CYP51), which is involved in the biosynthesis of sterols, has been identified as an attractive target for development of new therapeutic agents. In this study, the sequence and structure of CYP51 in a laboratory strain (MRHO/IR/75/ER) of L. major were determined and compared to the wild-type strain. The results showed 19 mutations including seven non-synonymous and 12 synonymous ones in the CYP51 sequence of strain MRHO/IR/75/ER. Importantly, an arginine to lysine substitution at position of 474 resulted in destabilization of CYP51 (ΔΔG = 1.17 kcal/mol) in the laboratory strain; however, when the overall effects of all substitutions were evaluated by 100 ns molecular dynamics simulation, the final structure did not show any significant changes (p-value < 0.05) in stability parameter of the strain MRHO/IR/75/ER compared to the wild-type protein. The energy level for the CYP51 of wild-type and MRHO/IR/75/ER strain were −40,027.1 and −39,706.48 Kcal/mol respectively. The overall Root-mean-square deviation (RMSD) deviation between two proteins was less than 1 Å throughout the simulation and Root-mean-square fluctuation (RMSF) plot also showed no substantial differences between amino acids fluctuation of the both protein. The results also showed that, these mutations were located on the protein periphery that neither interferes with protein folding nor with substrate/inhibitor binding. Therefore, L. major strain MRHO/IR/75/ER is suggested as a suitable laboratory model for studying biological role of CYP51 and inhibitory effects of sterol 14α-demethylase inhibitors. Full article

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17 pages, 2590 KiB

Open AccessArticle

Feature-Based and String-Based Models for Predicting RNA-Protein Interaction

by Donald Adjeroh, Maen Allaga, Jun Tan, Jie Lin, Yue Jiang, Ahmed Abbasi and Xiaobo Zhou

Molecules 2018, 23(3), 697; https://doi.org/10.3390/molecules23030697 - 19 Mar 2018

Cited by 16 | Viewed by 4693

Abstract

In this work, we study two approaches for the problem of RNA-Protein Interaction (RPI). In the first approach, we use a feature-based technique by combining extracted features from both sequences and secondary structures. The feature-based approach enhanced the prediction accuracy as it included [...] Read more.

In this work, we study two approaches for the problem of RNA-Protein Interaction (RPI). In the first approach, we use a feature-based technique by combining extracted features from both sequences and secondary structures. The feature-based approach enhanced the prediction accuracy as it included much more available information about the RNA-protein pairs. In the second approach, we apply search algorithms and data structures to extract effective string patterns for prediction of RPI, using both sequence information (protein and RNA sequences), and structure information (protein and RNA secondary structures). This led to different string-based models for predicting interacting RNA-protein pairs. We show results that demonstrate the effectiveness of the proposed approaches, including comparative results against leading state-of-the-art methods. Full article

(This article belongs to the Special Issue Selected Papers from the 10th Computational Structural Bioinformatics Workshop (CSBW-2017))

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19 pages, 7554 KiB

Open AccessArticle

Structure-Based Discovery of a Series of 5H-Pyrrolo[2,3-b]pyrazine FGFR Kinase Inhibitors

by Alan Jiang, Qiufeng Liu, Ruifeng Wang, Peng Wei, Yang Dai, Xin Wang, Yechun Xu, Yuchi Ma, Jing Ai, Jingkang Shen, Jian Ding and Bing Xiong

Molecules 2018, 23(3), 698; https://doi.org/10.3390/molecules23030698 - 19 Mar 2018

Cited by 11 | Viewed by 4634

Abstract

Fibroblast growth factor receptors (FGFRs), a subfamily of receptor tyrosine kinases, are aberrant in various cancer types, and considered to be promising targets for cancer therapy. We started with a weak-active compound that was identified from our internal hepatocyte growth factor receptor (also [...] Read more.

Fibroblast growth factor receptors (FGFRs), a subfamily of receptor tyrosine kinases, are aberrant in various cancer types, and considered to be promising targets for cancer therapy. We started with a weak-active compound that was identified from our internal hepatocyte growth factor receptor (also called c-Met) inhibitor project, and optimized it with the guidance of a co-crystal structure of compound 8 with FGFR1. Through rational design, synthesis, and the biological evaluation of a series of 5H-pyrrolo[2,3-b]pyrazine derivatives, we discovered several potent FGFR kinase inhibitors. Among them, compound 13 displayed high selectivity and favorable metabolic properties, demonstrating a promising lead for further development. Full article

(This article belongs to the Section Medicinal Chemistry)

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11 pages, 2705 KiB

Open AccessArticle

Chalcogen ‘like-like’ Interactions Involving Trisulphide and Triselenide Compounds: A Combined CSD and Ab Initio Study

by Antonio Bauzá and Antonio Frontera

Molecules 2018, 23(3), 699; https://doi.org/10.3390/molecules23030699 - 19 Mar 2018

Cited by 21 | Viewed by 4023

Abstract

In this manuscript, we combined a search in the Cambridge Structural Database (CSD) and ab initio calculations (RI-MP2/def2-TZVPD level of theory) to analyze the ability of trisulphide and triselenide moieties to establish chalcogen ‘like-like’ interactions. A preliminary CSD inspection revealed two predominant structural [...] Read more.

In this manuscript, we combined a search in the Cambridge Structural Database (CSD) and ab initio calculations (RI-MP2/def2-TZVPD level of theory) to analyze the ability of trisulphide and triselenide moieties to establish chalcogen ‘like-like’ interactions. A preliminary CSD inspection revealed two predominant structural patterns, depending on the anti or syn conformation adopted by the substituents of the S₃/Se₃ bridge, leading to bifurcated or double chalcogen bonding interactions, respectively. In order to analyze these two relevant structural motifs we have used a series of S and Se derivatives Ch₃X₂ (Ch = S and Se and X = H, F, CN, and CF₃) which act as both electron donor (using the lone pairs) and acceptor (using the σ-holes) entities. Besides, we have carried out “atoms in molecules” (AIM) and natural bonding orbital (NBO) analyses to further describe and characterize the chalcogen bonding interactions described herein. As far as we know, chalcogen···chalcogen interactions involving trichalconides (S₃/Se₃) have not been previously described in literature a may be of great importance in the preparation and characterization of new solids based on this subclass of σ-hole bonding. Full article

(This article belongs to the Special Issue Noncovalent Interactions: A Useful Tool for Crystal Design)

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12 pages, 3784 KiB

Open AccessArticle

Friedelin in Maytenus ilicifolia Is Produced by Friedelin Synthase Isoforms

by Thaís B. Alves, Tatiana M. Souza-Moreira, Sandro R. Valentini, Cleslei F. Zanelli and Maysa Furlan

Molecules 2018, 23(3), 700; https://doi.org/10.3390/molecules23030700 - 20 Mar 2018

Cited by 15 | Viewed by 6148

Abstract

Triterpenes are interesting compounds because they play an important role in cell homeostasis and a wide variety exhibiting defense functions is produced by plant secondary metabolism. Those same plant secondary metabolites also exhibit biological properties with promising therapeutic potential as anti-inflammatory and antitumor [...] Read more.

Triterpenes are interesting compounds because they play an important role in cell homeostasis and a wide variety exhibiting defense functions is produced by plant secondary metabolism. Those same plant secondary metabolites also exhibit biological properties with promising therapeutic potential as anti-inflammatory and antitumor agents. Friedelin is a triterpene ketone with anti-inflammatory and gastroprotective activities and it is a precursor of relevant antitumor quinonemethides. Although many triterpene synthases have been described, only two friedelin synthases were characterized and there is no information about their genomic features and alleles. In the present work, we aimed to identify the gene and new isoforms of friedelin synthase in Maytenus ilicifolia leaves to be functionally characterized in Saccharomyces cerevisiae. The gene sequence analysis elucidated the exon/intron structure and confirmed the presence of single nucleotide polymorphisms with four non-synonymous mutations outside the active site of the enzyme. Therefore, two new isoforms were observed and the heterologous production of the enzymes in yeast showed similar production of friedelin. This first description of different alleles of the gene of friedelin synthase in M. ilicifolia can guide their validation as markers for friedelin-producer specimens. Full article

(This article belongs to the Special Issue Diversity of Terpenoids)

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9 pages, 2485 KiB

Open AccessArticle

Synthesis, Characterization, Crystal Structure, and DFT Study of a New Square Planar Cu(II) Complex Containing Bulky Adamantane Ligand

by Monther A. Khanfar, Areej M. Jaber, Murad A. AlDamen and Raed A. Al-Qawasmeh

Molecules 2018, 23(3), 701; https://doi.org/10.3390/molecules23030701 - 20 Mar 2018

Cited by 13 | Viewed by 5091

Abstract

A copper complex with square planar geometry, [(L)CuBr₂] (1), (L = N′-(furan-2-ylmethylene)adamantne-1-carbohydrazide) has been synthesized and characterized by Fourier transfer infrared (FTIR) spectroscopy, elemental analysis, mass spectrometry, and single crystal X-ray diffraction. The crystal of 1 is solved [...] Read more.

