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Special Issue "Natural Products and Drug Discovery"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (15 June 2019).

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Special Issue Editor

Prof. Dr. Pinarosa Avato
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Guest Editor
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro Via Orabona 4, 70125 Bari, Italy
Interests: phytochemicals; natural products; plant biodiversity; medicinal plants; food plants; bioactivity; polyphenols; glucosinolates; biocides
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Special Issue Information

Dear Colleagues,

Natural products hold a prominent position in the discovery and development of many drugs used nowadays, with diverse indications for human and animal health. Especially, plants have played a leading role as a source of specialized metabolites with medical effects; other organisms such as marine and terrestrial animals and microorganisms produce very important drug candidate molecules. Specialized metabolites from all these natural sources can be used directly as bioactive compounds, or as drug precursors. Due to their wide chemical diversity they can act as drug prototypes and/or be used as pharmacological tools for different targets. Some examples of natural metabolites which have been developed into useful medical drugs are the cardiotonic digoxin from Digitalis sp., the antimalarial artemisinin from Artemisia annua, the anti-cancer taxol, from Taxus sp., or the podophyllotoxin from Podophyllum peltatum, which served as synthetic model for the anti-cancer etoposide. The study of natural products is still attracting a great scientific attention and their current importance as valuable leads for drug discovery is undebatable. I cordially invite authors to contribute original articles, as well as survey articles, that will give the readers of Molecules updated and new perspective about natural products in drug discovery including, but not limited to natural sources, identification and separation of bioactive phytochemicals, standardization, new biological targets, pre-clinical and clinical trials, pharmacological effects/side effects, and bioassays.

Prof. Dr. Pinarosa Avato
Guest Editor

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Keywords

  • natural products
  • drug discovery
  • phytochemicals
  • biocidal compounds
  • human and animal health
  • natural sources

Published Papers (22 papers)

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Editorial

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Editorial
Editorial to the Special Issue–“Natural Products and Drug Discovery”
Molecules 2020, 25(5), 1128; https://doi.org/10.3390/molecules25051128 - 03 Mar 2020
Cited by 1 | Viewed by 774
Abstract
Natural products hold a prominent position in the discovery and development of many drugs used nowadays, with diverse indications for human and animal health [...] Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)

