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Topical Collection "Herbal Medicine Research"

A topical collection in Molecules (ISSN 1420-3049). This collection belongs to the section "Medicinal Chemistry".

Editor

Prof. Dr. Thomas Efferth
E-Mail Website
Collection Editor
Department of Pharmaceutical Biology, Institute of Pharmacy and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
Interests: Natural products; Transcriptomics; Network pharmacology; Personalized medicine; Virtual drug screening
Special Issues and Collections in MDPI journals

Topical Collection Information

Dear Colleagues,

Herbal medicine is practiced widely in different cultures of the world because it is usually affordable, locally accessible, and generally efficacious. Government statistics (2011) in Hong Kong, China showed that about 27% of all primary healthcare consultations were provided by Chinese medicine (CM) practitioners, while 90% of cancer patients used both CM and western medicine. An ongoing survey initiated by the State Council of the People’s Republic of China from 1988 found 11,146 registered herbal Chinese medicines that were currently in use in the last 5-year cycle. These together with herbal medicines of other territories constitute a wealth of natural botanical resources of traditional and newer drugs or more often, prototype compounds for candidate drugs. Herbal medicine research encompasses old and modern disciplines of plant biology, medicinal chemistry and biochemistry, cell and molecular biology, pharmcogenomics, proteomics, and metabolomics. It utilizes traditional and rapidly advancing analytical methods and instrumentation such as gas or liquid chromatography coupled with tandem mass spectrometry, nuclear magnetic resonance and electron-spin resonance, and gene and protein arrays for fractionation, purification, chemical and genetic fingerprinting, derivatization, modification, synthesis, and clinical trials of herbal medicines starting from cell-line to animal and patient studies. Such multidisciplinary efforts will continue to foster novel therapeutic applications of herbal medicines, such as accelerating apoptosis of pro-inflammatory cells in autoimmune diseases, inducing autophagy for anti-aging and oncosuppression, and overcoming resistance of cancer cells to cytotoxic chemotherapy.

This collection of Molecules on “Herbal Medicine Research” welcomes submission of previously unpublished manuscripts from original work on all the above aspects. We plan to receive submissions from 1 August 2015 to 31 January 2016.

With kind regards and best wishes,

Prof. Dr. Thomas Efferth
Collection Editor

Manuscript Submission Information

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Keywords

  • herbal medicines
  • analytical chemistry
  • medicinal chemistry
  • pharmacology and pharamacogenomics
  • proteomics and metabolomics
  • drug synthesis and modification
  • clinical trials

Published Papers (114 papers)

2021

Jump to: 2020, 2019, 2018, 2017, 2016, 2015

Open AccessArticle
Increased Stress Resistance and Lifespan in Chaenorhabditis elegans Wildtype and Knockout Mutants—Implications for Depression Treatment by Medicinal Herbs
Molecules 2021, 26(7), 1827; https://doi.org/10.3390/molecules26071827 - 24 Mar 2021
Viewed by 441
Abstract
Depression and anxiety disorders are widespread diseases, and they belong to the leading causes of disability and greatest burdens on healthcare systems worldwide. It is expected that the numbers will dramatically rise during the COVID-19 pandemic. Established medications are not sufficient to adequately [...] Read more.
Depression and anxiety disorders are widespread diseases, and they belong to the leading causes of disability and greatest burdens on healthcare systems worldwide. It is expected that the numbers will dramatically rise during the COVID-19 pandemic. Established medications are not sufficient to adequately treat depression and are not available for everyone. Plants from traditional medicine may be promising alternatives to treat depressive symptoms. The model organism Chaenorhabditis elegans was used to assess the stress reducing effects of methanol/dichlormethane extracts from plants used in traditional medicine. After initial screening for antioxidant activity, nine extracts were selected for in vivo testing in oxidative stress, heat stress, and osmotic stress assays. Additionally, anti-aging properties were evaluated in lifespan assay. The extracts from Acanthopanax senticosus, Campsis grandiflora, Centella asiatica, Corydalis yanhusuo, Dan Zhi, Houttuynia cordata, Psoralea corylifolia, Valeriana officinalis, and Withaniasomnifera showed antioxidant activity of more than 15 Trolox equivalents per mg extract. The extracts significantly lowered ROS in mutants, increased resistance to heat stress and osmotic stress, and the extended lifespan of the nematodes. The plant extracts tested showed promising results in increasing stress resistance in the nematode model. Further analyses are needed, in order to unravel underlying mechanisms and transfer results to humans. Full article
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2020

