Molecules

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Open AccessArticle

Time-dependent Inhibition of CYP2C8 and CYP2C19 by Hedera helix Extracts, A Traditional Respiratory Herbal Medicine

by Shaheed Ur Rehman, In Sook Kim, Min Sun Choi, Seung Hyun Kim, Yonghui Zhang and Hye Hyun Yoo

Molecules 2017, 22(7), 1241; https://doi.org/10.3390/molecules22071241 - 24 Jul 2017

Cited by 8 | Viewed by 6948

The extract of Hedera helix L. (Araliaceae), a well-known folk medicine, has been popularly used to treat respiratory problems, worldwide. It is very likely that this herbal extract is taken in combination with conventional drugs. The present study aimed to evaluate the effects [...] Read more.

The extract of Hedera helix L. (Araliaceae), a well-known folk medicine, has been popularly used to treat respiratory problems, worldwide. It is very likely that this herbal extract is taken in combination with conventional drugs. The present study aimed to evaluate the effects of H. helix extract on cytochrome P450 (CYP) enzyme-mediated metabolism to predict the potential for herb–drug interactions. A cocktail probe assay was used to measure the inhibitory effect of CYP. H. helix extracts were incubated with pooled human liver microsomes or CYP isozymes with CYP-specific substrates, and the formation of specific metabolites was investigated to measure the inhibitory effects. H. helix showed significant inhibitory effects on CYP2C8, CYP2C19 and CYP2D6 in a concentration-dependent manner. In recombinant CYP2C8, CYP2C19 and CYP2D6 isozymes, the IC₅₀ values of the extract were 0.08 ± 0.01, 0.58 ± 0.03 and 6.72 ± 0.22 mg/mL, respectively. Further investigation showed that H. helix extract has a positive time-dependent inhibition property on both CYP2C8 and CYP2C19 with IC₅₀ shift value of 2.77 ± 0.12 and 6.31 ± 0.25, respectively. Based on this in vitro investigation, consumption of herbal medicines or dietary supplements containing H. helix extracts requires careful attention to avoid any CYP-based interactions. Full article

(This article belongs to the Special Issue Herbal Remedies Meet Modern Day Medicine: Challenges and Opportunities)

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Open AccessFeature PaperReview

Role of G Protein-Coupled Receptors in the Regulation of Structural Plasticity and Cognitive Function

by Crystal C. Y. Leung and Yung H. Wong

Molecules 2017, 22(7), 1239; https://doi.org/10.3390/molecules22071239 - 24 Jul 2017

Cited by 34 | Viewed by 15465

Abstract

Cognition and other higher brain functions are known to be intricately associated with the capacity of neural circuits to undergo structural reorganization. Structural remodelling of neural circuits, or structural plasticity, in the hippocampus plays a major role in learning and memory. Dynamic modifications [...] Read more.

Cognition and other higher brain functions are known to be intricately associated with the capacity of neural circuits to undergo structural reorganization. Structural remodelling of neural circuits, or structural plasticity, in the hippocampus plays a major role in learning and memory. Dynamic modifications of neuronal connectivity in the form of dendritic spine morphology alteration, as well as synapse formation and elimination, often result in the strengthening or weakening of specific neural circuits that determine synaptic plasticity. Changes in dendritic complexity and synapse number are mediated by cellular processes that are regulated by extracellular signals such as neurotransmitters and neurotrophic factors. As many neurotransmitters act on G protein-coupled receptors (GPCRs), it has become increasingly apparent that GPCRs can regulate structural plasticity through a myriad of G protein-dependent pathways and non-canonical signals. A thorough understanding of how GPCRs exert their regulatory influence on dendritic spine morphogenesis may provide new insights for treating cognitive impairment and decline in various age-related diseases. In this article, we review the evidence of GPCR-mediated regulation of structural plasticity, with a special emphasis on the involvement of common as well as distinct signalling pathways that are regulated by major neurotransmitters. Full article

(This article belongs to the Special Issue G-protein Coupled Receptor Structure and Function)

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Open AccessArticle

Quality Assessment of Gentiana rigescens from Different Geographical Origins Using FT-IR Spectroscopy Combined with HPLC

by Zhe Wu, Yanli Zhao, Ji Zhang and Yuanzhong Wang

Molecules 2017, 22(7), 1238; https://doi.org/10.3390/molecules22071238 - 24 Jul 2017

Cited by 30 | Viewed by 5487

Abstract

Gentiana rigescens is a precious herbal medicine in China because of its liver-protective and choleretic effects. A method for the qualitative identification and quantitative evaluation of G. rigescens from Yunnan Province, China, has been developed employing Fourier transform infrared (FT-IR) spectroscopy and high [...] Read more.

Gentiana rigescens is a precious herbal medicine in China because of its liver-protective and choleretic effects. A method for the qualitative identification and quantitative evaluation of G. rigescens from Yunnan Province, China, has been developed employing Fourier transform infrared (FT-IR) spectroscopy and high performance liquid chromatography (HPLC) with the aid of chemometrics such as partial least squares discriminant analysis (PLS-DA) and support vector machines (SVM) regression. Our results indicated that PLS-DA model could efficiently discriminate G. rigescens from different geographical origins. It was found that the samples which could not be determined accurately were in the margin or outside of the 95% confidence ellipses. Moreover, the result implied that geographical origins variation of root samples were more obvious than that of stems and leaves. The quantitative analysis was based on gentiopicroside content which was the main active constituent in G. rigescens. For the prediction of gentiopicroside, the performances of model based on the parameters selected through grid search algorithm (GS) with seven-fold cross validation were better than those based on genetic algorithm (GA) and particle swarm optimization algorithm (PSO). For the SVM-GS model, the result was satisfactory. FT-IR spectroscopy coupled with PLS-DA and SVM-GS can be an alternative strategy for qualitative identification and quantitative evaluation of G. rigescens. Full article

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Open AccessArticle

Synthesis and Biological Evaluation of Ginsenoside Compound K Derivatives as a Novel Class of LXRα Activator

by Yan Huang, Hongmei Liu, Yingxian Zhang, Jin Li, Chenping Wang, Li Zhou, Yi Jia and Xiaohui Li

Molecules 2017, 22(7), 1232; https://doi.org/10.3390/molecules22071232 - 24 Jul 2017

Cited by 24 | Viewed by 4806

Abstract

Compound K is one of the active metabolites of Panaxnotoginseng saponins, which could attenuate the formation of atherosclerosis in mice modelsvia activating LXRα. We synthesized and evaluated a series of ginsenoside compound K derivatives modified with short chain fatty acids. All of the [...] Read more.