Research

Jump to: Editorial, Review

Article
Early Celastrol Administration Prevents Ketamine-Induced Psychotic-Like Behavioral Dysfunctions, Oxidative Stress and IL-10 Reduction in The Cerebellum of Adult Mice
Molecules 2019, 24(21), 3993; https://doi.org/10.3390/molecules24213993 - 05 Nov 2019
Cited by 6 | Viewed by 973
Abstract
Administration of subanesthetic doses of ketamine during brain maturation represents a tool to mimic an early insult to the central nervous system (CNS). The cerebellum is a key player in psychosis pathogenesis, to which oxidative stress also contributes. Here, we investigated the impact [...] Read more.
Administration of subanesthetic doses of ketamine during brain maturation represents a tool to mimic an early insult to the central nervous system (CNS). The cerebellum is a key player in psychosis pathogenesis, to which oxidative stress also contributes. Here, we investigated the impact of early celastrol administration on behavioral dysfunctions in adult mice that had received ketamine (30 mg/kg i.p.) at postnatal days (PNDs) 7, 9, and 11. Cerebellar levels of 8-hydroxydeoxyguanosine (8-OHdG), NADPH oxidase (NOX) 1 and NOX2, as well as of the calcium-binding protein parvalbumin (PV), were also assessed. Furthermore, celastrol effects on ketamine-induced alterations of proinflammatory (TNF-α, IL-6 and IL-1β) and anti-inflammatory (IL-10) cytokines in this brain region were evaluated. Early celastrol administration prevented ketamine-induced discrimination index decrease at adulthood. The same was found for locomotor activity elevations and increased close following and allogrooming, whereas no beneficial effects on sniffing impairment were detected. Ketamine increased 8-OHdG in the cerebellum of adult mice, which was also prevented by early celastrol injection. Cerebellar NOX1 levels were enhanced at adulthood following postnatal ketamine exposure. Celastrol per se induced NOX1 decrease in the cerebellum. This effect was more significant in animals that were early administered with ketamine. NOX2 levels did not change. Ketamine administration did not affect PV amount in the cerebellum. TNF-α levels were enhanced in ketamine-treated animals; however, this was not prevented by early celastrol administration. While no changes were observed for IL-6 and IL-1β levels, ketamine determined a reduction of cerebellar IL-10 expression, which was prevented by early celastrol treatment. Our results suggest that NOX inhibition during brain maturation prevents the development of psychotic-like behavioral dysfunctions, as well as the increased cerebellar oxidative stress and the reduction of IL-10 in the same brain region following ketamine exposure in postnatal life. This opens novel neuroprotective opportunities against early detrimental insults occurring during brain development. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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Article
Insights into Heterologous Biosynthesis of Arteannuin B and Artemisinin in Physcomitrella patens
Molecules 2019, 24(21), 3822; https://doi.org/10.3390/molecules24213822 - 23 Oct 2019
Cited by 2 | Viewed by 1392
Abstract
Metabolic engineering is an integrated bioengineering approach, which has made considerable progress in producing terpenoids in plants and fermentable hosts. Here, the full biosynthetic pathway of artemisinin, originating from Artemisia annua, was integrated into the moss Physcomitrella patens. Different combinations of [...] Read more.
Metabolic engineering is an integrated bioengineering approach, which has made considerable progress in producing terpenoids in plants and fermentable hosts. Here, the full biosynthetic pathway of artemisinin, originating from Artemisia annua, was integrated into the moss Physcomitrella patens. Different combinations of the five artemisinin biosynthesis genes were ectopically expressed in P. patens to study biosynthesis pathway activity, but also to ensure survival of successful transformants. Transformation of the first pathway gene, ADS, into P. patens resulted in the accumulation of the expected metabolite, amorpha-4,11-diene, and also accumulation of a second product, arteannuin B. This demonstrates the presence of endogenous promiscuous enzyme activity, possibly cytochrome P450s, in P. patens. Introduction of three pathway genes, ADS-CYP71AV1-ADH1 or ADS-DBR2-ALDH1 both led to the accumulation of artemisinin, hinting at the presence of one or more endogenous enzymes in P. patens that can complement the partial pathways to full pathway activity. Transgenic P. patens lines containing the different gene combinations produce artemisinin in varying amounts. The pathway gene expression in the transgenic moss lines correlates well with the chemical profile of pathway products. Moreover, expression of the pathway genes resulted in lipid body formation in all transgenic moss lines, suggesting that these may have a function in sequestration of heterologous metabolites. This work thus provides novel insights into the metabolic response of P. patens and its complementation potential for A. annua artemisinin pathway genes. Identification of the related endogenous P. patens genes could contribute to a further successful metabolic engineering of artemisinin biosynthesis, as well as bioengineering of other high-value terpenoids in P. patens. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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Article
Eruca sativa Meal against Diabetic Neuropathic Pain: An H2S-Mediated Effect of Glucoerucin
Molecules 2019, 24(16), 3006; https://doi.org/10.3390/molecules24163006 - 19 Aug 2019
Cited by 9 | Viewed by 1808
Abstract
The management of pain in patients affected by diabetic neuropathy still represents an unmet therapeutic need. Recent data highlighted the pain-relieving efficacy of glucosinolates deriving from Brassicaceae. The purpose of this study was to evaluate the anti-hyperalgesic efficacy of Eruca sativa defatted seed [...] Read more.
