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239 KiB

Open AccessArticle

Synthesis and Isomerization of Some Novel Pyrazolopyrimidine and Pyrazolotriazolopyrimidine Derivatives

by Aymn E. Rashad, Ahmed H. Shamroukh, Randa E. Abdel-Megeid and Hatem S. Ali

Molecules 2014, 19(5), 5459-5469; https://doi.org/10.3390/molecules19055459 - 25 Apr 2014

Cited by 11 | Viewed by 7620

Abstract

4-Imino-1-p-tolyl-1,4-dihydropyrazolo[3,4-d]pyrimidin-5-ylamine (2) and (1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-hydrazine (3) were prepared starting from ethyl 4-cyano-1-p-tolyl-1H-pyrazol-5-ylimidoformate (1). The structure of compound 3 was confirmed through preparation of the [...] Read more.

4-Imino-1-p-tolyl-1,4-dihydropyrazolo[3,4-d]pyrimidin-5-ylamine (2) and (1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-hydrazine (3) were prepared starting from ethyl 4-cyano-1-p-tolyl-1H-pyrazol-5-ylimidoformate (1). The structure of compound 3 was confirmed through preparation of the pyrazole derivatives 4 and 5. Also, the synthesis and structural characterization of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives 7 and 9 and their isomerization to pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives 6 and 8, respectively, under different suitable reaction conditions were reported. Moreover, the syntheses of 2-substituted-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives 10 and 11 was described. Full article

(This article belongs to the Section Organic Chemistry)

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218 KiB

Open AccessArticle

Two Trypanocidal Dipeptides from the Roots of Zapoteca portoricensis (Fabaceae)

by Ngozi Justina Nwodo, Festus Basden C. Okoye, Daowan Lai, Abdessamad Debbab, Reto Brun and Peter Proksch

Molecules 2014, 19(5), 5470-5477; https://doi.org/10.3390/molecules19055470 - 25 Apr 2014

Cited by 26 | Viewed by 7496

Abstract

Zapoteca portoricensis (Jacq) HM Hernández is used with remarkable efficacy in ethnomedicinal management of tonsillitis in the Eastern part of Nigeria. Previous pharmacological studies have validated the antiinflammatory and antimicrobial activities of the crude extract. In this study, two dipeptides, saropeptate (aurantiamide acetate) [...] Read more.

Zapoteca portoricensis (Jacq) HM Hernández is used with remarkable efficacy in ethnomedicinal management of tonsillitis in the Eastern part of Nigeria. Previous pharmacological studies have validated the antiinflammatory and antimicrobial activities of the crude extract. In this study, two dipeptides, saropeptate (aurantiamide acetate) and anabellamide, were isolated from the methanol root extract of Zapoteca portoricensis and their chemical structures deduced by one dimensional and two dimensional NMR and mass spectrometry. These compounds were isolated for the first time from this plant, and no report has been found on their previous isolation from the genus Zapoteca. Evaluation of their trypanocidal activity showed that compound 1 exhibited potent activity against Trypanosoma brucei rhodesiense with an IC50 value of 3.63 μM and selectivity index of 25.3. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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427 KiB

Open AccessArticle

Mixed Antimony(V) Complexes with Different Sugars to Modulate the Oral Bioavailability of Pentavalent Antimonial Drugs

by Weverson A. Ferreira, Arshad Islam, Aretha Priscilla S. Andrade, Flaviana R. Fernandes, Frédéric Frézard and Cynthia Demicheli

Molecules 2014, 19(5), 5478-5489; https://doi.org/10.3390/molecules19055478 - 28 Apr 2014

Cited by 12 | Viewed by 6424

Abstract

Previous studies have shown that the association of the drug meglumine antimoniate (MA) with β-cyclodextrin can improve its bioavailability by the oral route. In this work, ribose and maltose were investigated for their ability to form mixed or association complexes with MA, release [...] Read more.

Previous studies have shown that the association of the drug meglumine antimoniate (MA) with β-cyclodextrin can improve its bioavailability by the oral route. In this work, ribose and maltose were investigated for their ability to form mixed or association complexes with MA, release MA and modulate the serum levels of Sb after oral administration in mice. Analysis of the MA/ribose composition by high performance liquid chromatography coupled to mass spectrometry (LCMS-IT-TOF) revealed the presence of mixed meglumine-Sb-ribose and Sb-ribose complexes. Analysis of the MA/maltose composition suggested the formation of MA-maltose association compounds. Circular dichroism characterization of these compositions following dilution in water at 37 °C suggested a partial and slow dissociation of the association compounds. When the MA/ribose composition was administered orally and compared to MA, the serum concentration of Sb was significantly lower after 1 h and greater after 3 h. On the other hand, the MA/maltose composition showed similar serum Sb concentration after 1 h and higher level of Sb after 3 h, when compared to MA. In conclusion, the present study has demonstrated the formation of mixed or association complexes of MA with sugars, such as maltose and ribose, which promoted sustained serum level of Sb after oral administration. Full article

(This article belongs to the Section Molecular Diversity)

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409 KiB

Open AccessArticle

Evaluation of Antioxidant and Antimicrobial Activities and Phenolic Profile for Hyssopus officinalis, Ocimum basilicum and Teucrium chamaedrys

by Laurian Vlase, Daniela Benedec, Daniela Hanganu, Grigore Damian, Ioan Csillag, Bogdan Sevastre, Augustin C. Mot, Radu Silaghi-Dumitrescu and Ioan Tilea

Molecules 2014, 19(5), 5490-5507; https://doi.org/10.3390/molecules19055490 - 28 Apr 2014

Cited by 181 | Viewed by 14004

Abstract

This study was designed to examine the in vitro antioxidant and antimicrobial activities and to characterize the polyphenolic composition of the ethanolic extracts of Hyssopus officinalis, Ocimum basilicum and Teucrium chamaedrys. Qualitative and quantitative analysis of the major phenolic compounds were conducted [...] Read more.

This study was designed to examine the in vitro antioxidant and antimicrobial activities and to characterize the polyphenolic composition of the ethanolic extracts of Hyssopus officinalis, Ocimum basilicum and Teucrium chamaedrys. Qualitative and quantitative analysis of the major phenolic compounds were conducted using high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS). The total polyphenols, caffeic acid derivatives and flavonoids content was spectrophotometrically determined. The phenolic profile showed the presence of phenolic acid derivatives (caftaric, gentisic, caffeic, p-coumaric, chlorogenic and ferulic acids), flavonoid glycosides (rutin, isoquercitrin and quercitrin) and free flavonoid aglycons (luteolin, quercetin), in different concentrations. DPPH radical scavenging assay, Trolox equivalent antioxidant capacity (TEAC) method, hemoglobin ascorbate peroxidase activity inhibition (HAPX) assay, and electron paramagnetic resonance (EPR) radicals detection were employed, revealing several aspects of the antioxidant activities of these species. The antimicrobial tests were performed using the disk diffusion assay. These extracts contained a large amount of the polyphenolic compounds (77.72, 175.57, and 243.65 mg/g, respectively), and they showed a good antioxidant activity, as witnessed by a number of methods. T. chamaedrys had a high antimicrobial activity. Besides their antioxidant activity, the antimicrobial effect of these extracts confirms the biological activities of these herbal medicinal products. Full article

(This article belongs to the Section Natural Products Chemistry)

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446 KiB

Open AccessArticle

Novel [^99mTcN]²⁺ Labeled EGFR Inhibitors as Potential Radiotracers for Single Photon Emission Computed Tomography (SPECT) Tumor Imaging

by Mingxia Zhao, Hongyu Ning, Man Feng, Shilei Li, Jin Chang and Chuanmin Qi

Molecules 2014, 19(5), 5508-5521; https://doi.org/10.3390/molecules19055508 - 29 Apr 2014

Cited by 8 | Viewed by 6182

Abstract

The epidermal growth factor receptor (EGFR) is overexpressed in many cancers, including breast, ovarian, endometrial and non-small cell lung cancer. An EGFR-specific imaging agent could facilitate clinical evaluation of primary tumors or metastases. To achieve this goal, 4-(2-aminoethylamino)-6,7-dimethoxyquinazoline (ADMQ) was synthesized based on [...] Read more.

The epidermal growth factor receptor (EGFR) is overexpressed in many cancers, including breast, ovarian, endometrial and non-small cell lung cancer. An EGFR-specific imaging agent could facilitate clinical evaluation of primary tumors or metastases. To achieve this goal, 4-(2-aminoethylamino)-6,7-dimethoxyquinazoline (ADMQ) was synthesized based on a 4-aminoquinazoline core and then conjugated with N-mercapto- acetylglycine (MAG) and N-mercaptoacetyltriglycine (MAG₃),respectively, to give compounds 1 and 2. The final complexes [^99mTcN]-1 and [^99mTcN]-2 were successfully obtained with radiochemical purities of >99% and >98% as measured by radio-HPLC. No decomposition of the two complexes at room temperature was observed over a period of 2 h. Their partition coefficients indicated they were hydrophilic and the electrophoresis results showed they were negatively charged. Biodistribution in tumor-bearing mice demonstrated that the two new complexes showed tumor accumulation, high tumor-tomuscle (T/M) ratios and fast clearance from blood and muscle. Between the two compounds, the ^99mTcN-MAG₃-ADMQ ([^99mTcN]-2) showed the better characteristics, with the tumor/muscle and tumor/blood ratios reached 2.11 and 1.90 at 60 min post-injection, 4.20 and 1.10 at 120 min post-injection, suggesting it could be a promising radiotracer for SPECT tumor imaging. Full article

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Open AccessArticle

Improved Metathesis Lifetime: Chelating Pyridinyl-Alcoholato Ligands in the Second Generation Grubbs Precatalyst

by Jean I. Du Toit, Margaritha Jordaan, Carlijn A. A. Huijsmans, Johannes H. L. Jordaan, Cornelia G. C. E. Van Sittert and Hermanus C. M. Vosloo

Molecules 2014, 19(5), 5522-5537; https://doi.org/10.3390/molecules19055522 - 29 Apr 2014

Cited by 14 | Viewed by 5739

Abstract

Hemilabile ligands can release a free coordination site “on demand” of an incoming nucleophilic substrate while occupying it otherwise. This is believed to increase the thermal stability and activity of catalytic systems and therefore prevent decomposition via free coordination sites. In this investigation [...] Read more.

Hemilabile ligands can release a free coordination site “on demand” of an incoming nucleophilic substrate while occupying it otherwise. This is believed to increase the thermal stability and activity of catalytic systems and therefore prevent decomposition via free coordination sites. In this investigation chelating pyridinyl-alcoholato ligands were identified as possible hemilabile ligands for incorporation into the second generation Grubbs precatalyst. The O,N-alcoholato ligands with different steric bulk could be successfully incorporated into the precatalysts. The incorporation of the sterically hindered, hemilabile O,N-ligands improved the thermal stability, activity, selectivity and lifetime of these complexes towards the metathesis of 1-octene. A decrease in the activity of the second generation Grubbs precatalyst was additionally observed after incorporating a hemilabile O,N-ligand with two phenyl groups into the system, while increasing their lifetime. Full article

(This article belongs to the Special Issue Ruthenium Complex)

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694 KiB

Open AccessArticle

Pharmacokinetics, Tissue Distribution, Excretion and Plasma Protein Binding Studies of Wogonin in Rats

by Amer Talbi, Di Zhao, Qingwang Liu, Junxiu Li, Ali Fan, Wei Yang, Xing Han and Xijing Chen

Molecules 2014, 19(5), 5538-5549; https://doi.org/10.3390/molecules19055538 - 29 Apr 2014

Cited by 51 | Viewed by 8174

Abstract

Wogonin is a natural anticancer candidate. The purpose of this study was to explore the pharmacokinetic profiles, tissue distribution, excretion and plasma protein binding of wogonin in Sprague—Dawley rats. A rapid, sensitive, and specific LC-MS/MS method has been developed for the determination of [...] Read more.

Wogonin is a natural anticancer candidate. The purpose of this study was to explore the pharmacokinetic profiles, tissue distribution, excretion and plasma protein binding of wogonin in Sprague—Dawley rats. A rapid, sensitive, and specific LC-MS/MS method has been developed for the determination of wogonin in different rat biological samples. After i.v. dosing of wogonin at different levels (10, 20 and 40 mg/kg) the elimination half-life was approximately 14 min, the AUC_0-∞ increased in a dose disproportional manner from 112.13 mg/L·min for 10 mg/kg to 758.19 mg/L·min for 40 mg/kg, indicating a non linear pharmacokinetic profile. After i.g. dosing at 100 mg/kg, plasma levels of wogonin peaked at 28 min with a C_max value of 300 ng/mL and a very low oral bioavailability (1.10%). Following i.v. single dose (20 mg/kg), wogonin was detected in all examined tissues (including testis) with the highest levels in kidney and liver. Approximately 21% of the administered dose was excreted as unchanged drug (mainly via non-biliairy fecal route (16.33%). Equilibrium dialysis was used to evaluate plasma protein binding of wogonin at three concentrations (0.1, 0.5 and 2 µg/mL). Results indicated a very high protein binding degree (over 90%), reducing substantially the free fraction of the compound. Full article

(This article belongs to the Section Natural Products Chemistry)

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3850 KiB

Open AccessArticle

In-Silico Analyses of Sesquiterpene-Related Compounds on Selected Leishmania Enzyme-Based Targets

by Freddy A. Bernal and Ericsson Coy-Barrera

Molecules 2014, 19(5), 5550-5569; https://doi.org/10.3390/molecules19055550 - 29 Apr 2014

Cited by 31 | Viewed by 8762

Abstract

A great number of sesquiterpenes are reported in the available literature as good antileishmanial leads. However, their mode of action at the molecular level has not been elucidated. The lack of molecular studies could be considered an impediment for studies seeking to improve [...] Read more.

A great number of sesquiterpenes are reported in the available literature as good antileishmanial leads. However, their mode of action at the molecular level has not been elucidated. The lack of molecular studies could be considered an impediment for studies seeking to improve sesquiterpene-based drug design. The present in silico study allows us to make important observations about the molecular details of the binding modes of a set of antileishmanial sesquiterpenes against four drug-enzyme targets [pteridine reductase-1 (PTR1), N-myristoyl transferase (NMT), cysteine synthase (CS), trypanothione synthetase (TryS)]. Through molecular docking it was found that two sesquiterpene coumarins are promising leads for the PTR1 and TryS inhibition purposes, and some xanthanolides also exhibited better affinity towards PTR1 and CS binding. In addition, the affinity values were clustered by Principal Component Analysis and drug-like properties were analyzed for the strongest-docking sesquiterpenes. The results are an excellent starting point for future studies of structural optimization of this kind of compounds. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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568 KiB

Open AccessArticle

Fatty Acids as a Tool to Understand Microbial Diversity and Their Role in Food Webs of Mediterranean Temporary Ponds

by Carla C. C. R. De Carvalho and Maria-José Caramujo

Molecules 2014, 19(5), 5570-5598; https://doi.org/10.3390/molecules19055570 - 30 Apr 2014

Cited by 36 | Viewed by 8088

Abstract

Temporary Mediterranean ponds are complex ecosystems which support a high diversity of organisms that include heterotrophic microorganisms, algae, crustaceans, amphibians and higher plants, and have the potential to supply food and a resting place to migratory birds. The role of heterotrophs at the [...] Read more.

Temporary Mediterranean ponds are complex ecosystems which support a high diversity of organisms that include heterotrophic microorganisms, algae, crustaceans, amphibians and higher plants, and have the potential to supply food and a resting place to migratory birds. The role of heterotrophs at the base of the food web in providing energy to the higher trophic levels was studied in temporary ponds in Central and Southern Portugal. The relative quantification of the hetero and autotrophic biomass at the base of the food web in each pond was derived from the polar fatty acid (PLFA) composition of seston through the application of the matrix factorization program CHEMTAX that used specific PLFA and their relative proportion as markers for e.g., classes of bacteria, algae and fungi. The species composition of the culturable microbial communities was identified through their fatty acid profiles. The biomass in the lower trophic level of some ponds presented an even proportion of auto to heterotrophic organisms whilst either bacteria or algae dominated in others. In a selected subset of ponds, the incorporation of bacterial fatty acids was observed to occur in potentially herbivorous zooplankton crustacean. Zooplankton consumed and incorporated bacterial fatty acids into their body tissues, including into their phospholipids, which indicates that energy of heterotrophic origin contributes to the aquatic food webs of temporary ponds. Full article

(This article belongs to the Special Issue Fatty Acids)

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241 KiB

Open AccessArticle

Non-Conventional Methodologies in the Synthesis of 1-Indanones

by Manuela Oliverio, Monica Nardi, Paola Costanzo, Luca Cariati, Giancarlo Cravotto, Salvatore Vincenzo Giofrè and Antonio Procopio

Molecules 2014, 19(5), 5599-5610; https://doi.org/10.3390/molecules19055599 - 30 Apr 2014

Cited by 26 | Viewed by 12047

Abstract

1-Indanones have been successfully prepared by means of three different non-conventional techniques, namely microwaves, high-intensity ultrasound and a Q-tube™ reactor. A library of differently substituted 1-indanones has been prepared via one-pot intramolecular Friedel-Crafts acylation and their efficiency and “greenness” have been compared. [...] Read more.

1-Indanones have been successfully prepared by means of three different non-conventional techniques, namely microwaves, high-intensity ultrasound and a Q-tube™ reactor. A library of differently substituted 1-indanones has been prepared via one-pot intramolecular Friedel-Crafts acylation and their efficiency and “greenness” have been compared. Full article

(This article belongs to the Section Organic Chemistry)

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200 KiB

Open AccessArticle

miRNAs for the Detection of MultiDrug Resistance: Overview and Perspectives

by Andreas Gisel, Mirna Valvano, Imane Ghafir El Idrissi, Patrizia Nardulli, Amalia Azzariti, Antonio Carrieri, Marialessandra Contino and Nicola Antonio Colabufo

Molecules 2014, 19(5), 5611-5623; https://doi.org/10.3390/molecules19055611 - 30 Apr 2014

Cited by 28 | Viewed by 7437

Abstract

The goal of the present paper is to establish and validate the link between cancer diagnosis and therapy by microRNAs detection. The induction in vitro of some specific microRNAs after treatment with MDR ligands has been outlined. Starting from the results obtained by [...] Read more.

The goal of the present paper is to establish and validate the link between cancer diagnosis and therapy by microRNAs detection. The induction in vitro of some specific microRNAs after treatment with MDR ligands has been outlined. Starting from the results obtained by in vitro induction of MDCK and MDCK-MDR1 cells treated by a MDR1 ligand, a new scenario in the early diagnosis and chemotherapy could be disclosed. To corroborate this perspective a short overview on pancreatic cancer diagnosis and chemotherapeutic treatment has been reported. Full article

(This article belongs to the Special Issue miRNAs as Probes to Monitor Cancer and Neurodegenerative Disorders)

499 KiB

Open AccessArticle

Effects of Piperine on the Intestinal Permeability and Pharmacokinetics of Linarin in Rats

by Xinchi Feng, Youping Liu, Xin Wang and Xin Di

Molecules 2014, 19(5), 5624-5633; https://doi.org/10.3390/molecules19055624 - 30 Apr 2014

Cited by 23 | Viewed by 8105

Abstract

Although linarin possesses diverse pharmacological activities, its poor oral bioavailability has been a concern for further development. The present study aimed to demonstrate the feasibility of improving the oral absorption of linarin in rats with a bioenhancer‒piperine. First, the intestinal permeability of linarin [...] Read more.

Although linarin possesses diverse pharmacological activities, its poor oral bioavailability has been a concern for further development. The present study aimed to demonstrate the feasibility of improving the oral absorption of linarin in rats with a bioenhancer‒piperine. First, the intestinal permeability of linarin in the presence and absence of verapamil or piperine was investigated using an in situ single-pass rat intestinal perfusion method. A significant increase in the P_eff when co-perfused with verapamil or piperine indicated that piperine effectively inhibited P-glycoprotein mediated efflux of linarin. Then, the pharmacokinetic profiles of linarin in rats after oral administration of linarin (50 mg/kg) alone and in combination with piperine (20 mg/kg) were determined using a validated LC–MS/MS method. The results showed that piperine increased the plasma exposure (AUC) of linarin by 381% along with an increase in the C_max by 346% and the T_max from 0.05 h to 0.2 h. The present study revealed that piperine significantly enhanced the oral absorption of linarin in rats by inhibiting P-glycoprotein mediated cellular efflux during the intestinal absorption and likely simultaneously by inhibiting the metabolism of linarin. Full article

(This article belongs to the Section Natural Products Chemistry)

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725 KiB

Open AccessArticle

β-Asarone Reverses Chronic Unpredictable Mild Stress-Induced Depression-Like Behavior and Promotes Hippocampal Neurogenesis in Rats

by Haiying Dong, Zhiying Gao, Hua Rong, Ming Jin and Xiaojie Zhang

Molecules 2014, 19(5), 5634-5649; https://doi.org/10.3390/molecules19055634 - 30 Apr 2014

Cited by 52 | Viewed by 8594

Abstract

In this study, we investigated the influence of β-asarone, the major ingredient of Acorus tatarinowii Schott, on depressive-like behavior induced by the chronic unpredictable mild stresses (CUMS) paradigm and to clarify the underlying mechanisms. The results show that β-asarone treatment partially reversed the [...] Read more.