Compound K is one of the active metabolites of Panaxnotoginseng saponins, which could attenuate the formation of atherosclerosis in mice modelsvia activating LXRα. We synthesized and evaluated a series of ginsenoside compound K derivatives modified with short chain fatty acids. All of the structures of this class of ginsenoside compound K derivative exhibited comparable or better biological activity than ginsenoside compound K. Especially structure 1 exhibited the best potency (cholesteryl ester content: 41.51%; expression of ABCA1 mRNA: 319%) and low cytotoxicity. Full article

(This article belongs to the Section Medicinal Chemistry)

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Open AccessArticle

Study on Chemical Profile and Neuroprotective Activity of Myrica rubra Leaf Extract

by Pinghong Chen, Xianzong Lin, Ching-Hsu Yang, Xu Tang, Yu-Wei Chang, Weibing Zheng, Lianzhong Luo, Changan Xu and Yung-Husan Chen

Molecules 2017, 22(7), 1226; https://doi.org/10.3390/molecules22071226 - 24 Jul 2017

Cited by 11 | Viewed by 5425

Abstract

The chemical profile of Myrica rubra (a native species in China) leaf extract was investigated by UPLC-PDA-HRMS, and the neuroprotective activity of two characteristic constituents, myricanol and myricetrin, was evaluated with N2a cells using H₂O₂-inducedoxidative challenge through a series [...] Read more.

The chemical profile of Myrica rubra (a native species in China) leaf extract was investigated by UPLC-PDA-HRMS, and the neuroprotective activity of two characteristic constituents, myricanol and myricetrin, was evaluated with N2a cells using H₂O₂-inducedoxidative challenge through a series of methods, e.g., MTT assay, ROS assay and [Ca²⁺]i assay. Among the 188 constituents detected in the extract of Myrica rubra leaf, 116 were identified definitely or tentatively by the comprehensive utilization of precise molecular weight and abundant multistage fragmentation information obtained by quadrupole orbitrap mass spectrometry. In addition, 14 potential new compounds were reported for the first time. This work established an example for the research of microconstituents in a complex analyte and revealed that suppression of H₂O₂-induced cytotoxicity in N2a cells was achieved by the pretreatment with myricanol. The evidence suggested myricanol may potentially serve as a remedy for prevention and therapy of neurodegenerative diseases induced by oxidative stress. Full article

(This article belongs to the Section Natural Products Chemistry)

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Open AccessArticle

Neighbor Affinity-Based Core-Attachment Method to Detect Protein Complexes in Dynamic PPI Networks

by Xiujuan Lei and Jing Liang

Molecules 2017, 22(7), 1223; https://doi.org/10.3390/molecules22071223 - 24 Jul 2017

Cited by 7 | Viewed by 5803

Abstract

Protein complexes play significant roles in cellular processes. Identifying protein complexes from protein-protein interaction (PPI) networks is an effective strategy to understand biological processes and cellular functions. A number of methods have recently been proposed to detect protein complexes. However, most of methods [...] Read more.

Protein complexes play significant roles in cellular processes. Identifying protein complexes from protein-protein interaction (PPI) networks is an effective strategy to understand biological processes and cellular functions. A number of methods have recently been proposed to detect protein complexes. However, most of methods predict protein complexes from static PPI networks, and usually overlook the inherent dynamics and topological properties of protein complexes. In this paper, we proposed a novel method, called NABCAM (Neighbor Affinity-Based Core-Attachment Method), to identify protein complexes from dynamic PPI networks. Firstly, the centrality score of every protein is calculated. The proteins with the highest centrality scores are regarded as the seed proteins. Secondly, the seed proteins are expanded to complex cores by calculating the similarity values between the seed proteins and their neighboring proteins. Thirdly, the attachments are appended to their corresponding protein complex cores by comparing the affinity among neighbors inside the core, against that outside the core. Finally, filtering processes are carried out to obtain the final clustering result. The result in the DIP database shows that the NABCAM algorithm can predict protein complexes effectively in comparison with other state-of-the-art methods. Moreover, many protein complexes predicted by our method are biologically significant. Full article

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

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Open AccessArticle

A Novel and Practical Chromatographic “Fingerprint-ROC-SVM” Strategy Applied to Quality Analysis of Traditional Chinese Medicine Injections: Using KuDieZi Injection as a Case Study

by Bin Yang, Yuan Wang, Lanlan Shan, Jingtao Zou, Yuanyuan Wu, Feifan Yang, Yani Zhang, Yubo Li and Yanjun Zhang

Molecules 2017, 22(7), 1237; https://doi.org/10.3390/molecules22071237 - 23 Jul 2017

Cited by 27 | Viewed by 6053

Abstract

Fingerprinting is widely and commonly used in the quality control of traditional Chinese medicine (TCM) injections. However, current studies informed that the fingerprint similarity evaluation was less sensitive and easily generated false positive results. For this reason, a novel and practical chromatographic “Fingerprint-ROC-SVM” [...] Read more.

Fingerprinting is widely and commonly used in the quality control of traditional Chinese medicine (TCM) injections. However, current studies informed that the fingerprint similarity evaluation was less sensitive and easily generated false positive results. For this reason, a novel and practical chromatographic “Fingerprint-ROC-SVM” strategy was established by using KuDieZi (KDZ) injection as a case study in the present article. Firstly, the chromatographic fingerprints of KDZ injection were obtained by UPLC and the common characteristic peaks were identified with UPLC/Q-TOF-MS under the same chromatographic conditions. Then, the receiver operating characteristic (ROC) curve was used to optimize common characteristic peaks by the AUCs value greater than 0.7. Finally, a support vector machine (SVM) model, with the accuracy of 97.06%, was established by the optimized characteristic peaks and applied to monitor the quality of KDZ injection. As a result, the established model could sensitively and accurately distinguish the qualified products (QPs) with the unqualified products (UPs), high-temperature processed samples (HTPs) and high-illumination processed samples (HIPs) of KDZ injection, and the prediction accuracy was 100.00%, 93.75% and 100.00%, respectively. Furthermore, through the comparison with other chemometrics methods, the superiority of the novel analytical strategy was more prominent. It indicated that the novel and practical chromatographic “Fingerprint-ROC-SVM” strategy could be further applied to facilitate the development of the quality analysis of TCM injections. Full article

(This article belongs to the Collection Herbal Medicine Research)

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Open AccessArticle

A Novel Brominated Alkaloid Securidine A, Isolated from the Marine Bryozoan Securiflustra securifrons

by Priyanka Michael, Kine Ø. Hansen, Johan Isaksson, Jeanette H. Andersen and Espen Hansen

Molecules 2017, 22(7), 1236; https://doi.org/10.3390/molecules22071236 - 23 Jul 2017

Cited by 12 | Viewed by 5539

Abstract

A novel brominated alkaloid, Securidine A, was isolated from the cold water marine bryozoan Securiflustra securifrons. Securidine A was isolated using semi-preparative HPLC, and the structure was elucidated by spectroscopic methods. The isolated Securidine A was tested for cytotoxic, antibacterial, and anti-diabetic [...] Read more.