The management of pain in patients affected by diabetic neuropathy still represents an unmet therapeutic need. Recent data highlighted the pain-relieving efficacy of glucosinolates deriving from Brassicaceae. The purpose of this study was to evaluate the anti-hyperalgesic efficacy of Eruca sativa defatted seed meal, along with its main glucosinolate, glucoerucin (GER), on diabetic neuropathic pain induced in mice by streptozotocin (STZ). The mechanism of action was also investigated. Hypersensitivity was assessed by paw pressure and cold plate tests after the acute administration of the compounds. Once bio-activated by myrosinase, both E. sativa defatted meal (1 g kg−1 p.o.) and GER (100 µmol kg−1 p.o., equimolar to meal content) showed a dose-dependent pain-relieving effect in STZ-diabetic mice, but the meal was more effective than the glucosinolate. The co-administration with H2S scavengers abolished the pain relief mediated by both E. sativa meal and GER. Their effect was also prevented by selectively blocking Kv7 potassium channels. Repeated treatments with E. sativa meal did not induce tolerance to the anti-hypersensitive effect. In conclusion, E. sativa meal can be suggested as a new nutraceutical tool for pain relief in patients with diabetic neuropathy. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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Article
Discovery of Lipid Peroxidation Inhibitors from Bacopa Species Prioritized through Multivariate Data Analysis and Multi-Informative Molecular Networking
Molecules 2019, 24(16), 2989; https://doi.org/10.3390/molecules24162989 - 17 Aug 2019
Cited by 5 | Viewed by 1525
Abstract
A major goal in the discovery of bioactive natural products is to rapidly identify active compound(s) and dereplicate known molecules from complex biological extracts. The conventional bioassay-guided fractionation process can be time consuming and often requires multi-step procedures. Herein, we apply a metabolomic [...] Read more.
A major goal in the discovery of bioactive natural products is to rapidly identify active compound(s) and dereplicate known molecules from complex biological extracts. The conventional bioassay-guided fractionation process can be time consuming and often requires multi-step procedures. Herein, we apply a metabolomic strategy merging multivariate data analysis and multi-informative molecular maps to rapidly prioritize bioactive molecules directly from crude plant extracts. The strategy was applied to 59 extracts of three Bacopa species (B. monnieri, B. caroliniana and B. floribunda), which were profiled by UHPLC-HRMS2 and screened for anti-lipid peroxidation activity. Using this approach, six lipid peroxidation inhibitors 16 of three Bacopa spp. were discovered, three of them being new compounds: monnieraside IV (4), monnieraside V (5) and monnieraside VI (6). The results demonstrate that this combined approach could efficiently guide the discovery of new bioactive natural products. Furthermore, the approach allowed to evidence that main semi-quantitative changes in composition linked to the anti-lipid peroxidation activity were also correlated to seasonal effects notably for B. monnieri. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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Article
Insights into the Phytochemistry of the Cuban Endemic Medicinal Plant Phyllanthus orbicularis: Fideloside, a Novel Bioactive 8-C-glycosyl 2,3-Dihydroflavonol
Molecules 2019, 24(15), 2855; https://doi.org/10.3390/molecules24152855 - 06 Aug 2019
Cited by 6 | Viewed by 1760
Abstract
Phyllanthus orbicularis (Phyllanthaceae) is an endemic evergreen tropical plant of Cuba that grows in the western part of the island and is used in traditional medicine as an infusion. The aqueous extract of this plant presents a wide range of pharmacological activitiessuch as [...] Read more.
Phyllanthus orbicularis (Phyllanthaceae) is an endemic evergreen tropical plant of Cuba that grows in the western part of the island and is used in traditional medicine as an infusion. The aqueous extract of this plant presents a wide range of pharmacological activitiessuch as antimutagenic, antioxidant and antiviral effects. Given the many beneficial effects and the great interest in the development of new pharmacological products from natural sources, the aim of this work was to investigate the phytochemistry of this species and to elucidate the structure of the main bioactive principles. Besides the presence of several known polyphenols, the major constituent was hitherto not described. The chemical structure of this compound, here named Fideloside, was elucidated by means of HR-ESIMS/MSn, 1D/2D NMR, FT-IR, and ECD as (2R,3R)-(−)-3’,4′,5,7-tetrahydroxydihydroflavonol-8-C-β-D-glucopyranoside. The compound, as well as the plant aqueous preparations, showed promising bioactive properties, i.e., anti-inflammatory capacity in human explanted monocytes, corroborating future pharmacological use for this new natural C-glycosyl flavanonol. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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Article
The Effects of 2′,4′-Dihydroxy-6′-methoxy-3′,5′- dimethylchalcone from Cleistocalyx operculatus Buds on Human Pancreatic Cancer Cell Lines
Molecules 2019, 24(14), 2538; https://doi.org/10.3390/molecules24142538 - 11 Jul 2019
Cited by 10 | Viewed by 1474
Abstract
2′,4′-Dihydroxy-6’-methoxy-3′,5′-dimethylchalcone (DMC), a principal natural chalcone of Cleistocalyx operculatus buds, suppresses the growth of many types of cancer cells. However, the effects of this compound on pancreatic cancer cells have not been evaluated. In our experiments, we explored the effects of this chalcone [...] Read more.