Jump to: 2021, 2019, 2018, 2017, 2016, 2015

Open AccessArticle
Two New Aristolochic Acid Analogues from the Roots of Aristolochia contorta with Significant Cytotoxic Activity
Molecules 2021, 26(1), 44; https://doi.org/10.3390/molecules26010044 - 23 Dec 2020
Viewed by 578
Abstract
Twelve compounds, including two new aristolochic acid analogues with a formyloxy moiety (9–10) and 10 known aristolochic acid derivates (1–8 and 11–12), were obtained from the roots of Aristolochiacontorta. Their structures were elucidated using extensive spectroscopic methods. Their cytotoxic activity in [...] Read more.
Twelve compounds, including two new aristolochic acid analogues with a formyloxy moiety (9–10) and 10 known aristolochic acid derivates (1–8 and 11–12), were obtained from the roots of Aristolochiacontorta. Their structures were elucidated using extensive spectroscopic methods. Their cytotoxic activity in human proximal tubular cells HK-2 was evaluated by the MTT method, which has been widely used to assess cell viability. Among these molecules, compounds 3 and 9 were found to be more cytotoxic. Furthermore, molecular modeling was used to evaluate, for the first time, the interactions of compounds 3 and 9 with the target protein organic anionic transporter 1 (OAT1) that plays a key role in mediating aristolochic acid nephropathy. Structure–activity relationships are briefly discussed. Full article
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Open AccessArticle
Variability of Volatile Compounds in the Medicinal Plant Dendrobium officinale from Different Regions
Molecules 2020, 25(21), 5046; https://doi.org/10.3390/molecules25215046 - 30 Oct 2020
Viewed by 509
Abstract
Dendrobium officinale Kimura et Migo, a rare and traditional medicinal plant, contains many nutrients such as polysaccharides, alkaloids, amino acids and so on. Different growth environment and intraspecific hybridization of different germplasm resources lead to large differences in the yield, quality and medicinal [...] Read more.
Dendrobium officinale Kimura et Migo, a rare and traditional medicinal plant, contains many nutrients such as polysaccharides, alkaloids, amino acids and so on. Different growth environment and intraspecific hybridization of different germplasm resources lead to large differences in the yield, quality and medicinal value of D. officinale. Here, the volatile compounds of D. officinale from four producing regions (Zhejiang, Fujian, Yunnan and Jiangxi) were analyzed to provide a certain reference value for the selection of a specific medicinal component in D. officinale breeding. Fresh stems of D. officinale germplasm resources were collected, and the chemical constituents were determined by gas chromatography-mass spectrometry. A total of 101 volatile compounds were identified, of which esters and alcohols accounted for 23 and 22. Hexacosane is the highest relative content of all volatile components. The highest content of hexacosane was observed in YA1 from Yunnan was 34.41%, and the lowest (23.41%) in JA1 from Jiangxi. Moreover, 5-10 unique substances were determined in different regions. A total of 17 medicinal components were detected, and three unique medicinal components were detected only in YA1, revealing that YA1 can provide raw materials for the application of specific medicinal substances extraction. A total of four toxic components were detected, but no toxic components were detected in JA1 from Jiangxi, suggested that the germplasm resources from Jiangxi could be exploited efficiently for breeding superior D. officinale specimens. The results provide a theoretical basis for the collection, protection and utilization of D. officinale germplasm resources in different regions. Full article
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Open AccessArticle
Induction of Apoptosis, Autophagy and Ferroptosis by Thymus vulgaris and Arctium lappa Extract in Leukemia and Multiple Myeloma Cell Lines
Molecules 2020, 25(21), 5016; https://doi.org/10.3390/molecules25215016 - 29 Oct 2020
Cited by 1 | Viewed by 1070
Abstract
Thymus vulgaris and Arctium lappa have been used as a folk remedy in the Iraqi Kurdistan region to deal with different health problems. The aim of the current study is to investigate the cytotoxicity of T. vulgaris and A. lappa in leukemia and [...] Read more.
Thymus vulgaris and Arctium lappa have been used as a folk remedy in the Iraqi Kurdistan region to deal with different health problems. The aim of the current study is to investigate the cytotoxicity of T. vulgaris and A. lappa in leukemia and multiple myeloma (MM) cell lines and determine the mode of cell death triggered by the most potent cytotoxic fractions of both plants in MM. Resazurin assay was used to evaluate cytotoxic and ferroptosis activity, apoptosis, and modulation in the cell cycle phase were investigated via Annexin V-FITC/PI dual stain and cell-cycle arrest assays. Furthermore, we used western blotting assay for the determination of autophagy cell death. n-Hexane, chloroform, ethyl acetate, and butanol fractions of T. vulgaris and A. lappa exhibited cytotoxicity in CCRF-CEM and CEM/ADR 5000 cell lines at concentration range 0.001–100 μg/mL with potential activity revealed by chloroform and ethyl acetate fractions. NCI-H929 displayed pronounced sensitivity towards T. vulgaris (TCF) and A. lappa (ACF) chloroform fractions with IC50 values of 6.49 ± 1.48 and 21.9 ± 0.69 μg/mL, respectively. TCF induced apoptosis in NCI-H929 cells with a higher ratio (71%), compared to ACF (50%) at 4 × IC50. ACF demonstrated more potent autophagy activity than TCF. TCF and ACF induced cell cycle arrest and ferroptosis. Apigenin and nobiletin were identified in TCF, while nobiletin, ursolic acid, and lupeol were the main compounds identified in ACF. T. vulgaris and A. lappa could be considered as potential herbal drug candidates, which arrest cancer cell proliferation by induction of apoptosis, autophagic, and ferroptosis. Full article
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Open AccessArticle
High Reserve in δ-Tocopherol of Peganum harmala Seeds Oil and Antifungal Activity of Oil against Ten Plant Pathogenic Fungi
Molecules 2020, 25(19), 4569; https://doi.org/10.3390/molecules25194569 - 06 Oct 2020
Cited by 1 | Viewed by 590
Abstract
This investigation included the chemical analysis of Peganum harmala (P. harmala) seed oil and its antifungal properties against 10 fungal species. Seed oils of six populations were analyzed using high performance liquid chromatography (HPLC) and gas chromatograph/mass spectrometry (GC-MS). The HPLC [...] Read more.
This investigation included the chemical analysis of Peganum harmala (P. harmala) seed oil and its antifungal properties against 10 fungal species. Seed oils of six populations were analyzed using high performance liquid chromatography (HPLC) and gas chromatograph/mass spectrometry (GC-MS). The HPLC analysis indicated that P. harmala seed oil exhibited a very high level of tocopherol contents, with values in the range of 2385.66–2722.68 mg/100 g. The most abundant tocopherol isomer was δ-tocopherol (90.39%), followed by γ-tocopherol (8.08%) and α-tocopherol (1.14%). We discovered for the first time the presence of tocotrenols in P. harmala seed oils of the six populations studied. The GC-MS analyses revealed that linoleic acid was the main fatty acid (65.17%), followed by oleic acid (23.12%), palmitic acid (5.36%) and stearic acid (3.08%). We also studied the antifungal activity of seed oil of the Medenine (MD) population on ten fungal pathogens. The antifungal effects differed among pathogens and depended on oil concentrations. Seed oil of the MD population caused a significant decrease in mycelial growth of all fungi tested, with values ranging 31.50–82.11%, except for Alternaria sp., which showed no inhibition. The antifungal activity against the 10 selected fungi can be explained by the richness in tocols of the extracted oil and make P. harmala a promising crop for biological control. Furthermore, the importance of fatty acids and the wide geographic spread in Tunisia of this species make this crop a potential source of renewable energy. Full article
Open AccessArticle
Sinensol-C Isolated from Spiranthes sinensis Inhibits Adipogenesis in 3T3-L1 Cells through the Regulation of Adipogenic Transcription Factors and AMPK Activation
Molecules 2020, 25(18), 4204; https://doi.org/10.3390/molecules25184204 - 14 Sep 2020
Viewed by 605
Abstract
Obesity is an abnormal medical condition caused by accumulation of body fat that presents negative health impacts. Adipocyte hyperplasia, also known as adipogenesis, is one of the major manifestations of obesity. In the present study, we isolated six phenanthrene derivatives (compounds 1 [...] Read more.
Obesity is an abnormal medical condition caused by accumulation of body fat that presents negative health impacts. Adipocyte hyperplasia, also known as adipogenesis, is one of the major manifestations of obesity. In the present study, we isolated six phenanthrene derivatives (compounds 16) from the ethyl acetate fraction of Spiranthes sinensis and investigated their anti-adipogenic activity. We found that among the six phenanthrene derivatives, compound 6 (sinensol-C) exhibited strong inhibitory activity against intracellular lipid accumulation in 3T3-L1 adipocytes, with an IC50 value of 12.67 μM. Sinensol-C remarkably suppressed the accumulation of lipid droplets and adipogenesis, via down-regulation of adipogenic transcription factors, including peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer binding protein α (C/EBPα), sterol regulatory element binding protein-1 (SREBP-1c), fatty acid synthase (FAS), and fatty acid binding protein 4 (FABP4), during adipocyte differentiation in 3T3-L1 cells. In addition, treatment with sinensol-C significantly increased the adenosine monophosphate-activated protein kinase (AMPK) activity in 3T3-L1 cells. Taken together, these data strongly suggest that sinensol-C regulates adiogenesis via down-regulation of adipogenic transcription factors and up-regulation of AMPK. Furthermore, this is the first study that demonstrates that sinensol-C has the capacity to modulate adipogenesis. Full article
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Open AccessReview
The War against Tuberculosis: A Review of Natural Compounds and Their Derivatives
Molecules 2020, 25(13), 3011; https://doi.org/10.3390/molecules25133011 - 30 Jun 2020
Cited by 1 | Viewed by 1347
Abstract
Tuberculosis (TB), caused by the bacterial organism Mycobacterium tuberculosis, pose a major threat to public health, especially in middle and low-income countries. Worldwide in 2018, approximately 10 million new cases of TB were reported to the World Health Organization (WHO). There are [...] Read more.
Tuberculosis (TB), caused by the bacterial organism Mycobacterium tuberculosis, pose a major threat to public health, especially in middle and low-income countries. Worldwide in 2018, approximately 10 million new cases of TB were reported to the World Health Organization (WHO). There are a limited number of medications available to treat TB; additionally, multi-drug resistant TB and extensively-drug resistant TB strains are becoming more prevalent. As a result of various factors, such as increased costs of developing new medications and adverse side effects from current medications, researchers continue to evaluate natural compounds for additional treatment options. These substances have the potential to target bacterial cell structures and may contribute to successful treatment. For example, a study reported that green and black tea, which contains epigallocatechin gallate (a phenolic antioxidant), may decrease the risk of contracting TB in experimental subjects; cumin (a seed from the parsley plant) has been demonstrated to improve the bioavailability of rifampicin, an important anti-TB medication, and propolis (a natural substance produced by honeybees) has been shown to improve the binding affinity of anti-TB medications to bacterial cell structures. In this article, we review the opportunistic pathogen M. tuberculosis, various potential therapeutic targets, available therapies, and natural compounds that may have anti-TB properties. In conclusion, different natural compounds alone as well as in combination with already approved medication regimens should continue to be investigated as treatment options for TB. Full article
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Open AccessCommunication
Osteomeles schwerinae Extract and Its Major Compounds Inhibit Methylglyoxal-Induced Apoptosis in Human Retinal Pigment Epithelial Cells
Molecules 2020, 25(11), 2605; https://doi.org/10.3390/molecules25112605 - 03 Jun 2020
Cited by 1 | Viewed by 669
Abstract
The accumulation and formation of advanced glycation end products (AGEs) are related to diabetes and age-related disease. Osteomeles schwerinae C. K. Schneid. (Rosaceae, OSSC) is used traditionally for the treatment of various diseases in Asia. Previous studies have shown that OSSC elicits preventive [...] Read more.
The accumulation and formation of advanced glycation end products (AGEs) are related to diabetes and age-related disease. Osteomeles schwerinae C. K. Schneid. (Rosaceae, OSSC) is used traditionally for the treatment of various diseases in Asia. Previous studies have shown that OSSC elicits preventive effects in an in vivo model of diabetes. This study was to evaluate the antiapoptotic effects of dried leaves and twigs of OSSC extract and its major compounds in ARPE-19 cells—spontaneously arising human retinal pigment epithelial cells—under diabetic conditions. To examine the effects of an OSSC extract and its active compounds (acetylvitexin, hyperoside and quercitrin) on apoptosis in methylglyoxal (MG, the active precursor in the formation of AGEs)-treated ARPE-19 cells and the mechanism by which these effects occur, apoptosis was measured using flow cytometry analysis. Protein expression levels of phospho-p53 (p-p53), Bax and Bcl-2 were determined by western blot analyses. The OSSC extract inhibited apoptosis in MG-treated ARPE-19 cells in a dose-dependent manner. The major compounds also reduced the rate of apoptosis. Both the extract and major compounds also inhibited the expression of p-p53 and Bax and increased the levels of Bcl-2 that had been previously reduced by MG treatment. The OSSC extract (0.1 μg/mL) and its major compounds (0.01 μM) attenuated apoptosis in ARPE-19 cells under toxic diabetic conditions by downregulating of expression of p-p53 and Bax. OSSC may serve as an alternative therapy to retard the development of diabetic retinopathy. Full article
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Open AccessArticle
Analysis of Phenolic Compounds in Commercial Cannabis sativa L. Inflorescences Using UHPLC-Q-Orbitrap HRMS
Molecules 2020, 25(3), 631; https://doi.org/10.3390/molecules25030631 - 31 Jan 2020
Cited by 12 | Viewed by 1844
Abstract
Industrial hemp (Cannabis sativa L. Family Cannabaceae) contains a vast number of bioactive relevant compounds, namely polyphenols including flavonoids, phenolic acids, phenol amides, and lignanamides, well known for their therapeutic properties. Nowadays, many polyphenols-containing products made of herbal extracts are marketed, claiming [...] Read more.
Industrial hemp (Cannabis sativa L. Family Cannabaceae) contains a vast number of bioactive relevant compounds, namely polyphenols including flavonoids, phenolic acids, phenol amides, and lignanamides, well known for their therapeutic properties. Nowadays, many polyphenols-containing products made of herbal extracts are marketed, claiming to exert health-promoting effects. In this context, industrial hemp inflorescence may represent an innovative source of bioactive compounds to be used in nutraceutical formulations. The aim of this work was to provide a comprehensive analysis of the polyphenolic fraction contained in polar extracts of four different commercial cultivars (Kompoti, Tiborszallasi, Antal, and Carmagnola Cs) of hemp inflorescences through spectrophotometric (TPC, DPPH tests) and spectrometry measurement (UHPLC-Q-Orbitrap HRMS). Results highlighted a high content of cannflavin A and B in inflorescence analyzed samples, which appear to be cannabis-specific, with a mean value of 61.8 and 84.5 mg/kg, meaning a ten-to-hundred times increase compared to other parts of the plant. Among flavonols, quercetin-3-glucoside reached up to 285.9 mg/kg in the Carmagnola CS cultivar. Catechin and epicatechin were the most representative flavanols, with a mean concentration of 53.3 and 66.2 mg/kg, respectively, for all cultivars. Total polyphenolic content in inflorescence samples was quantified in the range of 10.51 to 52.58 mg GAE/g and free radical-scavenging included in the range from 27.5 to 77.6 mmol trolox/kg. Therefore, C. sativa inflorescence could be considered as a potential novel source of polyphenols intended for nutraceutical formulations. Full article
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2019