A copper complex with square planar geometry, [(L)CuBr₂] (1), (L = N′-(furan-2-ylmethylene)adamantne-1-carbohydrazide) has been synthesized and characterized by Fourier transfer infrared (FTIR) spectroscopy, elemental analysis, mass spectrometry, and single crystal X-ray diffraction. The crystal of 1 is solved as monoclinic, space group P2₁/m with unit cell parameters: a = 10.8030(8), b = 6.6115(8), c = 12.1264(12) Å, β = 101.124(8)°, V = 849.84(15) Å³, Z = 2, and R₁ = 0.0751 with wR₂ = 0.1581 (I > 2 σ). The structure of 1 shows intramolecular hydrogen bonding between the N–H and the furan oxygen which stabilizes the configuration of the complex. Furthermore, inside the lattice there are other weak interactions between bromo ligands and the ligand L. DFT calculations where performed to study the stability of this geometry. Full article

(This article belongs to the Special Issue Metal Complexes of Biological Ligands)

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13 pages, 3722 KiB

Open AccessArticle

Bridging from Brain to Tumor Imaging: (S)-(−)- and (R)-(+)-[¹⁸F]Fluspidine for Investigation of Sigma-1 Receptors in Tumor-Bearing Mice

by Mathias Kranz, Ralf Bergmann, Torsten Kniess, Birgit Belter, Christin Neuber, Zhengxin Cai, Gang Deng, Steffen Fischer, Jiangbing Zhou, Yiyun Huang, Peter Brust, Winnie Deuther-Conrad and Jens Pietzsch

Molecules 2018, 23(3), 702; https://doi.org/10.3390/molecules23030702 - 20 Mar 2018

Cited by 8 | Viewed by 5258

Abstract

Sigma-1 receptors (Sig1R) are highly expressed in various human cancer cells and hence imaging of this target with positron emission tomography (PET) can contribute to a better understanding of tumor pathophysiology and support the development of antineoplastic drugs. Two Sig1R-specific radiolabeled enantiomers ( [...] Read more.

Sigma-1 receptors (Sig1R) are highly expressed in various human cancer cells and hence imaging of this target with positron emission tomography (PET) can contribute to a better understanding of tumor pathophysiology and support the development of antineoplastic drugs. Two Sig1R-specific radiolabeled enantiomers (S)-(−)- and (R)-(+)-[¹⁸F]fluspidine were investigated in several tumor cell lines including melanoma, squamous cell/epidermoid carcinoma, prostate carcinoma, and glioblastoma. Dynamic PET scans were performed in mice to investigate the suitability of both radiotracers for tumor imaging. The Sig1R expression in the respective tumors was confirmed by Western blot. Rather low radiotracer uptake was found in heterotopically (subcutaneously) implanted tumors. Therefore, a brain tumor model (U87-MG) with orthotopic implantation was chosen to investigate the suitability of the two Sig1R radiotracers for brain tumor imaging. High tumor uptake as well as a favorable tumor-to-background ratio was found. These results suggest that Sig1R PET imaging of brain tumors with [¹⁸F]fluspidine could be possible. Further studies with this tumor model will be performed to confirm specific binding and the integrity of the blood-brain barrier (BBB). Full article

(This article belongs to the Special Issue Current Aspects of Radiopharmaceutical Chemistry)

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12 pages, 1244 KiB

Open AccessArticle

Association of Melatonin Production with Seasonal Changes, Low Temperature, and Immuno-Responses in Hamsters

by Xiaoying Xu, Xiaoyan Liu, Shuran Ma, Ya Xu, Ying Xu, Xiazhen Guo and Dekui Li

Molecules 2018, 23(3), 703; https://doi.org/10.3390/molecules23030703 - 20 Mar 2018

Cited by 12 | Viewed by 4874

Abstract

Seasonal changes impact the melatonin production and immuno-activities in vertebrates. This is believed due to the photoperiodic alterations of the different seasons which impact the functions of pineal gland. The short photoperiod promotes pineal melatonin production. As a result, during the winter, animals [...] Read more.

Seasonal changes impact the melatonin production and immuno-activities in vertebrates. This is believed due to the photoperiodic alterations of the different seasons which impact the functions of pineal gland. The short photoperiod promotes pineal melatonin production. As a result, during the winter, animals have significantly higher levels of melatonin than in summer. However, the seasonal changes also include temperature changes. This factor has never been systemically investigated in animals. In the current study, we observed that increased temperature had limited influence on melatonin production. In contrast, cold temperature is the major factor to induce melatonin production in hamsters. Cold temperature per se can upregulate the expressions of melatonin synthetic gene AANAT and ASMT, which are the important enzymes for melatonin biosynthesis. The elevated melatonin levels induced by the cold exposure in hamster in turn, improve the immuno-responses of the animals with increased levels of IL1, 6, and 10 as well CD3. In addition, melatonin as a potent antioxidant and thermogenic agent would improve the survival chance of animals during cold weather. Full article

(This article belongs to the Special Issue Melatonin as an Antioxidant and a Functionally Pleiotropic Molecule: Synthesis, Metabolism and Activities in Organisms)

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16 pages, 3564 KiB

Open AccessArticle

Xylobiose Prevents High-Fat Diet Induced Mice Obesity by Suppressing Mesenteric Fat Deposition and Metabolic Dysregulation

by Soo-min Lim, Eunju Kim, Jae-Ho Shin, Pu Reum Seok, Sangwon Jung, Sang-Ho Yoo and Yuri Kim

Molecules 2018, 23(3), 705; https://doi.org/10.3390/molecules23030705 - 20 Mar 2018

Cited by 26 | Viewed by 6714

Abstract

Obesity is a public concern and is responsible for various metabolic diseases. Xylobiose (XB), an alternative sweetener, is a major component of xylo-oligosaccharide. The purpose of this study was to investigate the effects of XB on obesity and its associated metabolic changes in [...] Read more.

Obesity is a public concern and is responsible for various metabolic diseases. Xylobiose (XB), an alternative sweetener, is a major component of xylo-oligosaccharide. The purpose of this study was to investigate the effects of XB on obesity and its associated metabolic changes in related organs. For these studies, mice received a 60% high-fat diet supplemented with 15% d-xylose, 10% XB, or 15% XB as part of the total sucrose content of the diet for ten weeks. Body weight, fat and liver weights, fasting blood glucose, and blood lipids levels were significantly reduced with XB supplementation. Levels of leptin and adipokine were also improved and lipogenic and adipogenic genes in mesenteric fat and liver were down-regulated with XB supplementation. Furthermore, pro-inflammatory cytokines, fatty acid uptake, lipolysis, and β-oxidation-related gene expression levels in mesenteric fat were down-regulated with XB supplementation. Thus, XB exhibited therapeutic potential for treating obesity which involved suppression of fat deposition and obesity-related metabolic disorders. Full article

(This article belongs to the Special Issue Sugar Substitutes and Obesity, Diabetes and Metabolic Syndrome)

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17 pages, 6571 KiB

Open AccessArticle

Transcript Profiling and Gene Identification Involved in the Ethylene Signal Transduction Pathways of Creeping Bentgrass (Agrostis stolonifera) during ISR Response Induced by Butanediol

by Han-Yu Jiang, Jin-Lin Zhang, Jiang-Wei Yang and Hui-Ling Ma

Molecules 2018, 23(3), 706; https://doi.org/10.3390/molecules23030706 - 20 Mar 2018

Cited by 8 | Viewed by 4186

Abstract

Creeping bentgrass (Agrostis stolonifera) is the preferred green lawn grass, with excellent turf characteristics but poor disease resistance. At present, the mechanisms of disease resistance in creeping bentgrass are poorly understood, especially the ethylene signal transduction pathway under the induced systemic [...] Read more.

Creeping bentgrass (Agrostis stolonifera) is the preferred green lawn grass, with excellent turf characteristics but poor disease resistance. At present, the mechanisms of disease resistance in creeping bentgrass are poorly understood, especially the ethylene signal transduction pathway under the induced systemic resistance (ISR) response. In this study, butanediol (BDO), as a new type of disease-resistance compound, was applied to creeping bentgrass seedlings to induce the ISR response. Then, we measured ethylene production and related enzyme activities. Additionally, transcript profiling and gene identification were performed in association to ethylene signal transduction pathways. The changes of ethylene production and related enzyme 1-aminocyclopropane-1-carboxylic acid oxidase (ACO) and 1-aminocyclopropane-1-carboxylic acid synthases (ACS) activities showed significant difference at 24 h after Rhizoctonia solani inoculation among five treatments of various BDO concentrations. After 100 µmol L⁻¹ BDO treatment, ethylene production and related enzyme activities reached their peak levels. Additionally, 208,672 unigenes of creeping bentgrass were obtained by de novo assembly. In total, 15,903 annotated unigenes were grouped into 33 canonical pathways in the KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis. Among those, 1803 unigenes were classified as ‘signal transduction’. There were 6766 differentially expressed genes (DEGs) among B24 (inoculated-rhizobacteria in MS medium with 100 µmol L⁻¹ BDO for 24 h), NB24, B72 and NB24 (no rhizobacteria in MS medium with 100 µmol L⁻¹ BDO for 24 h) libraries, and 4,639 DEGs between B24 and B72 (inoculated-rhizobacteria in MS medium with 100 µmol L⁻¹ BDO for 72 h) libraries, with 4489 DEGs in all three libraries. As suggested by the RT-PCR assay, the expression levels of ethylene-responsive and defense-related genes were variable among treated samples during the BDO-induced ISR responses. The expression levels of EIN, ERF, NPR1, PR3 and PR4 genes increased and reached their peaks in the first 24 h after R. solani infection in the BDO-induced ISR reaction compared with NB24 treatments. This results is consistent with the changes of important ethylene biosynthetic enzymes and ethylene concentrations during the BDO-induced ISR responses. We further found the intermediate substances for the signaling pathway, and the relationships between the expression levels of BDO-induced ISR disease-resistance genes and those of the response genes for ethylene signal pathway. Our findings present a genetic basis for systemic resistance of creeping bentgrass through transcriptomic analysis and our study provides a theoretical and practical basis for the improvement of turfgrass disease resistance and quality. Full article

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11 pages, 3018 KiB

Open AccessArticle

Antioxidant Activity of Coconut (Cocos nucifera L.) Protein Fractions

by Yan Li, Yajun Zheng, Yufeng Zhang, Jianguo Xu and Gang Gao

Molecules 2018, 23(3), 707; https://doi.org/10.3390/molecules23030707 - 20 Mar 2018

Cited by 39 | Viewed by 7248

Abstract

Coconut cake is an abundant and good potential edible protein source. However, until now it has not been extensively used in the food industry. To promote its usage, the characterization, nutrition value and antioxidant activity of coconut cake protein fractions (albumin, globulin, prolamine, [...] Read more.