In this study, we investigated the influence of β-asarone, the major ingredient of Acorus tatarinowii Schott, on depressive-like behavior induced by the chronic unpredictable mild stresses (CUMS) paradigm and to clarify the underlying mechanisms. The results show that β-asarone treatment partially reversed the CUMS-induced depression-like behaviors in both the forced swim and sucrose preference tests. The behavioral effects were associated with increased hippocampal neurogenesis indicated by bromodeoxyuridine (BrdU) immunoreactivity. β-Asarone treatment significantly increased the expression of brain-derived neurotrophic factor (BDNF) at levels of transcription and translation. Moreover, CUMS caused significant reduction in ERK1/2 and CREB phosphorylation, both of which were partially attenuated by β-asarone administration. It is important to note that β-asarone treatment had no effect on total levels or phosphorylation state of any of the proteins examined in ERK1/2-CREB pathway in no stress rats, suggesting that β-asarone acts in a stress-dependent manner to block ERK1/2-CREB signaling. We did not observe a complete reversal of depression-like behaviors to control levels by β-asarone. To our knowledge, the present study is the first to demonstrate that adult neurogenesis is involved in the antidepressant-like behavioral effects of β-asarone, suggesting that β-asarone is a promising candidate for the treatment of depression. Full article

(This article belongs to the Section Natural Products Chemistry)

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1589 KiB

Open AccessArticle

Chemical Profile Analysis and Comparison of Two Versions of the Classic TCM Formula Danggui Buxue Tang by HPLC-DAD-ESI-IT-TOF-MSⁿ

by Ya-Zhou Zhang, Feng Xu, Tao Yi, Jian-Ye Zhang, Jun Xu, Yi-Na Tang, Xi-Chen He, Jing Liu and Hu-Biao Chen

Molecules 2014, 19(5), 5650-5673; https://doi.org/10.3390/molecules19055650 - 30 Apr 2014

Cited by 17 | Viewed by 8363

Abstract

Danggui Buxue Tang (DBT) is a Traditional Chinese Medicine (TCM) formula primarily used to treat symptoms associated with menopause in women. Usually, DBT is composed of one portion of Radix Angelicae Sinensis (RAS) and five portions of Radix Astragali (RA). Clinically, Radix Hedysari [...] Read more.

Danggui Buxue Tang (DBT) is a Traditional Chinese Medicine (TCM) formula primarily used to treat symptoms associated with menopause in women. Usually, DBT is composed of one portion of Radix Angelicae Sinensis (RAS) and five portions of Radix Astragali (RA). Clinically, Radix Hedysari (RH) is sometimes used by TCM physicians to replace RA in DBT. In order to verity whether the chemical constituents of the DBT1 (RA:RAS = 5:1, w/w) and DBT2 (RH:RAS = 5:1, w/w) share similarities the chemical profiles of the two DBTs crude extracts and urine samples were analyzed and compared with the aid of HPLC-DAD-ESI-IT-TOF-MSⁿ, which determines the total ion chromatogram (TIC) and multi-stage mass spectra (MSⁿ). Then, the DBT1 and DBT2 were identified and compared on the basis of the TIC and the MSⁿ. In the first experiment (with crude extracts), 69 compounds (C1–C69) were identified from the DBT1; 46 compounds (c1–c46) were identified from the DBT2. In the second experiment(with urine samples), 44 compounds (M1–M44) were identified from the urine samples of rats that had been administered DBT1, and 34 compounds (m1–m34) were identified from the urine samples of rats that had been administered DBT2. Identification and comparison of the chemical compositions were carried out between the DBT1 and DBT2 of the crude extracts and urine samples respectively. Our results showed that the two crude extracts of the DBTs have quite different chemical profiles. The reasons for their differences were that the special astragalosides in DBT1 and the isoflavonoid glycosides formed the malonic acid esters undergo single esterification and acetyl esters undergo acetylation in DBT1. In contrast, the urine from DBT1-treated rats strongly resembled that of DBT2-treated rats. These metabolites originate mainly from formononetin, calycosin and their related glycosides, and they were formed mainly by the metabolic process of reduction, deglycosylation, demethylation, hydrogenation and sulfation. The HPLC-DAD-ESI-IT-TOF-MSⁿ method was successfully applied for the rapid chemical profiles evaluation of two DBTs and their related urine samples. Full article

(This article belongs to the Section Metabolites)

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Open AccessArticle

Synthesis and Antifungal Activity of Benzamidine Derivatives Carrying 1,2,3-Triazole Moieties

by Guangyou Chen, Yiwan Zhou, Chonglin Cai, Jia Lu and Xing Zhang

Molecules 2014, 19(5), 5674-5691; https://doi.org/10.3390/molecules19055674 - 2 May 2014

Cited by 18 | Viewed by 7715

Abstract

Eighteen novel benzamidine derivatives containing 1,2,3-triazole moieties were synthesized. The in vitro and in vivo fungicidal acitivities of the title compounds and the arylamidine intermediates against Colletotrichum lagenarium and Botrytis cinerea were tested. The synthesized benzamidines exhibited weak antifungal activities in vitro against [...] Read more.

Eighteen novel benzamidine derivatives containing 1,2,3-triazole moieties were synthesized. The in vitro and in vivo fungicidal acitivities of the title compounds and the arylamidine intermediates against Colletotrichum lagenarium and Botrytis cinerea were tested. The synthesized benzamidines exhibited weak antifungal activities in vitro against the tested fungi, but some of the compounds showed excellent activities in vivo to the same strains. Among the compounds tested, 9b showed 79% efficacy in vivo against C. lagenarium at a concentration of 200 μg/mL, and the efficacy of compound 16d (90%) toward the same strain was even superior than that of the commercial fungicide carbendazim (85%). Full article

(This article belongs to the Section Organic Chemistry)

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233 KiB

Open AccessArticle

Leishmanicidal Evaluation of Tetrahydroprotoberberine and Spirocyclic Erythrina-Alkaloids

by Daniel R. Callejon, Thalita B. Riul, Luis G. P. Feitosa, Thais Guaratini, Denise B. Silva, Achyut Adhikari, Ram L. Shrestha, Lucas M. M. Marques, Marcelo D. Baruffi, João L. C. Lopes and Norberto P. Lopes

Molecules 2014, 19(5), 5692-5703; https://doi.org/10.3390/molecules19055692 - 5 May 2014

Cited by 38 | Viewed by 8770

Abstract

Leishmaniasis is one of the World’s most problematic diseases in developing countries. Traditional medicines to treat leishmaniasis have serious side effects, as well as significant parasite resistance problems. In this work, two alkaloids 1 and 2 were obtained from Corydalis govaniana Wall and [...] Read more.

Leishmaniasis is one of the World’s most problematic diseases in developing countries. Traditional medicines to treat leishmaniasis have serious side effects, as well as significant parasite resistance problems. In this work, two alkaloids 1 and 2 were obtained from Corydalis govaniana Wall and seven alkaloids 3–9, were obtained from Erythrina verna. The structures of the compounds were confirmed by mass spectrometry and 1D- and 2D-NMR spectroscopy. The leishmanicidal activity of compounds 1–9 against Leishmania amazonensis was tested on promastigote forms and cytotoxicity against J774 (macrophage cell line) was assessed in vitro. Compound 1 showed potent activity (IC₅₀ = 0.18 µg/mL), compared with the standard amphotericin B (IC₅₀ = 0.20 µg/mL). The spirocyclic erythrina-alkaloids showed lower leishmanicidal activity than dibenzoquinolizine type alkaloids. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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291 KiB

Open AccessArticle

In Vitro Inhibitory Effects of Scutellarin on Six Human/Rat Cytochrome P450 Enzymes and P-glycoprotein

by Yong-Long Han, Dan Li, Quan-Jun Yang, Zhi-Yong Zhou, Li-Ya Liu, Bin Li, Jin Lu and Cheng Guo

Molecules 2014, 19(5), 5748-5760; https://doi.org/10.3390/molecules19055748 - 5 May 2014

Cited by 21 | Viewed by 7804

Abstract

Inhibition of cytochrome P450 (CYP) and P-glycoprotein (P-gp) are regarded as the most frequent and clinically important pharmacokinetic causes among the various possible factors for drug-drug interactions. Scutellarin is a flavonoid which is widely used for the treatment of cardiovascular diseases. In this [...] Read more.

Inhibition of cytochrome P450 (CYP) and P-glycoprotein (P-gp) are regarded as the most frequent and clinically important pharmacokinetic causes among the various possible factors for drug-drug interactions. Scutellarin is a flavonoid which is widely used for the treatment of cardiovascular diseases. In this study, the in vitro inhibitory effects of scutellarin on six major human CYPs (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and six rat CYPs (CYP1A2, CYP2C7, CYP2C11, CYP2C79, CYP2D4, and CYP3A2) activities were examined by using liquid chromatography-tandem mass spectrometry. Meanwhile, the inhibitory effects of scutellarin on P-gp activity were examined on a human metastatic malignant melanoma cell line WM-266-4 by calcein-AM fluorometry screening assay. Results demonstrated that scutellarin showed negligible inhibitory effects on the six major CYP isoenzymes in human/rat liver microsomes with almost all of the IC₅₀ values exceeding 100 μM, whereas it showed values of 63.8 μM for CYP2C19 in human liver microsomes, and 63.1 and 85.6 μM for CYP2C7 and CYP2C79 in rat liver microsomes, respectively. Scutellarin also showed weak inhibitory effect on P-gp. In conclusion, this study demonstrates that scutellarin is unlikely to cause any clinically significant herb-drug interactions in humans when co-administered with substrates of the six CYPs (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and P-gp. Full article

(This article belongs to the Section Natural Products Chemistry)

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Antiparasitic Activity of Natural and Semi-Synthetic Tirucallane Triterpenoids from Schinus terebinthifolius (Anacardiaceae): Structure/Activity Relationships

by Thiago R. Morais, Thais A. Da Costa-Silva, Andre G. Tempone, Samanta Etel T. Borborema, Marcus T. Scotti, Raquel Maria F. De Sousa, Ana Carolina C. Araujo, Alberto De Oliveira, Sérgio Antônio L. De Morais, Patricia Sartorelli and João Henrique G. Lago

Molecules 2014, 19(5), 5761-5776; https://doi.org/10.3390/molecules19055761 - 5 May 2014

Cited by 38 | Viewed by 8456

Abstract

Leishmaniasis and Chagas are diseases caused by parasitic protozoans that affect the poorest population in the World, causing a high mortality and morbidity. As a result of highly toxic and long-term treatments, the discovery of novel, safe and more efficacious drugs is essential. [...] Read more.

Leishmaniasis and Chagas are diseases caused by parasitic protozoans that affect the poorest population in the World, causing a high mortality and morbidity. As a result of highly toxic and long-term treatments, the discovery of novel, safe and more efficacious drugs is essential. In this work, the in vitro antiparasitic activity and mammalian cytotoxicity of three natural tirucallane triterpenoids, isolated from leaves of Schinus terebinthifolius (Anacardiaceae), and nine semi-synthetic derivatives were investigated against Leishmania (L.) infantum and Trypanosoma cruzi. Trypomastigotes of T. cruzi were the most susceptible parasites and seven compounds demonstrated a trypanocidal activity with IC₅₀ values in the range between 15 and 58 µg/mL. Four compounds demonstrated selectivity towards the intracellular amastigotes of Leishmania, with IC₅₀ values in the range between 28 and 97 µg/mL. The complete characterization of triterpenoids was afforded after thorough analysis of nuclear magnetic resonance (NMR) data as well as electrospray ionization mass spectrometry (ESI-MS). Additionally, structure-activity relationships were performed using Decision Trees. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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Open AccessArticle

Exploiting Illumina Sequencing for the Development of 95 Novel Polymorphic EST-SSR Markers in Common Vetch (Vicia sativa subsp. sativa)

by Zhipeng Liu, Peng Liu, Dong Luo, Wenxian Liu and Yanrong Wang

Molecules 2014, 19(5), 5777-5789; https://doi.org/10.3390/molecules19055777 - 5 May 2014

Cited by 31 | Viewed by 6555

Abstract

The common vetch (Vicia sativa subsp. sativa), a self-pollinating and diploid species, is one of the most important annual legumes in the world due to its short growth period, high nutritional value, and multiple usages as hay, grain, silage, and green [...] Read more.

The common vetch (Vicia sativa subsp. sativa), a self-pollinating and diploid species, is one of the most important annual legumes in the world due to its short growth period, high nutritional value, and multiple usages as hay, grain, silage, and green manure. The available simple sequence repeat (SSR) markers for common vetch, however, are insufficient to meet the developing demand for genetic and molecular research on this important species. Here, we aimed to develop and characterise several polymorphic EST-SSR markers from the vetch Illumina transcriptome. A total number of 1,071 potential EST-SSR markers were identified from 1025 unigenes whose lengths were greater than 1,000 bp, and 450 primer pairs were then designed and synthesized. Finally, 95 polymorphic primer pairs were developed for the 10 common vetch accessions, which included 50 individuals. Among the 95 EST-SSR markers, the number of alleles ranged from three to 13, and the polymorphism information content values ranged from 0.09 to 0.98. The observed heterozygosity values ranged from 0.00 to 1.00, and the expected heterozygosity values ranged from 0.11 to 0.98. These 95 EST-SSR markers developed from the vetch Illumina transcriptome could greatly promote the development of genetic and molecular breeding studies pertaining to in this species. Full article

(This article belongs to the Section Molecular Diversity)

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Open AccessArticle

An Isoflavone from Dipteryx alata Vogel is Active against the in Vitro Neuromuscular Paralysis of Bothrops jararacussu Snake Venom and Bothropstoxin I, and Prevents Venom-Induced Myonecrosis

by Miriéle C. Ferraz, Edson H. Yoshida, Renata V.S. Tavares, José C. Cogo, Adélia C.O. Cintra, Cháriston A. Dal Belo, Luiz M. Franco, Márcio G. Dos Santos, Flávia A. Resende, Eliana A. Varanda, Stephen Hyslop, Pilar Puebla, Arturo San Feliciano and Yoko Oshima-Franco

Molecules 2014, 19(5), 5790-5805; https://doi.org/10.3390/molecules19055790 - 6 May 2014

Cited by 20 | Viewed by 8323

Abstract

Snakebite is a neglected disease and serious health problem in Brazil, with most bites being caused by snakes of the genus Bothrops. Although serum therapy is the primary treatment for systemic envenomation, it is generally ineffective in neutralizing the local effects of [...] Read more.

Snakebite is a neglected disease and serious health problem in Brazil, with most bites being caused by snakes of the genus Bothrops. Although serum therapy is the primary treatment for systemic envenomation, it is generally ineffective in neutralizing the local effects of these venoms. In this work, we examined the ability of 7,8,3'-trihydroxy-4'-methoxyisoflavone (TM), an isoflavone from Dipteryx alata, to neutralize the neurotoxicity (in mouse phrenic nerve-diaphragm preparations) and myotoxicity (assessed by light microscopy) of Bothrops jararacussu snake venom in vitro. The toxicity of TM was assessed using the Salmonella microsome assay (Ames test). Incubation with TM alone (200 μg/mL) did not alter the muscle twitch tension whereas incubation with venom (40 μg/mL) caused irreversible paralysis. Preincubation of TM (200 μg/mL) with venom attenuated the venom-induced neuromuscular blockade by 84% ± 5% (mean ± SEM; n = 4). The neuromuscular blockade caused by bothropstoxin-I (BthTX-I), the major myotoxic PLA₂ of this venom, was also attenuated by TM. Histological analysis of diaphragm muscle incubated with TM showed that most fibers were preserved (only 9.2% ± 1.7% were damaged; n = 4) compared to venom alone (50.3% ± 5.4% of fibers damaged; n = 3), and preincubation of TM with venom significantly attenuated the venom-induced damage (only 17% ± 3.4% of fibers damaged; n = 3; p < 0.05 compared to venom alone). TM showed no mutagenicity in the Ames test using Salmonella strains TA98 and TA97a with (+S9) and without (−S9) metabolic activation. These findings indicate that TM is a potentially useful compound for antagonizing the neuromuscular effects (neurotoxicity and myotoxicity) of B. jararacussu venom. Full article

(This article belongs to the Section Metabolites)

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Anti-Candida, Anti-Enzyme Activity and Cytotoxicity of 3,5-Diaryl-4,5-dihydro-1H-pyrazole-1-carboximidamides

by Simone Oliveira, Lucas Pizzuti, Frank Quina, Alex Flores, Rafael Lund, Claiton Lencina, Bruna S. Pacheco, Claudio M. P. De Pereira and Evandro Piva

Molecules 2014, 19(5), 5806-5820; https://doi.org/10.3390/molecules19055806 - 6 May 2014

Cited by 17 | Viewed by 6501

Abstract

Because of the need for more effective and less harmful antifungal therapies, and interest in the synthesis of new carboximidamides, the goal of this study was to determine the antifungal and anti-enzyme activities of some new pyrazole carboximidamides and their cytotoxicity. For this [...] Read more.

Because of the need for more effective and less harmful antifungal therapies, and interest in the synthesis of new carboximidamides, the goal of this study was to determine the antifungal and anti-enzyme activities of some new pyrazole carboximidamides and their cytotoxicity. For this purpose, tests were performed to evaluate: minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC); production of proteinases and phospholipase, and cytotoxicity of the extracts. Data were analyzed by ANOVA and Tukey Tests (α = 5%). The results were: MIC and MFC ≥ 62.5 μg/mL (C. albicans, C. parapsilosis, C. famata, C. glabrata, and Rhodotorula mucillaginosa) and MIC and MFC ≥ 15.6 μg/mL (C. lipolytica). The values of proteinase and phospholipase (Pz) of C. albicans before and after exposure to the compounds were: 0.6 (±0.024) and 0.2 (±0.022) and 0.9 (±0.074) and 0.3 (±0.04), respectively. These proteinase results were not significant (p = 0.69), but those of phospholipase were (p = 0.01), and 15.6 μg/mL was the most effective concentration. The cytotoxicity means were similar among the tests (p = 0.32). These compounds could be useful as templates for further development through modification or derivatization to design more potent antifungal agents. Data from this study provide evidence that these new pyrazole formulations could be an alternative source for the treatment of fungal infections caused by Candida. However, a specific study on the safety and efficacy of these in vivo and clinical trials is still needed, in order to evaluate the practical relevance of the in vitro results. Full article

(This article belongs to the Section Organic Chemistry)

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Norditerpenoids from Flickingeria fimbriata and Their Inhibitory Activities on Nitric Oxide and Tumor Necrosis Factor-α Production in Mouse Macrophages

by Jin-Long Chen, Wen-Jun Zhong, Gui-Hua Tang, Jing Li, Zhi-Min Zhao, De-Po Yang and Lin Jiang

Molecules 2014, 19(5), 5863-5875; https://doi.org/10.3390/molecules19055863 - 6 May 2014

Cited by 9 | Viewed by 5945

Abstract

Bioassay-guided fractionation of the ethanolic extract of the leaves of Flickingeria flimbriata led to the isolation of two new degraded diterpenoids 1 and 2, a new ent-pimarane type diterpenoid 3, and four known steroids 4–7. The structures [...] Read more.

Bioassay-guided fractionation of the ethanolic extract of the leaves of Flickingeria flimbriata led to the isolation of two new degraded diterpenoids 1 and 2, a new ent-pimarane type diterpenoid 3, and four known steroids 4–7. The structures of 1–3 were elucidated by spectroscopic analysis, and their absolute configurations were determined by chemical methods, TDDFT quantum chemical calculations of ECD spectra, and CD exiton chirality method. Compounds 1 and 2, named flickinflimilins A and B, possess a rare 15,16-dinor-ent-pimarane skeleton. Compounds 1–7 were screened for the inhibitory activity against lipopolysaccharide (LPS)-induced NO and TNF-α production in RAW264.7 cells. Compounds 1–3 exhibited potent inhibitory activities, with IC₅₀ values of less than 10 µM. Full article

(This article belongs to the Section Natural Products Chemistry)

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Cobalt-Catalyzed Methoxycarbonylation of Substituted Dichlorobenzenes as an Example of a Facile Radical Anion Nucleophilic Substitution in Chloroarenes

by Tatyana S. Khaibulova, Irina A. Boyarskaya, Evgeny Larionov and Vadim P. Boyarskiy

Molecules 2014, 19(5), 5876-5897; https://doi.org/10.3390/molecules19055876 - 6 May 2014

Cited by 9 | Viewed by 6974

Abstract

A thorough mechanistic study on cobalt-catalysed direct methoxycarbonylation reactions of chlorobenzenes in the presence of methyl oxirane on a wide range of substrates, including poly- and monochloro derivatives with multiple substituents, is reported. The results demonstrate that the reaction is potentially useful as [...] Read more.