Jump to: 2021, 2020, 2018, 2017, 2016, 2015

Open AccessArticle
Lipidomic Analysis of the Protective Effects of Shenling Baizhu San on Non-Alcoholic Fatty Liver Disease in Rats
Molecules 2019, 24(21), 3943; https://doi.org/10.3390/molecules24213943 - 31 Oct 2019
Cited by 4 | Viewed by 1184
Abstract
Shenling Baizhu San (SLBZS), a famous traditional Chinese medicine, has been demonstrated to exert protective effects against non-alcoholic fatty liver disease (NAFLD), but its exact mechanisms have not been well understood. The aim of this study was to investigate the mechanisms underlying the [...] Read more.
Shenling Baizhu San (SLBZS), a famous traditional Chinese medicine, has been demonstrated to exert protective effects against non-alcoholic fatty liver disease (NAFLD), but its exact mechanisms have not been well understood. The aim of this study was to investigate the mechanisms underlying the protective effects of SLBZS in a rat model of NAFLD using lipidomics and to evaluate the role of Sirtuin 1 (SIRT1) in the mechanism of SLBZS against NAFLD. The rat model of NAFLD was induced by high-fat feeding. An ultra-performance liquid chromatography-mass spectrometry (UHPLC-MS)-based untargeted lipidomics approach was applied to analyze hepatic lipid alterations, and the SIRT1-selective inhibitor EX 527 was used to inhibit SIRT expression in the liver. The results of body and biochemical parameters, as well as histological changes, indicated that SLBZS administration exerted protective effects against NAFLD. Lipidomic analysis showed that 30 lipid species were effectively regulated by SLBZS administration in rats fed a high-fat diet. Pathway analysis indicated that glycerophospholipid metabolism and glycerolipid metabolism were potential target pathways closely involved in the mechanism of SLBZS against NAFLD. Moreover, the beneficial effects of SLBZS on hepatic steatosis, some biochemical parameters and hepatic lipid species were partly diminished by SIRT1 inhibition. In conclusion, our results suggested that SLBZS administration could effectively alter some hepatic lipid species in rats fed a high-fat diet, which was mainly associated with the regulation of glycerophospholipid and glycerolipid metabolism. Furthermore, the beneficial effects of SLBZS on hepatic lipid metabolism may be at least partly attributed to SIRT1 activation in the liver. Full article
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Open AccessArticle
Comparative In Vitro Evaluation of Antibacterial and Osteogenic Activity of Polysaccharide and Flavonoid Fractions Isolated from the leaves of Saussurea controversa
Molecules 2019, 24(20), 3680; https://doi.org/10.3390/molecules24203680 - 12 Oct 2019
Cited by 2 | Viewed by 1514
Abstract
The osteogenic, cytotoxic, and antibacterial activities of polysaccharide (PS-SC) and flavonoid (F-SC) fractions isolated from the leaves extract of Saussurea controversa were studied in vitro. F-SC consists of the five quercetin glycosides in the ratio 2:8:10:1:4, which were isolated from the leaves extract [...] Read more.
The osteogenic, cytotoxic, and antibacterial activities of polysaccharide (PS-SC) and flavonoid (F-SC) fractions isolated from the leaves extract of Saussurea controversa were studied in vitro. F-SC consists of the five quercetin glycosides in the ratio 2:8:10:1:4, which were isolated from the leaves extract of S. controversa and have been characterized previously. PS-SC was first isolated from the leaves extract of S. controversa and has been described. PS-SC consists in 30 compounds is characterized by a high degree of heterogeneity with a heterogeneity index of 19.74. The Mw and Mn of PS-SC were 108.6 and 5.5 kDa, respectively. Structural fragments are represented by galactose, arabinose, xylose, glucose, uronic acids, mannose, and rhamnose in a 10.1:3.3:2.2:2.1:1.7:0.9:0.5 molar ratio. F-SC as compared with PS-SC showed in vitro microbicidal (50 g/L) and better bacteriostatic (6.25 g/L versus 25 g/L of PS-SC) effects against the 24-h growth of Staphylococcus aureus strain 209 P and a 21-day absence of cytotoxicity on human adipose-derived multipotent mesenchymal stromal cells (hAMMSCs). Both fractions (PS-SC > F-SC) at doses of 10–50 mg/L stimulated differentiation of hAMMSCs into secreting osteoblasts accompanied by local mineralization of extracellular matrix. These fractions of S. controversa and especially F-SC, might be promising peroral drugs in the complex treatment of bone fractures and for prophylaxis of their infectious complications. Full article
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Open AccessArticle
Antiplatelet Activity of Acylphloroglucinol Derivatives Isolated from Dryopteris crassirhizoma
Molecules 2019, 24(12), 2212; https://doi.org/10.3390/molecules24122212 - 13 Jun 2019
Cited by 2 | Viewed by 1129
Abstract
Platelets are an important component of the initial response to vascular endothelial injury; however, platelet dysfunction induces the acute clinical symptoms of thrombotic disorders, which trigger severe cardiovascular diseases such as myocardial infarction, ischemia, and stroke. In this study, we investigated the Dryopteris [...] Read more.
Platelets are an important component of the initial response to vascular endothelial injury; however, platelet dysfunction induces the acute clinical symptoms of thrombotic disorders, which trigger severe cardiovascular diseases such as myocardial infarction, ischemia, and stroke. In this study, we investigated the Dryopteris crassirhizoma’s antiplatelet activity. A water extract of D. crassirhizoma (WDC) was partitioned into dichloromethane (DCM), ethyl acetate, n-butyl alcohol, and water. Among these four fractions, the DCM fraction potently inhibited the collagen-stimulated platelet aggregation in a concentration-dependent manner. From this fraction, five different acylphloroglucinol compounds and one flavonoid were isolated by activity-guided column chromatography. They were identified by comparing their mass, 1H-, and 13C-NMR spectral data with those reported in the literature. Quantifying the six compounds in WDC and its DCM fraction by high-performance liquid chromatography (HPLC) revealed that butyryl-3-methylphloroglucinol (compound 4) was the most abundant in these samples. Additionally, butyryl-3-methylphloroglucinol showed the strongest inhibitory activity in the collagen- and arachidonic acid (AA)-induced platelet aggregation, with inhibition ratios of 92.36% and 89.51% in the collagen and AA-induced platelet aggregation, respectively, without cytotoxicity. On the active concentrations, butyryl-3-methylphloroglucinol significantly suppressed the convulxin-induced platelet activation. Regarding the structure–activity relationships for the five acylphloroglucinol compounds, our results demonstrated that the functional butanonyl, methoxy, and hydroxy groups in butyryl-3-methylphloroglucinol play important roles in antiplatelet activity. The findings indicate that acylphloroglucinols, including butyryl-3-methylphloroglucinol from D. crassirhizom, possess an antiplatelet activity, supporting the use of this species for antiplatelet remedies. Full article
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Open AccessArticle
The Antidepressant-like Effect of Flavonoids from Trigonella Foenum-Graecum Seeds in Chronic Restraint Stress Mice via Modulation of Monoamine Regulatory Pathways
Molecules 2019, 24(6), 1105; https://doi.org/10.3390/molecules24061105 - 20 Mar 2019
Cited by 10 | Viewed by 1502
Abstract
Fenugreek (Trigonella Foenum-Graecum) seeds flavonoids (FSF) have diverse biological activities, while the antidepressant-like effect of FSF has been seldom explored. The aim of this study was to evaluate the antidepressant-like effect of FSF and to identify the potential molecular mechanisms. LC-MS/MS [...] Read more.
Fenugreek (Trigonella Foenum-Graecum) seeds flavonoids (FSF) have diverse biological activities, while the antidepressant-like effect of FSF has been seldom explored. The aim of this study was to evaluate the antidepressant-like effect of FSF and to identify the potential molecular mechanisms. LC-MS/MS was used for the determination of FSF. Chronic restraint stress (CRS) was used to establish the animal model of depression. Observation of exploratory behavior in the forced swimming test (FST), tail suspension test (TST) and sucrose preference test (SPT) indicated the stress level. The serum corticosterone (CORT) level was measured. The monoamine neurotransmitters (5-HT, NE and DA) and their metabolites, as well as monoamine oxidase A (MAO-A) enzyme activity in the prefrontal cortex, hippocampus and striatum, were evaluated. The protein expression levels of KLF11, SIRT1, MAO-A were also determined by western blot analysis. The results showed that FSF treatment significantly reversed the CRS-induced behavioral abnormalities, including reduced sucrose preference and increased immobility time. FSF administration markedly restored CRS induced changes in concentrations of serum corticosterone, prefrontal cortex neurotransmitters (NE, 5-HT and DA), hippocampus neurotransmitters (NE, 5-HT and DA) and striatum neurotransmitters (NE). FSF treatment exhibited significant inhibition of MAO-A activity in the prefrontal cortex and hippocampus. FSF also significantly down-regulated the KLF11, SIRT1 and MAO-A protein expression levels in the prefrontal cortex and hippocampus. These findings indicate that FSF could exhibit an antidepressant-like effect by down-regulating the KLF11/SIRT1-MAO-A pathways, inhibiting MAO-A expression and activity, as well as up-regulating monoamine neurotransmitters levels. Full article
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Open AccessArticle
The Proanthocyanidin-Rich Fraction Obtained from Red Rice Germ and Bran Extract Induces HepG2 Hepatocellular Carcinoma Cell Apoptosis
Molecules 2019, 24(4), 813; https://doi.org/10.3390/molecules24040813 - 23 Feb 2019
Cited by 8 | Viewed by 1696
Abstract
This study aims to determine the anti-carcinogenic effects of the proanthocyanidin-rich fraction (PRFR) obtained from red rice germ and bran extract on HepG2 cells. The PRFR obtained from red rice germ and bran extract could reduce the cell viability of HepG2 cells as [...] Read more.
This study aims to determine the anti-carcinogenic effects of the proanthocyanidin-rich fraction (PRFR) obtained from red rice germ and bran extract on HepG2 cells. The PRFR obtained from red rice germ and bran extract could reduce the cell viability of HepG2 cells as shown by the IC50 value at 20 µg/mL. Notably, PRFR concentrations at 20 and 40 µg/mL significantly increased the number of cells in the G2/M phase from 25.7% ± 1.4%in the control group to 36.2% ± 3.4% (p < 0.01) and 48.9% ± 2.6% (p < 0.0001), respectively, suggesting that the cells were arrested in this phase, which was confirmed by the reduction of survival proteins, including cyclin B1 and cdc25. Moreover, the PRFR at 20 and 40 µg/mL could induce cell death via the apoptosis cascade, indicated by the percentage of total apoptotic cells from 9.9% ± 3.1% in the control group to 41.1 ± 3.9 (p < 0.0001) and 82.2% ± 5.8% (p < 0.0001), respectively. This was clarified by increasing apoptotic proteins (such as cleaved PARP-1, cleaved caspase-8 and cleaved caspase-3) and decreasing anti-apoptotic protein survivin without p53 alterations. These results demonstrated that the PRFR obtained from red rice germ and bran extract could inhibit cell proliferation and induce cell apoptosis in HepG2 cells via survivin, which could potentially serve as a new target for cancer therapeutics making it an excellent “lead candidate” molecule for in vivo proof-of concept studies. Full article
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Open AccessArticle
Mori Ramulus (Chin.Ph.)—the Dried Twigs of Morus alba L./Part 1: Discovery of Two Novel Coumarin Glycosides from the Anti-Hyperuricemic Ethanol Extract
Molecules 2019, 24(3), 629; https://doi.org/10.3390/molecules24030629 - 11 Feb 2019
Cited by 2 | Viewed by 1670
Abstract
In Traditional Chinese Medicine (TCM), Mori ramulus (Chin.Ph.)—the dried twigs of Morus alba L.—is extensively used as an antirheumatic agent and also finds additional use in asthma therapy. As a pathological high xanthine oxidase (XO, EC 1.1.3.22) activity is strongly correlated to hyperuricemy [...] Read more.
In Traditional Chinese Medicine (TCM), Mori ramulus (Chin.Ph.)—the dried twigs of Morus alba L.—is extensively used as an antirheumatic agent and also finds additional use in asthma therapy. As a pathological high xanthine oxidase (XO, EC 1.1.3.22) activity is strongly correlated to hyperuricemy and gout, standard anti-hyperuremic therapy typically involves XO inhibitors like allopurinol, which often cause adverse effects by inhibiting other enzymes involved in purine metabolism. Mori ramulus may therefore be a promissing source for the development of new antirheumatic therapeutics with less side effects. Coumarins, one of the dominant groups of bioactive constituents of M. alba, have been demonstrated to possess anti-inflammatory, antiplatelet aggregation, antitumor, and acetylcholinesterase (AChE) inhibitory activities. The combination of HPLC (DAD) and Q-TOF technique could give excellent separating and good structural characterization abilities which make it suitable to analyze complex multi-herbal extracts in TCM. The aim of this study was to develop a HPLC (DAD)/ESI-Q-TOF-MS/MS method for the identification and profiling of pharmacologically active coumarin glycosides in Mori ramulus refined extracts for used in TCM. This HPLC (DAD)/ESI-Q-TOF-MS/MS method provided a rapid and accurate method for identification of coumarin glycosides—including new natural products described here for the first time—in the crude extract of M. alba L. In the course of this project, two novel natural products moriramulosid A (umbelliferone-6-β-d-apiofuranosyl-(1→6)-β-d-glucopyranoside) and moriramulosid B (6-[[6-O-(6-deoxy-α-l-mannopyranosyl)-β-d-glucopyranosyl]oxy]-2H-1-benzopyran-1-one) were newly discovered and the known natural product Scopolin was identified in M. alba L. for the first time. Full article
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2018