Coconut cake is an abundant and good potential edible protein source. However, until now it has not been extensively used in the food industry. To promote its usage, the characterization, nutrition value and antioxidant activity of coconut cake protein fractions (albumin, globulin, prolamine, glutelin-1 and glutelin-2) were studied. Results revealed that all the albumin, globulin, glutelin-1 and glutelin-2 fractions showed a high nutrition value. The prolamine, glutelin-1 and glutelin-2 all exhibited good radical scavenging activity and reducing power, and the globulin and prolamine showed high ion chelating ability (89.14–80.38%). Moreover, all the fractions except glutelin-2 could effectively protect DNA against oxidative damage. Several peptides containing five to eight amino acids with antioxidant activity were also identified by LC-MS/MS from the globulin and glutelin-2 fractions. The results demonstrated that the coconut cake protein fractions have potential usages in functional foods. Full article

(This article belongs to the Special Issue Plant Derived Natural Products and Age Related Diseases)

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11 pages, 2403 KiB

Open AccessFeature PaperArticle

Potent GH20 N-Acetyl-β-d-hexosaminidase Inhibitors: N-Substituted 3-acetamido-4-amino-5-hydroxymethyl-cyclopentanediols

by Patrick Weber, Seyed A. Nasseri, Bettina M. Pabst, Ana Torvisco, Philipp Müller, Eduard Paschke, Marion Tschernutter, Werner Windischhofer, Stephen G. Withers, Tanja M. Wrodnigg and Arnold E. Stütz

Molecules 2018, 23(3), 708; https://doi.org/10.3390/molecules23030708 - 20 Mar 2018

Cited by 8 | Viewed by 4953

Abstract

From 1,2;3,4-di-O-isopropylidene-d-galactopyranose, a preliminary series of highly functionalized amino(hydroxymethyl)cyclopentanes was easily available. These amine-containing basic carbasugars featuring the d-galacto configuration are potent inhibitors of the GH20 β-d-hexosaminidases probed and may bear potential as regulators of [...] Read more.

From 1,2;3,4-di-O-isopropylidene-d-galactopyranose, a preliminary series of highly functionalized amino(hydroxymethyl)cyclopentanes was easily available. These amine-containing basic carbasugars featuring the d-galacto configuration are potent inhibitors of the GH20 β-d-hexosaminidases probed and may bear potential as regulators of N-acetyl-d-hexosaminidase activities in vivo. Full article

(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)

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Jump to: Editorial, Research, Other

38 pages, 4531 KiB

Open AccessReview

Recent Advances in Solvents for the Dissolution, Shaping and Derivatization of Cellulose: Quaternary Ammonium Electrolytes and their Solutions in Water and Molecular Solvents

by Marc Kostag, Kerstin Jedvert, Christian Achtel, Thomas Heinze and Omar A. El Seoud

Molecules 2018, 23(3), 511; https://doi.org/10.3390/molecules23030511 - 25 Feb 2018

Cited by 55 | Viewed by 10653

Abstract

There is a sustained interest in developing solvents for physically dissolving cellulose, i.e., without covalent bond formation. The use of ionic liquids, ILs, has generated much interest because of their structural versatility that results in efficiency as cellulose solvents. Despite some limitations, imidazole-based [...] Read more.

There is a sustained interest in developing solvents for physically dissolving cellulose, i.e., without covalent bond formation. The use of ionic liquids, ILs, has generated much interest because of their structural versatility that results in efficiency as cellulose solvents. Despite some limitations, imidazole-based ILs have received most of the scientific community’s attention. The objective of the present review is to show the advantages of using quaternary ammonium electrolytes, QAEs, including salts of super bases, as solvents for cellulose dissolution, shaping, and derivatization, and as a result, increase the interest in further investigation of these important solvents. QAEs share with ILs structural versatility; many are liquids at room temperature or are soluble in water and molecular solvents (MSs), in particular dimethyl sulfoxide. In this review we first give a historical background on the use of QAEs in cellulose chemistry, and then discuss the common, relatively simple strategies for their synthesis. We discuss the mechanism of cellulose dissolution by QAEs, neat or as solutions in MSs and water, with emphasis on the relevance to cellulose dissolution efficiency of the charge and structure of the cation and. We then discuss the use of cellulose solutions in these solvents for its derivatization under homogeneous and heterogeneous conditions. The products of interest are cellulose esters and ethers; our emphasis is on the role of solvent and possible side reactions. The final part is concerned with the use of cellulose dopes in these solvents for its shaping as fibers, a field with potential commercial application. Full article

(This article belongs to the Special Issue Cellulose Chemical Modifications—Towards Sustainable Materials)

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17 pages, 283 KiB

Open AccessReview

Neuroprotective Effects and Mechanisms of Tea Bioactive Components in Neurodegenerative Diseases

by Shu-Qing Chen, Ze-Shi Wang, Yi-Xiao Ma, Wei Zhang, Jian-Liang Lu, Yue-Rong Liang and Xin-Qiang Zheng

Molecules 2018, 23(3), 512; https://doi.org/10.3390/molecules23030512 - 25 Feb 2018

Cited by 82 | Viewed by 11574

Abstract

As the population ages, neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) impose a heavy burden on society and families. The pathogeneses of PD and AD are complex. There are no radical cures for the diseases, and existing therapeutic agents [...] Read more.

As the population ages, neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) impose a heavy burden on society and families. The pathogeneses of PD and AD are complex. There are no radical cures for the diseases, and existing therapeutic agents for PD and AD have diverse side effects. Tea contains many bioactive components such as polyphenols, theanine, caffeine, and theaflavins. Some investigations of epidemiology have demonstrated that drinking tea can decrease the risk of PD and AD. Tea polyphenols can lower the morbidity of PD and AD by reducing oxidative stress and regulating signaling pathways and metal chelation. Theanine can inhibit the glutamate receptors and regulate the extracellular concentration of glutamine, presenting neuroprotective effects. Additionally, the neuroprotective mechanisms of caffeine and theaflavins may contribute to the ability to antagonize the adenosine receptor A_2AR and the antioxidant properties, respectively. Thus, tea bioactive components might be useful for neuronal degeneration treatment in the future. In the present paper, the neuro protection and the mechanisms of tea and its bioactive components are reviewed. Moreover, the potential challenges and future work are also discussed. Full article

(This article belongs to the Collection Recent Advances in Flavors and Fragrances)

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17 pages, 1402 KiB

Open AccessReview

Melatonin and Cancer Hallmarks

by Wamidh H. Talib

Molecules 2018, 23(3), 518; https://doi.org/10.3390/molecules23030518 - 26 Feb 2018

Cited by 146 | Viewed by 16430

Abstract

Melatonin is a natural indoleamine produced by the pineal gland that has many functions, including regulation of the circadian rhythm. Many studies have reported the anticancer effect of melatonin against a myriad of cancer types. Cancer hallmarks include sustained proliferation, evading growth suppressors, [...] Read more.

Melatonin is a natural indoleamine produced by the pineal gland that has many functions, including regulation of the circadian rhythm. Many studies have reported the anticancer effect of melatonin against a myriad of cancer types. Cancer hallmarks include sustained proliferation, evading growth suppressors, metastasis, replicative immortality, angiogenesis, resisting cell death, altered cellular energetics, and immune evasion. Melatonin anticancer activity is mediated by interfering with various cancer hallmarks. This review summarizes the anticancer role of melatonin in each cancer hallmark. The studies discussed in this review should serve as a solid foundation for researchers and physicians to support basic and clinical studies on melatonin as a promising anticancer agent. Full article

(This article belongs to the Special Issue Melatonin as an Antioxidant and a Functionally Pleiotropic Molecule: Synthesis, Metabolism and Activities in Organisms)

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36 pages, 2194 KiB

Open AccessReview

Melatonin: A Versatile Protector against Oxidative DNA Damage

by Annia Galano, Dun-Xian Tan and Russel J. Reiter

Molecules 2018, 23(3), 530; https://doi.org/10.3390/molecules23030530 - 27 Feb 2018

Cited by 198 | Viewed by 13305

Abstract

Oxidative damage to DNA has important implications for human health and has been identified as a key factor in the onset and development of numerous diseases. Thus, it is evident that preventing DNA from oxidative damage is crucial for humans and for any [...] Read more.