A thorough mechanistic study on cobalt-catalysed direct methoxycarbonylation reactions of chlorobenzenes in the presence of methyl oxirane on a wide range of substrates, including poly- and monochloro derivatives with multiple substituents, is reported. The results demonstrate that the reaction is potentially useful as it proceeds under very mild conditions (t = 62 °C, P_CO = 1 bar) and converts aryl chlorides to far more valuable products (especially ortho-substituted benzoic acids and esters) in high yields. This transformation also offers another opportunity for the utilization of environmentally harmful polychlorinated benzenes and biphenyls (PCBs). This study is the first to discover an unexpected universal positive ortho-effect: the proximity of any substituent (including Me, Ph, and MeO groups and halogen atoms) to the reaction centre accelerates the methoxycarbonylation in chlorobenzenes. The effect of the ortho-substituents is discussed in detail and explained in terms of a radical anion reaction mechanism. The advantages of the methoxycarbonylation as a model for the mechanistic study of radical anion reactions are also illustrated. Full article

(This article belongs to the Special Issue Carbonylation Chemistry)

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Comparative Study on the Antioxidant and Anti-Toxoplasma Activities of Vanillin and Its Resorcinarene Derivative

by Claudio B. S. Oliveira, Ywlliane S. R. Meurer, Marianne G. Oliveira, Wendy M. T. Q. Medeiros, Francisco O. N. Silva, Ana C. F. Brito, Daniel De L. Pontes and Valter F. Andrade-Neto

Molecules 2014, 19(5), 5898-5912; https://doi.org/10.3390/molecules19055898 - 7 May 2014

Cited by 42 | Viewed by 9998

Abstract

A resorcinarene derivative of vanillin, resvan, was synthesized and characterized by spectroscopic techniques. We measured the cytotoxicity (in vivo and in vitro), antioxidant and anti-Toxoplasma activities of vanillin and the resorcinarene compound. Here we show that vanillin has a dose-dependent [...] Read more.

A resorcinarene derivative of vanillin, resvan, was synthesized and characterized by spectroscopic techniques. We measured the cytotoxicity (in vivo and in vitro), antioxidant and anti-Toxoplasma activities of vanillin and the resorcinarene compound. Here we show that vanillin has a dose-dependent behavior with IC₅₀ of 645 µg/mL through an in vitro cytotoxicity assay. However, we could not observe any cytotoxic response at higher concentrations of resvan (IC₅₀ > 2,000 µg/mL). The in vivo acute toxicity assays of vanillin and resvan exhibited a significant safety margin indicated by a lack of systemic and behavioral toxicity up to 300 mg/kg during the first 30 min, 24 h or 14 days after administration. The obtained derivative showed greater antioxidative activity (84.9%) when comparing to vanillin (19.4%) at 1,000 μg/mL. In addition, vanillin presents anti-Toxoplasma activity, while resvan does not show that feature. Our findings suggest that this particular derivative has an efficient antioxidant activity and a negligible cytotoxic effect, making it a potential target for further biological investigations. Full article

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Hydrogen Peroxide and Nitric Oxide are Involved in Salicylic Acid-Induced Salvianolic Acid B Production in Salvia miltiorrhiza Cell Cultures

by Hongbo Guo, Xiaolin Dang and Juane Dong

Molecules 2014, 19(5), 5913-5924; https://doi.org/10.3390/molecules19055913 - 8 May 2014

Cited by 21 | Viewed by 6991

Abstract

Hydrogen peroxide (H₂O₂) and nitric oxide (NO) are key signaling molecules in cells whose levels are increased in response to various stimuli and are involved in plant secondary metabolite synthesis. In this paper, the roles of H₂O [...] Read more.

Hydrogen peroxide (H₂O₂) and nitric oxide (NO) are key signaling molecules in cells whose levels are increased in response to various stimuli and are involved in plant secondary metabolite synthesis. In this paper, the roles of H₂O₂ and NO on salvianolic acid B (Sal B) production in salicylic acid (SA)-induced Salvia miltiorrhiza cell cultures were investigated. The results showed that H₂O₂ could be significantly elicited by SA, even though IMD (an inhibitor of NADPH oxidase) or DMTU (a quencher of H₂O₂) were employed to inhibit or quench intracellular H₂O₂. These elicited H₂O₂ levels significantly increased NO production by 1.6- and 1.46 fold in IMD+SA and DMTU+SA treatments, respectively, and induced 4.58- and 4.85-fold Sal B accumulation, respectively. NO was also markedly elicited by SA, in which L-NNA (an inhibitor of NO synthase) and cPTIO (a quencher of NO) were used to inhibit or quench NO within cells, and the induced NO could significantly enhance H₂O₂ production by 1.92- and 1.37-fold in L-NNA+SA and cPTIO+SA treatments, respectively, and 3.27- and 1.50-fold for Sal B accumulation, respectively. These results indicate that elicitation of SA for either H₂O₂ or NO was independent, and the elicited H₂O₂ or NO could act independently or synergistically to induce Sal B accumulation in SA-elicited cells. Full article

(This article belongs to the Section Metabolites)

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Aqueous Solubility and Degradation Kinetics of the Phytochemical Anticancer Thymoquinone; Probing the Effects of Solvents, pH and Light

by Jumah Masoud M. Salmani, Sajid Asghar, Huixia Lv and Jianping Zhou

Molecules 2014, 19(5), 5925-5939; https://doi.org/10.3390/molecules19055925 - 8 May 2014

Cited by 123 | Viewed by 12199

Abstract

Thymoquinone (TQ) is a potent anticancer phytochemical with confirmed in vitro efficacy. Its clinical use has not yet established, and very few reports have documented its formulation. There also are no reports about the aqueous solubility and stability of this valuable drug, despite [...] Read more.

Thymoquinone (TQ) is a potent anticancer phytochemical with confirmed in vitro efficacy. Its clinical use has not yet established, and very few reports have documented its formulation. There also are no reports about the aqueous solubility and stability of this valuable drug, despite their direct correlation with the in vivo efficacy. In the current research, we have established and validated a stability-indicating HPLC method for the detection of TQ and its degradation products under different conditions. We then investigated the solubility and stability profiles of TQ in aqueous solutions. The stability study was aimed to determine the effect of pH, solvent type and light on the degradation process of TQ, along with the investigation of the kinetics of this degradation. The solubility of TQ varied in different aqueous solvents, and might be compromised due to stability issues. However, these findings confirm that the aqueous solubility is not the major obstacle for the drug formulations mainly due to the considerable water solubility (>500 μg/mL) that may be enough to exert pharmacologic effects if administered via parenteral route. Stability study results showed a very low stability profile of TQ in all the aqueous solutions with rapid degradation that varied with solvent type. The study of the degradation kinetics showed a significant effect of pH on the degradation process. The process followed first order kinetics at more acidic and alkaline pH values, and second order kinetics at pH 5–7.4, regardless of the solvent type. The results also expressed that light has a greater impact on the stability of TQ as a shorter period of exposure led to severe degradation, independent of the solution pH and solvent type. Our results also addressed some discrepancies in previously published researches regarding the formulation and quantification of TQ with suggested solutions. Overall, the current study concludes that TQ is unstable in aqueous solutions, particularly at an alkaline pH, in addition to presenting severe light sensitivity. This data indicates the inappropriateness of aqueous solutions as pharmaceutical vehicles for TQ preparations. To the best of our knowledge, this is the first study describing TQ aqueous solubility and stability that may lead to the development of a stable and effective TQ formulation. 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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Open AccessArticle

Two Polycyclic Geranylhydroquinone-Derived Metabolites from Roots of Arnebia hispidissima (Lehm.) DC.

by Atallah F. Ahmed, Hassan-Elrady A. Saad and Eman M. Abd El-Karim

Molecules 2014, 19(5), 5940-5951; https://doi.org/10.3390/molecules19055940 - 9 May 2014

Cited by 11 | Viewed by 5860

Abstract

A phytochemical investigation of the least polar organic extracts of Arnebia hispidissima (Lehm.) DC. roots has led to the isolation of two unique polycyclic geranylhydroquinone-derived metabolites, arnebacene (1) and arnebidin (2), along with some known phenolic metabolites viz., [...] Read more.

A phytochemical investigation of the least polar organic extracts of Arnebia hispidissima (Lehm.) DC. roots has led to the isolation of two unique polycyclic geranylhydroquinone-derived metabolites, arnebacene (1) and arnebidin (2), along with some known phenolic metabolites viz., arnebin-7 (3) and vanillic acid (4). The chemical identification of the new isolated compounds, including their relative stereochemistry, was achieved via spectroscopic analyses, including 2D NMR, and spectral comparison with related compounds. A biosynthetic pathway is proposed for the new compounds on the basis of their structure-relationship with previously isolated metabolites. Full article

(This article belongs to the Section Natural Products Chemistry)

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Guest-Host Complex Formed between Ascorbic Acid and β-Cyclodextrin Immobilized on the Surface of an Electrode

by María Teresa Ramírez-Silva, Manuel Palomar-Pardavé, Silvia Corona-Avendaño, Mario Romero-Romo and Georgina Alarcón-Angeles

Molecules 2014, 19(5), 5952-5964; https://doi.org/10.3390/molecules19055952 - 9 May 2014

Cited by 13 | Viewed by 7478

Abstract

This work deals with the formation of supramolecular complexes between ascorbic acid (AA), the guest, and β-cyclodextrin (β-CD), the host, that was first potentiodynamically immobilized on the surface of a carbon paste electrode (CPE) throughout the formation of a β-CD-based conducting polymer (poly-β-CD). [...] Read more.

This work deals with the formation of supramolecular complexes between ascorbic acid (AA), the guest, and β-cyclodextrin (β-CD), the host, that was first potentiodynamically immobilized on the surface of a carbon paste electrode (CPE) throughout the formation of a β-CD-based conducting polymer (poly-β-CD). With the bare CPE and the β-CD-modified CPE, an electrochemical study was performed to understand the effect of such surface modification on the electrochemical response of the AA. From this study it was shown that on the modified-CPE, the AA was surface-immobilized through formation of an inclusion complex with β-CD, which provoked the adsorption of AA in such a way that this stage became the limiting step for the electrochemical oxidation of AA. Moreover, from the analysis of the experimental voltammetric plots recorded during AA oxidation on the CPE/poly-β-CD electrode surfaces, the Gibbs’ standard free energy of the inclusion complex formed by the oxidation product of AA and β-CD has been determined for the first time, ∆G⁰_inclus = −36.4 kJ/mol. Full article

(This article belongs to the Section Molecular Diversity)

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Design, Synthesis, Characterization of Novel Ruthenium(II) Catalysts: Highly Efficient and Selective Hydrogenation of Cinnamaldehyde to (E)-3-Phenylprop-2-en-1-ol

by Hany W. Darwish, Assem Barakat, Ayman Nafady, Mohammed Suleiman, Mousa Al-Noaimi, Belkheir Hammouti, Smaail Radi, Taibi Ben Hadda, Ahmad Abu-Obaid, Mohammad S. Mubarak and Ismail Warad

Molecules 2014, 19(5), 5965-5980; https://doi.org/10.3390/molecules19055965 - 9 May 2014

Cited by 3 | Viewed by 7983

Abstract

In this contribution, two novel supported and non-supported ruthenium(II) complexes of type [RuCl₂(dppme)(NN)] where [dppme is H₂C=C(CH₂PPh₂)₂ and NN is N1-(3-(trimethoxysilyl)propyl)ethane-1,2-diamine] were prepared. The NN co-ligand caused release of one of the dppme ligands [...] Read more.

In this contribution, two novel supported and non-supported ruthenium(II) complexes of type [RuCl₂(dppme)(NN)] where [dppme is H₂C=C(CH₂PPh₂)₂ and NN is N1-(3-(trimethoxysilyl)propyl)ethane-1,2-diamine] were prepared. The NN co-ligand caused release of one of the dppme ligands from [RuCl₂(dppme)₂] precursor to yield complex 1. The process of substitution of dppme by NN was monitored by ³¹P{¹H}-NMR. Taking advantage of the presence of trimethoxysilane group in the backbone of complex 1, polysiloxane xerogel counterpart, X1, was prepared via sol-gel immobilization using tetraethoxysilane as cross-linker. Both complexes 1 and X1 have been characterized via elemental analysis, CV and a number of spectroscopic techniques including FT-IR, ¹H-, ¹³C-, and ³¹P-NMR, and mass spectrometry. Importantly, carbonyl selective hydrogenation was successfully accomplished under mild conditions using complex 1 as a homogenous catalyst and X1 as a heterogeneous catalyst, respectively. Full article

(This article belongs to the Section Organic Chemistry)

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Fucoidan Inhibits the Proliferation of Human Urinary Bladder Cancer T24 Cells by Blocking Cell Cycle Progression and Inducing Apoptosis

by Hye Young Park, Gi-Young Kim, Sung-Kwon Moon, Wun Jae Kim, Young Hyun Yoo and Yung Hyun Choi

Molecules 2014, 19(5), 5981-5998; https://doi.org/10.3390/molecules19055981 - 9 May 2014

Cited by 62 | Viewed by 12038

Abstract

Although fucoidan has been shown to exert anticancer activity against several types of cancer cell lines, no reports have explored fucoidan-affected cell growth in human urinary bladder cancer cells. In this study, we investigated the anti-proliferative effects of fucoidan in human bladder cancer [...] Read more.

Although fucoidan has been shown to exert anticancer activity against several types of cancer cell lines, no reports have explored fucoidan-affected cell growth in human urinary bladder cancer cells. In this study, we investigated the anti-proliferative effects of fucoidan in human bladder cancer T24 cells. Our results indicated that fucoidan decreased the viability of T24 cells through the induction of G1 arrest and apoptosis. Fucoidan-induced G1 arrest is associated with the enhanced expression of the Cdk inhibitor p21WAF1/CIP1 and dephosphorylation of the pRB along with enhanced binding of p21 to Cdk4/6 as well as pRB to the transcription factor E2Fs. Further investigations showed the loss of mitochondrial membrane potential and the release of cytochrome c from mitochondria to cytosol, proving mitochondrial dysfunction upon fucoidan treatment with a corresponding increase in the Bax/Bcl-2 expression ratio. Fucoidan-triggered apoptosis was also accompanied by the up-regulation of Fas and truncated Bid as well as the sequential activation of caspase-8. Furthermore, a significant increased activation of caspase-9/-3 was detected in response to fucoidan treatment with the decreased expression of IAPs and degradation of PARP, whereas a pan-caspase inhibitor significantly suppressed apoptosis and rescued the cell viability reduction. In conclusion, these observations suggest that fucoidan attenuates G1-S phase cell cycle progression and serves as an important mediator of crosstalk between caspase-dependent intrinsic and extrinsic apoptotic pathways in T24 cells. Full article

(This article belongs to the Collection Bioactive Compounds)

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Nanostructured Lipid Systems as a Strategy to Improve the in Vitro Cytotoxicity of Ruthenium(II) Compounds

by Eduardo Sinesio De Freitas, Patricia Bento Da Silva, Marlus Chorilli, Alzir Azevedo Batista, Érica De Oliveira Lopes, Monize Martins da Silva, Clarice Queico Fujimura Leite and Fernando Rogério Pavan

Molecules 2014, 19(5), 5999-6008; https://doi.org/10.3390/molecules19055999 - 9 May 2014

Cited by 22 | Viewed by 6316

Abstract

Tuberculosis is an ancient disease that is still present as a global public health problem. Our group has been investigating new molecules with anti-TB activity. In this context, inorganic chemistry has been a quite promising source of such molecules, with excellent results seen [...] Read more.

Tuberculosis is an ancient disease that is still present as a global public health problem. Our group has been investigating new molecules with anti-TB activity. In this context, inorganic chemistry has been a quite promising source of such molecules, with excellent results seen with ruthenium compounds. Nanostructured lipid systems may potentiate the action of drugs by reducing the required dosage and side effects and improving the antimicrobial effects. The aim of this study was to develop a nanostructured lipid system and then characterize and apply these encapsulated compounds (SCARs 1, 2 and 4) with the goal of improving their activity by decreasing the Minimum Inhibitory Concentration (MIC₉₀) and reducing the cytotoxicity (IC₅₀). The nanostructured system was composed of 10% phase oil (cholesterol), 10% surfactant (soy oleate, soy phosphatidylcholine and Eumulgin^®) and 80% aqueous phase (phosphate buffer pH = 7.4). Good activity against Mycobacterium tuberculosis was maintained after the incorporation of the compounds into the nanostructured lipid system, while the cytotoxicity decreased dramatically, in some cases up to 20 times less toxic than the unencapsulated drug. Full article

(This article belongs to the Special Issue Ruthenium Complex)

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Novel Triphenylantimony(V) and Triphenylbismuth(V) Complexes with Benzoic Acid Derivatives: Structural Characterization, in Vitro Antileishmanial and Antibacterial Activities and Cytotoxicity against Macrophages

by Arshad Islam, Jeferson Gomes Da Silva, Filipe Moan Berbet, Sydnei Magno Da Silva, Bernardo Lages Rodrigues, Heloisa Beraldo, Maria Norma Melo, Frédéric Frézard and Cynthia Demicheli

Molecules 2014, 19(5), 6009-6030; https://doi.org/10.3390/molecules19056009 - 12 May 2014

Cited by 67 | Viewed by 11057

Abstract

Two novel organoantimony(V) and two organobismuth(V) complexes of the type ML₂ were synthesized, with L = acetylsalicylic acid (HL1) or 3-acetoxybenzoic acid (HL2) and M = triphenylantimony(V) (M1) or triphenylbismuth(V) (M2). Complexes, [M1(L1)₂](1), [M1(L2)₂]∙CHCl₃ [...] Read more.

Two novel organoantimony(V) and two organobismuth(V) complexes of the type ML₂ were synthesized, with L = acetylsalicylic acid (HL1) or 3-acetoxybenzoic acid (HL2) and M = triphenylantimony(V) (M1) or triphenylbismuth(V) (M2). Complexes, [M1(L1)₂](1), [M1(L2)₂]∙CHCl₃ (2), [M2(L1)₂], (3) and [M2(L2)₂] (4), were characterized by elemental analysis, IR and NMR. Crystal structures of triphenylantimony(V) dicarboxylate complexes 1 and 2 were determined by single crystal X-ray diffraction. Structural analyses revealed that 1 and 2 adopt five-coordinated extremely distorted trigonal bipyramidal geometries, binding with three phenyl groups in the equatorial position and two deprotonated organic ligands (L) in the axial sites. The metal complexes, their metal salts and ligands were evaluated in vitro for their activities against Leishmania infantum and amazonensis promastigotes and Staphylococcus aureus and Pseudomonas aeruginosa bacteria. Both the metal complexes showed antileishmanial and antibacterial activities but the bismuth complexes were the most active. Intriguingly, complexation of organobismuth(V) salt reduced its activity against Leishmania, but increased it against bacteria. In vitro cytotoxic test of these complexes against murine macrophages showed that antimony(V) complexes were the least toxic. Considering the selectivity indexes, organoantimony(V) complexes emerge as the most promising antileishmanial agents and organobismuth(V) complex 3 as the best antibacterial agent. Full article

(This article belongs to the Section Medicinal Chemistry)

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Open AccessArticle

Exploiting Natural Products to Build Metalla-Assemblies: The Anticancer Activity of Embelin-Derived Rh(III) and Ir(III) Metalla-Rectangles

by Gajendra Gupta, Jerald Mahesh Kumar, Amine Garci, Narayana Nagesh and Bruno Therrien

Molecules 2014, 19(5), 6031-6046; https://doi.org/10.3390/molecules19056031 - 12 May 2014

Cited by 32 | Viewed by 8096

Abstract

Six new pentamethylcyclopentadienyl Rh(III) and Ir(III) metalla-rectangles ([3](CF₃SO₃)₄–[8](CF₃SO₃)₄) have been prepared by a self-assembly strategy using the embelin-derived metalla-clips (η⁵-C₅Me₅)₂ [...] Read more.