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Open AccessArticle
Evaluation of the Absorption Behavior of Main Component Compounds of Salt-Fried Herb Ingredients in Qing’e Pills by Using Caco-2 Cell Model
Molecules 2018, 23(12), 3321; https://doi.org/10.3390/molecules23123321 - 14 Dec 2018
Cited by 5 | Viewed by 1282
Abstract
Qing’e Pills is a Chinese traditional herbal product, which is often used to strengthen muscles and bones in TCM (traditional Chinese Medicine) practice. Its two main component herbs, namely, Cortex Eucommiae and Fructus Psoraleae are both required to be salt-fried according to TCM [...] Read more.
Qing’e Pills is a Chinese traditional herbal product, which is often used to strengthen muscles and bones in TCM (traditional Chinese Medicine) practice. Its two main component herbs, namely, Cortex Eucommiae and Fructus Psoraleae are both required to be salt-fried according to TCM theory. We have evaluated the effects of salt-frying treated herbs on Caco-2 cell uptake behavior for those active ingredients of Qing’e Pills. By investigating of various variables, including MTT, temperature, inhibitors, pH, salt concentration and herb processing methods, we tried to clarify whether the salt-processing on herbs was necessary or not. Results showed that, compared to other processing methods, the salt-frying process significantly (p < 0.01) enhanced the absorption of effective components of Qing’e Pills. The way that psoralen, isopsoralen, psoralenoside and geniposide acid entered Caco-2 cells at low concentrations was via passive diffusion. These components were not substrates of P-glycoprotein. It demonstrated that the salt-frying process not only enhanced the concentration of active components in herb extract, but also changed their absorption behaviors. Nevertheless, the mechanism of absorption behavior changing needs to be further investigated. Full article
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Open AccessArticle
Chromosome Doubling-Enhanced Biomass and Dihydrotanshinone I Production in Salvia miltiorrhiza, A Traditional Chinese Medicinal Plant
Molecules 2018, 23(12), 3106; https://doi.org/10.3390/molecules23123106 - 27 Nov 2018
Cited by 2 | Viewed by 1742
Abstract
The root of Chinese sage (Salvia miltiorrhiza Bunge) was regarded as top-grade Chinese medicine two thousand years ago, according to Shen Nong Materia Medica. The aim of this study is to develop an easy and reliable means for obtaining tetraploids (4 [...] Read more.
The root of Chinese sage (Salvia miltiorrhiza Bunge) was regarded as top-grade Chinese medicine two thousand years ago, according to Shen Nong Materia Medica. The aim of this study is to develop an easy and reliable means for obtaining tetraploids (4x plants) via thidiazuron-induced direct organogenesis in the presence of colchicine. The resulting 4x plants showed significantly enhanced agronomic traits, including the size of stomata, leaflet, pollen, and seed as well as shoot length, root diameter, number of leaves, and fresh weight of plant. In addition, an obvious reduction of length to width ratio was found in the 4x plants, including stomata, leaflets, pollens, seeds, and roots. The 4x ploidy state of the plants was stable as was proved by evaluation of selection indicators as well as consistent ploidy level at 10th generation plantlets and also on 4x seedlings obtained via self-pollination. The major bioactive compounds, salvianolic acid B, tanshinone I, tanshinone IIA, dihydrotanshinone I and cryptotanshinone, as well as total tanshinones were determined by high performance liquid chromatography (HPLC). The concentrations of dihydrotanshinone I and total tanshinones in the root extract of the 4x plants were significantly higher when compared with the 2x plants. This present study developed a simple and efficient system for inducing and subculture of tetrapolids which have stable ploidy level, enhanced growth characteristics as well as the content of dihydrotanshinone I in the root of S. miltiorrhiza. Full article
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Open AccessArticle
Effects of Red Ginseng Extract on the Pharmacokinetics and Elimination of Methotrexate via Mrp2 Regulation
Molecules 2018, 23(11), 2948; https://doi.org/10.3390/molecules23112948 - 12 Nov 2018
Cited by 9 | Viewed by 2014
Abstract
We aimed to investigate the effects of red ginseng extract (RGE) on the expression of efflux transporters and to study the pharmacokinetics of representative substrate. For this, rats received single or repeated administration of RGE (1.5 g/kg/day) for 1 and 2 weeks via [...] Read more.
We aimed to investigate the effects of red ginseng extract (RGE) on the expression of efflux transporters and to study the pharmacokinetics of representative substrate. For this, rats received single or repeated administration of RGE (1.5 g/kg/day) for 1 and 2 weeks via oral gavage. mRNA and protein levels of multidrug resistance-associated protein2 (Mrp2), bile salt export pump (Bsep), and P-glycoprotein (P-gp) in the rat liver were measured via real-time polymerase chain reaction and Western blot analysis. Ginsenosides concentrations from the rat plasma were also monitored using a liquid chromatography–tandem mass spectrometry (LC–MS/MS) system. Plasma concentrations of ginsenoside Rb1, Rb2, Rc, and Rd following repeated administration of RGE for 1 and 2 weeks were comparable but significantly higher than those after single administration of RGE. These dosing regimens did not induce significant biochemical abnormalities in the liver, kidneys, and lipid homeostasis. In the RGE repeated oral administration groups, the mRNA and protein levels of Mrp2 significantly decreased. Accordingly, we investigated the changes in the pharmacokinetics of methotrexate, a probe substrate for Mrp2, following intravenous administration of 3 mg/kg methotrexate to rats in the RGE 1-week repeated oral administration group, compared to that in the control group. Biliary excretion, but not urinary excretion, of methotrexate decreased in the RGE repeated administration group, compared to that in the control group. Consequently, the plasma concentrations of methotrexate slightly increased in the RGE repeated administration group. In conclusion, repeated administration of RGE for 1 week resulted in a decrease in Mrp2 expression without inducing significant liver or kidney damage. Pharmacokinetic herb–drug interaction between RGE and methotrexate might occur owing to the decrease in the mRNA and protein levels of Mrp2. Full article
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Open AccessArticle
Inhibitory Effects of Ginsenoside Rb1 on Early Atherosclerosis in ApoE-/- Mice via Inhibition of Apoptosis and Enhancing Autophagy
Molecules 2018, 23(11), 2912; https://doi.org/10.3390/molecules23112912 - 08 Nov 2018
Cited by 21 | Viewed by 2174
Abstract
Inflammation is a major contributing factor to the progression of atherosclerosis. Ginsenoside Rb1 (Rb1), an active saponin of Panax notoginseng, has been found to exert beneficial effects on inflammation and oxidative stress. This study investigated the ability of Rb1 to inhibit the [...] Read more.
Inflammation is a major contributing factor to the progression of atherosclerosis. Ginsenoside Rb1 (Rb1), an active saponin of Panax notoginseng, has been found to exert beneficial effects on inflammation and oxidative stress. This study investigated the ability of Rb1 to inhibit the formation of atherosclerotic plaques and the potential mechanisms. In this study, the effects of Rb1 on the development of atherosclerosis were investigated in ApoE-/- deficient mice fed with a western diet. Mice were intragastrically administrated with Rb1 (10 mg/kg) for 8 weeks. This study is that ginsenoside Rb1 exerted an inhibitory effect on early atherosclerosis in ApoE-/- mice via decreasing body weight and food intake daily, upregulating the lipid levels of serum plasma, including those of TC, TG and LDL-C and HDL-C and reducing the atherosclerotic plaque area, suppressing inflammatory cytokines (levels of IL-1β, IL-6 and TNF-α) in the serum of ApoE-/- mice, changing the expression levels of BCL-2, BAX, cleaved caspase-3 and cleaved caspase-9 and weakening apoptosis associated with anti-inflammatory activity. Hence, all these effects against atherosclerosis were tightly associated with regulation of necrosis or apoptosis associated with anti-inflammatory activity. Additionally, the results found that ginsenoside Rb1 increased autophagy flux to inhibit apoptosis via acceleration of autophagy by promoting transformation of LC3 from type I to type II in high-fat diet-induced atherosclerosis in ApoE-/- mice. This finding, along with those of the previous study, provides evidence that Rb1 promotes the process of autophagy to protect against atherosclerosis via regulating BCL-2 family-related apoptosis. These results indicate that Rb1 exhibits therapeutic effects in atherosclerosis by reversing the imbalance between apoptosis and autophagy. Full article
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Open AccessArticle
Anti-Proliferative Effects of HBX-5 on Progression of Benign Prostatic Hyperplasia
Molecules 2018, 23(10), 2638; https://doi.org/10.3390/molecules23102638 - 14 Oct 2018
Cited by 6 | Viewed by 2492
Abstract
Benign prostatic hyperplasia (BPH), an age-dependent disorder with a prevalence percentage of 60% in the 60s, has been found to involve an androgenic hormone imbalance that causes confusion between cell apoptosis and proliferation. Because general medications for BPH treatment have undesirable side effects, [...] Read more.
Benign prostatic hyperplasia (BPH), an age-dependent disorder with a prevalence percentage of 60% in the 60s, has been found to involve an androgenic hormone imbalance that causes confusion between cell apoptosis and proliferation. Because general medications for BPH treatment have undesirable side effects, the development of effective alternative medicines has been considered. HBX-5 is a newly developed formula with the aim of improving BPH, and is composed of nine medicinal herbs. BPH was induced in the rats by intramuscular injection of testosterone propionate after castration. Rats were divided into six groups, and the efficacy of HBX-5 on testosterone-induced BPH in rats was estimated. In addition, RWPE-1 and WPMY-1 cells were used to demonstrate the effect of HBX-5 on BPH in vitro model. Compared with the control group, HBX-5 administration group suppressed BPH manifestations, such as excessive development of prostate, and increase of serum dihydrotestosterone and 5α-reductase concentrations. Furthermore, immunohistochemistry analysis revealed that HBX-5 significantly decreased the expression of androgen receptor (AR) and proliferating cell nuclear antigen (PCNA). In addition, results of RWPE-1 and WPMY-1 cells showed that HBX-5 inhibited the over-expression of AR and PSA in DHT-induced prostate hyperplastic microenvironments. Full article
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Open AccessArticle
Chemical Composition, Antioxidant Activity and α-Glucosidase Inhibitory Activity of Chaenomeles Speciosa from Four Production Areas in China
Molecules 2018, 23(10), 2518; https://doi.org/10.3390/molecules23102518 - 01 Oct 2018
Cited by 7 | Viewed by 1442
Abstract
Chaenomeles speciosa (Sweet) Nakai is a medicinal plant. Until date, there are no studies focusing on comparing the chemical profiles, antioxidant activity and α-glucosidase inhibitory activity of the dried fruits of C. speciosa from different production regions. In the study, we investigated [...] Read more.