Oxidative damage to DNA has important implications for human health and has been identified as a key factor in the onset and development of numerous diseases. Thus, it is evident that preventing DNA from oxidative damage is crucial for humans and for any living organism. Melatonin is an astonishingly versatile molecule in this context. It can offer both direct and indirect protection against a wide variety of damaging agents and through multiple pathways, which may (or may not) take place simultaneously. They include direct antioxidative protection, which is mediated by melatonin’s free radical scavenging activity, and also indirect ways of action. The latter include, at least: (i) inhibition of metal-induced DNA damage; (ii) protection against non-radical triggers of oxidative DNA damage; (iii) continuous protection after being metabolized; (iv) activation of antioxidative enzymes; (v) inhibition of pro-oxidative enzymes; and (vi) boosting of the DNA repair machinery. The rather unique capability of melatonin to exhibit multiple neutralizing actions against diverse threatening factors, together with its low toxicity and its ability to cross biological barriers, are all significant to its efficiency for preventing oxidative damage to DNA. Full article

(This article belongs to the Special Issue Melatonin as an Antioxidant and a Functionally Pleiotropic Molecule: Synthesis, Metabolism and Activities in Organisms)

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8 pages, 3567 KiB

Open AccessFeature PaperReview

The Pharmaceutical Industry in 2017. An Analysis of FDA Drug Approvals from the Perspective of Molecules

by Beatriz G. De la Torre and Fernando Albericio

Molecules 2018, 23(3), 533; https://doi.org/10.3390/molecules23030533 - 27 Feb 2018

Cited by 47 | Viewed by 8770

Abstract

This is an analysis from a chemical point of view of the 46 drugs (34 New Chemical Entities and 12 Biologics) approved by the FDA during 2017. The drugs included in the 2017 “harvest” have been classified on the basis of their chemical [...] Read more.

This is an analysis from a chemical point of view of the 46 drugs (34 New Chemical Entities and 12 Biologics) approved by the FDA during 2017. The drugs included in the 2017 “harvest” have been classified on the basis of their chemical structure: biologics (antibodies and proteins); peptides; amino acids and natural products; drug combinations; and small molecules. Full article

(This article belongs to the Section Medicinal Chemistry)

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21 pages, 308 KiB

Open AccessReview

Antimicrobial Activity and Chemical Composition of Essential Oils from Verbenaceae Species Growing in South America

by Cristina M. Pérez Zamora, Carola A. Torres and María B. Nuñez

Molecules 2018, 23(3), 544; https://doi.org/10.3390/molecules23030544 - 1 Mar 2018

Cited by 51 | Viewed by 7368

Abstract

The Verbenaceae family includes 2600 species grouped into 100 genera with a pantropical distribution. Many of them are important elements of the floras of warm-temperature and tropical regions of America. This family is known in folk medicine, and its species are used as [...] Read more.

The Verbenaceae family includes 2600 species grouped into 100 genera with a pantropical distribution. Many of them are important elements of the floras of warm-temperature and tropical regions of America. This family is known in folk medicine, and its species are used as digestive, carminative, antipyretic, antitussive, antiseptic, and healing agents. This review aims to collect information about the essential oils from the most reported species of the Verbenaceae family growing in South America, focusing on their chemical composition, antimicrobial activity, and synergism with commercial antimicrobials. The information gathered comprises the last twenty years of research within the South American region and is summarized taking into consideration the most representative species in terms of their essential oils. These species belong to Aloysia, Lantana, Lippia, Phyla, and Stachytarpheta genera, and the main essential oils they contain are monoterpenes and sesquiterpenes, such as β-caryophyllene, thymol, citral, 1,8-cineole, carvone, and limonene. These compounds have been found to possess antimicrobial activities. The synergism of these essential oils with antibiotics is being studied by several research groups. It constitutes a resource of interest for the potential use of combinations of essential oils and antibiotics in infection treatments. Full article

(This article belongs to the Special Issue Essential Oils as Antimicrobial and Anti-infectious Agents)

13 pages, 2941 KiB

Open AccessReview

The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors

by Fangyuan Cao, Martijn R. H. Zwinderman and Frank J. Dekker

Molecules 2018, 23(3), 551; https://doi.org/10.3390/molecules23030551 - 2 Mar 2018

Cited by 43 | Viewed by 6629

Abstract

Histone deacetylases (HDACs) are epigenetic drug targets that have gained major scientific attention. Inhibition of these important regulatory enzymes is used to treat cancer, and has the potential to treat a host of other diseases. However, currently marketed HDAC inhibitors lack selectivity for [...] Read more.

Histone deacetylases (HDACs) are epigenetic drug targets that have gained major scientific attention. Inhibition of these important regulatory enzymes is used to treat cancer, and has the potential to treat a host of other diseases. However, currently marketed HDAC inhibitors lack selectivity for the various HDAC isoenzymes. Several studies have shown that HDAC3, in particular, plays an important role in inflammation and degenerative neurological diseases, but the development of selective HDAC3 inhibitors has been challenging. This review provides an up-to-date overview of selective HDAC3 inhibitors, and aims to support the development of novel HDAC3 inhibitors in the future. Full article

(This article belongs to the Special Issue Modulators of Histone Acetylation: A Medicinal Chemistry Perspective)

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21 pages, 2869 KiB

Open AccessReview

Chemical and Biological Significance of Oenothein B and Related Ellagitannin Oligomers with Macrocyclic Structure

by Takashi Yoshida, Morio Yoshimura and Yoshiaki Amakura

Molecules 2018, 23(3), 552; https://doi.org/10.3390/molecules23030552 - 2 Mar 2018

Cited by 39 | Viewed by 5912

Abstract

In 1990, Okuda et al. reported the first isolation and characterization of oenothein B, a unique ellagitannin dimer with a macrocyclic structure, from the Oenothera erythrosepala leaves. Since then, a variety of macrocyclic analogs, including trimeric–heptameric oligomers have been isolated from various medicinal [...] Read more.

In 1990, Okuda et al. reported the first isolation and characterization of oenothein B, a unique ellagitannin dimer with a macrocyclic structure, from the Oenothera erythrosepala leaves. Since then, a variety of macrocyclic analogs, including trimeric–heptameric oligomers have been isolated from various medicinal plants belonging to Onagraceae, Lythraceae, and Myrtaceae. Among notable in vitro and in vivo biological activities reported for oenothein B are antioxidant, anti-inflammatory, enzyme inhibitory, antitumor, antimicrobial, and immunomodulatory activities. Oenothein B and related oligomers, and/or plant extracts containing them have thus attracted increasing interest as promising targets for the development of chemopreventive agents of life-related diseases associated with oxygen stress in human health. In order to better understand the significance of this type of ellagitannin in medicinal plants, this review summarizes (1) the structural characteristics of oenothein B and related dimers; (2) the oxidative metabolites of oenothein B up to heptameric oligomers; (3) the distribution of oenotheins and other macrocyclic analogs in the plant kingdom; and (4) the pharmacological activities hitherto documented for oenothein B, including those recently found by our laboratory. Full article

(This article belongs to the Special Issue Special Issue Dedicated to Late Professor Takuo Okuda, “Tannins and Related Polyphenols Revisited: Chemistry, Biochemistry and Biological Activities”)

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16 pages, 6815 KiB

Open AccessReview

Targeting Receptor-Type Protein Tyrosine Phosphatases with Biotherapeutics: Is Outside-in Better than Inside-Out?

by Yotis A. Senis and Alastair J. Barr

Molecules 2018, 23(3), 569; https://doi.org/10.3390/molecules23030569 - 2 Mar 2018

Cited by 29 | Viewed by 8237

Abstract

Protein tyrosine phosphatases (PTPs), of the receptor and non-receptor classes, are key signaling molecules that play critical roles in cellular regulation underlying diverse physiological events. Aberrant signaling as a result of genetic mutation or altered expression levels has been associated with several diseases [...] Read more.

Protein tyrosine phosphatases (PTPs), of the receptor and non-receptor classes, are key signaling molecules that play critical roles in cellular regulation underlying diverse physiological events. Aberrant signaling as a result of genetic mutation or altered expression levels has been associated with several diseases and treatment via pharmacological intervention at the level of PTPs has been widely explored; however, the challenges associated with development of small molecule phosphatase inhibitors targeting the intracellular phosphatase domain (the “inside-out” approach) have been well documented and as yet there are no clinically approved drugs targeting these enzymes. The alternative approach of targeting receptor PTPs with biotherapeutic agents (such as monoclonal antibodies or engineered fusion proteins; the “outside-in” approach) that interact with the extracellular ectodomain offers many advantages, and there have been a number of exciting recent developments in this field. Here we provide a brief overview of the receptor PTP family and an update on the emerging area of receptor PTP-targeted biotherapeutics for CD148, vascular endothelial-protein tyrosine phosphatase (VE-PTP), receptor-type PTPs σ, γ, ζ (RPTPσ, RPTPγ, RPTPζ) and CD45, and discussion of future potential in this area. Full article

(This article belongs to the Special Issue Protein-Tyrosine Phosphatase Inhibitors)

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13 pages, 1876 KiB

Open AccessReview

Effects of the Usage of l-Cysteine (l-Cys) on Human Health

by Noelia Clemente Plaza, Manuel Reig García-Galbis and Rosa María Martínez-Espinosa

Molecules 2018, 23(3), 575; https://doi.org/10.3390/molecules23030575 - 3 Mar 2018

Cited by 66 | Viewed by 16439

Abstract

This review summarizes recent knowledge about the use of the amino acid l-Cysteine (l-Cys) through diet, nutritional supplements or drugs with the aim to improve human health or treat certain diseases. Three databases (PubMed, Scopus, and Web of Science) and [...] Read more.