Six new pentamethylcyclopentadienyl Rh(III) and Ir(III) metalla-rectangles ([3](CF₃SO₃)₄–[8](CF₃SO₃)₄) have been prepared by a self-assembly strategy using the embelin-derived metalla-clips (η⁵-C₅Me₅)₂M₂(μ₄-C₆HRO₄-κO)Cl₂ (M = Rh, 1; M = Ir, 2; R = (CH₂)₁₀CH₃) and the linear ditopic ligands, pyrazine, 4,4'-bipyridine and 1,2-bis (4-pyridyl)ethylene. These new metalla-rectangles have been obtained in high yield and isolated as their triflate salts. The complexes have been fully characterized by standard spectroscopic techniques and the antiproliferative activity of these tetranuclear complexes was evaluated in vitro on cancerous (DU-145, A-549, HeLa) and noncancerous (HEK-293) cell lines. The biological study has showed a better activity for the rhodium derivatives over the iridium analogs and for all complexes a very good selectivity for cancerous over noncancerous cells. The presence of lipophilic side chains coupled with the positive charge of the tetranuclear complexes suggested a cytotoxic activity involving the mitochondrial machinery, as demonstrated by multiple biological experiments. Full article

(This article belongs to the Special Issue Practical Applications of Metal Complexes)

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Open AccessArticle

Bufalin Alters Gene Expressions Associated DNA Damage, Cell Cycle, and Apoptosis in Human Lung Cancer NCI-H460 Cells in Vitro

by Shin-Hwar Wu, Yung-Ting Hsiao, Jaw-Chyum Chen, Ju-Hwa Lin, Shu-Chun Hsu, Te-Chun Hsia, Su-Tso Yang, Wu-Huei Hsu and Jing-Gung Chung

Molecules 2014, 19(5), 6047-6057; https://doi.org/10.3390/molecules19056047 - 13 May 2014

Cited by 24 | Viewed by 7139

Abstract

Lung cancer is the leading cause of cancer related death and there is no effective treatment to date. Bufalin has been shown effective in inducing apoptosis and DNA damage in lung cancer cells. However, the genetic mechanisms underlying these actions have not been [...] Read more.

Lung cancer is the leading cause of cancer related death and there is no effective treatment to date. Bufalin has been shown effective in inducing apoptosis and DNA damage in lung cancer cells. However, the genetic mechanisms underlying these actions have not been elucidated yet. Cultured NCI-H460 cells were treated with or without 2 μM of bufalin for 24 h. The total RNA was extracted from each treatment for cDNA synthesis and labeling, microarray hybridization, and then followed by flour-labeled cDNA hybridized on chip. The localized concentrations of fluorescent molecules were detected and quantitated and analyzed by Expression Console software (Affymetrix) with default RMA parameters. The key genes involved and their possible interaction pathways were mapped by GeneGo software. About 165 apoptosis-related genes were affected. CASP9 was up-regulated by 5.51 fold and THAP1 by 2.75-fold while CCAR1 was down-regulated by 2.24 fold. 107 genes related to DNA damage/repair were affected. MDC1 was down-regulated by 2.22-fold, DDIT4 by 2.52 fold while GADD45B up-regulated by 3.72 fold. 201 genes related to cell cycles were affected. CCPG1 was down-regulated by 2.11 fold and CDCA7L by 2.71 fold. Many genes about apoptosis, cell cycle regulation and DNA repair are changed significantly following bufalin treatment in NCI-H460 cells. These changes provide an in depth understanding of cytotoxic mechanism of bufalin in genetic level and also offer many potentially useful biomarkers for diagnosis and treatment of lung cancer in future. Full article

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Open AccessArticle

A Study of Palladium Catalyzed Intra/Intermolecular Cascade Cross Coupling/Cyclizations Involving Bicyclopropylidene

by Aydin Demircan

Molecules 2014, 19(5), 6058-6069; https://doi.org/10.3390/molecules19056058 - 13 May 2014

Cited by 3 | Viewed by 5645

Abstract

The compounds [3-(2-Bromocyclohex-2-enyloxy)prop-1-ynyl]-tert-butyl-dimethylsilane 3, [4-(2-bromocyclohex-2-en-1-yloxy)but-2-yn-1-yloxy]tert-butyldimethylsilane 5 and dimethyl 2-(2-bromocyclohex-2-enyl)-2-(3-(tert-butyldimethylsilanyl)prop-2-ynyl)malonate 9 were prepared and subjected to palladium-catalyzed intra-intermolecular cascade cross couplings incorporating bicyclopropylidene 10 under two types of conditions. In the presence of Pd(OAc)₂, PPh [...] Read more.

The compounds [3-(2-Bromocyclohex-2-enyloxy)prop-1-ynyl]-tert-butyl-dimethylsilane 3, [4-(2-bromocyclohex-2-en-1-yloxy)but-2-yn-1-yloxy]tert-butyldimethylsilane 5 and dimethyl 2-(2-bromocyclohex-2-enyl)-2-(3-(tert-butyldimethylsilanyl)prop-2-ynyl)malonate 9 were prepared and subjected to palladium-catalyzed intra-intermolecular cascade cross couplings incorporating bicyclopropylidene 10 under two types of conditions. In the presence of Pd(OAc)₂, PPh₃ and K₂CO₃ in acetonitrile at 80 °C, the products were indene analogues, cross-conjugated tetraenes 11, 12 and 13, respectively. The corresponding spirocyclopropanated tricycle 16 in dimethylformamide at 110 °C was obtained, albeit in low yield (24%), and observed as an equimolar mixture of diastereomers, whereas 14, 15 were not fully isolated. Full article

(This article belongs to the Section Organic Chemistry)

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Open AccessArticle

In Vitro Leishmanicidal Activities of Sesquiterpene Lactones from Tithonia diversifolia against Leishmania braziliensis Promastigotes and Amastigotes

by Juliano S. De Toledo, Sergio R. Ambrósio, Carly H. G. Borges, Viviane Manfrim, Daniel G. Cerri, Angela K. Cruz and Fernando B. Da Costa

Molecules 2014, 19(5), 6070-6079; https://doi.org/10.3390/molecules19056070 - 14 May 2014

Cited by 34 | Viewed by 8832

Abstract

Natural compounds represent a rich and promising source of novel, biologically active chemical entities for treating leishmaniasis. Sesquiterpene lactones are a recognized class of terpenoids with a wide spectrum of biological activities, including activity against Leishmania spp. In this work, a sesquiterpene lactone-rich [...] Read more.

Natural compounds represent a rich and promising source of novel, biologically active chemical entities for treating leishmaniasis. Sesquiterpene lactones are a recognized class of terpenoids with a wide spectrum of biological activities, including activity against Leishmania spp. In this work, a sesquiterpene lactone-rich preparation—a leaf rinse extract (LRE) from Tithonia diversifolia—was tested against promastigote forms of L. braziliensis. The results revealed that the LRE is a rich source of potent leishmanicidal compounds, with an LD₅₀ value 1.5 ± 0.50 µg·mL⁻¹. Therefore, eight sesquiterpene lactones from the LRE were initially investigated against promastigote forms of L. braziliensis. One of them did not present any significant leishmanicidal effect (LD₅₀ > 50 µg·mL⁻¹). Another had a cytotoxic effect against macrophages (4.5 µg·mL⁻¹). The five leishmanicidal compounds with the highest level of selectivity were further evaluated against intracellular parasites (amastigotes) using peritoneal macrophages. Tirotundin 3-O-methyl ether, tagitinin F, and a guaianolide reduced the internalization of parasites after 48 h, in comparison with the negative control. This is the first report on sesquiterpene lactones that have potent leishmanicidal effects on both developmental stages of L. braziliensis. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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Open AccessArticle

Molecular Docking and Fluorescence Characterization of Benzothieno[3,2-d]pyrimidin-4-one Sulphonamide Thio-Derivatives, a Novel Class of Selective Cyclooxygenase-2 Inhibitors

by Mariarita Barone, Giovanna Pannuzzo, Andrea Santagati, Alfio Catalfo, Guido De Guidi and Venera Cardile

Molecules 2014, 19(5), 6106-6122; https://doi.org/10.3390/molecules19056106 - 14 May 2014

Cited by 10 | Viewed by 6923

Abstract

The aims of this study were: (i) to explore the structure-activity relationship of some new anti-inflammatory benzothieno[3,2-d]pyrimidin-4-one sulphonamide thio-derivatives 1–11; and (ii) to evaluate the possibility of using the most active compounds as fluorescent probes to determine tumours or their [...] Read more.

The aims of this study were: (i) to explore the structure-activity relationship of some new anti-inflammatory benzothieno[3,2-d]pyrimidin-4-one sulphonamide thio-derivatives 1–11; and (ii) to evaluate the possibility of using the most active compounds as fluorescent probes to determine tumours or their progression. Therefore, to know the precise mechanism by which these compounds interact with cyclooxygenase (COX)-2 enzyme, a molecular docking study was carried out; to assess spectroscopic characteristics, their absorption and emission properties were determined. The results demonstrated that some derivatives of benzothieno[3,2-d] pyrimidine exhibit interesting anti-inflammatory properties related to interactions with active sites of COX-2 and are fluorescent. The antipyrine-bearing compound 4 displayed high COX-2 affinity (ΔG = −9.4) and good fluorescent properties (Φ_fl = 0.032). Thus, some members of this new class of anti-inflammatory may be promising for fluorescence imaging of cancer cells that express the COX-2 enzyme. Further in vitro and in vivo studies are needed to confirm this hypothesis. Full article

(This article belongs to the Special Issue Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry)

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Open AccessArticle

Distribution of Nucleosides in Populations of Cordyceps cicadae

by Wen-Bo Zeng, Hong Yu, Feng Ge, Jun-Yuan Yang, Zi-Hong Chen, Yuan-Bing Wang, Yong-Dong Dai and Alison Adams

Molecules 2014, 19(5), 6123-6141; https://doi.org/10.3390/molecules19056123 - 14 May 2014

Cited by 51 | Viewed by 10839

Abstract

A rapid HPLC method had been developed and used for the simultaneous determination of 10 nucleosides (uracil, uridine, 2'-deoxyuridine, inosine, guanosine, thymidine, adenine, adenosine, 2'-deoxyadenosine and cordycepin) in 10 populations of Cordyceps cicadae, in order to compare four populations of Ophicordyceps sinensis [...] Read more.

A rapid HPLC method had been developed and used for the simultaneous determination of 10 nucleosides (uracil, uridine, 2'-deoxyuridine, inosine, guanosine, thymidine, adenine, adenosine, 2'-deoxyadenosine and cordycepin) in 10 populations of Cordyceps cicadae, in order to compare four populations of Ophicordyceps sinensis and one population of Cordyceps militaris. Statistical analysis system (SAS) 8.1 was used to analyze the nucleoside data. The pattern of nucleoside distribution was analyzed in the sampled populations of C. cicadae, O. sinensis and C. militaris, using descriptive statistical analysis, nested analysis and Q cluster analysis. The total amount of the 10 nucleosides in coremium was 1,463.89–5,678.21 µg/g in 10 populations of C. cicadae, 1,369.80–3,941.64 µg/g in sclerotium. The average contents of the 10 analytes were 4,392.37 µg/g and 3,016.06 µg/g in coremium and sclerotium, respectively. The coefficient of variation (CV) of nucleosides ranged from 8.36% to 112.36% in coremium of C. cicadae, and from 10.77% to 155.87% in sclerotium of C. cicadae. The CV of the nucleosides was wide within C. cicadae populations. The nested variation analysis by the nine nucleosides’ distribution indicated that about 42.29% of the nucleoside variability in coremium was attributable to the differentiation among populations, and the remaining 57.71% resided in the populations. It was also shown that about 28.94% of the variation in sclerotium was expressed between populations, while most of the variation (71.06%) corresponded to the populations. Full article

(This article belongs to the Section Metabolites)

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Open AccessArticle

Anticancer Activities of Polyynes from the Root Bark of Oplopanax horridus and Their Acetylated Derivatives

by Lan-Zhen Meng, Wei-Hua Huang, Chong-Zhi Wang, Chun-Su Yuan and Shao-Ping Li

Molecules 2014, 19(5), 6142-6162; https://doi.org/10.3390/molecules19056142 - 14 May 2014

Cited by 20 | Viewed by 6686 | Correction

Abstract

Six polyynes OH-1~6, some of which are occur naturally in acetylated form, had been isolated and identified from the root bark of Oplopanax horridus (Devil’s Club), a natural dietary supplement and medicinal plant in North America. During the evaluation of [...] Read more.

Six polyynes OH-1~6, some of which are occur naturally in acetylated form, had been isolated and identified from the root bark of Oplopanax horridus (Devil’s Club), a natural dietary supplement and medicinal plant in North America. During the evaluation of the polyynes’ potential anticancer activities, sixteen more acetylated derivatives OHR-1~16 have synthesized and their anti-proliferation activity on MCF-7, MDA-MB-231, A549, HepG2 and LO2 cells assayed to elucidate their structure-activity relationships. The results showed that OH-1 ((3S, 8S)-falcarindiol) had the most potent anticancer activity, with IC₅₀ values of 15.3, 23.5, 7.7 and 4.7 μM on MCF-7, A549, HepG2 and MDA-MB-231 cells, respectively. For the primary structure-activity relationship, the anticancer activities of polyynes become weaker if their hydroxyl groups are acetylated, the terminal double bonds transformed into single bonds or they contain one more methylene group in the main skeleton chain. Full article

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Open AccessArticle

Synthesis and Biological Evaluation of Novel Urea- and Guanidine-Based Derivatives for the Treatment of Obesity-Related Hepatic Steatosis

by Xiaolin Liang, Heying Pei, Liang Ma, Yan Ran, Jinying Chen, Guangcheng Wang and Lijuan Chen

Molecules 2014, 19(5), 6163-6183; https://doi.org/10.3390/molecules19056163 - 15 May 2014

Cited by 11 | Viewed by 7258

Abstract

Leptin, the product of the obese gene, is an adipocyte-secreted protein hormone playing a key role in the progression of obesity and hepatic steatosis. In this study, 28 novel (thio)urea and guanidine-based analogues have been synthesized and N-(1-(4-(3-(2-chloroethyl)ureido)benzyl)piperidin-4-yl)-3-(trifluoromethyl) benzamide (7i) was [...] Read more.

Leptin, the product of the obese gene, is an adipocyte-secreted protein hormone playing a key role in the progression of obesity and hepatic steatosis. In this study, 28 novel (thio)urea and guanidine-based analogues have been synthesized and N-(1-(4-(3-(2-chloroethyl)ureido)benzyl)piperidin-4-yl)-3-(trifluoromethyl) benzamide (7i) was found to be a potent regulator of leptin expression in 3T3-L1 adipocytes. Treatment with 7i at a dose of 50 mg/kg/day for 35 days reduced the body weight and liver weight of diet-induced obesity mice by 13.5% and 18.4%, respectively, while also improving the serum levels of triglyceride, total cholesterol, leptin, adiponectin, LDL-c, HDL-c. Hematoxylin-eosin (H&E) and Oil Red O staining also confirmed that 7i ameliorated fat deposition in liver tissue and restricted the size of adipocytes in obesity-related fatty liver disease. Full article

(This article belongs to the Section Medicinal Chemistry)

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Open AccessArticle

Antiprotozoal Activity of Buxus sempervirens and Activity-Guided Isolation of O-tigloylcyclovirobuxeine-B as the Main Constituent Active against Plasmodium falciparum

by Julia B. Althaus, Gerold Jerz, Peter Winterhalter, Marcel Kaiser, Reto Brun and Thomas J. Schmidt

Molecules 2014, 19(5), 6184-6201; https://doi.org/10.3390/molecules19056184 - 15 May 2014

Cited by 23 | Viewed by 7615

Abstract

Buxus sempervirens L. (European Box, Buxaceae) has been used in ethnomedicine to treat malaria. In the course of our screening of plant extracts for antiprotozoal activity, a CH₂Cl₂ extract from leaves of B. sempervirens showed selective in vitro activity against [...] Read more.

Buxus sempervirens L. (European Box, Buxaceae) has been used in ethnomedicine to treat malaria. In the course of our screening of plant extracts for antiprotozoal activity, a CH₂Cl₂ extract from leaves of B. sempervirens showed selective in vitro activity against Plasmodium falciparum (IC₅₀ = 2.79 vs. 20.2 µg/mL for cytotoxicity against L6 rat cells). Separation of the extract by acid/base extraction into a basic and a neutral non-polar fraction led to a much more active and even more selective fraction with alkaloids while the fraction of non-polar neutral constituents was markedly less active than the crude extract. Thus, the activity of the crude extract could clearly be attributed to alkaloid constituents. Identification of the main triterpene-alkaloids and characterization of the complex pattern of this alkaloid fraction was performed by UHPLC/+ESI-QTOF-MS analyses. ESI-MS/MS target-guided larger scale preparative separation of the alkaloid fraction was performed by ‘spiral coil-countercurrent chromatography’. From the most active subfraction, the cycloartane alkaloid O-tigloylcyclovirobuxeine-B was isolated and evaluated for antiplasmodial activity which yielded an IC₅₀ of 0.455 µg/mL (cytotoxicity against L6 rat cells: IC₅₀ = 9.38 µg/mL). O-tigloylcyclovirobuxeine-B is thus most significantly responsible for the high potency of the crude extract. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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Open AccessArticle

n-Butyl Cyanoacrylate Synthesis. A New Quality Step Using Microwaves

by Yaquelin Ramos Carriles, Rubén Álvarez Brito, Ricardo Martínez Sánchez, Elayma Sánchez Acevedo, Paola Rodríguez Domínguez and Wolf-Dieter Mueller

Molecules 2014, 19(5), 6220-6227; https://doi.org/10.3390/molecules19056220 - 15 May 2014

Cited by 7 | Viewed by 7804

Abstract

Alkyl cyanoacrylates are interesting products for use in industry because of their properties enabling them to stick together a wide range of substrates. n-Butyl cyanoacrylate is one of the most successfully used tissue adhesives in the field of medicine because it exhibits [...] Read more.

Alkyl cyanoacrylates are interesting products for use in industry because of their properties enabling them to stick together a wide range of substrates. n-Butyl cyanoacrylate is one of the most successfully used tissue adhesives in the field of medicine because it exhibits bacteriostatic and haemostatic characteristics, in addition to its adhesive properties. At present, its synthesis is performed with good yields via Knoevenagel condensation using conventional sources of heating, but this requires a long processing time. The aim of this work was to look for a new way of synthesising n-butyl cyanoacrylate using microwave irradiation as the source of heating. This non-conventional source of heating most likely reduces the process time of the synthesis. In comparison with a conventional heating source, such as an oil bath, the results showed the advantages of this method whereby the n-butyl cyanoacrylate gave the same yield and quality with a reduction in the reaction time by a factor of 3-5-fold. Full article

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Open AccessArticle

Cloning, 3D Modeling and Expression Analysis of Three Vacuolar Invertase Genes from Cassava (Manihot Esculenta Crantz)

by Yuan Yao, Xiao-Hui Wu, Meng-Ting Geng, Rui-Mei Li, Jiao Liu, Xin-Wen Hu and Jian-Chun Guo

Molecules 2014, 19(5), 6228-6245; https://doi.org/10.3390/molecules19056228 - 15 May 2014

Cited by 13 | Viewed by 7931

Abstract

Vacuolar invertase is one of the key enzymes in sucrose metabolism that irreversibly catalyzes the hydrolysis of sucrose to glucose and fructose in plants. In this research, three vacuolar invertase genes, named MeVINV1-3, and with 653, 660 and 639 amino acids, respectively, [...] Read more.

Vacuolar invertase is one of the key enzymes in sucrose metabolism that irreversibly catalyzes the hydrolysis of sucrose to glucose and fructose in plants. In this research, three vacuolar invertase genes, named MeVINV1-3, and with 653, 660 and 639 amino acids, respectively, were cloned from cassava. The motifs of NDPNG (β-fructosidase motif), RDP and WECVD, which are conserved and essential for catalytic activity in the vacuolar invertase family, were found in MeVINV1 and MeVINV2. Meanwhile, in MeVINV3, instead of NDPNG we found the motif NGPDG, in which the three amino acids GPD are different from those in other vacuolar invertases (DPN) that might result in MeVINV3 being an inactivated protein. The N-terminal leader sequence of MeVINVs contains a signal anchor, which is associated with the sorting of vacuolar invertase to vacuole. The overall predicted 3D structure of the MeVINVs consists of a five bladed β-propeller module at N-terminus domain, and forms a β-sandwich module at the C-terminus domain. The active site of the protein is situated in the β-propeller module. MeVINVs are classified in two subfamilies, α and β groups, in which α group members of MeVINV1 and 2 are highly expressed in reproductive organs and tuber roots (considered as sink organs), while β group members of MeVINV3 are highly expressed in leaves (source organs). All MeVINVs are highly expressed in leaves, while only MeVINV1 and 2 are highly expressed in tubers at cassava tuber maturity stage. Thus, MeVINV1 and 2 play an important role in sucrose unloading and starch accumulation, as well in buffering the pools of sucrose, hexoses and sugar phosphates in leaves, specifically at later stages of plant development. Full article

(This article belongs to the Section Molecular Diversity)

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Open AccessArticle

Synthesis and Application of Hybrid Polymer Composites Based on Silver Nanoparticles as Corrosion Protection for Line Pipe Steel

by Ayman M. Atta, Gamal A. El-Mahdy, Hamad A. Al-Lohedan and Abdurrahman O. Ezzat

Molecules 2014, 19(5), 6246-6262; https://doi.org/10.3390/molecules19056246 - 16 May 2014

Cited by 43 | Viewed by 10072

Abstract

A facile method was developed to synthesize in high yield dispersed silver nanoparticles (AgNPs) with small particle sizes of less than 10 nm. Silver nitrate was reduced to silver nanoparticles by p-chloroaniline in the presence of polyoxyethylene maleate 4-nonyl-2-propylene-phenol (NMA) as a [...] Read more.