Chaenomeles speciosa (Sweet) Nakai is a medicinal plant. Until date, there are no studies focusing on comparing the chemical profiles, antioxidant activity and α-glucosidase inhibitory activity of the dried fruits of C. speciosa from different production regions. In the study, we investigated the chemical components of dried fruits of C. speciosa from Yunnan, Chongqing, Zhejiang and Anhui provinces in China in relation to the antioxidant activity and α-glucosidase inhibitory activity. C. speciosa from Yunnan had higher total flavonoid (47.92 ± 3.79 mg/g), total polyphenol (29.15 ± 0.29 mg/g) and polysaccharide (27.60 ± 1.56 mg/g) contents than plants from other production areas. Samples from Yunnan, Zhejiang and Anhui (all > 3200 mg/kg) had higher free amino acid contents than those from Chongqing (2286.66 mg/kg). Oleanolic acid and ursolic acid levels were highest in samples from Zhejiang (555.98 ± 20.88 μg/g) and Anhui (321.06 ± 14.64 μg/g), respectively. C. speciosa from Chongqing had low total flavonoid, total polyphenol, polysaccharide, free amino acid, oleanolic acid and ursolic acid contents but high levels of palmitic acid (12.04 ± 0.02 mg/g) and stearic acid (2.23 ± 0.08 mg/g). Among four production areas, Yunnan represented the highest antioxidant activity and α-glucosidase inhibitory activity. In addition, correlation analysis revealed that total flavonoid, total polyphenol, polysaccharide and ursolic acid were the major components responsible for the antioxidant activity of C. speciosa, while total flavonoid and polysaccharide were the main contributors for α-glucosidase inhibitory activity of the plant. These results would be helpful for evaluating the quality of C. speciosa in the different production areas. Full article
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Open AccessArticle
Neuroprotective Effects of Radix Scrophulariae on Cerebral Ischemia and Reperfusion Injury via MAPK Pathways
Molecules 2018, 23(9), 2401; https://doi.org/10.3390/molecules23092401 - 19 Sep 2018
Cited by 23 | Viewed by 2233 | Correction
Abstract
Ischemic stroke is a clinically common cerebrovascular disease whose main risks include necrosis, apoptosis and cerebral infarction, all caused by cerebral ischemia and reperfusion (I/R). Ischemia and reperfusion-induced injury or apoptosis inhibition in human brain tissue may exert an irreplaceable protective effect on [...] Read more.
Ischemic stroke is a clinically common cerebrovascular disease whose main risks include necrosis, apoptosis and cerebral infarction, all caused by cerebral ischemia and reperfusion (I/R). Ischemia and reperfusion-induced injury or apoptosis inhibition in human brain tissue may exert an irreplaceable protective effect on ischemic nerves. This process has particular significance for the treatment of stroke patients. However, the development of neuroprotective drugs remains challenging. Radix Scrophulariae, traditionally considered a valuable medicine, has been discovered to have neuroprotective effects. To explore the neuroprotective effects of an aqueous extract of Radix Scrophulariae (RSAE) on cerebral ischemia/reperfusion and their underlying mechanisms, oxygen-glucose deprivation and reperfusion (OGD/R)-induced PC12 cells were used, and a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model was established. In vitro results showed that 12.5 μg/mL RSAE markedly improved cell viability; inhibited LDH leakage; increased SOD, GSH-Px and CAT enzyme activity; stabilized the mitochondrial membrane potential; and reduced OGD-induced cell injury and apoptosis. Additionally, in vivo results preliminarily suggested that in MCAO/R model mice, RSAE treatments attenuated infarct volume; reduced brain water content and nitric oxide (NO) and malondialdehyde (MDA) concentrations; inhibited I/R-induced neurological deficits; reduced the levels of lactate dehydrogenase (LDH) leakage release; improved antioxidant capacity by upregulating SOD, GSH-Px and CAT enzyme activity; and reduced neuronal apoptosis, necrosis and loss of neurons. Moreover, it was found that RSAE upregulated the expression of Bcl-2 and downregulated the expression of Bax. In addition, the phosphorylation levels of MAPK signal pathways were elucidated via western blot analysis and immunohistochemical evaluation. In summary, this study investigated the neuroprotective effects and potential mechanisms of RSAE on focal cerebral I/R injury in mice. Radix Scrophulariae has been previously identified as a potential neuroprotective natural plant. Hence, our results may offer insight into discovering new active compounds or drugs for the treatment of ischemic stroke. Many new natural active chemicals in this extract may be discovered by chemical separation and identification and may provide new insights into therapeutic targets in stroke patients. Full article
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Open AccessArticle
Sinomenine Protects Against Morphine Dependence through the NMDAR1/CAMKII/CREB Pathway: A Possible Role of Astrocyte-Derived Exosomes
Molecules 2018, 23(9), 2370; https://doi.org/10.3390/molecules23092370 - 17 Sep 2018
Cited by 10 | Viewed by 1729
Abstract
Sinomenine is a nonaddictive alkaloid used to prevent morphine dependence, even thoughits mechanism isnot fully understood. Astrocytes aggravate the pathological process in their neighboring cellsthrough exosomes in central nervous system diseases. However, the effect of sinomenine on astrocyte-derived exosomes for the amelioration of [...] Read more.
Sinomenine is a nonaddictive alkaloid used to prevent morphine dependence, even thoughits mechanism isnot fully understood. Astrocytes aggravate the pathological process in their neighboring cellsthrough exosomes in central nervous system diseases. However, the effect of sinomenine on astrocyte-derived exosomes for the amelioration of morphine dependence has not been reported yet. In this study, we found that sinomenine prevented the morphine-induced conditionedplace preference in mice. Sinomenine reduced the levels of cAMP and intracellular Ca2+ in morphine-treated SH-SY5Y cells. Moreover, sinomenine inhibited the expressions of p-NMDAR1/NMDAR1, p-CAMKII/CAMKII, and p-CREB/CREB in the hippocampusof morphine-dependent mice and SH-SY5Y cells. Furthermore, we found that sinomenine inhibitedthe morphine-induced activation of astrocytesin vivo and in vitro. Afterwards, exosomes were isolated from cultured primary astrocytes treated with phosphate buffer saline (PBS, ctl-exo), morphine (mor-exo), or morphine and sinomenine (Sino-exo). Subsequently, morphine-treated SH-SY5Y cells were treated with ctl-exo, mor-exo, and Sino-exo. Results showed that Sino-exo reduced the level of cAMP, intracellular Ca2+, and the expression of p-CAMKII/CAMKII and p-CREB/CREB in morphine-treated SH-SY5Y cells. In conclusion, we demonstrated that sinomenine exhibited protective effects against morphine dependencein vivo and in vitro through theNMDAR1/CAMKII/CREB pathway. Sinomenine-induced alterationof the function of astrocyte-derived exosomes may contribute to the antidependence effects of sinomenine in morphine dependence. Full article
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Open AccessArticle
Correlation between Quality and Geographical Origins of Poria cocos Revealed by Qualitative Fingerprint Profiling and Quantitative Determination of Triterpenoid Acids
Molecules 2018, 23(9), 2200; https://doi.org/10.3390/molecules23092200 - 31 Aug 2018
Cited by 14 | Viewed by 1765
Abstract
Poria cocos (Schw.) Wolf (PC) is a well-known saprophytic fungus, and its sclerotium without the epidermis (PCS) is widely used in traditional Chinese medicine and as a functional food in many countries. PCS is normally collected from multiple geographical regions, but whether and [...] Read more.
Poria cocos (Schw.) Wolf (PC) is a well-known saprophytic fungus, and its sclerotium without the epidermis (PCS) is widely used in traditional Chinese medicine and as a functional food in many countries. PCS is normally collected from multiple geographical regions, but whether and how the quality of PCS correlates with where it grows have not been determined. This correlation could be significant both for quality control and optimum utilization of PCS as a natural resource. In this study, a qualitative fingerprint profiling method performed by ultra-performance liquid chromatography (UHPLC) with diode array detection (DAD) combining quadrupole time-of-flight-mass spectrometry (QTOF-MS/MS) and a quantitative UHPLC coupled with triple quadrupole mass spectrometry (QqQ-MS/MS) approach were established to investigate whether and how the quality of PCS correlates with its collection location. A standard fingerprint of PCS was generated by median simulation of 25 tested samples collected from four main producing areas of China, and similarity analysis was applied to evaluate the similarities between the fingerprints of samples and the standard fingerprint. Twenty three common peaks occurring in the fingerprint were unequivocally or tentatively identified by UHPLC-QTOF-MS/MS. Meanwhile, principal component analysis (PCA), supervised orthogonal partial least squares-discriminate analysis (OPLS-DA) and hierarchical cluster analysis (HCA) were employed to classify 25 batches of PCS samples into four groups, which were highly consistent with the four geographical regions. Ten compounds were screened out as potential markers to distinguish the quality of PCS. Nine triterpene acids, including five compounds that played important roles in the clusters between different samples collected from the four collection locations, were simultaneously quantified by using the multiple reaction monitoring (MRM) mode of UHPLC-QqQ-MS/MS. The current strategy not only clearly expounded the correlation between quality and geographical origins of PCS, but also provided a fast, accurate and comprehensive qualitative and quantitative method for assessing the quality of PCS. Full article
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Open AccessArticle
An In Vitro Estimation of the Cytotoxicity and Genotoxicity of Root Extract from Leonurus sibiricus L. Overexpressing AtPAP1 against Different Cancer Cell Lines
Molecules 2018, 23(8), 2049; https://doi.org/10.3390/molecules23082049 - 16 Aug 2018
Cited by 9 | Viewed by 1622
Abstract
As the current cancer treatment success rate is not sufficient, interest has grown in plants as possible sources of anti-cancer compounds. One such plant with a broad spectrum of activity is Lenourus sibiricus of the family Lamiaceae. This study investigates for the first [...] Read more.
As the current cancer treatment success rate is not sufficient, interest has grown in plants as possible sources of anti-cancer compounds. One such plant with a broad spectrum of activity is Lenourus sibiricus of the family Lamiaceae. This study investigates for the first time both the genotoxic and cytotoxic activities of TR (transformed) and AtPAP1 TR (with over-expression of transcriptional factor) root extracts of Lenourus sibiricus against various cancer cell lines (CCRF-CEM, K-562 and A549). Both tested extracts showed a cytotoxic effect on CCRF-CEM and K-562 cell lines, but strongest activity was observed for the AtPAP1 TR extract. No cytotoxic effect was observed against the A549 cell line in the tested concentration range, and it was found that both tested extracts may induce apoptosis by decreasing mitochondrial membrane potential and inducing nDNA damage lesion in the TP53 region and mtDNA in ND1 (mitochondrially encoded NADH: ubiquinone oxidoreductase core subunit 1) and ND5 (mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 5) regions in K-562 and CCRF-CEM. Our results confirmed that TR and AtPAP1 TR root extracts from L. sibiricus are cytotoxic and genotoxic against different model cell lines (CCRF-CEM and K-562). However, the observed genotoxicity of both extracts needs to be confirmed by additional studies. These preclinical observations support the use of L. sibiricus with other pharmacological purposes. Full article