This review summarizes recent knowledge about the use of the amino acid l-Cysteine (l-Cys) through diet, nutritional supplements or drugs with the aim to improve human health or treat certain diseases. Three databases (PubMed, Scopus, and Web of Science) and different keywords have been used to create a database of documents published between 1950 and 2017 in scientific journals in English or Spanish. A total of 60,885 primary publications were ultimately selected to compile accurate information about the use of l-Cys in medicine and nutritional therapies and to identify the reported benefits of l-Cys on human health. The number of publications about the use of l-Cys for these purposes has increased significantly during the last two decades. This increase seems to be closely related to the rise of nutraceutical industries and personalized medicine. The main evidence reporting benefits of l-Cys usage is summarized. However, the lack of accurate information and studies based on clinical trials hampers consensus among authors. Thus, the debate about the role and effectiveness of supplements/drugs containing l-Cys is still open. Full article

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18 pages, 2385 KiB

Open AccessReview

Progress in Targeted Alpha-Particle Therapy. What We Learned about Recoils Release from In Vivo Generators

by Ján Kozempel, Olga Mokhodoeva and Martin Vlk

Molecules 2018, 23(3), 581; https://doi.org/10.3390/molecules23030581 - 5 Mar 2018

Cited by 74 | Viewed by 14082

Abstract

This review summarizes recent progress and developments as well as the most important pitfalls in targeted alpha-particle therapy, covering single alpha-particle emitters as well as in vivo alpha-particle generators. It discusses the production of radionuclides like ²¹¹At, ²²³Ra, ²²⁵Ac/²¹³ [...] Read more.

This review summarizes recent progress and developments as well as the most important pitfalls in targeted alpha-particle therapy, covering single alpha-particle emitters as well as in vivo alpha-particle generators. It discusses the production of radionuclides like ²¹¹At, ²²³Ra, ²²⁵Ac/²¹³Bi, labelling and delivery employing various targeting vectors (small molecules, chelators for alpha-emitting nuclides and their biomolecular targets as well as nanocarriers), general radiopharmaceutical issues, preclinical studies, and clinical trials including the possibilities of therapy prognosis and follow-up imaging. Special attention is given to the nuclear recoil effect and its impacts on the possible use of alpha emitters for cancer treatment, proper dose estimation, and labelling chemistry. The most recent and important achievements in the development of alpha emitters carrying vectors for preclinical and clinical use are highlighted along with an outlook for future developments. Full article

(This article belongs to the Special Issue Current Aspects of Radiopharmaceutical Chemistry)

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12 pages, 601 KiB

Open AccessReview

Progress on the Studies of the Key Enzymes of Ginsenoside Biosynthesis

by Jin-Ling Yang, Zong-Feng Hu, Ting-Ting Zhang, An-Di Gu, Ting Gong and Ping Zhu

Molecules 2018, 23(3), 589; https://doi.org/10.3390/molecules23030589 - 6 Mar 2018

Cited by 63 | Viewed by 7040

Abstract

As the main bioactive constituents of Panax species, ginsenosides possess a wide range of notable medicinal effects such as anti-cancer, anti-oxidative, antiaging, anti-inflammatory, anti-apoptotic and neuroprotective activities. However, the increasing medical demand for ginsenosides cannot be met due to the limited resource of [...] Read more.

As the main bioactive constituents of Panax species, ginsenosides possess a wide range of notable medicinal effects such as anti-cancer, anti-oxidative, antiaging, anti-inflammatory, anti-apoptotic and neuroprotective activities. However, the increasing medical demand for ginsenosides cannot be met due to the limited resource of Panax species and the low contents of ginsenosides. In recent years, biotechnological approaches have been utilized to increase the production of ginsenosides by regulating the key enzymes of ginsenoside biosynthesis, while synthetic biology strategies have been adopted to produce ginsenosides by introducing these genes into yeast. This review summarizes the latest research progress on cloning and functional characterization of key genes dedicated to the production of ginsenosides, which not only lays the foundation for their application in plant engineering, but also provides the building blocks for the production of ginsenosides by synthetic biology. Full article

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14 pages, 2825 KiB

Open AccessReview

PET Imaging of Microglial Activation—Beyond Targeting TSPO

by Bieneke Janssen, Danielle J. Vugts, Albert D. Windhorst and Robert H. Mach

Molecules 2018, 23(3), 607; https://doi.org/10.3390/molecules23030607 - 8 Mar 2018

Cited by 80 | Viewed by 12913

Abstract

Neuroinflammation, which involves microglial activation, is thought to play a key role in the development and progression of neurodegenerative diseases and other brain pathologies. Positron emission tomography is an ideal imaging technique for studying biochemical processes in vivo, and particularly for studying the [...] Read more.

Neuroinflammation, which involves microglial activation, is thought to play a key role in the development and progression of neurodegenerative diseases and other brain pathologies. Positron emission tomography is an ideal imaging technique for studying biochemical processes in vivo, and particularly for studying the living brain. Neuroinflammation has been traditionally studied using radiotracers targeting the translocator protein 18 kDa, but this comes with certain limitations. The current review describes alternative biological targets that have gained interest for the imaging of microglial activation over recent years, such as the cannabinoid receptor type 2, cyclooxygenase-2, the P2X₇ receptor and reactive oxygen species, and some promising radiotracers for these targets. Although many advances have been made in the field of neuroinflammation imaging, current radiotracers all target the pro-inflammatory (M1) phenotype of activated microglia, since the number of known biological targets specific for the anti-inflammatory (M2) phenotype that are also suited as a target for radiotracer development is still limited. Next to proceeding the currently available tracers for M1 microglia into the clinic, the development of a suitable radiotracer for M2 microglia would mean a great advance in the field, as this would allow for imaging of the dynamics of microglial activation in different diseases. Full article

(This article belongs to the Special Issue Current Aspects of Radiopharmaceutical Chemistry)

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11 pages, 6433 KiB

Open AccessFeature PaperReview

From the Synthesis of Nanovehicles to Participation in the First Nanocar Race—View from the French Team

by Henri-Pierre Jacquot de Rouville, Claire Kammerer and Gwénaël Rapenne

Molecules 2018, 23(3), 612; https://doi.org/10.3390/molecules23030612 - 8 Mar 2018

Cited by 14 | Viewed by 5409

Abstract

This review article presents our accomplished work on the synthesis of molecular triptycene wheels and their introduction into nanovehicles such as wheelbarrows and nanocars, equipped with two and four wheels, respectively. The architecture of nanovehicles is based on polycyclic aromatic hydrocarbons, which provide [...] Read more.

This review article presents our accomplished work on the synthesis of molecular triptycene wheels and their introduction into nanovehicles such as wheelbarrows and nanocars, equipped with two and four wheels, respectively. The architecture of nanovehicles is based on polycyclic aromatic hydrocarbons, which provide a potential cargo zone. Our strategy allowed us to obtain planar or curved nanocars, exhibiting different mobilities on metallic surfaces. Our curved nanocar participated in the first nanocar race organized in Toulouse (France) on 28 and 29 April 2017. Full article

(This article belongs to the Special Issue Interlocked Molecules, Molecular Machines, Motors and Muscles)

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14 pages, 931 KiB

Open AccessFeature PaperReview

The Application of Embelin for Cancer Prevention and Therapy

by Jeong-Hyeon Ko, Seok-Geun Lee, Woong Mo Yang, Jae-Young Um, Gautam Sethi, Srishti Mishra, Muthu K. Shanmugam and Kwang Seok Ahn

Molecules 2018, 23(3), 621; https://doi.org/10.3390/molecules23030621 - 9 Mar 2018

Cited by 49 | Viewed by 7646

Abstract

Embelin is a naturally-occurring benzoquinone compound that has been shown to possess many biological properties relevant to human cancer prevention and treatment, and increasing evidence indicates that embelin may modulate various characteristic hallmarks of tumor cells. This review summarizes the information related to [...] Read more.

Embelin is a naturally-occurring benzoquinone compound that has been shown to possess many biological properties relevant to human cancer prevention and treatment, and increasing evidence indicates that embelin may modulate various characteristic hallmarks of tumor cells. This review summarizes the information related to the various oncogenic pathways that mediate embelin-induced cell death in multiple cancer cells. The mechanisms of the action of embelin are numerous, and most of them induce apoptotic cell death that may be intrinsic or extrinsic, and modulate the NF-κB, p53, PI3K/AKT, and STAT3 signaling pathways. Embelin also induces autophagy in cancer cells; however, these autophagic cell-death mechanisms of embelin have been less reported than the apoptotic ones. Recently, several autophagy-inducing agents have been used in the treatment of different human cancers, although they require further exploration before being transferred from the bench to the clinic. Therefore, embelin could be used as a potential agent for cancer therapy. Full article

(This article belongs to the Special Issue Small Molecule Catalysts with Therapeutic Potential)

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12 pages, 1387 KiB

Open AccessFeature PaperReview

Which Dendrimer to Attain the Desired Properties? Focus on Phosphorhydrazone Dendrimers

by Anne-Marie Caminade and Jean-Pierre Majoral

Molecules 2018, 23(3), 622; https://doi.org/10.3390/molecules23030622 - 9 Mar 2018

Cited by 18 | Viewed by 4394

Abstract

Among the six Critical Nanoscale Design Parameters (CNDPs) proposed by Prof. Donald A. Tomalia, this review illustrates the influence of the sixth one, which concerns the elemental composition, on the properties of dendrimers. After a large introduction that summarizes different types of dendrimers [...] Read more.