A facile method was developed to synthesize in high yield dispersed silver nanoparticles (AgNPs) with small particle sizes of less than 10 nm. Silver nitrate was reduced to silver nanoparticles by p-chloroaniline in the presence of polyoxyethylene maleate 4-nonyl-2-propylene-phenol (NMA) as a stabilizer. The produced AgNPs were used to prepare hybrid polymer based on N-isopropylacrylamide (NIPAm), 2-acrylamido-2-methylpropane sulfonic acid (AMPS), N,N-methylenebisacrylamide (MBA) and potassium persulfate (KPS) using a semi-batch solution polymerization method. The prepared AgNPs and hybrid polymer were characterized by Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD) patterns and transmission electron microscopy (TEM). The corrosion inhibition activity of the AgNPs and hybrid polymer towards steel corrosion in the presence of hydrochloric acid has been investigated by polarization and electrochemical impedance spectroscopy (EIS) methods. Polarization measurements indicate that the AgNPs and hybrid polymer acts as a mixed type-inhibitor and the inhibition efficiency increases with inhibitor concentration. The results of potentiodynamic polarization and EIS measurements clearly showed that the inhibition mechanism involves blocking of the steel surface by inhibitor molecules via adsorption. Full article

(This article belongs to the Section Molecular Diversity)

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Open AccessCommunication

Increased Circulating MicroRNA-155 as a Potential Biomarker for Breast Cancer Screening: A Meta-Analysis

by Faliang Wang, Jinchao Hou, Wei Jin, Jiaqiu Li, Yongfang Yue, Hongchuan Jin and Xian Wang

Molecules 2014, 19(5), 6282-6293; https://doi.org/10.3390/molecules19056282 - 16 May 2014

Cited by 36 | Viewed by 7973

Abstract

The objective of this meta-analysis was to determine the diagnostic accuracy of circulating microRNA-155 (miR-155) for breast cancer (BC). PubMed, Embase, EBSCO (ASP/BSP), Cochrane Library and China National Knowledge Infrastructure (CNKI) were searched up to 30 January 2014 for eligible studies. Quality Assessment [...] Read more.

The objective of this meta-analysis was to determine the diagnostic accuracy of circulating microRNA-155 (miR-155) for breast cancer (BC). PubMed, Embase, EBSCO (ASP/BSP), Cochrane Library and China National Knowledge Infrastructure (CNKI) were searched up to 30 January 2014 for eligible studies. Quality Assessment of Diagnostic Accuracy Studies (QUADAS) was employed to assess the quality of the included studies. Meta-analysis were performed in Meta-Disc 1.4 and Stata 12.0. Three studies with total 184 BC patients and 75 control individuals were included in this meta-analysis. All of the included studies are of high quality (QUADAS scores 12 or 13). The summary estimates revealed that the pooled sensitivity is 79% (95% confidence interval (CI): 72%–84%) and the specificity is 85% (95% CI: 75%–92%), for the diagnosis of breast cancer. In addition, the area under the summary ROC curve (AUC) is 0.9217. The current evidence suggests that circulating miR-155 has the potential diagnostic value with a high sensitivity and specificity for BC. More prospective studies on the diagnostic value of circulating miR-155 for BC are needed in the future. Full article

(This article belongs to the Special Issue miRNAs as Probes to Monitor Cancer and Neurodegenerative Disorders)

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Open AccessArticle

Evaluation of Four Different Analytical Tools to Determine the Regional Origin of Gastrodia elata and Rehmannia glutinosa on the Basis of Metabolomics Study

by Dong-Kyu Lee, Dong Kyu Lim, Jung A. Um, Chang Ju Lim, Ji Yeon Hong, Young A Yoon, Yeonsuk Ryu, Hyo Jin Kim, Hi Jae Cho, Jeong Hill Park, Young Bae Seo, Kyunga Kim, Johan Lim, Sung Won Kwon and Jeongmi Lee

Molecules 2014, 19(5), 6294-6308; https://doi.org/10.3390/molecules19056294 - 16 May 2014

Cited by 18 | Viewed by 7853

Abstract

Chemical profiles of medicinal plants could be dissimilar depending on the cultivation environments, which may influence their therapeutic efficacy. Accordingly, the regional origin of the medicinal plants should be authenticated for correct evaluation of their medicinal and market values. Metabolomics has been found [...] Read more.

Chemical profiles of medicinal plants could be dissimilar depending on the cultivation environments, which may influence their therapeutic efficacy. Accordingly, the regional origin of the medicinal plants should be authenticated for correct evaluation of their medicinal and market values. Metabolomics has been found very useful for discriminating the origin of many plants. Choosing the adequate analytical tool can be an essential procedure because different chemical profiles with different detection ranges will be produced according to the choice. In this study, four analytical tools, Fourier transform near‑infrared spectroscopy (FT-NIR), ¹H-nuclear magnetic resonance spectroscopy (¹H‑NMR), liquid chromatography-mass spectrometry (LC-MS), and gas chromatography-mass spectroscopy (GC-MS) were applied in parallel to the same samples of two popular medicinal plants (Gastrodia elata and Rehmannia glutinosa) cultivated either in Korea or China. The classification abilities of four discriminant models for each plant were evaluated based on the misclassification rate and Q² obtained from principal component analysis (PCA) and orthogonal projection to latent structures-discriminant analysis (OPLS‑DA), respectively. ¹H-NMR and LC-MS, which were the best techniques for G. elata and R. glutinosa, respectively, were generally preferable for origin discrimination over the others. Reasoned by integrating all the results, ¹H-NMR is the most prominent technique for discriminating the origins of two plants. Nonetheless, this study suggests that preliminary screening is essential to determine the most suitable analytical tool and statistical method, which will ensure the dependability of metabolomics-based discrimination. Full article

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Open AccessArticle

Bifunctionalized Allenes. Part XIII. A Convenient and Efficient Method for Regioselective Synthesis of Phosphorylated α-Hydroxyallenes with Protected and Unprotected Hydroxy Group

by Ismail E. Ismailov, Ivaylo K. Ivanov and Valerij Ch. Christov

Molecules 2014, 19(5), 6309-6329; https://doi.org/10.3390/molecules19056309 - 16 May 2014

Cited by 11 | Viewed by 5711

Abstract

The paper describes a convenient and efficient method for regioselective synthesis of phosphorylated α-hydroxyallenes using an atom economical [2,3]-sigmatropic rearrangement of intermediate propargyl phosphites or phosphinites. These can be readily prepared via reaction of protected alkynols with dimethyl chlorophosphite or chlorodiphenyl phosphine respectively [...] Read more.

The paper describes a convenient and efficient method for regioselective synthesis of phosphorylated α-hydroxyallenes using an atom economical [2,3]-sigmatropic rearrangement of intermediate propargyl phosphites or phosphinites. These can be readily prepared via reaction of protected alkynols with dimethyl chlorophosphite or chlorodiphenyl phosphine respectively in the presence of a base. Full article

(This article belongs to the Section Organic Chemistry)

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Open AccessArticle

Synthesis, Molecular Docking and Biological Evaluation of Glycyrrhizin Analogs as Anticancer Agents Targeting EGFR

by Yong-An Yang, Wen-Jian Tang, Xin Zhang, Ji-Wen Yuan, Xin-Hua Liu and Hai-Liang Zhu

Molecules 2014, 19(5), 6368-6381; https://doi.org/10.3390/molecules19056368 - 19 May 2014

Cited by 35 | Viewed by 7929

Abstract

Glycyrrhizin (GA) analogs in the form of 3-glucuronides and 18-epimers were synthesized and their anticancer activities were evaluated. Alkaline isomerization of monoglucuronides is reported. In vitro and in vivo studies showed that glycyrrhetinic acid monoglucuronides (GAMGs) displayed higher anticancer activities than those of [...] Read more.

Glycyrrhizin (GA) analogs in the form of 3-glucuronides and 18-epimers were synthesized and their anticancer activities were evaluated. Alkaline isomerization of monoglucuronides is reported. In vitro and in vivo studies showed that glycyrrhetinic acid monoglucuronides (GAMGs) displayed higher anticancer activities than those of bisglucuronide GA analogs, while anticancer activity of the 18α-epimer was superior to that of the 18β-epimer. 18α-GAMG was firstly nicely bound to epidermal growth factor receptor (EGFR) via six hydrogen bonds and one charge interaction, and the docking calculation proved the correlation between anticancer activities and EGFR inhibitory activities. Highly active 18α-GAMG is thus of interest for the further studies as a potential anticancer agent. Full article

(This article belongs to the Section Medicinal Chemistry)

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Open AccessArticle

⁶⁰Co-γ Irradiation Affects the Enzymatic Antioxidant System of the Citrus Red Mite Panonychus citri (Acari: Tetranychidae)

by Ke Zhang, Zhibin Li, Shaowen Zhu and Qunfang Weng

Molecules 2014, 19(5), 6382-6392; https://doi.org/10.3390/molecules19056382 - 19 May 2014

Cited by 10 | Viewed by 5607

Abstract

Radio-(⁶⁰Co), which emits γ rays, has been used worldwide in pest control. The aim of the present study was to analyze the effect of effective-low-power ⁶⁰Co-γ irradiation on the enzymatic antioxidant system of the citrus red mite Panonychus [...] Read more.

Radio-(⁶⁰Co), which emits γ rays, has been used worldwide in pest control. The aim of the present study was to analyze the effect of effective-low-power ⁶⁰Co-γ irradiation on the enzymatic antioxidant system of the citrus red mite Panonychus citri. One day old female adults were exposed to 0.4 kGy ⁶⁰Co-γ irradiation and on the, 6th h, 1st day, 2nd day, and 5th day post treatment, the mites were euthanized for biochemical analysis. The activity of superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), phenoloxidase (PO) and acetylocholinesterase (AchE) were investigated. POD and CAT activities, as well as SOD were higher in the irradiated mites. We found that exposure to ⁶⁰Co-γ radiation resulted in increased activities of SOD, CAT, POD and decreased AchE activity. When the recovery time lasted till the 5th day, the activities of POD and PO were significantly lower than the control, whereas the SOD, CAT and AchE activities returned to control levels. Cells possess protein repair pathways to rescue oxidized proteins and restore their functions, but if these repair processes fail, oxidized proteins may become cytotoxic. Our results confirm the hypothesis that low dosages of ⁶⁰Co-γ irradiation increase the level of oxidative stress in P. citri adults in a short time, causing meanwhile damage and sterility. The results of this study also indicate that stress caused by exposure to irradiation could inhibit the cholinergic system in P. citri. Full article

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Open AccessArticle

CopA3 Peptide Prevents Ultraviolet-Induced Inhibition of Type-I Procollagen and Induction of Matrix Metalloproteinase-1 in Human Skin Fibroblasts

by Dong-Hee Kim, Han-Hyuk Kim, Hyeon-Jeong Kim, Hyun-Gug Jung, Jae-Myo Yu, Eun-Su Lee, Yong-Hun Cho, Dong-In Kim and Bong-Jeun An

Molecules 2014, 19(5), 6407-6414; https://doi.org/10.3390/molecules19056407 - 20 May 2014

Cited by 8 | Viewed by 6900

Abstract

Ultraviolet (UV) exposure is well-known to induce premature aging, which is mediated by matrix metalloproteinase-1 (MMP-1) activity. A 9-mer peptide, CopA3 (CopA3) was synthesized from a natural peptide, coprisin, which is isolated from the dung beetle Copris tripartitus. As part of our [...] Read more.

Ultraviolet (UV) exposure is well-known to induce premature aging, which is mediated by matrix metalloproteinase-1 (MMP-1) activity. A 9-mer peptide, CopA3 (CopA3) was synthesized from a natural peptide, coprisin, which is isolated from the dung beetle Copris tripartitus. As part of our continuing search for novel bioactive natural products, CopA3 was investigated for its in vitro anti-skin photoaging activity. UV-induced inhibition of type-I procollagen and induction of MMP-1 were partially prevented in human skin fibroblasts by CopA3 peptide in a dose-dependent manner. At a concentration of 25 μM, CopA3 nearly completely inhibited MMP-1 expression. These results suggest that CopA3, an insect peptide, is a potential candidate for the prevention and treatment of skin aging. Full article

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Open AccessArticle

2,5-PRODAN Derivatives as Highly Sensitive Sensors of Low Solvent Acidity

by Alexandra H. Yoon, Laura C. Whitworth, Joel D. Wagner and Christopher J. Abelt

Molecules 2014, 19(5), 6415-6427; https://doi.org/10.3390/molecules19056415 - 20 May 2014

Cited by 4 | Viewed by 6277

Abstract

Two 5-acyl-2-dimethylaminonaphthalene derivatives, one with a propionyl group and the other with a fused cyclohexanone ring, are investigated as sensors of H-bond-donating ability in protic solvents of low solvent acidity. Their fluorescence is highly quenched in protic solvents, and the quenching order of [...] Read more.

Two 5-acyl-2-dimethylaminonaphthalene derivatives, one with a propionyl group and the other with a fused cyclohexanone ring, are investigated as sensors of H-bond-donating ability in protic solvents of low solvent acidity. Their fluorescence is highly quenched in protic solvents, and the quenching order of magnitude is linearly related to the H-bond-donating ability of the solvent as quantified by the solvent acidity (SA) scale. As the solvent acidity increases from 0.15 to 0.40, the fluorescence for both is quenched by more than a factor of ten; thus, they are extremely sensitive sensors of the hydrogen-bond-donating ability in this weakly acidic range. Preferential solvation studies suggest that quenching occurs from a doubly H-bonded excited state. Full article

(This article belongs to the Special Issue Fluorescent Probes)

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Open AccessArticle

Antiprotozoal Activity of Achillea ptarmica (Asteraceae) and Its Main Alkamide Constituents

by Julia B. Althaus, Marcel Kaiser, Reto Brun and Thomas J. Schmidt

Molecules 2014, 19(5), 6428-6438; https://doi.org/10.3390/molecules19056428 - 20 May 2014

Cited by 39 | Viewed by 8026

Abstract

In the course of our ongoing screening of plants of the family Asteraceae for antiprotozoal activity, a CH2Cl2-extract from the flowering aerial parts of Achillea ptarmica L. (sneezewort yarrow) was found to be active in vitro against Trypanosoma brucei rhodesiense (IC50 = 0.67 [...] Read more.

In the course of our ongoing screening of plants of the family Asteraceae for antiprotozoal activity, a CH2Cl2-extract from the flowering aerial parts of Achillea ptarmica L. (sneezewort yarrow) was found to be active in vitro against Trypanosoma brucei rhodesiense (IC50 = 0.67 µg/mL) and Plasmodium falciparum (IC50 = 6.6 μg/mL). Bioassay guided fractionation led to the isolation and identification of five alkamides from the most active fractions. Pellitorine and 8,9-Z-dehyropellitorine are the main components of the extract. Beside these olefinic acid amides, four alkamides with diene-diyne structures were isolated. All alkamides were tested for antiprotozoal activity in vitro. Pellitorine was the most active compound so far within this study against P. falciparum (IC50 = 3.3 µg/mL), while 8,9-Z-dehydropellitorine was most active against T. b. rhodesiense (IC50 = 2.0 µg/mL). The activity of pure pellitorine against Plasmodium is higher than that of the crude extract and thus explains the activity of the latter. None of the isolated alkamides, however, was as active against T. b. rhodesiense as the crude extract whose antitrypanosomal activity must therfore be due to a synergistic effect of the isolated compounds or to more active yet to be identified constituents. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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Open AccessArticle

Palladium-Catalyzed Direct Addition of 2-Aminobenzonitriles to Sodium Arylsulfinates: Synthesis of o-Aminobenzophenones

by Jiuxi Chen, Jianjun Li and Weike Su

Molecules 2014, 19(5), 6439-6449; https://doi.org/10.3390/molecules19056439 - 20 May 2014

Cited by 16 | Viewed by 7472

Abstract

The first example of the palladium-catalyzed synthesis of o-aminobenzophenones in moderate to excellent yields via a direct addition of sodium arylsulfinates to unprotected 2-aminobenzonitriles was reported. A plausible mechanism for the formation of o-aminobenzophenones involving desulfination and addition reactions was proposed. [...] Read more.

The first example of the palladium-catalyzed synthesis of o-aminobenzophenones in moderate to excellent yields via a direct addition of sodium arylsulfinates to unprotected 2-aminobenzonitriles was reported. A plausible mechanism for the formation of o-aminobenzophenones involving desulfination and addition reactions was proposed. The utility of this transformation was demonstrated by its compatibility with a wide range of functional groups. Thus, the method represents a convenient and practical strategy for synthesis of o-aminobenzophenones. Full article

(This article belongs to the Special Issue Palladium Catalysts)

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Open AccessArticle

Chlorine Isotope Effects from Isotope Ratio Mass Spectrometry Suggest Intramolecular C-Cl Bond Competition in Trichloroethene (TCE) Reductive Dehalogenation

by Stefan Cretnik, Anat Bernstein, Orfan Shouakar-Stash, Frank Löffler and Martin Elsner

Molecules 2014, 19(5), 6450-6473; https://doi.org/10.3390/molecules19056450 - 20 May 2014

Cited by 42 | Viewed by 9670

Abstract

Chlorinated ethenes are prevalent groundwater contaminants. To better constrain (bio)chemical reaction mechanisms of reductive dechlorination, the position-specificity of reductive trichloroethene (TCE) dehalogenation was investigated. Selective biotransformation reactions (i) of tetrachloroethene (PCE) to TCE in cultures of Desulfitobacterium sp. strain Viet1; and (ii) of [...] Read more.

Chlorinated ethenes are prevalent groundwater contaminants. To better constrain (bio)chemical reaction mechanisms of reductive dechlorination, the position-specificity of reductive trichloroethene (TCE) dehalogenation was investigated. Selective biotransformation reactions (i) of tetrachloroethene (PCE) to TCE in cultures of Desulfitobacterium sp. strain Viet1; and (ii) of TCE to cis-1,2-dichloroethene (cis-DCE) in cultures of Geobacter lovleyi strain SZ were investigated. Compound-average carbon isotope effects were −19.0‰ ± 0.9‰ (PCE) and −12.2‰ ± 1.0‰ (TCE) (95% confidence intervals). Using instrumental advances in chlorine isotope analysis by continuous flow isotope ratio mass spectrometry, compound-average chorine isotope effects were measured for PCE (−5.0‰ ± 0.1‰) and TCE (−3.6‰ ± 0.2‰). In addition, position-specific kinetic chlorine isotope effects were determined from fits of reactant and product isotope ratios. In PCE biodegradation, primary chlorine isotope effects were substantially larger (by −16.3‰ ± 1.4‰ (standard error)) than secondary. In TCE biodegradation, in contrast, the product cis-DCE reflected an average isotope effect of −2.4‰ ± 0.3‰ and the product chloride an isotope effect of −6.5‰ ± 2.5‰, in the original positions of TCE from which the products were formed (95% confidence intervals). A greater difference would be expected for a position-specific reaction (chloride would exclusively reflect a primary isotope effect). These results therefore suggest that both vicinal chlorine substituents of TCE were reactive (intramolecular competition). This finding puts new constraints on mechanistic scenarios and favours either nucleophilic addition by Co(I) or single electron transfer as reductive dehalogenation mechanisms. Full article

(This article belongs to the Collection Isotope Effects)

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Open AccessArticle

Capsaicin and Dihydrocapsaicin Determination in Chili Pepper Genotypes Using Ultra-Fast Liquid Chromatography

by Magaji G. Usman, Mohd Y. Rafii, Mohd R. Ismail, Md. Abdul Malek and Mohammad Abdul Latif

Molecules 2014, 19(5), 6474-6488; https://doi.org/10.3390/molecules19056474 - 21 May 2014

Cited by 63 | Viewed by 13547

Abstract

Research was carried out to estimate the levels of capsaicin and dihydrocapsaicin that may be found in some heat tolerant chili pepper genotypes and to determine the degree of pungency as well as percentage capsaicin content of each of the analyzed peppers. A [...] Read more.