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Open AccessCommunication
16-Hydroxycleroda-3,13-dien-15,16-olide and N-Methyl-Actinodaphine Potentiate Tamoxifen-Induced Cell Death in Breast Cancer
Molecules 2018, 23(8), 1966; https://doi.org/10.3390/molecules23081966 - 06 Aug 2018
Cited by 3 | Viewed by 1264
Abstract
In this study, we investigated whether 16-hydroxycleroda-3,13-dien-15,16-olide (HCD) and N-methyl-actinodaphine (MA) could sensitize breast cancer cells to Tamoxifen (TMX) treatment. MA or HCD alone or in combination with TMX dose-dependently inhibited MCF-7 and MDA-MB-231 cell growth, with a more potent inhibition on [...] Read more.
In this study, we investigated whether 16-hydroxycleroda-3,13-dien-15,16-olide (HCD) and N-methyl-actinodaphine (MA) could sensitize breast cancer cells to Tamoxifen (TMX) treatment. MA or HCD alone or in combination with TMX dose-dependently inhibited MCF-7 and MDA-MB-231 cell growth, with a more potent inhibition on MDA-MB 231 cells. Furthermore, this novel combination significantly induced S and G2/M cell cycle phase in MDA-MB 231 than MCF-7 cells. Further determination of the apoptotic induction showed that MA or HCD and TMX combination inhibited MDA-MB-231 and MCF-7 cancer cells by upregulating Bax and by downregulating Bcl-2 mRNA and protein expression without altering Caspase-8 and Caspase-12 expression. These results suggest that MA or HCD pretreatment may potentiate the anti-tumor effect of tamoxifen on breast cancer. Full article
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Open AccessArticle
Antiadipogenic Effects of Loganic Acid in 3T3-L1 Preadipocytes and Ovariectomized Mice
Molecules 2018, 23(7), 1663; https://doi.org/10.3390/molecules23071663 - 09 Jul 2018
Cited by 14 | Viewed by 1767
Abstract
Obesity is caused by an excess storage of body fat, resulting from a chronic imbalance between energy intake and expenditure. Gentiana lutea L. (GL) root has been reported to reduce lipid accumulation in the aortic wall of diabetic rats. Here, we performed fractionation [...] Read more.
Obesity is caused by an excess storage of body fat, resulting from a chronic imbalance between energy intake and expenditure. Gentiana lutea L. (GL) root has been reported to reduce lipid accumulation in the aortic wall of diabetic rats. Here, we performed fractionation and isolation of the bioactive constituent(s) that may be responsible for the antiadipogenic effects of the GL root extract. A single compound, loganic acid, was identified as a candidate component in the 30% ethanol extract of GL. Loganic acid treatment significantly decreased the adipocyte differentiation of 3T3-L1 preadipocytes in a dose-dependent manner. The expression of key adipogenesis-related genes such as adiponectin (Adipoq), peroxisome proliferator-activated receptor gamma (Pparg), lipoprotein lipase (Lpl), perilipin1 (Plin1), fatty acid binding protein 4 (Fabp4), glucose transporter type 4 (Slc2a4), CCAAT/enhancer-binding protein alpha (Cebpa), and tumor necrosis factor-alpha (Tnf) were significantly reduced following treatment with loganic acid. In vivo experiments in an ovariectomy-induced obesity mouse model showed that loganic acid (oral administration with 10 and 50 mg/kg/day) significantly inhibited body weight gain, total fat increase, fatty hepatocyte deposition in the liver, and adipocyte enlargement in the abdominal visceral fat tissues. These results suggest that loganic acid in the GL root extract has antiadipogenic effects in vitro and in vivo. Loganic acid may be beneficial for the prevention and treatment of obesity, particularly in menopausal obese women. Full article
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Open AccessReview
Essential Oils and Their Constituents Targeting the GABAergic System and Sodium Channels as Treatment of Neurological Diseases
Molecules 2018, 23(5), 1061; https://doi.org/10.3390/molecules23051061 - 02 May 2018
Cited by 25 | Viewed by 3608
Abstract
Essential oils and the constituents in them exhibit different pharmacological activities, such as antinociceptive, anxiolytic-like, and anticonvulsant effects. They are widely applied as a complementary therapy for people with anxiety, insomnia, convulsion, pain, and cognitive deficit symptoms through inhalation, oral administration, and aromatherapy. [...] Read more.
Essential oils and the constituents in them exhibit different pharmacological activities, such as antinociceptive, anxiolytic-like, and anticonvulsant effects. They are widely applied as a complementary therapy for people with anxiety, insomnia, convulsion, pain, and cognitive deficit symptoms through inhalation, oral administration, and aromatherapy. Recent studies show that essential oils are emerging as a promising source for modulation of the GABAergic system and sodium ion channels. This review summarizes the recent findings regarding the pharmacological properties of essential oils and compounds from the oils and the mechanisms underlying their effects. Specifically, the review focuses on the essential oils and their constituents targeting the GABAergic system and sodium channels, and their antinociceptive, anxiolytic, and anticonvulsant properties. Some constituents target transient receptor potential (TRP) channels to exert analgesic effects. Some components could interact with multiple therapeutic target proteins, for example, inhibit the function of sodium channels and, at the same time, activate GABAA receptors. The review concentrates on perspective compounds that could be better candidates for new drug development in the control of pain and anxiety syndromes. Full article
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Open AccessReview
Panax Notoginseng Saponins: A Review of Its Mechanisms of Antidepressant or Anxiolytic Effects and Network Analysis on Phytochemistry and Pharmacology
Molecules 2018, 23(4), 940; https://doi.org/10.3390/molecules23040940 - 17 Apr 2018
Cited by 27 | Viewed by 4229
Abstract
Panax notoginseng (Burk) F. H. Chen, as traditional Chinese medicine, has a long history of high clinical value, such as anti-inflammatory, anti-oxidation, inhibition of platelet aggregation, regulation of blood glucose and blood pressure, inhibition of neuronal apoptosis, and neuronal protection, and its [...] Read more.
Panax notoginseng (Burk) F. H. Chen, as traditional Chinese medicine, has a long history of high clinical value, such as anti-inflammatory, anti-oxidation, inhibition of platelet aggregation, regulation of blood glucose and blood pressure, inhibition of neuronal apoptosis, and neuronal protection, and its main ingredients are Panax notoginseng saponins (PNS). Currently, Panax notoginseng (Burk) F. H. Chen may improve mental function, have anti-insomnia and anti-depression effects, alleviate anxiety, and decrease neural network excitation. However, the underlying effects and the mechanisms of Panax notoginseng (Burk) F. H. Chen and its containing chemical constituents (PNS) on these depression-related or anxiety-related diseases has not been completely established. This review summarized the antidepressant or anxiolytic effects and mechanisms of PNS and analyzed network targets of antidepressant or anxiolytic actions with network pharmacology tools to provide directions and references for further pharmacological studies and new ideas for clinical treatment of nervous system diseases and drug studies and development. The review showed PNS and its components may exert these effects through regulating neurotransmitter mechanism (5-HT, DA, NE), modulation of the gamma-amino butyric acid (GABA) neurotransmission, glutamatergic system, hypo-thalamus-pituitary-adrenal (HPA) axis, brain-derived neurotrophic factor (BDNF), and its intracellular signaling pathways in the central nervous system; and produce neuronal protection by anti-inflammatory, anti-oxidation, or inhibition of neuronal apoptosis, or platelet aggregation and its intracellular signaling pathways. Network target analysis indicated PNS and its components also may have anti-inflammatory and anti-apoptotic effects, which leads to the preservation of brain nerves, and regulate the activity and secretion of nerve cells, exerting anti-depression and anxiolytic effects, which may provide new directions for further in-depth researches of related mechanisms. Full article
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Open AccessArticle
Coumarin Content, Morphological Variation, and Molecular Phylogenetics of Melilotus
Molecules 2018, 23(4), 810; https://doi.org/10.3390/molecules23040810 - 02 Apr 2018
Cited by 3 | Viewed by 1926
Abstract
Melilotus albus and Melilotus officinalis are widely used in forage production and herbal medicine due to the biological activity of their coumarins, which have many biological and pharmacological activities, including anti-HIV and anti-tumor effects. To comprehensively evaluate M. albus and M. officinalis coumarin [...] Read more.
Melilotus albus and Melilotus officinalis are widely used in forage production and herbal medicine due to the biological activity of their coumarins, which have many biological and pharmacological activities, including anti-HIV and anti-tumor effects. To comprehensively evaluate M. albus and M. officinalis coumarin content (Cou), morphological variation, and molecular phylogeny, we examined the Cou, five morphological traits and the molecular characterization based on the trnL-F spacer and internal transcribed spacer (ITS) regions of 93 accessions. Significant (p < 0.05) variation was observed in the Cou and all five morphological traits in both species. Analysis of population differentiation (Pst) of the phenotypic traits showed that powdery mildew resistance (PMR) had the greatest Pst, meaning that this trait demonstrated the largest genetic differentiation among the accessions. The Pst values of dry matter yield (DMY) and Cou were relatively high. Biplot analysis identified accessions with higher DMY and higher and lower Cou. Analysis of molecular sequence variation identified seven haplotypes of the trnL-F spacer and 13 haplotypes of the ITS region. Based on haplotype and sequence analyses, the genetic variation of M. officinalis was higher than that of M. albus. Additionally, ITS sequence analysis showed that the variation among accessions was larger than that among species across three geographical areas: Asia, Europe, and North America. Similarly, variation among accessions for both the trnL-F and ITS sequences were larger than the differences between the geographical areas. Our results indicate that there has been considerable gene flow between the two Melilotus species. Our characterization of Cou and the morphological and genetic variations of these two Melilotus species may provide useful insights into germplasm improvement to enhance DMY and Cou. Full article
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Open AccessArticle
Antifeedant Activities of Lignans from Stem Bark of Zanthoxylum armatum DC. against Tribolium castaneum
Molecules 2018, 23(3), 617; https://doi.org/10.3390/molecules23030617 - 09 Mar 2018
Cited by 5 | Viewed by 1762
Abstract
The speciation of a methanolic extract of Zanthoxylum armatum stem bark has enabled the isolation and characterization of 11 known lignans. Among them, five compounds (6, 811) are reported in this plant for the first time. All of [...] Read more.