Among the six Critical Nanoscale Design Parameters (CNDPs) proposed by Prof. Donald A. Tomalia, this review illustrates the influence of the sixth one, which concerns the elemental composition, on the properties of dendrimers. After a large introduction that summarizes different types of dendrimers that have been compared with PolyAMidoAMine (PAMAM) dendrimers, this review will focus on the properties of positively and negatively charged phosphorhydrazone (PPH) dendrimers, especially in the field of biology, compared with other types of dendrimers, in particular PAMAM dendrimers, as well as polypropyleneimine (PPI), carbosilane, and p-Lysine dendrimers. Full article

(This article belongs to the Special Issue Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 80th Birthday)

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18 pages, 430 KiB

Open AccessFeature PaperReview

Isothiocyanates: An Overview of Their Antimicrobial Activity against Human Infections

by Letizia Romeo, Renato Iori, Patrick Rollin, Placido Bramanti and Emanuela Mazzon

Molecules 2018, 23(3), 624; https://doi.org/10.3390/molecules23030624 - 9 Mar 2018

Cited by 142 | Viewed by 9526

Abstract

The use of plant-derived products as antimicrobial agents has been investigated in depth. Isothiocyanates (ITCs) are bioactive products resulting from enzymatic hydrolysis of glucosinolates (GLs), the most abundant secondary metabolites in the botanical order Brassicales. Although the antimicrobial activity of ITCs against foodborne [...] Read more.

The use of plant-derived products as antimicrobial agents has been investigated in depth. Isothiocyanates (ITCs) are bioactive products resulting from enzymatic hydrolysis of glucosinolates (GLs), the most abundant secondary metabolites in the botanical order Brassicales. Although the antimicrobial activity of ITCs against foodborne and plant pathogens has been well documented, little is known about their antimicrobial properties against human pathogens. This review collects studies that focus on this topic. Particular focus will be put on ITCs’ antimicrobial properties and their mechanism of action against human pathogens for which the current therapeutic solutions are deficient and therefore of prime importance for public health. Our purpose was the evaluation of the potential use of ITCs to replace or support the common antibiotics. Even though ITCs appear to be effective against the most important human pathogens, including bacteria with resistant phenotypes, the majority of the studies did not show comparable results and thus it is very difficult to compare the antimicrobial activity of the different ITCs. For this reason, a standard method should be used and further studies are needed. Full article

(This article belongs to the Special Issue Focusing on Sulfur in Medicinal Chemistry)

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19 pages, 1440 KiB

Open AccessFeature PaperReview

Selenides and Diselenides: A Review of Their Anticancer and Chemopreventive Activity

by Mónica Álvarez-Pérez, Wesam Ali, Małgorzata Anna Marć, Jadwiga Handzlik and Enrique Domínguez-Álvarez

Molecules 2018, 23(3), 628; https://doi.org/10.3390/molecules23030628 - 10 Mar 2018

Cited by 121 | Viewed by 7391

Abstract

Selenium and selenocompounds have attracted the attention and the efforts of scientists worldwide due to their promising potential applications in cancer prevention and/or treatment. Different organic selenocompounds, with diverse functional groups that contain selenium, have been reported to exhibit anticancer and/or chemopreventive activity. [...] Read more.

Selenium and selenocompounds have attracted the attention and the efforts of scientists worldwide due to their promising potential applications in cancer prevention and/or treatment. Different organic selenocompounds, with diverse functional groups that contain selenium, have been reported to exhibit anticancer and/or chemopreventive activity. Among them, selenocyanates, selenoureas, selenoesters, selenium-containing heterocycles, selenium nanoparticles, selenides and diselenides have been considered in the search for efficiency in prevention and treatment of cancer and other related diseases. In this review, we focus our attention on the potential applications of selenides and diselenides in cancer prevention and treatment that have been reported so far. The around 80 selenides and diselenides selected herein as representative compounds include promising antioxidant, prooxidant, redox-modulating, chemopreventive, anticancer, cytotoxic and radioprotective compounds, among other activities. The aim of this work is to highlight the possibilities that these novel organic selenocompounds can offer in an effort to contribute to inspire medicinal chemists in their search of new promising derivatives. Full article

(This article belongs to the Special Issue Small Molecule Catalysts with Therapeutic Potential)

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15 pages, 1012 KiB

Open AccessFeature PaperReview

Peptide Nucleic Acids as a Tool for Site-Specific Gene Editing

by Adele S. Ricciardi, Elias Quijano, Rachael Putman, W. Mark Saltzman and Peter M. Glazer

Molecules 2018, 23(3), 632; https://doi.org/10.3390/molecules23030632 - 11 Mar 2018

Cited by 55 | Viewed by 9747

Abstract

Peptide nucleic acids (PNAs) can bind duplex DNA in a sequence-targeted manner, forming a triplex structure capable of inducing DNA repair and producing specific genome modifications. Since the first description of PNA-mediated gene editing in cell free extracts, PNAs have been used to [...] Read more.

Peptide nucleic acids (PNAs) can bind duplex DNA in a sequence-targeted manner, forming a triplex structure capable of inducing DNA repair and producing specific genome modifications. Since the first description of PNA-mediated gene editing in cell free extracts, PNAs have been used to successfully correct human disease-causing mutations in cell culture and in vivo in preclinical mouse models. Gene correction via PNAs has resulted in clinically-relevant functional protein restoration and disease improvement, with low off-target genome effects, indicating a strong therapeutic potential for PNAs in the treatment or cure of genetic disorders. This review discusses the progress that has been made in developing PNAs as an effective, targeted agent for gene editing, with an emphasis on recent in vivo, nanoparticle-based strategies. Full article

(This article belongs to the Special Issue Molecular Properties and the Applications of Peptide Nucleic Acids)

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24 pages, 1791 KiB

Open AccessReview

Recent Advances in Zirconium-89 Chelator Development

by Nikunj B. Bhatt, Darpan N. Pandya and Thaddeus J. Wadas

Molecules 2018, 23(3), 638; https://doi.org/10.3390/molecules23030638 - 12 Mar 2018

Cited by 87 | Viewed by 8190

Abstract

The interest in zirconium-89 (⁸⁹Zr) as a positron-emitting radionuclide has grown considerably over the last decade due to its standardized production, long half-life of 78.2 h, favorable decay characteristics for positron emission tomography (PET) imaging and its successful use in a [...] Read more.

The interest in zirconium-89 (⁸⁹Zr) as a positron-emitting radionuclide has grown considerably over the last decade due to its standardized production, long half-life of 78.2 h, favorable decay characteristics for positron emission tomography (PET) imaging and its successful use in a variety of clinical and preclinical applications. However, to be utilized effectively in PET applications it must be stably bound to a targeting ligand, and the most successfully used ⁸⁹Zr chelator is desferrioxamine B (DFO), which is commercially available as the iron chelator Desferal^®. Despite the prevalence of DFO in ⁸⁹Zr-immuno-PET applications, the development of new ligands for this radiometal is an active area of research. This review focuses on recent advances in zirconium-89 chelation chemistry and will highlight the rapidly expanding ligand classes that are under investigation as DFO alternatives. Full article

(This article belongs to the Special Issue Current Aspects of Radiopharmaceutical Chemistry)

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15 pages, 3723 KiB

Open AccessReview

Synthesis of O-Amino Sugars and Nucleosides

by Na Chen and Juan Xie

Molecules 2018, 23(3), 641; https://doi.org/10.3390/molecules23030641 - 12 Mar 2018

Cited by 5 | Viewed by 8456

Abstract

Nucleic acids and carbohydrates are essential biomolecules involved in numerous biological and pathological processes. Development of multifunctional building blocks based on nucleosides and sugars is in high demand for the generation of novel oligonucleotide mimics and glycoconjugates for biomedical applications. Recently, aminooxyl-functionalized compounds [...] Read more.

Nucleic acids and carbohydrates are essential biomolecules involved in numerous biological and pathological processes. Development of multifunctional building blocks based on nucleosides and sugars is in high demand for the generation of novel oligonucleotide mimics and glycoconjugates for biomedical applications. Recently, aminooxyl-functionalized compounds have attracted increasing research interest because of their easy derivatization through oxime ligation or N-oxyamide formation reactions. Various biological applications have been reported for O-amino carbohydrate- and nucleoside-derived compounds. Here, we report our efforts in the design and synthesis of glyco-, glycosyl, nucleoside- and nucleo-aminooxy acid derivatives from readily available sugars and amino acids, and their use for the generation of N-oxyamide-linked oligosaccharides, glycopeptides, glycolipids, oligonucleosides and nucleopeptides as novel glycoconjugates or oligonucleotide mimics. Delicate and key points in the synthesis will be emphasized. Full article

(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)

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31 pages, 5373 KiB

Open AccessReview

Structural Diversity and Biological Activities of Novel Secondary Metabolites from Endophytes

by Han Gao, Gang Li and Hong-Xiang Lou

Molecules 2018, 23(3), 646; https://doi.org/10.3390/molecules23030646 - 13 Mar 2018

Cited by 86 | Viewed by 9746

Abstract

Exploration of structurally novel natural products greatly facilitates the discovery of biologically active pharmacophores that are biologically validated starting points for the development of new drugs. Endophytes that colonize the internal tissues of plant species, have been proven to produce a large number [...] Read more.