A novel brominated alkaloid, Securidine A, was isolated from the cold water marine bryozoan Securiflustra securifrons. Securidine A was isolated using semi-preparative HPLC, and the structure was elucidated by spectroscopic methods. The isolated Securidine A was tested for cytotoxic, antibacterial, and anti-diabetic activities as well as for its potential for inhibition of biofilm formation. No significant biological activity was observed in the applied bioassays, thus expanded bioactivity profiling is required, in order to reveal any potential applications for Securidine A. Full article

(This article belongs to the Section Natural Products Chemistry)

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Open AccessArticle

Molecular Dynamics Simulations of the Host Defense Peptide Temporin L and Its Q3K Derivative: An Atomic Level View from Aggregation in Water to Bilayer Perturbation

by Andrea Farrotti, Paolo Conflitti, Saurabh Srivastava, Jimut Kanti Ghosh, Antonio Palleschi, Lorenzo Stella and Gianfranco Bocchinfuso

Molecules 2017, 22(7), 1235; https://doi.org/10.3390/molecules22071235 - 22 Jul 2017

Cited by 13 | Viewed by 6893

Abstract

Temporin L (TempL) is a 13 residue Host Defense Peptide (HDP) isolated from the skin of frogs. It has a strong affinity for lipopolysaccharides (LPS), which is related to its high activity against Gram-negative bacteria and also to its strong tendency to neutralize [...] Read more.

Temporin L (TempL) is a 13 residue Host Defense Peptide (HDP) isolated from the skin of frogs. It has a strong affinity for lipopolysaccharides (LPS), which is related to its high activity against Gram-negative bacteria and also to its strong tendency to neutralize the pro-inflammatory response caused by LPS release from inactivated bacteria. A designed analog with the Q3K substitution shows an enhancement in both these activities. In the present paper, Molecular Dynamics (MD) simulations have been used to investigate the origin of these improved properties. To this end, we have studied the behavior of the peptides both in water solution and in the presence of LPS lipid-A bilayers, demonstrating that the main effect through which the Q3K substitution improves the peptide activities is the destabilization of peptide aggregates in water. Full article

(This article belongs to the Special Issue Biomolecular Simulations)

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Open AccessArticle

New Cinchona Oximes Evaluated as Reactivators of Acetylcholinesterase and Butyrylcholinesterase Inhibited by Organophosphorus Compounds

by Maja Katalinić, Antonio Zandona, Alma Ramić, Tamara Zorbaz, Ines Primožič and Zrinka Kovarik

Molecules 2017, 22(7), 1234; https://doi.org/10.3390/molecules22071234 - 22 Jul 2017

Cited by 28 | Viewed by 6579

Abstract

For the last six decades, researchers have been focused on finding efficient reactivators of organophosphorus compound (OP)-inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). In this study, we have focused our research on a new oxime scaffold based on the Cinchona structure since it was [...] Read more.

For the last six decades, researchers have been focused on finding efficient reactivators of organophosphorus compound (OP)-inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). In this study, we have focused our research on a new oxime scaffold based on the Cinchona structure since it was proven to fit the cholinesterases active site and reversibly inhibit their activity. Three Cinchona oximes (C1, C2, and C3), derivatives of the 9-oxocinchonidine, were synthesized and investigated in reactivation of various OP-inhibited AChE and BChE. As the results showed, the tested oximes were more efficient in the reactivation of BChE and they reactivated enzyme activity to up to 70% with reactivation rates similar to known pyridinium oximes used as antidotes in medical practice today. Furthermore, the oximes showed selectivity towards binding to the BChE active site and the determined enzyme-oxime dissociation constants supported work on the future development of inhibitors in other targeted studies (e.g., in treatment of neurodegenerative disease). Also, we monitored the cytotoxic effect of Cinchona oximes on two cell lines Hep G2 and SH-SY5Y to determine the possible limits for in vivo application. The cytotoxicity results support future studies of these compounds as long as their biological activity is targeted in the lower micromolar range. 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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Open AccessArticle

Synthesis, Physico-chemical Characterization, Crystal Structure and Influence on Microbial and Tumor Cells of Some Co(II) Complexes with 5,7-Dimethyl-1,2,4-triazolo[1,5-a]pyrimidine

by Luminiţa Măruţescu, Larisa Calu, Mariana Carmen Chifiriuc, Coralia Bleotu, Constantin-Gabriel Daniliuc, Denisa Fălcescu, Crina Maria Kamerzan, Mihaela Badea and Rodica Olar

Molecules 2017, 22(7), 1233; https://doi.org/10.3390/molecules22071233 - 22 Jul 2017

Cited by 9 | Viewed by 5505

Abstract

Three complexes, namely [Co(dmtp)₂(OH₂)₄][CoCl₄] (1), [Co(dmtp)₂Cl₂] (2) and [Co(dmtp)₂(OH₂)₄]Cl₂∙2H₂O (3) (dmtp: 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine), were [...] Read more.

Three complexes, namely [Co(dmtp)₂(OH₂)₄][CoCl₄] (1), [Co(dmtp)₂Cl₂] (2) and [Co(dmtp)₂(OH₂)₄]Cl₂∙2H₂O (3) (dmtp: 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine), were synthesized and characterized by spectral (IR, UV-Vis-NIR), and magnetic measurements at room temperature, as well as single crystal X-ray diffraction. Complex (1) crystallizes in monoclinic system (space group C2/c), complex (2) adopts an orthorhombic system (space group Pbca), and complex (3) crystallizes in triclinic system (space group P1). Various types of extended hydrogen bonds and π–π interactions provide a supramolecular architecture for all complexes. All species were evaluated for antimicrobial activity towards planktonic and biofilm-embedded microbial cells and influence on HEp-2 cell viability, cellular cycle and gene expression. Full article

(This article belongs to the Section Organometallic Chemistry)

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Open AccessArticle

Spectrum Effect Relationship and Component Knock-Out in Angelica Dahurica Radix by High Performance Liquid Chromatography-Q Exactive Hybrid Quadrupole-Orbitrap Mass Spectrometer

by Jinmei Wang, Linna Peng, Mengjun Shi, Changqin Li, Yan Zhang and Wenyi Kang

Molecules 2017, 22(7), 1231; https://doi.org/10.3390/molecules22071231 - 21 Jul 2017

Cited by 28 | Viewed by 6956

Abstract

Different extracts of Angelica dahuricae were available for whitening or treating vitiligo clinically. They showed inhibitory or activating effects on tyrosinase, a rate-limiting enzyme of melanogenesis. This study aimed to identify active compounds on tyrosinase in water extract of Angelica dahurica Radix. We [...] Read more.