2′,4′-Dihydroxy-6’-methoxy-3′,5′-dimethylchalcone (DMC), a principal natural chalcone of Cleistocalyx operculatus buds, suppresses the growth of many types of cancer cells. However, the effects of this compound on pancreatic cancer cells have not been evaluated. In our experiments, we explored the effects of this chalcone on two human pancreatic cancer cell lines. A cell proliferation assay revealed that DMC exhibited concentration-dependent cytotoxicity against PANC-1 and MIA PACA2 cells, with IC50 values of 10.5 ± 0.8 and 12.2 ± 0.9 µM, respectively. Treatment of DMC led to the apoptosis of PANC-1 by caspase-3 activation as revealed by annexin-V/propidium iodide double-staining. Western blotting indicated that DMC induced proteolytic activation of caspase-3 and -9, degradation of caspase-3 substrate proteins (including poly[ADP-ribose] polymerase [PARP]), augmented bak protein level, while attenuating the expression of bcl-2 in PANC-1 cells. Taken together, our results provide experimental evidence to support that DMC may serve as a useful chemotherapeutic agent for control of human pancreatic cancer cells. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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Article
Quality Assessment of Commercial Spagyric Tinctures of Harpagophytum procumbens and Their Antioxidant Properties
Molecules 2019, 24(12), 2251; https://doi.org/10.3390/molecules24122251 - 17 Jun 2019
Cited by 3 | Viewed by 1289
Abstract
Preparations from the dried tubers of Harpagophytum procumbens (Burch.) DC ex Meisn, commonly known as devil’s claw, are mainly used in modern medicine to relieve joint pain and inflammation in patients suffering from rheumatic and arthritic disorders. This paper describes for the first [...] Read more.
Preparations from the dried tubers of Harpagophytum procumbens (Burch.) DC ex Meisn, commonly known as devil’s claw, are mainly used in modern medicine to relieve joint pain and inflammation in patients suffering from rheumatic and arthritic disorders. This paper describes for the first time the chemical profile of a commercial spagyric tincture (named 019) prepared from the roots of the plant. For comparison purposes, a commercial not-spagyric devil’s claw tincture (NST) was also analyzed. Chemical investigation of the content of specialized metabolites in the three samples indicated that harpagoside was the main compound, followed by the two isomers acteoside and isoacteoside. Compositional consistence over time was obtained by the chemical fingerprinting of another spagyric tincture (named 014) from the same producer that was already expired according to the recommendation on the label of the product. The two spagyric preparations did not show significant compositional differences as revealed by HPLC and MS analyses, except for a decrease in harpagide content in the expired 014 tincture. Moreover, their antioxidant capacities as assessed by 2,2’-di-phenyl-1-picrylhydrazyl (DPPH) and 2.2’-azin-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) methods resulted in very similar IC50 values. The expired 014 tincture showed instead a lower IC50 value compared to the 019 and NST tinctures with the ferric reducing antioxidant potential (FRAP) assay, indicating a higher ferric-reducing antioxidant ability. Overall, these results indicated that the two preparations could generally maintain good stability and biological activity at least for the four years from the production to the expiration date. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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Article
Spectroscopic Characterization and Cytotoxicity Assessment towards Human Colon Cancer Cell Lines of Acylated Cycloartane Glycosides from Astragalus boeticus L.
Molecules 2019, 24(9), 1725; https://doi.org/10.3390/molecules24091725 - 03 May 2019
Cited by 4 | Viewed by 1264
Abstract
In several European countries, especially in Sweden, the seeds of the species Astragalus boeticus L. were widely used as coffee substitutes during the 19th century. Nonetheless, data regarding the phytochemistry and the pharmacological properties of this species are currently extremely limited. Conversely, other [...] Read more.
In several European countries, especially in Sweden, the seeds of the species Astragalus boeticus L. were widely used as coffee substitutes during the 19th century. Nonetheless, data regarding the phytochemistry and the pharmacological properties of this species are currently extremely limited. Conversely, other species belonging to the Astragalus genus have already been extensively investigated, as they were used for millennia for treating various diseases, including cancer. The current work was addressed to characterize cycloartane glycosides from A. boeticus, and to evaluate their cytotoxicity towards human colorectal cancer (CRC) cell lines. The isolation of the metabolites was performed by using different chromatographic techniques, while their chemical structures were elucidated by nuclear magnetic resonance (NMR) (1D and 2D techniques) and electrospray-ionization quadrupole time-of-flight (ESI-QTOF) mass spectrometry. The cytotoxic assessment was performed in vitro by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays in Caco-2, HT-29 and HCT-116 CRC cells. As a result, the targeted phytochemical study of A. boeticus enabled the isolation of three new cycloartane glycosides, 6-O-acetyl-3-O-(4-O-malonyl)-β-d-xylopyranosylcycloastragenol (1), 3-O-(4-O-malonyl)-β-d-xylopyranosylcycloastragenol (2), 6-O-acetyl-25-O-β-d-glucopyranosyl-3-O-β-d-xylopyranosylcycloastragenol (3) along with two known compounds, 6-O-acetyl-3-O-β-d-xylopyranosylcycloastragenol (4) and 3-O-β-d-xylopyranosylcycloastragenol (5). Importantly, this work demonstrated that the acetylated cycloartane glycosides 1 and 4 might preferentially inhibit cell growth in the CRC cell model resistant to epidermal growth factor receptor (EGFR) inhibitors. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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Article
Phenolic Compounds from Humulus lupulus as Natural Antimicrobial Products: New Weapons in the Fight against Methicillin Resistant Staphylococcus aureus, Leishmania mexicana and Trypanosoma brucei Strains
Molecules 2019, 24(6), 1024; https://doi.org/10.3390/molecules24061024 - 14 Mar 2019
Cited by 15 | Viewed by 1809
Abstract
New anti-infective agents are urgently needed to fight microbial resistance. Methicillin-resistant Staphylococcus aureus (MRSA) strains are particularly responsible for complicated pathologies that are difficult to treat due to their virulence and the formation of persistent biofilms forming a complex protecting shell. Parasitic infections [...] Read more.