Exploration of structurally novel natural products greatly facilitates the discovery of biologically active pharmacophores that are biologically validated starting points for the development of new drugs. Endophytes that colonize the internal tissues of plant species, have been proven to produce a large number of structurally diverse secondary metabolites. These molecules exhibit remarkable biological activities, including antimicrobial, anticancer, anti-inflammatory and antiviral properties, to name but a few. This review surveys the structurally diverse natural products with new carbon skeletons, unusual ring systems, or rare structural moieties that have been isolated from endophytes between 1996 and 2016. It covers their structures and bioactivities. Biosynthesis and/or total syntheses of some important compounds are also highlighted. Some novel secondary metabolites with marked biological activities might deserve more attention from chemists and biologists in further studies. Full article

(This article belongs to the Collection Bioactive Compounds)

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21 pages, 931 KiB

Open AccessReview

Antitumour, Antimicrobial, Antioxidant and Antiacetylcholinesterase Effect of Ganoderma Lucidum Terpenoids and Polysaccharides: A Review

by Darija Cör, Željko Knez and Maša Knez Hrnčič

Molecules 2018, 23(3), 649; https://doi.org/10.3390/molecules23030649 - 13 Mar 2018

Cited by 275 | Viewed by 27920

Abstract

Ganoderma lucidum (Reishi) is a popular medicinal mushroom and has been used in oriental medicine because of its promoting effects on health and life expectancy. G. lucidum contains various compounds with a high grade of biological activty, which increase the immunity and show [...] Read more.

Ganoderma lucidum (Reishi) is a popular medicinal mushroom and has been used in oriental medicine because of its promoting effects on health and life expectancy. G. lucidum contains various compounds with a high grade of biological activty, which increase the immunity and show antitumour, antimicrobial, anti-inflammatory, antioxidant and acetylcholinesterase inhibitory activity. Several of these substances belong to the triterpenoids and polysaccharides classes. Proteins, lipids, phenols, sterols, etc. are also present. In the present review, an extensive overview of the presence of antitumour, antimicrobial, antioxidant and antiacetylcholinesterase compounds in G. lucidum extracts will be given, along with an evaluation of their therapeutic effects. Full article

(This article belongs to the Collection Efficient Pharmaceutical and Chemical Approaches for Anticancer Therapy: Design, Preliminary Evaluations, and Further Developments)

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53 pages, 3302 KiB

Open AccessReview

Seasonal Reproduction in Vertebrates: Melatonin Synthesis, Binding, and Functionality Using Tinbergen’s Four Questions

by Dax ViviD and George E. Bentley

Molecules 2018, 23(3), 652; https://doi.org/10.3390/molecules23030652 - 13 Mar 2018

Cited by 34 | Viewed by 8550

Abstract

One of the many functions of melatonin in vertebrates is seasonal reproductive timing. Longer nights in winter correspond to an extended duration of melatonin secretion. The purpose of this review is to discuss melatonin synthesis, receptor subtypes, and function in the context of [...] Read more.

One of the many functions of melatonin in vertebrates is seasonal reproductive timing. Longer nights in winter correspond to an extended duration of melatonin secretion. The purpose of this review is to discuss melatonin synthesis, receptor subtypes, and function in the context of seasonality across vertebrates. We conclude with Tinbergen’s Four Questions to create a comparative framework for future melatonin research in the context of seasonal reproduction. Full article

(This article belongs to the Special Issue Melatonin as an Antioxidant and a Functionally Pleiotropic Molecule: Synthesis, Metabolism and Activities in Organisms)

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20 pages, 3761 KiB

Open AccessFeature PaperReview

Recent Advances in Modified Cellulose for Tissue Culture Applications

by James C. Courtenay, Ram I. Sharma and Janet L. Scott

Molecules 2018, 23(3), 654; https://doi.org/10.3390/molecules23030654 - 14 Mar 2018

Cited by 96 | Viewed by 11842

Abstract

Tissue engineering is a rapidly advancing field in regenerative medicine, with much research directed towards the production of new biomaterial scaffolds with tailored properties to generate functional tissue for specific applications. Recently, principles of sustainability, eco-efficiency and green chemistry have begun to guide [...] Read more.

Tissue engineering is a rapidly advancing field in regenerative medicine, with much research directed towards the production of new biomaterial scaffolds with tailored properties to generate functional tissue for specific applications. Recently, principles of sustainability, eco-efficiency and green chemistry have begun to guide the development of a new generation of materials, such as cellulose, as an alternative to conventional polymers based on conversion of fossil carbon (e.g., oil) and finding technologies to reduce the use of animal and human derived biomolecules (e.g., foetal bovine serum). Much of this focus on cellulose is due to it possessing the necessary properties for tissue engineering scaffolds, including biocompatibility, and the relative ease with which its characteristics can be tuned through chemical modification to adjust mechanical properties and to introduce various surface modifications. In addition, the sustainability of producing and manufacturing materials from cellulose, as well as its modest cost, makes cellulose an economically viable feedstock. This review focusses specifically on the use of modified cellulose materials for tissue culturing applications. We will investigate recent techniques used to promote scaffold function through physical, biochemical and chemical scaffold modifications, and describe how these have been utilised to reduce reliance on the addition of matrix ligands such as foetal bovine serum. Full article

(This article belongs to the Special Issue Cellulose Chemical Modifications—Towards Sustainable Materials)

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21 pages, 4930 KiB

Open AccessReview

Hyperbranched Macromolecules: From Synthesis to Applications

by In-Yup Jeon, Hyuk-Jun Noh and Jong-Beom Baek

Molecules 2018, 23(3), 657; https://doi.org/10.3390/molecules23030657 - 14 Mar 2018

Cited by 46 | Viewed by 7371

Abstract

Hyperbranched macromolecules (HMs, also called hyperbranched polymers) are highly branched three-dimensional (3D) structures in which all bonds converge to a focal point or core, and which have a multiplicity of reactive chain-ends. This review summarizes major types of synthetic strategies exploited to produce [...] Read more.

Hyperbranched macromolecules (HMs, also called hyperbranched polymers) are highly branched three-dimensional (3D) structures in which all bonds converge to a focal point or core, and which have a multiplicity of reactive chain-ends. This review summarizes major types of synthetic strategies exploited to produce HMs, including the step-growth polycondensation, the self-condensing vinyl polymerization and ring opening polymerization. Compared to linear analogues, the globular and dendritic architectures of HMs endow new characteristics, such as abundant functional groups, intramolecular cavities, low viscosity, and high solubility. After discussing the general concepts, synthesis, and properties, various applications of HMs are also covered. HMs continue being materials for topical interest, and thus this review offers both concise summary for those new to the topic and for those with more experience in the field of HMs. Full article

(This article belongs to the Special Issue Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 80th Birthday)

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13 pages, 1637 KiB

Open AccessReview

Therapeutic Perspectives of 8-Prenylnaringenin, a Potent Phytoestrogen from Hops

by Kateřina Štulíková, Marcel Karabín, Jakub Nešpor and Pavel Dostálek

Molecules 2018, 23(3), 660; https://doi.org/10.3390/molecules23030660 - 15 Mar 2018

Cited by 62 | Viewed by 13942

Abstract

Hop (Humulus lupulus L.), as a key ingredient for beer brewing, is also a source of many biologically active molecules. A notable compound, 8-prenylnaringenin (8-PN), structurally belonging to the group of prenylated flavonoids, was shown to be a potent phytoestrogen, and thus, [...] Read more.

Hop (Humulus lupulus L.), as a key ingredient for beer brewing, is also a source of many biologically active molecules. A notable compound, 8-prenylnaringenin (8-PN), structurally belonging to the group of prenylated flavonoids, was shown to be a potent phytoestrogen, and thus, became the topic of active research. Here, we overview the pharmacological properties of 8-PN and its therapeutic opportunities. Due to its estrogenic effects, administration of 8-PN represents a novel therapeutic approach to the treatment of menopausal and post-menopausal symptoms that occur as a consequence of a progressive decline in hormone levels in women. Application of 8-PN in the treatment of menopause has been clinically examined with promising results. Other activities that have already been assessed include the potential to prevent bone-resorption or inhibition of tumor growth. On the other hand, the use of phytoestrogens is frequently questioned regarding possible adverse effects associated with long-term consumption. In conclusion, we emphasize the implications of using 8-PN in future treatments of menopausal and post-menopausal symptoms, including the need for precise evidence and further investigations to define the safety risks related to its therapeutic use. Full article

(This article belongs to the Special Issue Biological Activity of Secondary Metabolites)

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16 pages, 777 KiB

Open AccessReview

Transdermal and Topical Drug Administration in the Treatment of Pain

by Wojciech Leppert, Malgorzata Malec–Milewska, Renata Zajaczkowska and Jerzy Wordliczek

Molecules 2018, 23(3), 681; https://doi.org/10.3390/molecules23030681 - 17 Mar 2018

Cited by 105 | Viewed by 18407

Abstract

The comprehensive treatment of pain is multidimodal, with pharmacotherapy playing a key role. An effective therapy for pain depends on the intensity and type of pain, the patients’ age, comorbidities, and appropriate choice of analgesic, its dose and route of administration. This review [...] Read more.