Different extracts of Angelica dahuricae were available for whitening or treating vitiligo clinically. They showed inhibitory or activating effects on tyrosinase, a rate-limiting enzyme of melanogenesis. This study aimed to identify active compounds on tyrosinase in water extract of Angelica dahurica Radix. We applied spectrum-effect relationship and component knock-out methods to make it clear. HPLC was used to obtain the specific chromatograms. The effects on tyrosinase activity were examined by measuring the oxidation rate of levodopa in vitro. Partial least squares method was used to examine the spectrum-effect relationships. The knocked-out samples were prepared by HPLC method, and the identification of knocked-out compounds was conducted by the high performance liquid chromatography-four stage rod-electrostatic field orbit trap high resolution mass spectrometry. Results showed that S6, S14, S18, S21, S35, S36, S37, S40, and S41 were positively correlated to inhibitory activity of Angelica dahuricae on tyrosinase whereas S9, S11, S8, S12, S22, and S30 were negatively correlated. When the concentration of each sample was 1 g·mL⁻¹, equal to the amount of raw medicinal herbs, oxypeucedanin hydrate, imperatorin, cnidilin, and isoimperatorin had inhibitory effects on tyrosinase activity whereas byakangelicin and bergapten had activating effects. Full article

(This article belongs to the Collection Herbal Medicine Research)

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Open AccessArticle

The Influence of Glycosylation of Natural and Synthetic Prenylated Flavonoids on Binding to Human Serum Albumin and Inhibition of Cyclooxygenases COX-1 and COX-2

by Tomasz Tronina, Paulina Strugała, Jarosław Popłoński, Aleksandra Włoch, Sandra Sordon, Agnieszka Bartmańska and Ewa Huszcza

Molecules 2017, 22(7), 1230; https://doi.org/10.3390/molecules22071230 - 21 Jul 2017

Cited by 38 | Viewed by 6953

Abstract

The synthesis of different classes of prenylated aglycones (α,β-dihydroxanthohumol (2) and (Z)-6,4’-dihydroxy-4-methoxy-7-prenylaurone (3)) was performed in one step reactions from xanthohumol (1)—major prenylated chalcone naturally occurring in hops. Obtained flavonoids (2–3) [...] Read more.

The synthesis of different classes of prenylated aglycones (α,β-dihydroxanthohumol (2) and (Z)-6,4’-dihydroxy-4-methoxy-7-prenylaurone (3)) was performed in one step reactions from xanthohumol (1)—major prenylated chalcone naturally occurring in hops. Obtained flavonoids (2–3) and xanthohumol (1) were used as substrates for regioselective fungal glycosylation catalyzed by two Absidia species and Beauveria bassiana. As a result six glycosides (4–9) were formed, of which four glycosides (6–9) have not been published so far. The influence of flavonoid skeleton and the presence of glucopyranose and 4-O-methylglucopyranose moiety in flavonoid molecule on binding to main protein in plasma, human serum albumin (HSA), and inhibition of cyclooxygenases COX-1 and COX-2 were investigated. Results showed that chalcone (1) had the highest binding affinity to HSA (8.624 × 10⁴ M⁻¹) of all tested compounds. It has also exhibited the highest inhibition of cyclooxygenases activity, and it was a two-fold stronger inhibitor than α,β-dihydrochalcone (2) and aurone (3). The presence of sugar moiety in flavonoid molecule caused the loss of HSA binding activity as well as the decrease in inhibition of cyclooxygenases activity. Full article

(This article belongs to the Special Issue Synthesis and Biological Applications of Glycoconjugates)

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Open AccessArticle

Effects of K11R and G31P Mutations on the Structure and Biological Activities of CXCL8: Solution Structure of Human CXCL8_(3-72)K11R/G31P

by Hsi-Tsung Cheng, Hui-Yuan Yu, John R. Gordon, Fang Li and Jya-Wei Cheng

Molecules 2017, 22(7), 1229; https://doi.org/10.3390/molecules22071229 - 21 Jul 2017

Cited by 5 | Viewed by 5318

Abstract

The ELR-CXC chemokines are important to neutrophil inflammation in many acute and chronic diseases. Among them, CXCL8 (interleukin-8, IL-8), the expression levels of which are elevated in many inflammatory diseases, binds to both the CXCR1 and CXCR2 receptors with high affinity. Recently, an [...] Read more.

The ELR-CXC chemokines are important to neutrophil inflammation in many acute and chronic diseases. Among them, CXCL8 (interleukin-8, IL-8), the expression levels of which are elevated in many inflammatory diseases, binds to both the CXCR1 and CXCR2 receptors with high affinity. Recently, an analogue of human CXCL8, CXCL8_(3–72)K11R/G31P (hG31P) has been developed. It has been demonstrated that hG31P is a high affinity antagonist for both the CXCR1 and CXCR2. Herein, we have determined the solution structure and the CXCR1 N-terminal peptide binding sites of hG31P by NMR spectroscopy. We have found that the displacement within the tertiary structure of the 30 s loop and the N-terminal region and more specifically change of the loop conformation (especially H33), of hG31P may affect its binding to the CXCR1 receptor and thereby inhibit human neutrophil chemotactic responses induced by ELR-CXC chemokines. Our results provide a structural basis for future clinical investigations of this CXCR1/CXCR2 receptor antagonist and for the further development of CXCL8 based antagonists. Full article

(This article belongs to the Special Issue Recent Advances in Biomolecular NMR Spectroscopy)

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Open AccessArticle

Effects of Chlorhexidine-Encapsulated Mesoporous Silica Nanoparticles on the Anti-Biofilm and Mechanical Properties of Glass Ionomer Cement

by Huiyi Yan, Hongye Yang, Kang Li, Jian Yu and Cui Huang

Molecules 2017, 22(7), 1225; https://doi.org/10.3390/molecules22071225 - 21 Jul 2017

Cited by 42 | Viewed by 7516

Abstract

One of the primary causes for the failure of glass ionomer cement (GIC) is secondary caries. To enhance the anti-microbial performance of GIC without affecting its mechanical properties, chlorhexidine (CHX) was encapsulated in expanded-pore mesoporous silica nanoparticles (pMSN) to synthesize CHX@pMSN. CHX@pMSN was [...] Read more.

One of the primary causes for the failure of glass ionomer cement (GIC) is secondary caries. To enhance the anti-microbial performance of GIC without affecting its mechanical properties, chlorhexidine (CHX) was encapsulated in expanded-pore mesoporous silica nanoparticles (pMSN) to synthesize CHX@pMSN. CHX@pMSN was added at three mass fractions (1%, 5%, and 10% (w/w)) to GIC powder as the experimental groups. Pure GIC was set as the control group. The mechanical and anti-biofilm properties of GIC from each group were tested. The results demonstrated that CHX was successfully encapsulated on/into pMSN, and the encapsulating efficiency of CHX was 44.62% in CHX@pMSN. The anti-biofilm ability was significantly enhanced in all experimental groups (p < 0.001) compared with that in the control group. CHX was continuously released, and anti-biofilm ability was maintained up to 30 days. In addition, the mechanical properties (compressive strength, surface hardness, elastic modulus, water sorption, and solubility) of 1% (w/w) group were maintained compared with those in the control group (p > 0.05). In conclusion, adding 1% (w/w) CHX@pMSN to GIC led to conspicuous anti-biofilm ability and had no adverse effect on the mechanical properties of this restorative material. This study proposes a new strategy for preventing secondary caries by using CHX@pMSN-modified GIC. Full article

(This article belongs to the Special Issue Mesoporous Silica in Biomedical Applications)

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Open AccessArticle

Application of Ammonium Persulfate for Selective Oxidation of Guanines for Nucleic Acid Sequencing

by Yafen Wang, Chaoxing Liu, Tingting Hong, Fan Wu, Shuyi Yu, Zhiyong He, Wuxiang Mao and Xiang Zhou

Molecules 2017, 22(7), 1222; https://doi.org/10.3390/molecules22071222 - 21 Jul 2017

Cited by 2 | Viewed by 6603

Abstract

Nucleic acids can be sequenced by a chemical procedure that partially damages the nucleotide positions at their base repetition. Many methods have been reported for the selective recognition of guanine. The accurate identification of guanine in both single and double regions of DNA [...] Read more.