New anti-infective agents are urgently needed to fight microbial resistance. Methicillin-resistant Staphylococcus aureus (MRSA) strains are particularly responsible for complicated pathologies that are difficult to treat due to their virulence and the formation of persistent biofilms forming a complex protecting shell. Parasitic infections caused by Trypanosoma brucei and Leishmania mexicana are also of global concern, because of the mortality due to the low number of safe and effective treatments. Female inflorescences of hop produce specialized metabolites known for their antimicrobial effects but underexploited to fight against drug-resistant microorganisms. In this study, we assessed the antimicrobial potential of phenolic compounds against MRSA clinical isolates, T. brucei and L. mexicana. By fractionation process, we purified the major prenylated chalcones and acylphloroglucinols, which were quantified by UHPLC-UV in different plant parts, showing their higher content in the active flowers extract. Their potent antibacterial action (MIC < 1 µg/mL for the most active compound) was demonstrated against MRSA strains, through kill curves, post-antibiotic effects, anti-biofilm assays and synergy studies with antibiotics. An antiparasitic activity was also shown for some purified compounds, particularly on T. brucei (IC50 < 1 to 11 µg/mL). Their cytotoxic activity was assessed both on cancer and non-cancer human cell lines. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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Article
Identification of Phytoconstituents in Leea indica (Burm. F.) Merr. Leaves by High Performance Liquid Chromatography Micro Time-of-Flight Mass Spectrometry
Molecules 2019, 24(4), 714; https://doi.org/10.3390/molecules24040714 - 16 Feb 2019
Cited by 11 | Viewed by 1682
Abstract
Leea indica (Vitaceae) is a Southeast Asian medicinal plant. In this study, an ethyl acetate fraction of L. indica leaves was studied for its phytoconstituents using high-performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-microTOF-Q-MS/MS) analysis. A total of 31 compounds of different classes, including benzoic [...] Read more.
Leea indica (Vitaceae) is a Southeast Asian medicinal plant. In this study, an ethyl acetate fraction of L. indica leaves was studied for its phytoconstituents using high-performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-microTOF-Q-MS/MS) analysis. A total of 31 compounds of different classes, including benzoic acid derivatives, phenolics, flavonoids, catechins, dihydrochalcones, coumarins, megastigmanes, and oxylipins were identified using LC-MS/MS. Among them, six compounds including gallic acid, methyl gallate, (−)-epigallocatechin-3-O-gallate, myricetin-3-O-rhamnoside, quercetin-3-O-rhamnoside, and 4′,6′-dihydroxy-4-methoxydihydrochalcone 2′-O-β-d-glucopyranoside were isolated and identified by NMR analysis. The LC-MS/MS analysis led to the tentative identification of three novel dihydrochalcones namely 4′,6′-dihydroxy-4-methoxydihydrochalcone 2′-O-rutinoside, 4′,6′-dihydroxy-4-methoxydihydrochalcone 2′-O-glucosylpentoside and 4′,6′-dihydroxy-4-methoxydihydrochalcone 2′-O-(3″-O-galloyl)-β-d-glucopyranoside. The structural identification of novel dihydrochalcones was based on the basic skeleton of the isolated dihydrochalcone, 4′,6′-dihydroxy-4-methoxydihydrochalcone 2′-O-β-d-glucopyranoside and characteristic LC-MS/MS fragmentation patterns. This is the first comprehensive analysis for the identification of compounds from L. indica using LC-MS. A total 24 compounds including three new dihydrochalcones were identified for the first time from the genus Leea. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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Article
Phenolic Content and Antioxidant Activity in Trifolium Germplasm from Different Environments
Molecules 2019, 24(2), 298; https://doi.org/10.3390/molecules24020298 - 15 Jan 2019
Cited by 7 | Viewed by 1217
Abstract
Phenolics are important mediators in plant-environment interactions. The presence and concentration of phenolic compounds and their antioxidant activity were evaluated in leaves and flowers of a set of Trifolium species originating from contrasting environments encompassing lowland and mountain sites. The current germplasm proved [...] Read more.
Phenolics are important mediators in plant-environment interactions. The presence and concentration of phenolic compounds and their antioxidant activity were evaluated in leaves and flowers of a set of Trifolium species originating from contrasting environments encompassing lowland and mountain sites. The current germplasm proved a great reservoir of phenolic compounds, with different chemical structure and, possibly, diversified biological activity. Germplasm groups with specific phenolic composition were observed. In some cases, different patterns bore a taxonomic meaning. Lowland germplasm showed higher concentration of total phenolics in leaves than mountain accessions (50.30 vs. 34.19 mg/g dry matter (DM)), while the latter had higher concentration in flowers (114.16 vs. 57.44 mg/g DM). Outstanding concentration of isoflavones was observed in leaves of lowland germplasm (24.19 mg/g DM), and of both proanthocyanidins and flavonoids in flowers of mountain germplasm (53.81 and 56.62 mg/g DM, respectively). The pattern of phenolic composition in lowland and mountain germplasm was suggestive of different adaptive strategies. Three assays of antioxidant activity were tested, which were characterised by rather different reactivity towards phenolic composition. The scavenging activity was higher for leaf extracts of lowland germplasm, and for flower extracts of mountain germplasm. Besides identifying germplasm of interest, this study also suggested possible links between environmental factors and concentration and composition of phenolic compounds. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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Article