The comprehensive treatment of pain is multidimodal, with pharmacotherapy playing a key role. An effective therapy for pain depends on the intensity and type of pain, the patients’ age, comorbidities, and appropriate choice of analgesic, its dose and route of administration. This review is aimed at presenting current knowledge on analgesics administered by transdermal and topical routes for physicians, nurses, pharmacists, and other health care professionals dealing with patients suffering from pain. Analgesics administered transdermally or topically act through different mechanisms. Opioids administered transdermally are absorbed into vessels located in subcutaneous tissue and, subsequently, are conveyed in the blood to opioid receptors localized in the central and peripheral nervous system. Non–steroidal anti–inflammatory drugs (NSAIDs) applied topically render analgesia mainly through a high concentration in the structures of the joint and a provision of local anti–inflammatory effects. Topically administered drugs such as lidocaine and capsaicin in patches, capsaicin in cream, EMLA cream, and creams containing antidepressants (i.e., doxepin, amitriptyline) act mainly locally in tissues through receptors and/or ion channels. Transdermal and topical routes offer some advantages over systemic analgesic administration. Analgesics administered topically have a much better profile for adverse effects as they relieve local pain with minimal systemic effects. The transdermal route apart from the above-mentioned advantages and provision of long period of analgesia may be more convenient, especially for patients who are unable to take drugs orally. Topically and transdermally administered opioids are characterised by a lower risk of addiction compared to oral and parenteral routes. Full article

(This article belongs to the Special Issue Medicinal Chemistry in Europe)

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21 pages, 4810 KiB

Open AccessReview

Thiazoles and Thiazolidinones as COX/LOX Inhibitors

by Konstantinos Liaras, Maria Fesatidou and Athina Geronikaki

Molecules 2018, 23(3), 685; https://doi.org/10.3390/molecules23030685 - 18 Mar 2018

Cited by 114 | Viewed by 9641

Abstract

Inflammation is a natural process that is connected to various conditions and disorders such as arthritis, psoriasis, cancer, infections, asthma, etc. Based on the fact that cyclooxygenase isoenzymes (COX-1, COX-2) are responsible for the production of prostaglandins that play an important role in [...] Read more.

Inflammation is a natural process that is connected to various conditions and disorders such as arthritis, psoriasis, cancer, infections, asthma, etc. Based on the fact that cyclooxygenase isoenzymes (COX-1, COX-2) are responsible for the production of prostaglandins that play an important role in inflammation, traditional treatment approaches include administration of non-steroidal anti-inflammatory drugs (NSAIDs), which act as selective or non-selective COX inhibitors. Almost all of them present a number of unwanted, often serious, side effects as a consequence of interference with the arachidonic acid cascade. In search for new drugs to avoid side effects, while maintaining high potency over inflammation, scientists turned their interest to the synthesis of dual COX/LOX inhibitors, which could provide numerous therapeutic advantages in terms of anti-inflammatory activity, improved gastric protection and safer cardiovascular profile compared to conventional NSAIDs. Τhiazole and thiazolidinone moieties can be found in numerous biologically active compounds of natural origin, as well as synthetic molecules that possess a wide range of pharmacological activities. This review focuses on the biological activity of several thiazole and thiazolidinone derivatives as COX-1/COX-2 and LOX inhibitors. Full article

(This article belongs to the Special Issue Recent Trends on Enzymes Inhibitors and Activators in Drug Research)

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21 pages, 601 KiB

Open AccessReview

Anticancer Activity of Toxins from Bee and Snake Venom—An Overview on Ovarian Cancer

by Marius Alexandru Moga, Oana Gabriela Dimienescu, Cristian Andrei Arvătescu, Petru Ifteni and Liana Pleş

Molecules 2018, 23(3), 692; https://doi.org/10.3390/molecules23030692 - 19 Mar 2018

Cited by 43 | Viewed by 9415

Abstract

Cancer represents the disease of the millennium, a major problem in public health. The proliferation of tumor cells, angiogenesis, and the relationship between the cancer cells and the components of the extracellular matrix are important in the events of carcinogenesis, and these pathways [...] Read more.

Cancer represents the disease of the millennium, a major problem in public health. The proliferation of tumor cells, angiogenesis, and the relationship between the cancer cells and the components of the extracellular matrix are important in the events of carcinogenesis, and these pathways are being used as targets for new anticancer treatments. Various venoms and their toxins have shown possible anticancer effects on human cancer cell lines, providing new perspectives in drug development. In this review, we observed the effects of natural toxins from bee and snake venom and the mechanisms through which they can inhibit the growth and proliferation of cancer cells. We also researched how several types of natural molecules from venom can sensitize ovarian cancer cells to conventional chemotherapy, with many toxins being helpful for developing new anticancer drugs. This approach could improve the efficiency of standard therapies and could allow the administration of decreased doses of chemotherapy. Natural toxins from bee and snake venom could become potential candidates for the future treatment of different types of cancer. It is important to continue these studies concerning therapeutic drugs from natural resource and, more importantly, to investigate their mechanism of action on cancer cells. Full article

(This article belongs to the Special Issue Natural Toxins/Molecules (and Derivatives) from Animal Venoms: From Basic Research to Therapeutic Applications)

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Jump to: Editorial, Research, Review

14 pages, 7707 KiB

Open AccessFeature PaperPerspective

Thermogelling 3D Systems towards Stem Cell-Based Tissue Regeneration Therapies

by Xiaoyuan Wang, David James Young, Yun-Long Wu and Xian Jun Loh

Molecules 2018, 23(3), 553; https://doi.org/10.3390/molecules23030553 - 2 Mar 2018

Cited by 17 | Viewed by 5096

Abstract

Stem cell culturing and differentiation is a very important research direction for tissue engineering. Thermogels are well suited for encapsulating cells because of their non-biotoxic nature and mild sol-gel transition as temperature increases. In particular, thermogels provide a 3D growth environment for stem [...] Read more.

Stem cell culturing and differentiation is a very important research direction for tissue engineering. Thermogels are well suited for encapsulating cells because of their non-biotoxic nature and mild sol-gel transition as temperature increases. In particular, thermogels provide a 3D growth environment for stem cell growth, which is more similar to the extracellular matrix than flat substrates, so thermogels as a medium can overcome many of the cell abnormalities caused by 2D cell growth. In this review, we summarize the applications of thermogels in cell and stem cell culture in recent years. We also elaborate on the methods to induce stem cell differentiation by using thermogel-based 3D scaffolds. In particular, thermogels, encapsulating specific differentiation-inducing factor and having specific structures and moduli, can induce the differentiation into the desired tissue cells. Three dimensional thermogel scaffolds that control the growth and differentiation of cells will undoubtedly have a bright future in regenerative medicine. Full article

(This article belongs to the Special Issue Functional Molecular Materials)

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11 pages, 3328 KiB

Open AccessFeature PaperConcept Paper

Development of Dipicolylamine-Modified Cyclodextrins for the Design of Selective Guest-Responsive Receptors for ATP

by Tatsuru Yamada, Shoji Fujiwara, Kyohhei Fujita, Yuji Tsuchido, Takeshi Hashimoto and Takashi Hayashita

Molecules 2018, 23(3), 635; https://doi.org/10.3390/molecules23030635 - 12 Mar 2018

Cited by 15 | Viewed by 5730

Abstract

The construction of supramolecular recognition systems based on specific host–guest interactions has been studied in order to design selective chemical sensors. In this study, guest-responsive receptors for ATP have been designed with cyclodextrins (CyDs) as a basic prototype of the turn-on type fluorescent [...] Read more.

The construction of supramolecular recognition systems based on specific host–guest interactions has been studied in order to design selective chemical sensors. In this study, guest-responsive receptors for ATP have been designed with cyclodextrins (CyDs) as a basic prototype of the turn-on type fluorescent indicator. We synthesized dipicolylamine (DPA)-modified CyD–Cu²⁺ complexes (Cu·1α, Cu·1β, and Cu·1γ), and evaluated their recognition capabilities toward phosphoric acid derivatives in water. The UV-Vis absorption and fluorescence spectra revealed that Cu·1β selectively recognized ATP over other organic and inorganic phosphates, and that β-CyD had the most suitable cavity size for complexation with ATP. The 1D and 2D NMR analyses suggested that the ATP recognition was based on the host–guest interaction between the adenine moiety of ATP and the CyD cavity, as well as the recognition of phosphoric moieties by the Cu²⁺–DPA complex site. The specific interactions between the CyD cavity and the nucleobases enabled us to distinguish ATP from other nucleoside triphosphates, such as guanosine triphosphate (GTP), uridine triphosphate (UTP), and cytidine triphosphate (CTP). This study clarified the basic mechanisms of molecular recognition by modified CyDs, and suggested the potential for further application of CyDs in the design of highly selective supramolecular recognition systems for certain molecular targets in water. Full article

(This article belongs to the Special Issue Cyclodextrin Chemistry 2018)

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