Nucleic acids can be sequenced by a chemical procedure that partially damages the nucleotide positions at their base repetition. Many methods have been reported for the selective recognition of guanine. The accurate identification of guanine in both single and double regions of DNA and RNA remains a challenging task. Herein, we present a new, non-toxic and simple method for the selective recognition of guanine in both DNA and RNA sequences via ammonium persulfate modification. This strategy can be further successfully applied to the detection of 5-methylcytosine by using PCR. Full article

(This article belongs to the Special Issue Nucleic Acid Chemistry and Nucleic Acid Drugs: A Themed Issue in Honor of Professor Lihe Zhang on the Occasion of His 80th Birthday)

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Open AccessArticle

High-Resolution Inhibition Profiling Combined with HPLC-HRMS-SPE-NMR for Identification of PTP1B Inhibitors from Vietnamese Plants

by Binh Thi Dieu Trinh, Anna K. Jäger and Dan Staerk

Molecules 2017, 22(7), 1228; https://doi.org/10.3390/molecules22071228 - 20 Jul 2017

Cited by 12 | Viewed by 6275

Abstract

Protein tyrosine phosphatase 1B (PTP1B) plays a key role as a negative regulator in insulin signal transduction by deactivating the insulin receptor. Thus, PTP1B inhibition has emerged as a potential therapeutic strategy for curing insulin resistance. In this study, 40 extracts from 18 [...] Read more.

Protein tyrosine phosphatase 1B (PTP1B) plays a key role as a negative regulator in insulin signal transduction by deactivating the insulin receptor. Thus, PTP1B inhibition has emerged as a potential therapeutic strategy for curing insulin resistance. In this study, 40 extracts from 18 different plant species were investigated for PTP1B inhibitory activity in vitro. The most promising one, the EtOAc extract of Ficus racemosa, was investigated by high-resolution PTP1B inhibition profiling combined with HPLC-HRMS-SPE-NMR analysis. This led to the identification of isoderrone (1), derrone (2), alpinumisoflavone (3) and mucusisoflavone B (4) as PTP1B inhibitors. IC₅₀ of these compounds were 22.7 ± 1.7, 12.6 ± 1.6, 21.2 ± 3.8 and 2.5 ± 0.2 µM, respectively. Kinetics analysis revealed that these compounds inhibited PTP1B non-competitively with K_i values of 21.3 ± 2.8, 7.9 ± 1.9, 14.3 ± 2.0, and 3.0 ± 0.5 µM, respectively. These findings support the important role of F. racemosa as a novel source of new drugs and/or as a herbal remedy for treatment of type 2 diabetes. Full article

(This article belongs to the Special Issue Bioactive Compounds for Metabolic Syndrome and Type 2 Diabetes)

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Open AccessArticle

Characterization and Purification of Bergamottin from Citrus grandis (L.) Osbeck cv. Yongjiazaoxiangyou and Its Antiproliferative Activity and Effect on Glucose Consumption in HepG2 cells

by Yilong Liu, Chuanhong Ren, Yunlin Cao, Yue Wang, Wenyi Duan, Linfeng Xie, Chongde Sun and Xian Li

Molecules 2017, 22(7), 1227; https://doi.org/10.3390/molecules22071227 - 20 Jul 2017

Cited by 32 | Viewed by 5856

Abstract

Bergamottin is a natural furanocoumarin compound with weak polarity. Characterization and quantification of bergamottin were carried out in different fruit tissues of various citrus cultivars. Among the four citrus tissues tested, i.e., flavedo, albedo, segment membrane (SM), and juice sacs (JS) in eight [...] Read more.

Bergamottin is a natural furanocoumarin compound with weak polarity. Characterization and quantification of bergamottin were carried out in different fruit tissues of various citrus cultivars. Among the four citrus tissues tested, i.e., flavedo, albedo, segment membrane (SM), and juice sacs (JS) in eight citrus cultivars, the highest bergamottin content was found in the flavedo of Citrus grandis (L.) Osbeck cv. Yongjiazaoxiangyou (YJZXY, 666.54 μg·g⁻¹ DW). A combination of silica gel column chromatography and high-speed counter-current chromatography (HSCCC) was established to efficiently purify bergamottin from the flavedo of YJZXY. Bergamottin showed significant antiproliferative activity on three cancer cell lines, i.e., human liver cancer HepG2, promyelocytic leukemia HL-60, and gastric cancer BGC-823 cells, which showed a marked inhibition effect on these cell lines in a dose-dependent manner. In addition, bergamottin significantly increased glucose consumption in HepG2 cells also in a dose-dependent manner, which is the first report of its potential in anti-diabetes applications. Full article

(This article belongs to the Section Natural Products Chemistry)

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Open AccessArticle

Characterization of Essential Oil Composition in Different Basil Species and Pot Cultures by a GC-MS Method

by Andrea Muráriková, Anton Ťažký, Jarmila Neugebauerová, Alexandra Planková, Josef Jampílek, Pavel Mučaji and Peter Mikuš

Molecules 2017, 22(7), 1221; https://doi.org/10.3390/molecules22071221 - 20 Jul 2017

Cited by 61 | Viewed by 8986

Abstract

Basil (Ocimum L.) species are used as medicinal plants due to their essential oils exhibiting specific biological activity. The present work demonstrated that both the variety and season/conditions of cultivation had a significant effect on (i) the produced amount (extraction yield), (ii) [...] Read more.