The speciation of a methanolic extract of Zanthoxylum armatum stem bark has enabled the isolation and characterization of 11 known lignans. Among them, five compounds (6, 811) are reported in this plant for the first time. All of the chemical structures were elucidated on the basis of NMR spectral analysis. Additionally, their antifeedant activities against Tribolium castaneum were evaluated scientifically. Among them, asarinin (1), with an EC50 of 25.64 ppm, exhibited a much stronger antifeedant activity than the positive control, toosendanin (EC50 = 71.69 ppm). Moreover, fargesin (2), horsfieldin (3), and magnolone (10), with EC50 values of 63.24, 68.39, and 78.37 ppm, showed almost the same antifeedant activity as the positive control. From the perspective of structure-effectiveness relationship, compounds with the chemical group of methylenedioxy exhibited higher antifeedant activities and have potential to be developed into novel antifeedants or potential lead compounds to protect food and crops in storage. Full article
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Open AccessArticle
The Effect of Ginger Juice Processing on the Chemical Profiles of Rhizoma coptidis
Molecules 2018, 23(2), 380; https://doi.org/10.3390/molecules23020380 - 10 Feb 2018
Cited by 4 | Viewed by 1493
Abstract
Rhizoma coptidis (RC) has been used as an herbal medicine in China for over one thousand years, and it was subjected to specific processing before use as materia medica. Processing is a pharmaceutical technique that aims to enhance the efficacy and/or reduce the [...] Read more.
Rhizoma coptidis (RC) has been used as an herbal medicine in China for over one thousand years, and it was subjected to specific processing before use as materia medica. Processing is a pharmaceutical technique that aims to enhance the efficacy and/or reduce the toxicity of crude drugs according to traditional Chinese medicine theory. In this study, the chemical profiles of RC, ginger juice processed RC (GRC), and water processed RC (WRC) was determined to reveal the mechanism of processing of RC. UPLC-QTOF-MS analysis of methanol extract of RC, GRC, and WRC has been conducted to investigate the effect of processing on the composition of RC. HPLC-PDA was used to determine the variance of total alkaloids and seven alkaloids of RC during the processing. The volatiles of RC, GRC and ginger juice were separated by distillation, the change of volatiles content was recorded and analyzed, and the qualitative analysis of the volatiles was carried out using GC-MS. The microstructures of RC, GRC and WRC were observed using a light microscope. Results showed that ginger juice/water processing had limited influence on the composition of RC’s methanol extract, but significant influence on the content of some alkaloids in RC. Ginger juice processing significantly increased (p < 0.05) the volatiles content of RC and changed the volatiles composition obviously. Processing also had an influence on the microstructure of RC. This research comprehensively revealed the mechanism of ginger juice processing of RC. Full article
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Open AccessArticle
Hepatoprotective Effects of a Functional Formula of Three Chinese Medicinal Herbs: Experimental Evidence and Network Pharmacology-Based Identification of Mechanism of Action and Potential Bioactive Components
Molecules 2018, 23(2), 352; https://doi.org/10.3390/molecules23020352 - 07 Feb 2018
Cited by 15 | Viewed by 3091
Abstract
Various Chinese herbal medicines (CHMs) have shown beneficial liver protection effects. Jian-Gan-Bao (JGB), a functional herbal formula, consists of three famous CHMs, including Coriolus versicolor, Salvia miltiorrhiza and Schisandra chinensis, which has been used as a folk medicine for several chronic [...] Read more.
Various Chinese herbal medicines (CHMs) have shown beneficial liver protection effects. Jian-Gan-Bao (JGB), a functional herbal formula, consists of three famous CHMs, including Coriolus versicolor, Salvia miltiorrhiza and Schisandra chinensis, which has been used as a folk medicine for several chronic liver diseases. In the present study, we aim systemically to evaluate the effects of JGB on acute and chronic alcoholic liver diseases (ALD) as well as non-alcoholic fatty liver disease (NAFLD) in mouse models, and identify its potential bioactive components and mechanism of action. JGB showed preventive effects for acute and chronic ALD as well as NAFLD, while post-treatment of JGB showed no significant effect, suggesting the nature of JGB as a health supplement rather than a drug. Furthermore, a compound-target network was constructed to identify the potential bioactive compounds and pathways that regulate its hepatoprotective effects. There are 40 bioactive compounds and 15 related targets that have been identified via this network pharmacology study. Among them are miltirone, neocryptotanshinone II and deoxyshikonin, with desirable pharmaceutical properties. Pathways relating to inflammation, fatty acid oxidation, tumor necrosis factor (TNF) production and cell proliferation were predicted as bioactive compounds and potential underlying mechanisms, which should be the focus of study in this field in the future. Full article
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Open AccessArticle
Rapid Characterization and Identification of Non-Diterpenoid Constituents in Tinospora sinensis by HPLC-LTQ-Orbitrap MSn
Molecules 2018, 23(2), 274; https://doi.org/10.3390/molecules23020274 - 29 Jan 2018
Cited by 6 | Viewed by 2007
Abstract
Tinospora sinensis, a kind of Chinese folk medicine, has functions of harmonizing qi and blood, dredging the channels and collaterals, calming and soothing the nerves. In the present study, a method based on high-performance liquid chromatography coupled with linear ion trap-Orbitrap mass [...] Read more.
Tinospora sinensis, a kind of Chinese folk medicine, has functions of harmonizing qi and blood, dredging the channels and collaterals, calming and soothing the nerves. In the present study, a method based on high-performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometry (HPLC-LTQ-Orbitrap) was developed for the systematical characterization of the non-diterpenoid constituents which possessed remarkable biological activities in T. sinensis, like anti-tumor, anti-inflammatory, hypoglycemic activity and immunomodulatory activity. Based on the accurate mass measurement (<5 ppm), retention times and MS fragmentation ions, 60 non-diterpenoid constituents were unambiguously or tentatively characterized from T. sinensis extract, including 27 alkaloids, 23 phenylpropanoids, seven sesquiterpenoids and three other constituents. Among them, 13 compounds were tentatively identified as new compounds. Finally, three of the non-diterpenoid constituents were purified and identified, which further confirmed the validity of the results. This study demonstrated that the HPLC-LTQ-Orbitrap MSn platform was a useful and efficient analytical tool to screen and identify constituents in natural medicine. Full article
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Open AccessArticle
Interaction between Saikosaponin D, Paeoniflorin, and Human Serum Albumin
Molecules 2018, 23(2), 249; https://doi.org/10.3390/molecules23020249 - 27 Jan 2018
Cited by 9 | Viewed by 1973
Abstract
Saikosaponin D (SSD) and paeoniflorin (PF) are the major active constituents of Bupleuri Radix and Paeonia lactiflora Pall, respectively, and have been widely used in China to treat liver and other diseases for many centuries. We explored the binding of SSD/PF to [...] Read more.
Saikosaponin D (SSD) and paeoniflorin (PF) are the major active constituents of Bupleuri Radix and Paeonia lactiflora Pall, respectively, and have been widely used in China to treat liver and other diseases for many centuries. We explored the binding of SSD/PF to human serum albumin (HSA) by using fluorospectrophotometry, circular dichroism (CD) and molecular docking. Both SSD and PF produced a conformational change in HSA. Fluorescence quenching was accompanied by a blue shift in the fluorescence spectra. Co-binding of PF and SSD also induced quenching and a conformational change in HSA. The Stern-Volmer equation showed that quenching was dominated by static quenching. The binding constant for ternary interaction was below that for binary interaction. Site-competitive experiments demonstrated that SSD/PF bound to site I (subdomain IIA) and site II (subdomain IIIA) in HSA. Analysis of thermodynamic parameters indicated that hydrogen bonding and van der Waals forces were mostly responsible for the binary association. Also, there was energy transfer upon binary interaction. Molecular docking supported the experimental findings in conformation, binding sites and binding forces. Full article
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Open AccessArticle
Quercetin Suppresses CYR61-Mediated Multidrug Resistance in Human Gastric Adenocarcinoma AGS Cells
Molecules 2018, 23(2), 209; https://doi.org/10.3390/molecules23020209 - 24 Jan 2018
Cited by 14 | Viewed by 1915
Abstract
Cysteine-rich angiogenic inducer 61 (CYR61) is an extracellular matrix-associated protein involved in survival, tumorigenesis, and drug resistance. Therefore, we examined the effects of flavones against CYR61-overexpressing human gastric adenocarcinoma AGS (AGS-cyr61) cells, which show remarkable resistance to 5-fluorouracil (5-FU), adriamycin (ADR), tamoxifen (TAM), [...] Read more.
Cysteine-rich angiogenic inducer 61 (CYR61) is an extracellular matrix-associated protein involved in survival, tumorigenesis, and drug resistance. Therefore, we examined the effects of flavones against CYR61-overexpressing human gastric adenocarcinoma AGS (AGS-cyr61) cells, which show remarkable resistance to 5-fluorouracil (5-FU), adriamycin (ADR), tamoxifen (TAM), paclitaxel (PAC), and docetaxel (DOC). Among the tested flavones, quercetin had the lowest 50% inhibitory concentration (IC50) and significantly reduced the viability of AGS-cyr61 cells compared with AGS cells. Quercetin: (1) reduced multidrug resistance-associated protein 1 and nuclear factor (NF)-kappa B p65 subunit levels; (2) reversed multidrug resistance (MDR); (3) inhibited colony formation and induced caspase-dependent apoptosis; and (4) suppressed migration and down-regulated epithelial–mesenchymal transition-related proteins in AGS-cyr61. Moreover, AGS-cyr61 cells treated with quercetin concentrations close to the IC50 and simultaneously treated with 5-FU or ADR in the sub-lethal range showed strong synergism between quercetin and these two drugs. These findings indicate that CYR61 is a potential regulator of drug resistance and that quercetin may be a novel agent for improving the efficacy of anticancer drugs in AGS-cyr61 cells. Full article
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Open AccessArticle
Chemical Constituents from Apios americana and Their Inhibitory Activity on Tyrosinase
Molecules 2018, 23(1), 232; https://doi.org/10.3390/molecules23010232 - 22 Jan 2018
Cited by 5 | Viewed by 2415
Abstract
The goal of this study was to identify phytochemicals with inhibitory activity against tyrosinase. Nine compounds 19 were isolated from the tubers of Apios americana. This is the first report of aromadendrin 5-methyl ether (1) being isolated from the [...] Read more.
The goal of this study was to identify phytochemicals with inhibitory activity against tyrosinase. Nine compounds 19 were isolated from the tubers of Apios americana. This is the first report of aromadendrin 5-methyl ether (1) being isolated from the Apios species. Among them, compounds 2 and 8 showed inhibitory activity toward tyrosinase. Based on a Dixon plot, the potential Ki values of competitive inhibitors 2 and 8 were calculated as 10.3 ± 0.8 µM and 44.2 ± 1.7 µM, respectively. An IC50 value of 13.2 ± 1.0 µM was calculated for the slow-binding inhibitor 2 after preincubation with tyrosinase. Additionally, the predicted binding sites between the receptor and ligand, as well as secondary structure changes, in the presence of 2 were examined by molecular simulation. Full article
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2017