Studies on the Design and Synthesis of Marine Peptide Analogues and Their Ability to Promote Proliferation in HUVECs and Zebrafish
Molecules 2019, 24(1), 66; https://doi.org/10.3390/molecules24010066 - 25 Dec 2018
Cited by 3 | Viewed by 1081
Abstract
In our previous studies, tripeptide 1 was found to induce angiogenesis in zebrafish embryos and in HUVECs. Based on the lead compound 1, seven new marine tripeptide analogues 28 have been designed and synthesized in this paper to evaluate the [...] Read more.
In our previous studies, tripeptide 1 was found to induce angiogenesis in zebrafish embryos and in HUVECs. Based on the lead compound 1, seven new marine tripeptide analogues 28 have been designed and synthesized in this paper to evaluate the effects on promoting cellular proliferation in human endothelial cells (HUVECs) and zebrafish. Among them, compounds 57 possessed more remarkable increasing proliferation effects than other compounds, and the EC50 values of these and the leading compound 1 were 1.0 ± 0.002 μM, 1.0 ± 0.0005 μM, 0.88 ± 0.0972 μM, and 1.31 ± 0.0926 μM, respectively. Furthermore, 57 could enhance migrations (58.5%, 80.66% and 60.71% increment after culturing 48 h, respectively) and invasions (49.08%, 47.24% and 56.24% increase, respectively) in HUVECs compared with the vehicle control. The results revealed that the tripeptide including l-Tyrosine or d-Proline fragments instead of l-Alanine of leading compound 1 would contribute to HUVECs’ proliferation. Taking the place of the original (l-Lys-l-Ala) segment of leading compound 1, a new fragment (l-Arg-d-Val) expressed higher performance in bioactivity in HUVECs. In addition, compound 7 could promote angiogenesis in zebrafish assay and it was more interesting that it also could repair damaged blood vessels in PTK787-induced zebrafish at a low concentration. The above data indicate that these peptides have potential implications for further evaluation in cytothesis studies. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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Article
Ethanolic Extract of Folium Sennae Mediates the Glucose Uptake of L6 Cells by GLUT4 and Ca2+
Molecules 2018, 23(11), 2934; https://doi.org/10.3390/molecules23112934 - 09 Nov 2018
Cited by 5 | Viewed by 2021
Abstract
In today’s world, diabetes mellitus (DM) is on the rise, especially type 2 diabetes mellitus (T2DM), which is characterized by insulin resistance. T2DM has high morbidity, and therapies with natural products have attracted much attention in the recent past. In this paper, we [...] Read more.
In today’s world, diabetes mellitus (DM) is on the rise, especially type 2 diabetes mellitus (T2DM), which is characterized by insulin resistance. T2DM has high morbidity, and therapies with natural products have attracted much attention in the recent past. In this paper, we aimed to study the hypoglycemic effect and the mechanism of an ethanolic extract of Folium Sennae (FSE) on L6 cells. The glucose uptake of L6 cells was investigated using a glucose assay kit. We studied glucose transporter 4 (GLUT4) expression and AMP-activated protein kinase (AMPK), protein kinase B (PKB/Akt), and protein kinase C (PKC) phosphorylation levels using western blot analysis. GLUT4 trafficking and intracellular Ca2+ levels were monitored by laser confocal microscopy in L6 cells stably expressing IRAP-mOrange. GLUT4 fusion with plasma membrane (PM) was observed by myc-GLUT4-mOrange. FSE stimulated glucose uptake; GLUT4 expression and translocation; PM fusion; intracellular Ca2+ elevation; and the phosphorylation of AMPK, Akt, and PKC in L6 cells. GLUT4 translocation was weakened by the AMPK inhibitor compound C, PI3K inhibitor Wortmannin, PKC inhibitor Gö6983, G protein inhibitor PTX/Gallein, and PLC inhibitor U73122. Similarly, in addition to PTX/Gallein and U73122, the IP3R inhibitor 2-APB and a 0 mM Ca2+-EGTA solution partially inhibited the elevation of intracellular Ca2+ levels. BAPTA-AM had a significant inhibitory effect on FSE-mediated GLUT4 activities. In summary, FSE regulates GLUT4 expression and translocation by activating the AMPK, PI3K/Akt, and G protein–PLC–PKC pathways. FSE causes increasing Ca2+ concentration to complete the fusion of GLUT4 vesicles with PM, allowing glucose uptake. Therefore, FSE may be a potential drug for improving T2DM. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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Article
Phytochemical and Analytical Characterization of Novel Sulfated Coumarins in the Marine Green Macroalga Dasycladus vermicularis (Scopoli) Krasser
Molecules 2018, 23(11), 2735; https://doi.org/10.3390/molecules23112735 - 23 Oct 2018
Cited by 7 | Viewed by 1641
Abstract
The siphonous green algae form a morphologically diverse group of marine macroalgae which include two sister orders (Bryopsidales and Dasycladales) which share a unique feature among other green algae as they are able to form large, differentiated thalli comprising of a single, giant [...] Read more.
The siphonous green algae form a morphologically diverse group of marine macroalgae which include two sister orders (Bryopsidales and Dasycladales) which share a unique feature among other green algae as they are able to form large, differentiated thalli comprising of a single, giant tubular cell. Upon cell damage a cascade of protective mechanisms have evolved including the extrusion of sulfated metabolites which are involved in the formation of a rapid wound plug. In this study, we investigated the composition of sulfated metabolites in Dasycladus vermicularis (Dasycladales) which resulted in the isolation of two phenolic acids and four coumarins including two novel structures elucidated by nuclear magnetic resonance spectroscopy (NMR) as 5,8′-di-(6(6′),7(7′)-tetrahydroxy-3-sulfoxy-3′-sulfoxycoumarin), a novel coumarin called dasycladin A and 7-hydroxycoumarin-3,6-disulfate, which was named dasycladin B. In addition, an analytical assay for the chromatographic quantification of those compounds was developed and performed on a reversed phase C-18 column. Method validation confirmed that the new assay shows good linearity (R2 ≥ 0.9986), precision (intra-day R.S.D ≤ 3.71%, inter-day R.S.D ≤ 7.49%), and accuracy (recovery rates ranged from 104.06 to 97.45%). The analysis of several samples of Dasycladus vermicularis from different collection sites, water depths and seasons revealed differences in the coumarin contents, ranging between 0.26 to 1.61%. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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Article