Basil (Ocimum L.) species are used as medicinal plants due to their essential oils exhibiting specific biological activity. The present work demonstrated that both the variety and season/conditions of cultivation had a significant effect on (i) the produced amount (extraction yield), (ii) qualitative, as well as (iii) quantitative profile of basil essential oil. Among studied basil varieties, a new variety, ‘Mánes’, was characterized for the first time. Based on our quantitative evaluation of GC-MS profiles, the following chemotypes and average concentrations of a main component were detected in the studied basil varieties: ‘Ohře’, ‘Lettuce Leaf’, ‘Purple Opaal’, ‘Dark Green’ (linalool, 5.99, 2.49, 2.34, 2.01 mg/mL, respectively), and ‘Mammolo Genovese’, ‘Mánes’, ‘Red Rubin’ (eucalyptol, 1.34, 0.96, 0.76 mg/mL, respectively). At the same time, when considering other compounds identified in GC-MS profiles, all the studied varieties, except from ‘Lettuce Leaf’, were methyl eugenol-rich with a strong dependence of the eugenol:methyl eugenol ratio on the seasonal changes (mainly solar irradiation, but also temperature and relative humidity). More complex and/or variable (depending on the season and cultivation) chemotypes were observed with ‘Lettuce Leaf’ (plus estragole, 2.27 mg/mL), ‘Dark Green’ (plus eucalyptol, 1.36 mg/mL), ‘Mammolo Genovese’ (plus eugenol, 1.19 mg/mL), ‘Red Rubin’ (plus linalool and eugenol, 0.46 and 0.56 mg/mL, respectively), and ‘Mánes’ (plus linalool and eugenol, 0.58 and 0.40 mg/mL, respectively). When considering superior extraction yield (ca. 17 mL·kg⁻¹, i.e., two to five times higher than other examined varieties) and consistent amounts (yields) of essential oil when comparing inter-seasonal or inter-year data (RSD and inter-year difference in mean yield values ˂2.5%), this new basil variety is very promising for use in the pharmaceutical, food, and cosmetic industries. Full article

(This article belongs to the Section Natural Products Chemistry)

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Open AccessEditorial

Special Issue: Adenosine Receptors

by Francisco Ciruela and Eddy Sotelo

Molecules 2017, 22(7), 1220; https://doi.org/10.3390/molecules22071220 - 20 Jul 2017

Cited by 4 | Viewed by 3584

Abstract

Nearly 90 years ago, Drury and Szent-Györgyi revealed that adenosine produced profound hypotension and bradycardia, and it affected kidney function in mammals [1]. [...]
Full article

(This article belongs to the Special Issue Adenosine Receptors)

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Open AccessArticle

Fluorination of Naturally Occurring N⁶-Benzyladenosine Remarkably Increased Its Antiviral Activity and Selectivity

by Vladimir E. Oslovsky, Mikhail S. Drenichev, Liang Sun, Nikolay N. Kurochkin, Vladislav E. Kunetsky, Carmen Mirabelli, Johan Neyts, Pieter Leyssen and Sergey N. Mikhailov

Molecules 2017, 22(7), 1219; https://doi.org/10.3390/molecules22071219 - 20 Jul 2017

Cited by 17 | Viewed by 5198

Abstract

Recently, we demonstrated that the natural cytokinin nucleosides N⁶-isopentenyladenosine (iPR) and N⁶-benzyladenosine (BAPR) exert a potent and selective antiviral effect on the replication of human enterovirus 71. In order to further characterize the antiviral profile [...] Read more.

Recently, we demonstrated that the natural cytokinin nucleosides N⁶-isopentenyladenosine (iPR) and N⁶-benzyladenosine (BAPR) exert a potent and selective antiviral effect on the replication of human enterovirus 71. In order to further characterize the antiviral profile of this class of compounds, we generated a series of fluorinated derivatives of BAPR and evaluated their activity on the replication of human enterovirus 71 in a cytopathic effect (CPE) reduction assay. The monofluorination of the BAPR-phenyl group changed the selectivity index (SI) slightly because of the concomitant high cell toxicity. Interestingly, the incorporation of a second fluorine atom resulted in a dramatic improvement of selectivity. Moreover, N⁶-trifluoromethylbenzyladenosine derivatives (9–11) exhibited also a very interesting profile, with low cytotoxicity observed. In particular, the analogue N⁶-(3-trifluoromethylbenzyl)-adenosine (10) with a four-fold gain in potency as compared to BAPR and the best SI in the class represents a promising candidate for further development. Full article

(This article belongs to the Special Issue Nucleoside and Nucleotide Analogues)

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Open AccessArticle

Magnolol, a Natural Polyphenol, Attenuates Dextran Sulfate Sodium-Induced Colitis in Mice

by Ling Zhao, Hai-tao Xiao, Huai-xue Mu, Tao Huang, Ze-si Lin, Linda L. D. Zhong, Guang-zhi Zeng, Bao-min Fan, Cheng-yuan Lin and Zhao-xiang Bian

Molecules 2017, 22(7), 1218; https://doi.org/10.3390/molecules22071218 - 20 Jul 2017

Cited by 53 | Viewed by 9033

Abstract

Magnolol is a lignan with anti-inflammatory activity identified in Magnolia officinalis. Ulcerative colitis (UC), one of the types of inflammatory bowel disease (IBD), is a disease that causes inflammation and ulcers in the colon. To investigate the effect of magnolol in dextran [...] Read more.

Magnolol is a lignan with anti-inflammatory activity identified in Magnolia officinalis. Ulcerative colitis (UC), one of the types of inflammatory bowel disease (IBD), is a disease that causes inflammation and ulcers in the colon. To investigate the effect of magnolol in dextran sulfate sodium (DSS)-induced experimental UC model, male C57 mice were treated with 2% DSS drinking water for 5 consecutive days followed by intragastric administration with magnolol (5, 10 and 15 mg/kg) daily for 7 days. The results showed that magnolol significantly attenuated disease activity index, inhibited colonic shortening, reduced colonic lesions and suppressed myeloperoxidase (MPO) activity. Moreover, colonic pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) induced by colitis were dramatically decreased by magnolol. To further unveil the metabolic signatures upon magnolol treatment, mass spectrometry-based metabolomic analysis of the small molecular metabolites in mice serum were performed. Compared with controls, abnormality of serum metabolic phenotypes in DSS-treated mice were effectively reversed by different doses of magnolol. In particular, magnolol treatment effectively elevated the serum levels of tryptophan metabolites including kynurenic acid (KA), 5-hydroxyindoleacetic acid, indoleacetic acid (IAA), indolelactic acid and indoxylsulfuric acid, which are potential aryl hydrocarbon receptor (AHR) ligands to impact colitis. These findings suggest that magnolol exerts anti-inflammatory effect on DSS-induced colitis and its underlying mechanisms are associated with the restoring of tryptophan metabolites that inhibit the colonic inflammation. Full article

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Open AccessReview

Cyclic Peptides as Novel Therapeutic Microbicides: Engineering of Human Defensin Mimetics

by Annarita Falanga, Ersilia Nigro, Margherita Gabriella De Biasi, Aurora Daniele, Giancarlo Morelli, Stefania Galdiero and Olga Scudiero

Molecules 2017, 22(7), 1217; https://doi.org/10.3390/molecules22071217 - 20 Jul 2017

Cited by 79 | Viewed by 8834

Abstract

Cyclic peptides are receiving significant attention thanks to their antimicrobial activity and high serum stability, which is useful to develop and design novel antimicrobial agents. Antimicrobial peptides appear to be key components of innate defences against bacteria, viruses, and fungi. Among the others, [...] Read more.