Research was carried out to estimate the levels of capsaicin and dihydrocapsaicin that may be found in some heat tolerant chili pepper genotypes and to determine the degree of pungency as well as percentage capsaicin content of each of the analyzed peppers. A sensitive, precise, and specific ultra fast liquid chromatographic (UFLC) system was used for the separation, identification and quantitation of the capsaicinoids and the extraction solvent was acetonitrile. The method validation parameters, including linearity, precision, accuracy and recovery, yielded good results. Thus, the limit of detection was 0.045 µg/kg and 0.151 µg/kg for capsaicin and dihydrocapsaicin, respectively, whereas the limit of quantitation was 0.11 µg/kg and 0.368 µg/kg for capsaicin and dihydrocapsaicin. The calibration graph was linear from 0.05 to 0.50 µg/g for UFLC analysis. The inter- and intra-day precisions (relative standard deviation) were <5.0% for capsaicin and <9.9% for dihydrocapsaicin while the average recoveries obtained were quantitative (89.4%–90.1% for capsaicin, 92.4%–95.2% for dihydrocapsaicin), indicating good accuracy of the UFLC method. AVPP0705, AVPP0506, AVPP0104, AVPP0002, C05573 and AVPP0805 showed the highest concentration of capsaicin (12,776, 5,828, 4,393, 4,760, 3,764 and 4,120 µg/kg) and the highest pungency level, whereas AVPP9703, AVPP0512, AVPP0307, AVPP0803 and AVPP0102 recorded no detection of capsaicin and hence were non-pungent. All chili peppers studied except AVPP9703, AVPP0512, AVPP0307, AVPP0803 and AVPP0102 could serve as potential sources of capsaicin. On the other hand, only genotypes AVPP0506, AVPP0104, AVPP0002, C05573 and AVPP0805 gave a % capsaicin content that falls within the pungency limit that could make them recommendable as potential sources of capsaicin for the pharmaceutical industry. Full article

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Open AccessArticle

Seasonal Variation and Resin Composition in the Andean Tree Austrocedrus chilensis

by Verónica Rachel Olate, Alex Soto and Guillermo Schmeda-Hirschmann

Molecules 2014, 19(5), 6489-6503; https://doi.org/10.3390/molecules19056489 - 21 May 2014

Cited by 8 | Viewed by 5959

Abstract

Little is known about the changes in resin composition in South American gymnosperms associated with the different seasons of the year. The diterpene composition of 44 resin samples from seven Austrocedrus chilensis (Cupressaceae) trees, including male and female individuals, was investigated in three [...] Read more.

Little is known about the changes in resin composition in South American gymnosperms associated with the different seasons of the year. The diterpene composition of 44 resin samples from seven Austrocedrus chilensis (Cupressaceae) trees, including male and female individuals, was investigated in three different seasons of the year (February, June and November). Twelve main diterpenes were isolated by chromatographic means and identified by gas chromatography-mass spectrometry and nuclear magnetic resonance (NMR). The diterpene composition was submitted to multivariate analysis to find possible associations between chemical composition and season of the year. The principal component analysis showed a clear relation between diterpene composition and season. The most characteristic compounds in resins collected in summer were Z-communic acid (9) and 12-oxo-labda-8(17),13E-dien-19 oic acid methyl ester (10) for male trees and 8(17),12,14-labdatriene (7) for female trees. For the winter samples, a clear correlation of female trees with torulosic acid (6) was observed. In spring, E-communic acid (8) and Z-communic acid (9) were correlated with female trees and 18-hydroxy isopimar-15-ene (1) with male tree resin. A comparison between percent diterpene composition and collection time showed p < 0.05 for isopimara-8(9),15-diene (2), sandaracopimaric acid (4), compound (7) and ferruginol (11). Full article

(This article belongs to the Section Natural Products Chemistry)

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Open AccessArticle

Evaluation of Antioxidant Activity, Polyphenolic Compounds, Amino Acids and Mineral Elements of Representative Genotypes of Lonicera edulis

by Jiri Sochor, Tunde Jurikova, Miroslav Pohanka, Helena Skutkova, Mojmir Baron, Lenka Tomaskova, Stefan Balla, Borivoj Klejdus, Robert Pokluda, Jiri Mlcek, Zuzana Trojakova and Jan Saloun

Molecules 2014, 19(5), 6504-6523; https://doi.org/10.3390/molecules19056504 - 21 May 2014

Cited by 24 | Viewed by 10719

Abstract

The aim of this study was to evaluate the bioactive substances in 19 berry cultivars of edible honeysuckle (Lonicera edulis). A statistical evaluation was used to determine the relationship between the content of selected bioactive substances and individual cultivars. Regarding mineral [...] Read more.

The aim of this study was to evaluate the bioactive substances in 19 berry cultivars of edible honeysuckle (Lonicera edulis). A statistical evaluation was used to determine the relationship between the content of selected bioactive substances and individual cultivars. Regarding mineral elements, the content of sodium was measured using potentiometry and spectrophotometry. The content of selected polyphenolic compounds with high antioxidant activity was determined by a HPLC–UV/ED method. The total amount of polyphenols was determined by the Folin-Ciocalteu method. The antioxidant activity was determined using five methods (DPPH, FRAP, ABTS, FR and DMPD) that differ in their principles. The content of 13 amino acids was determined by ion-exchange chromatography. The experimental results obtained for the different cultivars were evaluated and compared by statistical and bioinformatic methods. A unique feature of this study lies in the exhaustive analysis of the chosen parameters (amino acids, mineral elements, polyphenolic compounds and antioxidant activity) during one growing season. Full article

(This article belongs to the Collection Bioactive Compounds)

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Open AccessCommunication

A Simple Hydrophilic Palladium(II) Complex as a Highly Efficient Catalyst for Room Temperature Aerobic Suzuki Coupling Reactions in Aqueous Media

by Mengping Guo, Shiwen Liu, Xiuling Zhou, Meiyun Lv, Sanbao Chen and Daoan Xiao

Molecules 2014, 19(5), 6524-6533; https://doi.org/10.3390/molecules19056524 - 21 May 2014

Cited by 13 | Viewed by 6685

Abstract

A study on room temperature Suzuki cross-coupling in an aqueous medium was carried out using a simple hydrophilic palladium (II) complex, trans-PdCl₂(NH₂CH₂COOH)₂ as catalyst in the presence of K₂CO₃ in air. This [...] Read more.

A study on room temperature Suzuki cross-coupling in an aqueous medium was carried out using a simple hydrophilic palladium (II) complex, trans-PdCl₂(NH₂CH₂COOH)₂ as catalyst in the presence of K₂CO₃ in air. This approach with a comparatively inexpensive and hydrophilic catalyst, mild reaction condition and aqueous media exhibits excellent catalytic activity towards the Suzuki coupling of aryl bromides and arylboronic acids, and good yields were obtained in the Suzuki coupling of activated aryl chlorides. Full article

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Open AccessArticle

Berberine Enhances the Antibacterial Activity of Selected Antibiotics against Coagulase-Negative Staphylococcus Strains in Vitro

by Robert D. Wojtyczka, Arkadiusz Dziedzic, Małgorzata Kępa, Robert Kubina, Agata Kabała-Dzik, Tomasz Mularz and Danuta Idzik

Molecules 2014, 19(5), 6583-6596; https://doi.org/10.3390/molecules19056583 - 22 May 2014

Cited by 96 | Viewed by 10313

Abstract

Synergistic interactions between commonly used antibiotics and natural bioactive compounds may exhibit therapeutic benefits in a clinical setting. Berberine, an isoquinoline-type alkaloid isolated from many kinds of medicinal plants, has proven efficacy against a broad spectrum of microorganisms. The aim of the presented [...] Read more.

Synergistic interactions between commonly used antibiotics and natural bioactive compounds may exhibit therapeutic benefits in a clinical setting. Berberine, an isoquinoline-type alkaloid isolated from many kinds of medicinal plants, has proven efficacy against a broad spectrum of microorganisms. The aim of the presented work was to assess the antibacterial activity of berberine chloride in light of the effect exerted by common antibiotics on fourteen reference strains of Staphylococccus spp., and to evaluate the magnitude of interactions of berberine with these antistaphylococcal antibiotics. In our study minimum inhibitory concentrations (MIC) of berberine chloride against CoNS ranged from 16 to 512 µg/mL. The most noticeable effects were observed for S. haemolyticus ATCC 29970, S. epidermidis ATCC 12228, S. capitis subsp. capitis ATCC 35661, S. galinarium ATCC 700401, S. hominis subsp. hominis ATCC 27844, S. intermedius ATCC 29663 and S. lugdunensis ATCC 49576. The most significant synergistic effect was noticed for berberine in combination with linezolid, cefoxitin and erythromycin. The synergy between berberine and antibiotics demonstrates the potential application of compound combinations as an efficient, novel therapeutic tool for antibiotic-resistant bacterial infections. Full article

(This article belongs to the Section Natural Products Chemistry)

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Open AccessArticle

Bioactive Secondary Metabolites from Phomopsis sp., an Endophytic Fungus from Senna spectabilis

by Vanessa Mara Chapla, Maria Luiza Zeraik, Valdecir F. Ximenes, Lisinéia Maria Zanardi, Márcia N. Lopes, Alberto José Cavalheiro, Dulce Helena S. Silva, Maria Cláudia M. Young, Luiz Marcos da Fonseca, Vanderlan S. Bolzani and Angela Regina Araújo

Molecules 2014, 19(5), 6597-6608; https://doi.org/10.3390/molecules19056597 - 22 May 2014

Cited by 57 | Viewed by 9552

Abstract

Chemical investigation of an acetonitrile fraction from the endophytic fungus Phomopsis sp. led to the isolation of the new natural product 2-hydroxy-alternariol (7) together with the known compounds cytochalasins J (1) and H (2), 5'-epialtenuene (3 [...] Read more.

Chemical investigation of an acetonitrile fraction from the endophytic fungus Phomopsis sp. led to the isolation of the new natural product 2-hydroxy-alternariol (7) together with the known compounds cytochalasins J (1) and H (2), 5'-epialtenuene (3) and the mycotoxins alternariol monomethyl ether (AME, 4), alternariol (AOH, 5) and cytosporone C (6). The structure of the new compound was elucidated by using 1-D and 2-D NMR (nuclear magnetic resonance) and high resolution mass spectrometry. The cytochalasins J (1) and H (2) and AOH (5) exhibited potent inhibition of the total ROS (reactive oxygen species) produced by stimulated human neutrophils and acted as potent potential anti-inflammatory agents. Moreover, cytochalasin H (2) demonstrated antifungal and acetylcholinesterase enzyme (AChE) inhibition in vitro. Full article

(This article belongs to the Section Natural Products Chemistry)

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Open AccessArticle

In Silico Docking, Molecular Dynamics and Binding Energy Insights into the Bolinaquinone-Clathrin Terminal Domain Binding Site

by Mohammed K. Abdel-Hamid and Adam McCluskey

Molecules 2014, 19(5), 6609-6622; https://doi.org/10.3390/molecules19056609 - 22 May 2014

Cited by 48 | Viewed by 12222

Abstract

Clathrin-mediated endocytosis (CME) is a process that regulates selective internalization of important cellular cargo using clathrin-coated vesicles. Perturbation of this process has been linked to many diseases including cancer and neurodegenerative conditions. Chemical proteomics identified the marine metabolite, 2-hydroxy-5-methoxy-3-(((1S,4aS,8a [...] Read more.

Clathrin-mediated endocytosis (CME) is a process that regulates selective internalization of important cellular cargo using clathrin-coated vesicles. Perturbation of this process has been linked to many diseases including cancer and neurodegenerative conditions. Chemical proteomics identified the marine metabolite, 2-hydroxy-5-methoxy-3-(((1S,4aS,8aS)-1,4a,5-trimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-2-yl)methyl)cyclohexa- 2,5-diene-1,4-dione (bolinaquinone) as a clathrin inhibitor. While being an attractive medicinal chemistry target, the lack of data about bolinaquinone’s mode of binding to the clathrin enzyme represents a major limitation for its structural optimization. We have used a molecular modeling approach to rationalize the observed activity of bolinaquinone and to predict its mode of binding with the clathrin terminal domain (CTD). The applied protocol started by global rigid-protein docking followed by flexible docking, molecular dynamics and linear interaction energy calculations. The results revealed the potential of bolinaquinone to interact with various pockets within the CTD, including the clathrin-box binding site. The results also highlight the importance of electrostatic contacts over van der Waals interactions for proper binding between bolinaquinone and its possible binding sites. This study provides a novel model that has the potential to allow rapid elaboration of bolinaquinone analogues as a new class of clathrin inhibitors. Full article

(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)

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Open AccessArticle

New Flavanol and Cycloartane Glucosides from Landoltia punctata

by Nini Wang, Guobo Xu, Yang Fang, Tao Yang, Hai Zhao and Guoyou Li

Molecules 2014, 19(5), 6623-6634; https://doi.org/10.3390/molecules19056623 - 22 May 2014

Cited by 10 | Viewed by 6252

Abstract

Chemical investigation on the constituents of Landoltia punctata led to the isolation and identification of 17 compounds, four of which were new and identified as (3b,24S)-9,19-cycloartane-3,22,24,25-tetraol 3-O-[b-D-glucopyranosyl-(1→2)]-[b-D-glucopyranosyl-(1→6)]-b-D-glucopyranoside (1), (3 [...] Read more.

Chemical investigation on the constituents of Landoltia punctata led to the isolation and identification of 17 compounds, four of which were new and identified as (3b,24S)-9,19-cycloartane-3,22,24,25-tetraol 3-O-[b-D-glucopyranosyl-(1→2)]-[b-D-glucopyranosyl-(1→6)]-b-D-glucopyranoside (1), (3b,24S)-9,19-cycloartane-3,24,25-triol 3-O-[b-d-glucopyranosyl-(1→2)]-[b-D-glucopyranosyl-(1→6)]-b-D-glucopyranoside (2), 3,4'-dihydroxy-7,3'-dimethoxyflavan-5-O-b-D-glucopyranoside (3) and 3,4'-dihydroxy-4,7,3'-trimethoxyflavan-5-O-b-D-glucopyranoside (4). Their structures were elucidated by spectroscopic, chemical, and biochemical methods. Thus, cycloartane triterpenoids were discovered in the Lemnaceae family for the first time. Compound 3 showed antioxidant capacity in the positively charged 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid radical (ABTS^+•) and superoxide anion radical scavenging assays. Full article

(This article belongs to the Section Natural Products Chemistry)

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Open AccessArticle

A Novel Aqueous Two Phase System Composed of a Thermo-Separating Polymer and an Organic Solvent for Purification of Thermo-Acidic Amylase Enzyme from Red Pitaya (Hylocereus polyrhizus) Peel

by Mehrnoush Amid, Yazid Manap and Nor Khanani Zohdi

Molecules 2014, 19(5), 6635-6650; https://doi.org/10.3390/molecules19056635 - 22 May 2014

Cited by 20 | Viewed by 6617

Abstract

The purification of thermo-acidic amylase enzyme from red pitaya (Hylocereus polyrhizus) peel for the first time was investigated using a novel aqueous two-phase system (ATPS) consisting of a thermo-separating copolymer and an organic solvent. The effectiveness of different parameters such as [...] Read more.

The purification of thermo-acidic amylase enzyme from red pitaya (Hylocereus polyrhizus) peel for the first time was investigated using a novel aqueous two-phase system (ATPS) consisting of a thermo-separating copolymer and an organic solvent. The effectiveness of different parameters such as molecular weight of the thermo-separating ethylene oxide-propylene oxide (EOPO) copolymer and type and concentration of organic solvent on the partitioning behavior of amylase was investigated. In addition, the effects of phase components, volume ratio (V_R), pH and crude load of purification factor and yield of amylase were evaluated to achieve the optimum partition conditions of the enzyme. In the novel ATPS method, the enzyme was satisfactorily partitioned into the polymer-rich top phase in the system composed of 30% (w/w) EOPO 2500 and 15% (w/w) 2-propanol, at a volume ratio of 1.94 and with a crude load scale of 25% (w/w) at pH 5.0. Recovery and recycling of components was also measured in each successive step of the ATPS process. The enzyme was successfully recovered by the method with a high purification factor of 14.3 and yield of 96.6% and copolymer was also recovered and recycled at a rate above 97%, making the method was more economical than the traditional ATPS method. Full article

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Open AccessArticle

Synthesis, Cytotoxicity and Mechanistic Evaluation of 4-Oxoquinoline-3-carboxamide Derivatives: Finding New Potential Anticancer Drugs

by Luana Da S. M. Forezi, Nathalia M. C. Tolentino, Alessandra M. T. De Souza, Helena C. Castro, Raquel C. Montenegro, Rafael F. Dantas, Maria E. I. M. Oliveira, Floriano P. Silva, Jr., Leilane H. Barreto, Rommel M. R. Burbano, Bárbara Abrahim-Vieira, Riethe De Oliveira, Vitor F. Ferreira, Anna C. Cunha, Fernanda Da C. S. Boechat and Maria Cecília B. V. De Souza

Molecules 2014, 19(5), 6651-6670; https://doi.org/10.3390/molecules19056651 - 22 May 2014

Cited by 18 | Viewed by 8956

Abstract

As part of a continuing search for new potential anticancer candidates, we describe the synthesis, cytotoxicity and mechanistic evaluation of a series of 4-oxoquinoline-3-carboxamide derivatives as novel anticancer agents. The inhibitory activity of compounds 10–18 was determined against three cancer cell [...] Read more.

As part of a continuing search for new potential anticancer candidates, we describe the synthesis, cytotoxicity and mechanistic evaluation of a series of 4-oxoquinoline-3-carboxamide derivatives as novel anticancer agents. The inhibitory activity of compounds 10–18 was determined against three cancer cell lines using the MTT colorimetric assay. The screening revealed that derivatives 16b and 17b exhibited significant cytotoxic activity against the gastric cancer cell line but was not active against a normal cell line, in contrast to doxorubicin, a standard chemotherapeutic drug in clinical use. Interestingly, no hemolytical activity was observed when the toxicity of 16b and 17b was tested against blood cells. The in silico and in vitro mechanistic evaluation indicated the potential of 16b as a lead for the development of novel anticancer agents against gastric cancer cells. Full article

(This article belongs to the Section Medicinal Chemistry)

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Open AccessArticle

Synthesis and Antiproliferative Effects of Amino-Modified Perillyl Alcohol Derivatives

by Zi Hui, Meihui Zhang, Lin Cong, Mingyu Xia and Jinhua Dong

Molecules 2014, 19(5), 6671-6682; https://doi.org/10.3390/molecules19056671 - 22 May 2014

Cited by 13 | Viewed by 7389

Abstract

Two series of amino-modified derivatives of (S)-perillyl alcohol were designed and synthesized using (S)-perillaldehyde as the starting material. These derivatives showed increased antiproliferative activity in human lung cancer A549 cells, human melanoma A375-S2 cells and human fibrosarcoma HT-1080 cells [...] Read more.

Two series of amino-modified derivatives of (S)-perillyl alcohol were designed and synthesized using (S)-perillaldehyde as the starting material. These derivatives showed increased antiproliferative activity in human lung cancer A549 cells, human melanoma A375-S2 cells and human fibrosarcoma HT-1080 cells comparing with that of (S)-perillyl alcohol. Among these derivatives, compounds VI₅ and VI₇ were the most potent agents, with the IC₅₀s below 100 μM. It was demonstrated that the antiproliferative effect of VI₅ was mediated through the induction of apoptosis in A549 cells. Full article

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Open AccessArticle

Direct 2,3-O-Isopropylidenation of α-D-Mannopyranosides and the Preparation of 3,6-Branched Mannose Trisaccharides

by Rui Jiang, Guanghui Zong, Xiaomei Liang, Shuhui Jin, Jianjun Zhang and Daoquan Wang

Molecules 2014, 19(5), 6683-6693; https://doi.org/10.3390/molecules19056683 - 22 May 2014

Cited by 7 | Viewed by 7780

Abstract

A highly efficient, regioselective method for the direct 2,3-O-isopropylidenation of α-D-mannopyranosides is reported. Treatment of various α-D-mannopyranosides with 0.12 equiv of the TsOH·H₂O and 2-methoxypropene at 70 °C gave 2,3-O-isopropylidene-α-D-mannopyranosides directly in 80%~90% yields. Based on this [...] Read more.