Antinociceptive Effects of Cardamonin in Mice: Possible Involvement of TRPV1, Glutamate, and Opioid Receptors
Molecules 2018, 23(9), 2237; https://doi.org/10.3390/molecules23092237 - 03 Sep 2018
Cited by 12 | Viewed by 1726
Abstract
Pain is one of the most common cause for hospital visits. It plays an important role in inflammation and serves as a warning sign to avoid further injury. Analgesics are used to manage pain and provide comfort to patients. However, prolonged usage of [...] Read more.
Pain is one of the most common cause for hospital visits. It plays an important role in inflammation and serves as a warning sign to avoid further injury. Analgesics are used to manage pain and provide comfort to patients. However, prolonged usage of pain treatments like opioids and NSAIDs are accompanied with undesirable side effects. Therefore, research to identify novel compounds that produce analgesia with lesser side effects are necessary. The present study investigated the antinociceptive potentials of a natural compound, cardamonin, isolated from Boesenbergia rotunda (L) Mansf. using chemical and thermal models of nociception. Our findings showed that intraperitoneal and oral administration of cardamonin (0.3, 1, 3, and 10 mg/kg) produced significant and dose-dependent inhibition of pain in abdominal writhing responses induced by acetic acid. The present study also demonstrated that cardamonin produced significant analgesia in formalin-, capsaicin-, and glutamate-induced paw licking tests. In the thermal-induced nociception model, cardamonin exhibited significant increase in response latency time of animals subjected to hot-plate thermal stimuli. The rota-rod assessment confirmed that the antinociceptive activities elicited by cardamonin was not related to muscle relaxant or sedative effects of the compound. In conclusion, the present findings showed that cardamonin exerted significant peripheral and central antinociception through chemical- and thermal-induced nociception in mice through the involvement of TRPV1, glutamate, and opioid receptors. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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Article
Identification and Growth Inhibitory Activity of the Chemical Constituents from Imperata Cylindrica Aerial Part Ethyl Acetate Extract
Molecules 2018, 23(7), 1807; https://doi.org/10.3390/molecules23071807 - 21 Jul 2018
Cited by 7 | Viewed by 1912
Abstract
Imperata cylindrica (L.) Raeusch. (IMP) aerial part ethyl acetate extract has anti-proliferative, pro-apoptotic, and pro-oxidative effects towards colorectal cancer in vitro. The chemical constituents of IMP aerial part ethyl acetate extract were isolated using high-performance liquid chromatography (HPLC) and identified with tandem mass [...] Read more.
Imperata cylindrica (L.) Raeusch. (IMP) aerial part ethyl acetate extract has anti-proliferative, pro-apoptotic, and pro-oxidative effects towards colorectal cancer in vitro. The chemical constituents of IMP aerial part ethyl acetate extract were isolated using high-performance liquid chromatography (HPLC) and identified with tandem mass spectrometry (ESI-MS/MS) in combination with ultraviolet-visible spectrophotometry and 400 MHz NMR. The growth inhibitory effects of each identified component on BT-549 (breast) and HT-29 (colon) cancer cell lines were evaluated after 48/72 h treatment by MTT assay. Four isolated compounds were identified as trans-p-Coumaric acid (1); 2-Methoxyestrone (2); 11, 16-Dihydroxypregn-4-ene-3, 20-dione (3); and Tricin (4). Compounds (2), (3), and (4) exhibited considerable growth inhibitory activities against BT-549 and HT-29 cancer cell lines. Compounds (2), (3), and (4) are potential candidates for novel anti-cancer agents against breast and colorectal cancers. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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Article
Cytotoxicity-Guided Isolation of Two New Phenolic Derivatives from Dryopteris fragrans (L.) Schott
Molecules 2018, 23(7), 1652; https://doi.org/10.3390/molecules23071652 - 06 Jul 2018
Cited by 3 | Viewed by 1563
Abstract
Dryopteris fragrans is a valuable medicinal plant resource with extensive biological activities including anti-cancer, anti-oxidation, and anti-inflammation activities. This work aims to study further the cytotoxic constituents from Dryopteris fragrans. In this work, two new phenolic derivatives known as dryofragone (1 [...] Read more.
Dryopteris fragrans is a valuable medicinal plant resource with extensive biological activities including anti-cancer, anti-oxidation, and anti-inflammation activities. This work aims to study further the cytotoxic constituents from Dryopteris fragrans. In this work, two new phenolic derivatives known as dryofragone (1) and dryofracoumarin B (2) with six known compounds (38) were isolated from the petroleum ether fraction of the methanol extract of the aerial parts of Dryopteris fragrans (L.) Schott by two round cytotoxicity-guided tracking with the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and cell counting kit-8 (CCK-8) assay. Their structures were elucidated by the extensive spectroscopic analysis (1H-NMR, 13C-NMR, and two dimensions NMR), chemical derivatization, and comparison with data reported in the literature. All the isolates were evaluated for their cytotoxicity against nine cancer cell lines as well as their in vitro immunomodulatory activity. The results showed that compounds have a modest cytotoxicity toward human HeLa cell line with IC50 value below 30 μM and compounds 4 and 5 may modulate immunity to affect the growth of tumor cells. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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Review