Cyclic peptides are receiving significant attention thanks to their antimicrobial activity and high serum stability, which is useful to develop and design novel antimicrobial agents. Antimicrobial peptides appear to be key components of innate defences against bacteria, viruses, and fungi. Among the others, defensins possess a strong microbicidial activity. Defensins are cationic and amphipathic peptides with six cysteine residues connected by three disulfide bonds found in plants, insects, and mammals; they are divided in three families: α-, β-, and θ-defensins. α-Defensins are contained in the primary granules of human neutrophils; β-defensins are expressed in human epithelia; and θ-defensins are pseudo-cyclic defensins not found in humans, but in rhesus macaques. The structural diversities among the three families are reflected in a different antimicrobial action as well as in serum stability. The engineering of these peptides is an exciting opportunity to obtain more functional antimicrobial molecules highlighting their potential as therapeutic agents. The present review reports the most recent advances in the field of cyclic peptides with a specific regard to defensin analogs. Full article

(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)

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Open AccessArticle

Synthesis, Antitumor Evaluation and Molecular Docking of New Morpholine Based Heterocycles

by Zeinab A. Muhammad, Mastoura M. Edrees, Rasha A. M. Faty, Sobhi M. Gomha, Seham S. Alterary and Yahia N. Mabkhot

Molecules 2017, 22(7), 1211; https://doi.org/10.3390/molecules22071211 - 20 Jul 2017

Cited by 15 | Viewed by 6001

Abstract

A series of new morpholinylchalcones was prepared and then used as building blocks for constructing a series of 7-morpholino-2-thioxo-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-ones via their reaction with 6-aminothiouracil. The latter thiones reacted with the appropriate hydrazonoyl chloride to give the corresponding pyrido[2,3-d [...] Read more.

A series of new morpholinylchalcones was prepared and then used as building blocks for constructing a series of 7-morpholino-2-thioxo-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-ones via their reaction with 6-aminothiouracil. The latter thiones reacted with the appropriate hydrazonoyl chloride to give the corresponding pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones. The assigned structures for all the newly synthesized compounds were confirmed on the basis of elemental analyses and spectral data and the mechanisms of their formation were also discussed. Most of the synthesized compounds were tested for in vitro activity against human lung cancer (A-549) and human hepatocellular carcinoma (HepG-2) cell lines compared with the employed standard antitumor drug (cisplatin) and the results revealed that compounds 8, 4e and 7b have promising activities against the A-549 cell line (IC₅₀ values of 2.78 ± 0.86 μg/mL, 5.37 ± 0.95 μg/mL and 5.70 ± 0.91 μg/mL, respectively) while compound 7b has promising activity against the HepG-2 cell lines (IC₅₀ = 3.54 ± 1.11 μg/mL). Moreover, computational studies using MOE 2014.09 software supported the biological activity results. Full article

(This article belongs to the Collection Heterocyclic Compounds)

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Open AccessComment

The Hydrogen Sulfide-Vitamin B12-Folic Acid Axis: An Intriguing Issue in Chronic Kidney Disease. A Comment on Toohey JI: “Possible Involvement of Hydrosulfide in B12-Dependent Methyl Group Transfer”. Molecules 2017, 22, 582, pii: E582

by Giuseppe Cianciolo, Maria Cappuccilli and Gaetano La Manna

Molecules 2017, 22(7), 1216; https://doi.org/10.3390/molecules22071216 - 19 Jul 2017

Cited by 2 | Viewed by 4178

Abstract

Dear Editor, We read with great interest the recent article by John I. Toohey entitled “Possible Involvement of Hydrosulfide in B12-Dependent Methyl Group Transfer”, recently published in Molecules 2017, and we wish to discuss some additional insights raised by this important issue into [...] Read more.

Dear Editor, We read with great interest the recent article by John I. Toohey entitled “Possible Involvement of Hydrosulfide in B12-Dependent Methyl Group Transfer”, recently published in Molecules 2017, and we wish to discuss some additional insights raised by this important issue into the nephrological area [1].[...] Full article

(This article belongs to the Special Issue Sulfur Atom: Element for Adaptation to an Oxidative Environment 2016)

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Open AccessArticle

Identification of a Novel Vasodilatory Octapeptide from the Skin Secretion of the African Hyperoliid Frog, Kassina senegalensis

by Qiang Du, Hui Wang, Chengbang Ma, Yue Wu, Xinping Xi, Mei Zhou, Tianbao Chen, Chris Shaw and Lei Wang

Molecules 2017, 22(7), 1215; https://doi.org/10.3390/molecules22071215 - 19 Jul 2017

Cited by 3 | Viewed by 4425

Abstract

The defensive skin secretions of amphibians continue to be an excellent source of novel biologically-active peptides. Here we report the identification and pharmacological activity of a novel C-terminally amided myotropic octapeptide from the skin secretion of the African hyperoliid frog, Kassina senegalensis. [...] Read more.

The defensive skin secretions of amphibians continue to be an excellent source of novel biologically-active peptides. Here we report the identification and pharmacological activity of a novel C-terminally amided myotropic octapeptide from the skin secretion of the African hyperoliid frog, Kassina senegalensis. The 8-amino acid peptide has the following primary structure: WMSLGWSL-amide and has a molecular mass of 978 Da. The primary structure and organisation of the biosynthetic precursor of WL-8 amide was successfully deduced from cloned skin secretion-derived cDNA. The open-reading frame encoded a single copy of WL-8, located at the C-terminus. Synthetic WL-8 amide was found to cause relaxation of rat tail artery smooth muscle with an EC₅₀ of 25.98 nM. This peptide is unique in terms of its primary structure and is unlike any other peptide previously isolated from an amphibian source which has been archived in the NCBI database. WL-8 amide thus represents the prototype of a novel family of myotropic peptide from amphibian defensive skin secretions. Full article

(This article belongs to the Special Issue Bioactive Natural Peptides As A Pipeline For Therapeutics)

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Open AccessArticle

Molecular Weights of Bovine and Porcine Heparin Samples: Comparison of Chromatographic Methods and Results of a Collaborative Survey

by Sabrina Bertini, Giulia Risi, Marco Guerrini, Kevin Carrick, Anita Y. Szajek and Barbara Mulloy

Molecules 2017, 22(7), 1214; https://doi.org/10.3390/molecules22071214 - 19 Jul 2017

Cited by 11 | Viewed by 5911

Abstract

In a collaborative study involving six laboratories in the USA, Europe, and India the molecular weight distributions of a panel of heparin sodium samples were determined, in order to compare heparin sodium of bovine intestinal origin with that of bovine lung and porcine [...] Read more.