A highly efficient, regioselective method for the direct 2,3-O-isopropylidenation of α-D-mannopyranosides is reported. Treatment of various α-D-mannopyranosides with 0.12 equiv of the TsOH·H₂O and 2-methoxypropene at 70 °C gave 2,3-O-isopropylidene-α-D-mannopyranosides directly in 80%~90% yields. Based on this method, a 3,6-branched α-D-mannosyl trisaccharide was prepared in 50.4% total yield using p-nitrophenyl 2,3-O-isopropylidene-α-D-mannopyranoside as the starting material. Full article

(This article belongs to the Special Issue Oligosaccharides and Glyco-Conjugates)

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Open AccessArticle

Linalool Exhibits Cytotoxic Effects by Activating Antitumor Immunity

by Mei-Yin Chang and Yi-Ling Shen

Molecules 2014, 19(5), 6694-6706; https://doi.org/10.3390/molecules19056694 - 22 May 2014

Cited by 99 | Viewed by 10657

Abstract

According to recent studies, the Plantaginaceae, which are traditional Chinese herbal remedies, have potential for use in viral infection treatment and cancer therapy. Linalool and p-coumaric acid are two of the biologically active compounds that can be isolated from the Plantaginaceae. [...] Read more.

According to recent studies, the Plantaginaceae, which are traditional Chinese herbal remedies, have potential for use in viral infection treatment and cancer therapy. Linalool and p-coumaric acid are two of the biologically active compounds that can be isolated from the Plantaginaceae. This study mainly focused on investigating the bioactivity of linalool as well as the bioactivity of p-coumaric acid in terms of their cytotoxic effects on cancer cells. Whether the mechanisms of such effects are generated through apoptosis and immunoregulatory activity were also investigated. By using WST-1 analysis, it was shown that linalool and p-coumaric acid have good inhibitory effects against breast, colorectal and liver cancer cells. The IC₅₀ values of linalool for those cancer cell types were 224 μM, 222 μM, and 290 μM, respectively, and the IC₅₀ values of p-coumaric acid were 693 μM, 215 μM and 87 μM, respectively. Cell cycle analysis also confirmed that linalool and p-coumaric acid can lead to apoptosis. By using flow cytometry, it was determined that treatment with linalool rather than p-coumaric acid significantly increased the sub-G1 phase and that there were more cells concentrated in the G1 phase. Furthermore, by using cytokine array analysis, we found that linalool can stimulate IFN-γ, IL-13, IL-2, IL-21, IL-21R, IL-4, IL-6sR and TNF-α secretion. This demonstrated that in addition to the bidirectional regulation capabilities found in linalool, it also induces Th1 cellular immune response in T-47D cells. These results showed that linalool holds great potential for use in cancer therapy, and we believe that it could provide an alternative way to take action against tumors. Full article

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Open AccessArticle

Four New Flavonol Glycosides from the Leaves of Brugmansia suaveolens

by Fabiana Geller, Renato Murillo, Lisa Steinhauser, Berta Heinzmann, Klaus Albert, Irmgard Merfort and Stefan Laufer

Molecules 2014, 19(5), 6727-6736; https://doi.org/10.3390/molecules19056727 - 22 May 2014

Cited by 10 | Viewed by 6684

Abstract

Four new flavonol glycosides were isolated from the leaves of Brugmansia suaveolens: kaempferol 3-O-β-D-glucopyranosyl-(1'''→2'')-O-α-L-arabinopyranoside (1), kaempferol 3-O-β-D-glucopyranosyl-(1'''→2'')-O-α-L-arabinopyranoside-7-O-į-D-gluco-pyranoside (2), kaempferol 3-O-β-D-[6'''-O-(E-caffeoyl)]-glucopyranosyl-(1'''→2'')-O-α-l-arabinopyranoside-7-O-β-D-glucopyranoside (3), and kaempferol 3-O-β-D-[2'''-O-(E-caffeoyl)]-glucopyranosyl-(1'''→2'')-O-α-l-arabinopyranoside-7-O-β-D-glucopyranoside (4). The structure elucidation was performed by MS, 1D and 2D NMR analyses. Full article

(This article belongs to the Section Natural Products Chemistry)

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Open AccessArticle

Synthesis of Silver Nanoparticles by Green Method Stabilized to Synthetic Human Stomach Fluid

by Ayman M. Atta, Hamad A. Al-Lohedan and Abdelrahman O. Ezzat

Molecules 2014, 19(5), 6737-6753; https://doi.org/10.3390/molecules19056737 - 23 May 2014

Cited by 35 | Viewed by 9890

Abstract

Silver nanoparticles (Ag NP) have been attracted much attention in recent years in biomedical applications due to their antimicrobial activity, but their drawbacks include toxicity and instability to aqueous hydrochloric acid solutions. Ag NPs have now been successfully prepared by a simple and [...] Read more.

Silver nanoparticles (Ag NP) have been attracted much attention in recent years in biomedical applications due to their antimicrobial activity, but their drawbacks include toxicity and instability to aqueous hydrochloric acid solutions. Ag NPs have now been successfully prepared by a simple and “green” synthesis method by reducing Ag⁺ ions in the presence of modified poly(vinyl alcohol) thiol (PVA-SH) in aqueous acidic solution. In this respect, Ag NPs were stabilized by coating different types of citrate-reduced Ag NPs with different weight ratios (1–3 Wt. %) of PVSH derivatives. The as-prepared Ag NPs were characterized using UV-Visible, high resolution transmission electron microscopy/ energy dispersive X-ray spectroscopy (TEM/EDS), dynamic light scattering (DLS) and X-ray powder diffraction (XRD) combined with Rietveld analysis. The changes in size, shape, and hydrodynamic diameter of Ag NPs after different duration exposure to synthetic stomach fluid (SSF) and1 M HCl were determined using TEM, XRD and UV-Visible analyses. The data indicated that these Ag NPs possessed high stability to SSF for more than 90 days, which was not previously reported in the literature. Full article

(This article belongs to the Collection Bioactive Compounds)

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Open AccessArticle

A Facile Route to Tailoring Peptide-Stabilized Gold Nanoparticles Using Glutathione as a Synthon

by Rosina Ho Wu, Tan P. Nguyen, Grant W. Marquart, Thomas J. Miesen, Theresa Mau and Marilyn R. Mackiewicz

Molecules 2014, 19(5), 6754-6775; https://doi.org/10.3390/molecules19056754 - 23 May 2014

Cited by 29 | Viewed by 12504

Abstract

The preparation of gold nanoparticles (AuNPs) of high purity and stability remains a major challenge for biological applications. This paper reports a simple synthetic strategy to prepare water-soluble peptide-stabilized AuNPs. Reduced glutathione, a natural tripeptide, was used as a synthon for the growth [...] Read more.

The preparation of gold nanoparticles (AuNPs) of high purity and stability remains a major challenge for biological applications. This paper reports a simple synthetic strategy to prepare water-soluble peptide-stabilized AuNPs. Reduced glutathione, a natural tripeptide, was used as a synthon for the growth of two peptide chains directly on the AuNP surface. Both nonpolar (tryptophan and methionine) and polar basic (histidine and dansylated arginine) amino acids were conjugated to the GSH-capped AuNPs. Ultracentrifugation concentrators with polyethersulfone (PES) membranes were used to purify precursor materials in each stage of the multi-step synthesis to minimize side reactions. Thin layer chromatography, transmission electron microscopy, UV-Visible, ¹H-NMR, and fluorescence spectroscopies demonstrated that ultracentrifugation produces high purity AuNPs, with narrow polydispersity, and minimal aggregation. More importantly, it allows for more control over the composition of the final ligand structure. Studies under conditions of varying pH and ionic strength revealed that peptide length, charge, and hydrophobicity influence the stability as well as solubility of the peptide-capped AuNPs. The synthetic and purification strategies used provide a facile route for developing a library of tailored biocompatible peptide-stabilized AuNPs for biomedical applications. Full article

(This article belongs to the Special Issue Bioconjugations)

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Avicequinone C Isolated from Avicennia marina Exhibits 5α-Reductase-Type 1 Inhibitory Activity Using an Androgenic Alopecia Relevant Cell-Based Assay System

by Ruchy Jain, Orawan Monthakantirat, Parkpoom Tengamnuay and Wanchai De-Eknamkul

Molecules 2014, 19(5), 6809-6821; https://doi.org/10.3390/molecules19056809 - 23 May 2014

Cited by 27 | Viewed by 11312

Abstract

Avicennia marina (AM) exhibits various biological activities and has been traditionally used in Egypt to cure skin diseases. In this study, the methanolic heartwood extract of AM was evaluated for inhibitory activity against 5α-reductase (5α-R) [E.C.1.3.99.5], the enzyme responsible for the over-production of [...] Read more.

Avicennia marina (AM) exhibits various biological activities and has been traditionally used in Egypt to cure skin diseases. In this study, the methanolic heartwood extract of AM was evaluated for inhibitory activity against 5α-reductase (5α-R) [E.C.1.3.99.5], the enzyme responsible for the over-production of 5α-dihydrotestosterone (5α-DHT) causing androgenic alopecia (AGA). An AGA-relevant cell-based assay was developed using human hair dermal papilla cells (HHDPCs), the main regulator of hair growth and the only cells within the hair follicle that are the direct site of 5α-DHT action, combined with a non-radioactive thin layer chromatography (TLC) detection technique. The results revealed that AM is a potent 5α-R type 1 (5α-R1) inhibitor, reducing the 5α-DHT production by 52% at the final concentration of 10 µg/mL. Activity-guided fractionation has led to the identification of avicequinone C, a furanonaphthaquinone, as a 5α-R1 inhibitor with an IC₅₀ of 9.94 ± 0.33 µg/mL or 38.8 ± 1.29 µM. This paper is the first to report anti-androgenic activity through 5α-R1 inhibition of AM and avicequinone C. Full article

(This article belongs to the Collection Bioactive Compounds)

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Open AccessArticle

Synthesis and Antibacterial Activity of Amino Acid and Dipeptide Prodrugs of IMB-070593, a Fluoroquinolone Candidate

by Tingting Zhang, Jinwei Wu, Shihong Chen, Kaixiang Liu, Yabin Lin, Huiyuan Guo and Mingliang Liu

Molecules 2014, 19(5), 6822-6837; https://doi.org/10.3390/molecules19056822 - 23 May 2014

Cited by 13 | Viewed by 6355

Abstract

A series of amino acid and dipeptide prodrugs of IMB-070593, a fluoroquinolone candidate discovered in our lab, were synthesized and evaluated for their water solubility and then antibacterial activity. Our results reveal that four amino acid prodrugs 4a,b,e, [...] Read more.

A series of amino acid and dipeptide prodrugs of IMB-070593, a fluoroquinolone candidate discovered in our lab, were synthesized and evaluated for their water solubility and then antibacterial activity. Our results reveal that four amino acid prodrugs 4a,b,e,f and two dipeptide prodrugs 4k,l have much greater solubility (>85 mg/mL) than IMB-070593 mesylate (22.5 mg/mL). Compounds 4a and 4k show good in vivo efficacy against MSSA 12-1 (p.o./i.v., 5.32–7.68 mg/kg) and S. pneumoniae12-10 (p.o., 18.39–23.13 mg/kg) which is 1.19–1.50 fold more active than the parent drug. Full article

(This article belongs to the Section Medicinal Chemistry)

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Open AccessCommunication

A New Diterpene from Litsea cubeba Fruits: Structure Elucidation and Capability to Induce Apoptosis in HeLa Cells

by Piyapat Trisonthi, Akihiko Sato, Hisashi Nishiwaki and Hirotoshi Tamura

Molecules 2014, 19(5), 6838-6850; https://doi.org/10.3390/molecules19056838 - 23 May 2014

Cited by 29 | Viewed by 6557

Abstract

A new diterpene, identified as (+)-6-(4-hydroxy-4-methyl-2-pentenoyl)-4,6-dimethyl-5-(3-methyl-2-butenyl)-1,3-cyclohexadienecarbaldehyde (1, cubelin), was isolated from a methanol extract of Litsea cubeba fruits by normal phase column chromatography and purified by preparative HPLC. The structure elucidation was conducted by spectroscopic methods (UV, IR, ESI-TOF-MS, 1-D and [...] Read more.

A new diterpene, identified as (+)-6-(4-hydroxy-4-methyl-2-pentenoyl)-4,6-dimethyl-5-(3-methyl-2-butenyl)-1,3-cyclohexadienecarbaldehyde (1, cubelin), was isolated from a methanol extract of Litsea cubeba fruits by normal phase column chromatography and purified by preparative HPLC. The structure elucidation was conducted by spectroscopic methods (UV, IR, ESI-TOF-MS, 1-D and 2-D NMR). Cubelin exhibited activity against HeLa cell viability and proliferation. The cells also exhibited changes in nuclear morphology which are hallmarks of apoptotic cell death. The presence of cleaved caspase-3/-7, caspase-8 and caspase-9 in the cubelin treated population indicated the potential of the compound to induce apoptosis in HeLa cells via both intrinsic and extrinsic pathways. Full article

(This article belongs to the Section Natural Products Chemistry)

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Open AccessArticle

Associations of nm23H1, VEGF-C, and VEGF-3 Receptor in Human Prostate Cancer

by Zui-Su Yang, Yin-Feng Xu, Fang-Fang Huang and Guo-Fang Ding

Molecules 2014, 19(5), 6851-6862; https://doi.org/10.3390/molecules19056851 - 23 May 2014

Cited by 16 | Viewed by 5488

Abstract

We studied the expression of the non-metastatic clone 23 type 1 (nm23H1) gene, vascular endothelial growth factor (VEGF)-C, and its receptor VEGFR-3 using an in situ hybridization technique and immunohistochemical analyses with prostate cancer tissues and adjacent benign tissues of 52 human archival [...] Read more.

We studied the expression of the non-metastatic clone 23 type 1 (nm23H1) gene, vascular endothelial growth factor (VEGF)-C, and its receptor VEGFR-3 using an in situ hybridization technique and immunohistochemical analyses with prostate cancer tissues and adjacent benign tissues of 52 human archival cases. The association between VEGF-C expression, microlymphatic count (MLC), and staining intensity for nm23H1 and VEGFR-3 was used to evaluate tumor metastasis and survival rate. MLC values were significantly higher in tumorous tissue than in non-cancerous tissue. VEGF-C mRNA, VEGFR-3, and nm23H1 were highly expressed in tumorous tissue. VEGFR-3 expression was greater in VEGF-C mRNA-positive tumors than in VEGF-C mRNA-negative tumors. The association of VEGFR-3 expression with VEGF-C mRNA and MLC suggested that the poor prognosis and tumor metastasis associated with VEGFR-3 expression may be due, in part, to its role in promoting angiogenesis. VEGF-C expression was significantly associated with tumor lymphangiogenesis, angiogenesis, and immune response as a potent multifunctional stimulating factor in prostate cancer. Expression of nm23H1 was significantly inversely correlated with lymph node metastasis. Furthermore, there was a strong negative correlation between the expression of nm23H1, VEGF-C mRNA, and MLC. These findings provide important information for prophylactic, diagnostic, and therapeutic strategies for prostate cancer. Full article

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Open AccessArticle

Calcium Influx Inhibition is Involved in the Hypotensive and Vasorelaxant Effects Induced by Yangambin

by Islania Giselia Albuquerque Araújo, Darizy Flávia Silva, Maria Do Carmo de Alustau, Katy Lísias Gondim Dias, Karla Veruska Marques Cavalcante, Robson Cavalcante Veras, José Maria Barbosa-Filho, Mario Dos Anjos Neto, Lusiane Maria Bendhack, Nadja De Azevedo Correia and Isac Almeida de Medeiros

Molecules 2014, 19(5), 6863-6876; https://doi.org/10.3390/molecules19056863 - 23 May 2014

Cited by 10 | Viewed by 6524

Abstract

The pharmacological effects on the cardiovascular system of yangambin, a lignan isolated from Ocotea duckei Vattimo (Lauraceae), were studied in rats using combined functional and biochemical approaches. In non-anaesthetized rats, yangambin (1, 5, 10, 20, 30 mg/kg, i.v.) induced hypotension (−3.5 ± 0.2; [...] Read more.

The pharmacological effects on the cardiovascular system of yangambin, a lignan isolated from Ocotea duckei Vattimo (Lauraceae), were studied in rats using combined functional and biochemical approaches. In non-anaesthetized rats, yangambin (1, 5, 10, 20, 30 mg/kg, i.v.) induced hypotension (−3.5 ± 0.2; −7.1 ± 0.8; −8.9 ± 1.3; −14 ± 2.3, −25.5% ± 2.6%, respectively) accompanied by tachycardia (5.9 ± 0.5; 5.9 ± 1.6; 8.8 ± 1.4; 11.6, 18.8% ± 3.4%, respectively). In isolated rat atria, yangambin (0.1 µM–1 mM) had very slight negative inotropic (Emax = 35.6% ± 6.4%) and chronotropic effects (Emax = 10.2% ± 2.9%). In endothelium-intact rat mesenteric artery, yangambin (0.1 µM–1 mM) induced concentration-dependent relaxation (pD₂ = 4.5 ± 0.06) of contractions induced by phenylephrine and this effect was not affected by removal of the endothelium. Interestingly, like nifedipine, the relaxant effect induced by yangambin was more potent on the contractile response induced by KCl 80 mM (pD₂ = 4.8 ± 0.05) when compared to that induced by phenylephrine. Furthermore, yangambin inhibited CaCl₂-induced contractions in a concentration-dependent manner. This lignan also induced relaxation (pD₂ = 4.0 ± 0.04) of isolated arteries pre-contracted with S(−)-Bay K 8644. In fura-2/AM-loaded myocytes of rat mesenteric arteries, yangambin inhibited the Ca²⁺ signal evoked by KCl 60 mM. In conclusion, these results suggest that the hypotensive effect of yangambin is probably due to a peripheral vasodilatation that involves, at least, the inhibition the Ca²⁺ influx through voltage-gated Ca²⁺ channels. Full article

(This article belongs to the Section Natural Products Chemistry)

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Open AccessArticle

Two-Stage Prediction of the Effects of Imidazolium and Pyridinium Ionic Liquid Mixtures on Luciferase

by Hui-Lin Ge, Shu-Shen Liu, Bing-Xia Su and Xiang-Wei Zhu

Molecules 2014, 19(5), 6877-6890; https://doi.org/10.3390/molecules19056877 - 23 May 2014

Cited by 11 | Viewed by 5602

Abstract

The predicted toxicity of mixtures of imidazolium and pyridinium ionic liquids (ILs) in the ratios of their EC₅₀, EC₁₀, and NOEC (no observed effect concentration) were compared to the observed toxicity of these mixtures on luciferase. The toxicities of [...] Read more.

The predicted toxicity of mixtures of imidazolium and pyridinium ionic liquids (ILs) in the ratios of their EC₅₀, EC₁₀, and NOEC (no observed effect concentration) were compared to the observed toxicity of these mixtures on luciferase. The toxicities of EC₅₀ ratio mixture can be effectively predicted by two-stage prediction (TSP) method, but were overestimated by the concentration addition (CA) model and underestimated by the independent action (IA) model. The toxicities of EC₁₀ ratio mixtures can be basically predicted by TSP and CA, but were underestimated by IA. The toxicities of NOEC ratio mixtures can be predicted by TSP and CA in a certain concentration range, but were underestimated by IA. Our results support the use of TSP as a default approach for predicting the combined effect of different types of ILs at the molecular level. In addition, mixtures of ILs mixed at NOEC and EC₁₀ could cause significant effects of 64.1% and 97.7%, respectively. Therefore, we should pay high attention to the combined effects in mixture risk assessment. Full article

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Review

Jump to: Research

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Open AccessReview

The Role of microRNA in Head and Neck Cancer: Current Knowledge and Perspectives

by Giulia Courthod, Pierfrancesco Franco, Loredana Palermo, Salvatore Pisconti and Gianmauro Numico

Molecules 2014, 19(5), 5704-5716; https://doi.org/10.3390/molecules19055704 - 5 May 2014

Cited by 32 | Viewed by 9390

Abstract

Head and neck cancer is one of the most commonly diagnosed malignancies worldwide. Patients with advanced disease stages frequently develop recurrences or distant metastasis, which results a five-year survival rates of less than 60% despite considerable advances in multimodality therapy. A better understanding [...] Read more.