Jump to: Editorial, Research

Review
Terpene Derivatives as a Potential Agent against Antimicrobial Resistance (AMR) Pathogens
Molecules 2019, 24(14), 2631; https://doi.org/10.3390/molecules24142631 - 19 Jul 2019
Cited by 44 | Viewed by 2699
Abstract
The evolution of antimicrobial resistance (AMR) in pathogens has prompted extensive research to find alternative therapeutics. Plants rich with natural secondary metabolites are one of the go-to reservoirs for discovery of potential resources to alleviate this problem. Terpenes and their derivatives comprising of [...] Read more.
The evolution of antimicrobial resistance (AMR) in pathogens has prompted extensive research to find alternative therapeutics. Plants rich with natural secondary metabolites are one of the go-to reservoirs for discovery of potential resources to alleviate this problem. Terpenes and their derivatives comprising of hydrocarbons, are usually found in essential oils (EOs). They have been reported to have potent antimicrobial activity, exhibiting bacteriostatic and bactericidal effects against tested pathogens. This brief review discusses the activity of terpenes and derivatives against pathogenic bacteria, describing the potential of the activity against AMR followed by the possible mechanism exerted by each terpene class. Finally, ongoing research and possible improvisation to the usage of terpenes and terpenoids in therapeutic practice against AMR are discussed. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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Review
Marine Organisms as Potential Sources of Bioactive Peptides that Inhibit the Activity of Angiotensin I-Converting Enzyme: A Review
Molecules 2019, 24(14), 2541; https://doi.org/10.3390/molecules24142541 - 12 Jul 2019
Cited by 17 | Viewed by 1487
Abstract
Angiotensin I-converting enzyme (ACE) is a paramount therapeutic target to treat hypertension. ACE inhibitory peptides derived from food protein sources are regarded as safer alternatives to synthetic antihypertensive drugs for treating hypertension. Recently, marine organisms have started being pursued as sources of potential [...] Read more.
Angiotensin I-converting enzyme (ACE) is a paramount therapeutic target to treat hypertension. ACE inhibitory peptides derived from food protein sources are regarded as safer alternatives to synthetic antihypertensive drugs for treating hypertension. Recently, marine organisms have started being pursued as sources of potential ACE inhibitory peptides. Marine organisms such as fish, shellfish, seaweed, microalgae, molluscs, crustaceans, and cephalopods are rich sources of bioactive compounds because of their high-value metabolites with specific activities and promising health benefits. This review aims to summarize the studies on peptides from different marine organisms and focus on the potential ability of these peptides to inhibit ACE activity. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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Review
Carotenoids: How Effective Are They to Prevent Age-Related Diseases?
Molecules 2019, 24(9), 1801; https://doi.org/10.3390/molecules24091801 - 09 May 2019
Cited by 22 | Viewed by 3033
Abstract
Despite an increase in life expectancy that indicates positive human development, a new challenge is arising. Aging is positively associated with biological and cognitive degeneration, for instance cognitive decline, psychological impairment, and physical frailty. The elderly population is prone to oxidative stress due [...] Read more.
Despite an increase in life expectancy that indicates positive human development, a new challenge is arising. Aging is positively associated with biological and cognitive degeneration, for instance cognitive decline, psychological impairment, and physical frailty. The elderly population is prone to oxidative stress due to the inefficiency of their endogenous antioxidant systems. As many studies showed an inverse relationship between carotenoids and age-related diseases (ARD) by reducing oxidative stress through interrupting the propagation of free radicals, carotenoid has been foreseen as a potential intervention for age-associated pathologies. Therefore, the role of carotenoids that counteract oxidative stress and promote healthy aging is worthy of further discussion. In this review, we discussed the underlying mechanisms of carotenoids involved in the prevention of ARD. Collectively, understanding the role of carotenoids in ARD would provide insights into a potential intervention that may affect the aging process, and subsequently promote healthy longevity. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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Review
Genuine and Sequestered Natural Products from the Genus Orobanche (Orobanchaceae, Lamiales)
Molecules 2018, 23(11), 2821; https://doi.org/10.3390/molecules23112821 - 30 Oct 2018
Cited by 11 | Viewed by 1649
Abstract
The present review gives an overview about natural products from the holoparasitic genus Orobanche (Orobanchaceae). We cover both genuine natural products as well as compounds sequestered by Orobanche taxa from their host plants. However, the distinction between these two categories is not always [...] Read more.
The present review gives an overview about natural products from the holoparasitic genus Orobanche (Orobanchaceae). We cover both genuine natural products as well as compounds sequestered by Orobanche taxa from their host plants. However, the distinction between these two categories is not always easy. In cases where the respective authors had not indicated the opposite, all compounds detected in Orobanche taxa were regarded as genuine Orobanche natural products. From the about 200 species of Orobanche s.l. (i.e., including Phelipanche) known worldwide, only 26 species have so far been investigated phytochemically (22 Orobanche and four Phelipanche species), from 17 Orobanche and three Phelipanche species defined natural products (and not only natural product classes) have been reported. For two species of Orobanche and one of Phelipanche dedicated studies have been performed to analyze the phenomenon of natural product sequestration by parasitic plants from their host plants. In total, 70 presumably genuine natural products and 19 sequestered natural products have been described from Orobanche s.l.; these form the basis of 140 chemosystematic records (natural product reports per taxon). Bioactivities described for Orobanche s.l. extracts and natural products isolated from Orobanche species include in addition to antioxidative and anti-inflammatory effects, e.g., analgesic, antifungal and antibacterial activities, inhibition of amyloid β aggregation, memory enhancing effects as well as anti-hypertensive effects, inhibition of blood platelet aggregation, and diuretic effects. Moreover, muscle relaxant and anti-spasmodic effects as well as anti-photoaging effects have been described. Full article
(This article belongs to the Special Issue Natural Products and Drug Discovery)
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