In a collaborative study involving six laboratories in the USA, Europe, and India the molecular weight distributions of a panel of heparin sodium samples were determined, in order to compare heparin sodium of bovine intestinal origin with that of bovine lung and porcine intestinal origin. Porcine samples met the current criteria as laid out in the USP Heparin Sodium monograph. Bovine lung heparin samples had consistently lower average molecular weights. Bovine intestinal heparin was variable in molecular weight; some samples fell below the USP limits, some fell within these limits and others fell above the upper limits. These data will inform the establishment of pharmacopeial acceptance criteria for heparin sodium derived from bovine intestinal mucosa. The method for MW determination as described in the USP monograph uses a single, broad standard calibrant to characterize the chromatographic profile of heparin sodium on high-resolution silica-based GPC columns. These columns may be short-lived in some laboratories. Using the panel of samples described above, methods based on the use of robust polymer-based columns have been developed. In addition to the use of the USP’s broad standard calibrant for heparin sodium with these columns, a set of conditions have been devised that allow light-scattering detected molecular weight characterization of heparin sodium, giving results that agree well with the monograph method. These findings may facilitate the validation of variant chromatographic methods with some practical advantages over the USP monograph method. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

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Open AccessArticle

The Anti-Inflammatory Properties of Citrus wilsonii Tanaka Extract in LPS-Induced RAW 264.7 and Primary Mouse Bone Marrow-Derived Dendritic Cells

by Liping Cheng, Yujie Ren, Dingbo Lin, Shu’ang Peng, Bo Zhong and Zhaocheng Ma

Molecules 2017, 22(7), 1213; https://doi.org/10.3390/molecules22071213 - 19 Jul 2017

Cited by 44 | Viewed by 8322

Abstract

‘Zhique’ (Citrus wilsonii Tanaka) is a traditional Chinese medicine. Its fruits have been used to treat inflammation-related symptoms, such as cough and sputum, though the underlying mechanism remains poorly understood. The aim of this study was to investigate the anti-inflammatory properties of ‘Zhique’ [...] Read more.

‘Zhique’ (Citrus wilsonii Tanaka) is a traditional Chinese medicine. Its fruits have been used to treat inflammation-related symptoms, such as cough and sputum, though the underlying mechanism remains poorly understood. The aim of this study was to investigate the anti-inflammatory properties of ‘Zhique’ pulp extract (ZQE) in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and primary mouse bone marrow-derived dendritic cells (BMDCs). The flavonoid profiles of the ZQE were determined by high performance liquid chromatography. The anti-inflammatory activity was evaluated in LPS-induced inflammatory RAW 264.7 macrophages and BMDCs through enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, and Western blot assays. Naringin was a predominant flavonoid occurring in ZQE, followed by eriocitrin, hesperidin, neohesperidin, rhoifolin, naringenin, and poncirin. ZQE exhibited a very low cytotoxicity in LPS-stimulated RAW 264.7 macrophages. Meanwhile, ZQE significantly inhibited the production of prostaglandins E2 and secretion of cyclooxygenase-2 protein in LPS-stimulated RAW 264.7 macrophages, and markedly suppressed the mRNA expression of inflammatory mediators, such as cyclooxygenase-2, tumor necrosis factor alpha, interleukin-1 beta (IL-1β), and IL-6 in LPS-induced RAW 264.7 macrophages and/or primary BMDCs. The ZQE inhibited the inflammatory responses in RAW 264.7 macrophages and BMDCs triggered by LPS. The results suggested that ‘Zhique’ has a high potential as a novel therapeutic agent to treat chronic inflammatory diseases. Full article

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Open AccessArticle

Isoegomaketone Alleviates the Development of Collagen Antibody-Induced Arthritis in Male Balb/c Mice

by Chang Hyun Jin, Yangkang So, Bomi Nam, Sung Nim Han and Jin-Baek Kim

Molecules 2017, 22(7), 1209; https://doi.org/10.3390/molecules22071209 - 19 Jul 2017

Cited by 9 | Viewed by 5695

Abstract

In this study, we attempted to identify and assess effects of isoegomaketone (IK) isolated from Perilla frutescens var. crispa on the development of rheumatoid arthritis (RA). RA was induced in male Balb/c mice by collagen antibody injection. Experimental animals were randomly divided into [...] Read more.

In this study, we attempted to identify and assess effects of isoegomaketone (IK) isolated from Perilla frutescens var. crispa on the development of rheumatoid arthritis (RA). RA was induced in male Balb/c mice by collagen antibody injection. Experimental animals were randomly divided into five groups: normal, collagen antibody-induced arthritis (CAIA), CAIA + IK (5 mg/kg/day), CAIA + IK (10 mg/kg/day), and CAIA + apigenin (16 mg/kg/day) and respective treatments were administered via oral gavage once per day for four days. Mice treated with IK (10 mg/kg/day) developed less severe arthritis than the control CAIA mice. Arthritic score, paw volume, and paw thickness were less significant compared to the control CAIA mice at day seven (73%, 15%, and 14% lower, respectively). Furthermore, histopathological examination of ankle for inflammation showed that infiltration of inflammatory cells and edema formation were reduced by IK treatment. Similarly, neutrophil to lymphocyte ratio (NLR) in whole blood was lower in mice treated with IK (10 mg/kg/day) by 85% when compared to CAIA mice. Taken together, treatment with IK delays the onset of the arthritis and alleviates the manifestations of arthritis in CAIA mice. Full article

(This article belongs to the Section Natural Products Chemistry)

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Open AccessArticle

Structural Insight into the Recognition of r(UAG) by Musashi-1 RBD2, and Construction of a Model of Musashi-1 RBD1-2 Bound to the Minimum Target RNA

by Ryo Iwaoka, Takashi Nagata, Kengo Tsuda, Takao Imai, Hideyuki Okano, Naohiro Kobayashi and Masato Katahira

Molecules 2017, 22(7), 1207; https://doi.org/10.3390/molecules22071207 - 19 Jul 2017

Cited by 23 | Viewed by 7236

Abstract

Musashi-1 (Msi1) controls the maintenance of stem cells and tumorigenesis through binding to its target mRNAs and subsequent translational regulation. Msi1 has two RNA-binding domains (RBDs), RBD1 and RBD2, which recognize r(GUAG) and r(UAG), respectively. These minimal recognition sequences are connected by variable [...] Read more.

Musashi-1 (Msi1) controls the maintenance of stem cells and tumorigenesis through binding to its target mRNAs and subsequent translational regulation. Msi1 has two RNA-binding domains (RBDs), RBD1 and RBD2, which recognize r(GUAG) and r(UAG), respectively. These minimal recognition sequences are connected by variable linkers in the Msi1 target mRNAs, however, the molecular mechanism by which Msi1 recognizes its targets is not yet understood. We previously determined the solution structure of the Msi1 RBD1:r(GUAGU) complex. Here, we determined the first structure of the RBD2:r(GUAGU) complex. The structure revealed that the central trinucleotide, r(UAG), is specifically recognized by the intermolecular hydrogen-bonding and aromatic stacking interactions. Importantly, the C-terminal region, which is disordered in the free form, took a certain conformation, resembling a helix. The observation of chemical shift perturbation and intermolecular NOEs, together with increases in the heteronuclear steady-state {¹H}-¹⁵N NOE values on complex formation, indicated the involvement of the C-terminal region in RNA binding. On the basis of the two complex structures, we built a structural model of consecutive RBDs with r(UAGGUAG) containing both minimal recognition sequences, which resulted in no steric hindrance. The model suggests recognition of variable lengths (n) of the linker up to n = 50 may be possible. Full article

(This article belongs to the Special Issue Recent Advances in Biomolecular NMR Spectroscopy)

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