Head and neck cancer is one of the most commonly diagnosed malignancies worldwide. Patients with advanced disease stages frequently develop recurrences or distant metastasis, which results a five-year survival rates of less than 60% despite considerable advances in multimodality therapy. A better understanding of molecular basis of tumorigenesis is required to improve clinical outcomes and to develop new anti-cancer drugs. microRNAs (miRNAs) are a class of small, non-coding, RNA molecules that modulate gene expression post-transcriptionally. They are important regulator in normal biological process; however miRNAs deregulation has been observed in many different tumors and is involved in tumorigenesis. miRNAs may act as tumor suppressors or as oncogenes. Several studies on head and neck cancer demonstrated how aberrant expression of miRNAs is involved in proliferation, metastasis, chemoresistence, and radioresistance. In addition, miRNAs are excellent biomarker targets because they circulate stable in human body fluids and can be obtained with non-invasive methods. Moreover, miRNAs up and down regulation has been correlated with specific cancer phenotype (poor prognosis, aggressiveness and resistance to treatment), playing a role as prognostic biomarkers. This review summarizes current finding on miRNAs in head and neck cancer and their potential role as target for next drug therapy. Full article

(This article belongs to the Special Issue miRNAs as Probes to Monitor Cancer and Neurodegenerative Disorders)

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Open AccessReview

Anti-Ulcer Activity of Essential Oil Constituents

by Francisco De Assis Oliveira, Luciana Nalone Andrade, Élida Batista Vieira De Sousa and Damião Pergentino De Sousa

Molecules 2014, 19(5), 5717-5747; https://doi.org/10.3390/molecules19055717 - 5 May 2014

Cited by 52 | Viewed by 12133

Abstract

Essential oils have attracted considerable worldwide attention over the last few decades. These natural products have wide-ranging pharmacological activities and biotechnological applications. Faced with the need to find new anti-ulcer agents and the great effort on the development of drugs for the treatment [...] Read more.

Essential oils have attracted considerable worldwide attention over the last few decades. These natural products have wide-ranging pharmacological activities and biotechnological applications. Faced with the need to find new anti-ulcer agents and the great effort on the development of drugs for the treatment of ulcers, in this review, the anti-ulcer activities of 21 bioactive compounds found in essential oils are discussed. Full article

(This article belongs to the Section Natural Products Chemistry)

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Open AccessReview

Significance and Therapeutic Value of miRNAs in Embryonal Neural Tumors

by Tarek Shalaby, Giulio Fiaschetti, Martin Baumgartner and Michael A. Grotzer

Molecules 2014, 19(5), 5821-5862; https://doi.org/10.3390/molecules19055821 - 6 May 2014

Cited by 13 | Viewed by 6853

Abstract

Embryonal tumors of the nervous system are the leading cause of childhood cancer-related morbidity and mortality. Medulloblastoma, supratentorial primitive neuroectodermal tumors, atypical teratoid/rhabdoid tumor and neuroblastoma account for more than 20% of childhood malignancies and typify the current neural embryonal tumor model in [...] Read more.

Embryonal tumors of the nervous system are the leading cause of childhood cancer-related morbidity and mortality. Medulloblastoma, supratentorial primitive neuroectodermal tumors, atypical teratoid/rhabdoid tumor and neuroblastoma account for more than 20% of childhood malignancies and typify the current neural embryonal tumor model in pediatric oncology. Mechanisms driving the formation of these tumors point towards impaired differentiation of neuronal and neuron-associated cells during the development of the nervous system as an important factor. The importance of microRNAs (miRNAs) for proper embryonic cell function has been confirmed and their aberrant expressions have been linked to tumor development. The role of miRNAs in controlling essential regulators of key pathways implicated in tumor development makes their use in diagnostics a powerful tool to be used for early detection of cancer, risk assessment and prognosis, as well as for the design of innovative therapeutic strategies. In this review we focus on the significance of miRNAs involved in the biology of embryonal neural tumors, delineate their clinical significance and discuss their potential as a novel therapeutic target. Full article

(This article belongs to the Special Issue miRNAs as Probes to Monitor Cancer and Neurodegenerative Disorders)

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Open AccessReview

Issues and Prospects of microRNA-Based Biomarkers in Blood and Other Body Fluids

by John R. Chevillet, Inyoul Lee, Hilary A. Briggs, Yuqing He and Kai Wang

Molecules 2014, 19(5), 6080-6105; https://doi.org/10.3390/molecules19056080 - 14 May 2014

Cited by 95 | Viewed by 9654

Abstract

Cell-free circulating microRNAs (miRNAs) in the blood are good diagnostic biomarker candidates for various physiopathological conditions, including cancer, neurodegeneration, diabetes and other diseases. Since their discovery in 2008 as blood biomarkers, the field has expanded rapidly with a number of important findings. Despite [...] Read more.

Cell-free circulating microRNAs (miRNAs) in the blood are good diagnostic biomarker candidates for various physiopathological conditions, including cancer, neurodegeneration, diabetes and other diseases. Since their discovery in 2008 as blood biomarkers, the field has expanded rapidly with a number of important findings. Despite the initial optimistic views of their potential for clinical application, there are currently no circulating miRNA-based diagnostics in use. In this article, we review the status of circulating miRNAs, examine different analytical approaches, and address some of the challenges and opportunities. Full article

(This article belongs to the Special Issue miRNAs as Probes to Monitor Cancer and Neurodegenerative Disorders)

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Open AccessReview

Ultraviolet Radiation, Aging and the Skin: Prevention of Damage by Topical cAMP Manipulation

by Alexandra Amaro-Ortiz, Betty Yan and John A. D'Orazio

Molecules 2014, 19(5), 6202-6219; https://doi.org/10.3390/molecules19056202 - 15 May 2014

Cited by 248 | Viewed by 33719

Abstract

Being the largest and most visible organ of the body and heavily influenced by environmental factors, skin is ideal to study the long-term effects of aging. Throughout our lifetime, we accumulate damage generated by UV radiation. UV causes inflammation, immune changes, physical changes, [...] Read more.

Being the largest and most visible organ of the body and heavily influenced by environmental factors, skin is ideal to study the long-term effects of aging. Throughout our lifetime, we accumulate damage generated by UV radiation. UV causes inflammation, immune changes, physical changes, impaired wound healing and DNA damage that promotes cellular senescence and carcinogenesis. Melanoma is the deadliest form of skin cancer and among the malignancies of highest increasing incidence over the last several decades. Melanoma incidence is directly related to age, with highest rates in individuals over the age of 55 years, making it a clear age-related disease. In this review, we will focus on UV-induced carcinogenesis and photo aging along with natural protective mechanisms that reduce amount of “realized” solar radiation dose and UV-induced injury. We will focus on the theoretical use of forskolin, a plant-derived pharmacologically active compound to protect the skin against UV injury and prevent aging symptoms by up-regulating melanin production. We will discuss its use as a topically-applied root-derived formulation of the Plectranthus barbatus (Coleus forskolii) plant that grows naturally in Asia and that has long been used in various Aryuvedic teas and therapeutic preparations. Full article

(This article belongs to the Special Issue Natural Antioxidants and Ageing)

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Open AccessReview

MicroRNAs in Cervical Cancer: Evidences for a miRNA Profile Deregulated by HPV and Its Impact on Radio-Resistance

by Abraham Pedroza-Torres, Eduardo López-Urrutia, Verónica García-Castillo, Nadia Jacobo-Herrera, Luis A. Herrera, Oscar Peralta-Zaragoza, César López-Camarillo, David Cantú De Leon, Jorge Fernández-Retana, Jorge F. Cerna-Cortés and Carlos Pérez-Plasencia

Molecules 2014, 19(5), 6263-6281; https://doi.org/10.3390/molecules19056263 - 16 May 2014

Cited by 60 | Viewed by 15514

Abstract

Cervical carcinoma (CC) is one of the most common cancers and a leading cause of mortality in women worldwide. Epidemiologic and experimental data have clearly demonstrated a causal role of high-risk Human Papillomavirus (HR-HPV) types in CC initiation and progression, affecting the cellular [...] Read more.

Cervical carcinoma (CC) is one of the most common cancers and a leading cause of mortality in women worldwide. Epidemiologic and experimental data have clearly demonstrated a causal role of high-risk Human Papillomavirus (HR-HPV) types in CC initiation and progression, affecting the cellular processes by targeting and inactivating p53 and pRB host proteins. HR-HPV E5, E6 and E7 oncoproteins have the ability to deregulate several cellular processes, mostly apoptosis, cell cycle control, migration, immune evasion, and induction of genetic instability, which promote the accumulation of mutations and aneuploidy. In this scenario, genomic profiles have shown that aberrant expression of cellular oncogenic and tumor suppressive miRNAs have an important role in CC carcinogenesis. It has been stated that HPV infection and E6/E7 expression are essential but not sufficient to lead to CC development; hence other genetic and epigenetic factors have to be involved in this complex disease. Recent evidence suggests an important level of interaction among E6/E7 viral proteins and cellular miRNA, and other noncoding RNAs. The aim of the current review is to analyze recent data that mainly describe the interaction between HR-HPV established infections and specific cellular miRNAs; moreover, to understand how those interactions could affect radio-therapeutic response in tumor cells. Full article

(This article belongs to the Special Issue miRNAs as Probes to Monitor Cancer and Neurodegenerative Disorders)

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Mixture-Based Combinatorial Libraries from Small Individual Peptide Libraries: A Case Study on α₁-Antitrypsin Deficiency

by Yi-Pin Chang and Yen-Ho Chu

Molecules 2014, 19(5), 6330-6348; https://doi.org/10.3390/molecules19056330 - 16 May 2014

Cited by 4 | Viewed by 7943

Abstract

The design, synthesis and screening of diversity-oriented peptide libraries using a “libraries from libraries” strategy for the development of inhibitors of α₁-antitrypsin deficiency are described. The major buttress of the biochemical approach presented here is the use of well-established solid-phase split-and-mix [...] Read more.

The design, synthesis and screening of diversity-oriented peptide libraries using a “libraries from libraries” strategy for the development of inhibitors of α₁-antitrypsin deficiency are described. The major buttress of the biochemical approach presented here is the use of well-established solid-phase split-and-mix method for the generation of mixture-based libraries. The combinatorial technique iterative deconvolution was employed for library screening. While molecular diversity is the general consideration of combinatorial libraries, exquisite design through systematic screening of small individual libraries is a prerequisite for effective library screening and can avoid potential problems in some cases. This review will also illustrate how large peptide libraries were designed, as well as how a conformation-sensitive assay was developed based on the mechanism of the conformational disease. Finally, the combinatorially selected peptide inhibitor capable of blocking abnormal protein aggregation will be characterized by biophysical, cellular and computational methods. Full article

(This article belongs to the Special Issue Combinatorial Synthesis)

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Utilization of Acidic α-Amino Acids as Acyl Donors: An Effective Stereo-Controllable Synthesis of Aryl-Keto α-Amino Acids and Their Derivatives

by Lei Wang, Yuta Murai, Takuma Yoshida, Masashi Okamoto, Zetryana Puteri Tachrim, Yasuyuki Hashidoko and Makoto Hashimoto

Molecules 2014, 19(5), 6349-6367; https://doi.org/10.3390/molecules19056349 - 16 May 2014

Cited by 9 | Viewed by 11159

Abstract

Aryl-keto-containing α-amino acids are of great importance in organic chemistry and biochemistry. They are valuable intermediates for the construction of hydroxyl α-amino acids, nonproteinogenic α-amino acids, as well as other biofunctional components. Friedel-Crafts acylation is an effective method to prepare [...] Read more.

Aryl-keto-containing α-amino acids are of great importance in organic chemistry and biochemistry. They are valuable intermediates for the construction of hydroxyl α-amino acids, nonproteinogenic α-amino acids, as well as other biofunctional components. Friedel-Crafts acylation is an effective method to prepare aryl-keto derivatives. In this review, we summarize the preparation of aryl-keto containing α-amino acids by Friedel-Crafts acylation using acidic α-amino acids as acyl-donors and Lewis acids or Brönsted acids as catalysts. Full article

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The role of Micro-RNAs in Hepatocellular Carcinoma: From Molecular Biology to Treatment

by Marco D'Anzeo, Luca Faloppi, Mario Scartozzi, Riccardo Giampieri, Maristella Bianconi, Michela Del Prete, Nicola Silvestris and Stefano Cascinu

Molecules 2014, 19(5), 6393-6406; https://doi.org/10.3390/molecules19056393 - 19 May 2014

Cited by 55 | Viewed by 8146

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer deaths. microRNAs (miRNAs) are evolutionary conserved small non-coding RNA that negatively regulate gene expression and protein translation. Recent evidences have shown that they are involved in [...] Read more.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer deaths. microRNAs (miRNAs) are evolutionary conserved small non-coding RNA that negatively regulate gene expression and protein translation. Recent evidences have shown that they are involved in many biological processes, from development and cell-cycle regulation to apoptosis. miRNAs can behave as tumor suppressor or promoter of oncogenesis depending on the cellular function of their targets. Moreover, they are frequently dysregulated in HCC. In this review we summarize the latest findings of miRNAs regulation in HCC and their role as potentially diagnostic and prognostic biomarkers for HCC. We highlight development of miRNAs as potential therapeutic targets for HCC. Full article

(This article belongs to the Special Issue miRNAs as Probes to Monitor Cancer and Neurodegenerative Disorders)

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Ruthenium Tetroxide and Perruthenate Chemistry. Recent Advances and Related Transformations Mediated by Other Transition Metal Oxo-species

by Vincenzo Piccialli

Molecules 2014, 19(5), 6534-6582; https://doi.org/10.3390/molecules19056534 - 21 May 2014

Cited by 56 | Viewed by 16069

Abstract

In the last years ruthenium tetroxide is increasingly being used in organic synthesis. Thanks to the fine tuning of the reaction conditions, including pH control of the medium and the use of a wider range of co-oxidants, this species has proven to be [...] Read more.

In the last years ruthenium tetroxide is increasingly being used in organic synthesis. Thanks to the fine tuning of the reaction conditions, including pH control of the medium and the use of a wider range of co-oxidants, this species has proven to be a reagent able to catalyse useful synthetic transformations which are either a valuable alternative to established methods or even, in some cases, the method of choice. Protocols for oxidation of hydrocarbons, oxidative cleavage of C–C double bonds, even stopping the process at the aldehyde stage, oxidative cleavage of terminal and internal alkynes, oxidation of alcohols to carboxylic acids, dihydroxylation of alkenes, oxidative degradation of phenyl and other heteroaromatic nuclei, oxidative cyclization of dienes, have now reached a good level of improvement and are more and more included into complex synthetic sequences. The perruthenate ion is a ruthenium (VII) oxo-species. Since its introduction in the mid-eighties, tetrapropylammonium perruthenate (TPAP) has reached a great popularity among organic chemists and it is mostly employed in catalytic amounts in conjunction with N-methylmorpholine N-oxide (NMO) for the mild oxidation of primary and secondary alcohols to carbonyl compounds. Its use in the oxidation of other functionalities is known and recently, its utility in new synthetic transformations has been demonstrated. New processes, synthetic applications, theoretical studies and unusual transformations, published in the last eight years (2006–2013), in the chemistry of these two oxo-species, will be covered in this review with the aim of offering a clear picture of their reactivity. When appropriate, related oxidative transformations mediated by other metal oxo-species will be presented to highlight similarities and differences. An historical overview of some aspects of the ruthenium tetroxide chemistry will be presented as well. Full article

(This article belongs to the Special Issue Ruthenium Complex)

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Role of Oligomeric Proanthocyanidins Derived from an Extract of Persimmon Fruits in the Oxidative Stress-Related Aging Process

by Takako Yokozawa, Chan Hum Park, Jeong Sook Noh and Seong Soo Roh

Molecules 2014, 19(5), 6707-6726; https://doi.org/10.3390/molecules19056707 - 22 May 2014

Cited by 13 | Viewed by 8832

Abstract

Many researchers have focused on the oligomeric form of proanthocyanidins with a lower level of polymerization found in foodstuffs such as grape seeds and blackberries. The present study indicated that the oral administration of oligomers isolated from persimmon fruits extended the lifespan of [...] Read more.

Many researchers have focused on the oligomeric form of proanthocyanidins with a lower level of polymerization found in foodstuffs such as grape seeds and blackberries. The present study indicated that the oral administration of oligomers isolated from persimmon fruits extended the lifespan of senescence-accelerated mouse prone/8 (SAMP8), a murine model of accelerated senescence. On the other hand, oligomer-treated SAMP8 did not show stereotypical behavior. We also revealed that the oral administration of oligomers improved spatial and object recognition memory in SAMP8. The density of axons in the hippocampal CA1 was significantly increased by oligomer administration. Moreover, the administration of oligomers increased the phosphorylation of vascular endothelial growth factor receptor (VEGFR)-2 in the hippocampal CA3, hypothalamus, and choroid plexus. We speculate that memory improvement accompanied by histological changes may be induced directly in the hippocampus and indirectly in the hypothalamus and choroid plexus through VEGFR-2 signaling. In the present study, we elucidated the protective effect of oligomers against memory impairment with aging. VEGFR-2 signaling may provide a new insight into ways to protect against memory deficit in the aging brain. Full article

(This article belongs to the Special Issue Natural Antioxidants and Ageing)

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Applications of Liquid-Phase Microextraction in the Sample Preparation of Environmental Solid Samples

by Helena Prosen

Molecules 2014, 19(5), 6776-6808; https://doi.org/10.3390/molecules19056776 - 23 May 2014

Cited by 42 | Viewed by 9685

Abstract

Solvent extraction remains one of the fundamental sample preparation techniques in the analysis of environmental solid samples, but organic solvents are toxic and environmentally harmful, therefore one of the possible greening directions is its miniaturization. The present review covers the relevant research from [...] Read more.

Solvent extraction remains one of the fundamental sample preparation techniques in the analysis of environmental solid samples, but organic solvents are toxic and environmentally harmful, therefore one of the possible greening directions is its miniaturization. The present review covers the relevant research from the field of application of microextraction to the sample preparation of environmental solid samples (soil, sediments, sewage sludge, dust etc.) published in the last decade. Several innovative liquid-phase microextraction (LPME) techniques that have emerged recently have also been applied as an aid in sample preparation of these samples: single-drop microextraction (SDME), hollow fiber-liquid phase microextraction (HF-LPME), dispersive liquid-liquid microextraction (DLLME). Besides the common organic solvents, surfactants and ionic liquids are also used. However, these techniques have to be combined with another technique to release the analytes from the solid sample into an aqueous solution. In the present review, the published methods were categorized into three groups: LPME in combination with a conventional solvent extraction; LPME in combination with an environmentally friendly extraction; LPME without previous extraction. The applicability of these approaches to the sample preparation for the determination of pollutants in solid environmental samples is discussed, with emphasis on their strengths, weak points and environmental impact. Full article

(This article belongs to the Special Issue Microextraction)

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Circulating miRNAs as Biomarkers for Neurodegenerative Disorders

by Margherita Grasso, Paola Piscopo, Annamaria Confaloni and Michela A. Denti

Molecules 2014, 19(5), 6891-6910; https://doi.org/10.3390/molecules19056891 - 23 May 2014

Cited by 163 | Viewed by 12540

Abstract

Neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and frontotemporal dementias (FTD), are considered distinct entities, however, there is increasing evidence of an overlap from the clinical, pathological and genetic points of view. All neurodegenerative diseases are characterized by neuronal loss [...] Read more.

Neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and frontotemporal dementias (FTD), are considered distinct entities, however, there is increasing evidence of an overlap from the clinical, pathological and genetic points of view. All neurodegenerative diseases are characterized by neuronal loss and death in specific areas of the brain, for example, hippocampus and cortex for AD, midbrain for PD, frontal and temporal lobes for FTD. Loss of neurons is a relatively late event in the progression of neurodegenerative diseases that is typically preceded by other events such as metabolic changes, synaptic dysfunction and loss, neurite retraction, and the appearance of other abnormalities, such as axonal transport defects. The brain’s ability to compensate for these dysfunctions occurs over a long period of time and results in late clinical manifestation of symptoms, when successful pharmacological intervention is no longer feasible. Currently, diagnosis of AD, PD and different forms of dementia is based primarily on analysis of the patient’s cognitive function. It is therefore important to find non-invasive diagnostic methods useful to detect neurodegenerative diseases during early, preferably asymptomatic stages, when a pharmacological intervention is still possible. Altered expression of microRNAs (miRNAs) in many disease states, including neurodegeneration, and increasing relevance of miRNAs in biofluids in different pathologies has prompted the study of their possible application as neurodegenerative diseases biomarkers in order to identify new therapeutic targets. Here, we review what is known about the role of miRNAs in the pathogenesis of neurodegeneration and the possibilities and challenges of using these small RNA molecules as a signature for neurodegenerative conditions. Full article

(This article belongs to the Special Issue miRNAs as Probes to Monitor Cancer and Neurodegenerative Disorders)

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Molecules, Volume 19, Issue 5 (May 2014) – 89 articles , Pages 5459-6910

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