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Open AccessCommunication
Cytotoxic Terpenoids from the Roots of Dracocephalum taliense
Molecules 2018, 23(1), 57; https://doi.org/10.3390/molecules23010057 - 27 Dec 2017
Cited by 2 | Viewed by 1983
Abstract
A chemical investigation of methanol extract from the roots of Dracocephalum taliense led to the isolation of a new aromatic abietane diterpenoid, 12-methoxy-18-hydroxy-sugiol (1), and one highly-oxygenated ursane triterpenoid, 2α,3α-dihydroxy-11α,12α-epoxy-urs-28,13β-olide (2), together with 15 known natural products (3 [...] Read more.
A chemical investigation of methanol extract from the roots of Dracocephalum taliense led to the isolation of a new aromatic abietane diterpenoid, 12-methoxy-18-hydroxy-sugiol (1), and one highly-oxygenated ursane triterpenoid, 2α,3α-dihydroxy-11α,12α-epoxy-urs-28,13β-olide (2), together with 15 known natural products (317). Among these, compounds 113 and 1517 were detected for the first time in the genus of Dracocephalum. The structures of all of these isolates were determined by extensively spectroscopic analyses. In the anti-inflammatory assay, compounds 1 and 2 had no obvious inhibitory activity on the release of cytokine IL-2 in lipopolysaccharide-induced RAW 264.7 macrophages. However, compound 2 exhibited significant cytotoxic activity against cell lines HepG2 (IC50 = 6.58 ± 0.14 μM) and NCI-H1975 (IC50 = 7.17 ± 0.26 μM). Full article
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Open AccessArticle
Hippeastrum reticulatum (Amaryllidaceae): Alkaloid Profiling, Biological Activities and Molecular Docking
Molecules 2017, 22(12), 2191; https://doi.org/10.3390/molecules22122191 - 09 Dec 2017
Cited by 12 | Viewed by 2479
Abstract
The Amaryllidaceae family has proven to be a rich source of active compounds, which are characterized by unique skeleton arrangements and a broad spectrum of biological activities. The aim of this work was to perform the first detailed study of the alkaloid constituents [...] Read more.
The Amaryllidaceae family has proven to be a rich source of active compounds, which are characterized by unique skeleton arrangements and a broad spectrum of biological activities. The aim of this work was to perform the first detailed study of the alkaloid constituents of Hippeastrum reticulatum (Amaryllidaceae) and to determine the anti-parasitological and cholinesterase (AChE and BuChE) inhibitory activities of the epimers (6α-hydroxymaritidine and 6β-hydroxymaritidine). Twelve alkaloids were identified in H. reticulatum: eight known alkaloids by GC-MS and four unknown (6α-hydroxymaritidine, 6β-hydroxymaritidine, reticulinine and isoreticulinine) by NMR. The epimer mixture (6α-hydroxymaritidine and 6β-hydroxymaritidine) showed low activity against all protozoan parasites tested and weak AChE-inhibitory activity. Finally, a molecular docking analysis of AChE and BuChE proteins showed that isoreticulinine may be classified as a potential inhibitory molecule since it can be stabilized in the active site through hydrogen bonds, π-π stacking and hydrophobic interactions. Full article
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Open AccessReview
Review of Ethnomedicinal Uses, Phytochemistry and Pharmacological Properties of Euclea natalensis A.DC.
Molecules 2017, 22(12), 2128; https://doi.org/10.3390/molecules22122128 - 02 Dec 2017
Cited by 5 | Viewed by 2173
Abstract
Euclea natalensis is traditionally used as herbal medicine for several human diseases and ailments in tropical Africa. This study reviews information on ethnomedicinal uses, botany, phytochemical constituents, pharmacology and toxicity of E. natalensis. Results of this study are based on literature search [...] Read more.
Euclea natalensis is traditionally used as herbal medicine for several human diseases and ailments in tropical Africa. This study reviews information on ethnomedicinal uses, botany, phytochemical constituents, pharmacology and toxicity of E. natalensis. Results of this study are based on literature search from several sources including electronic databases, books, book chapters, websites, theses and conference proceedings. This study showed that E. natalensis is used as traditional medicine in 57.1% of the countries where it is indigenous. Euclea natalensis has a high degree of consensus on abdominal pains, antidote for snake bites, diabetes, diarrhoea, malaria, roundworms, stomach problems, toothache, venereal diseases and wounds. Several ethnopharmacological studies have shown that crude extracts and chemical compounds from E. natalensis demonstrated many biological activities both in vitro and in vivo, which included antibacterial, antidiabetic, antifungal, antimycobacterial, antiviral, antioxidant, antiplasmodial, larvicidal, antischistosomal, molluscicidal, dentin permeability and hepatoprotective activities. Future studies should focus on the mechanism of biological activities of both crude extracts and chemical compounds from the species, as well as structure–function relationships of bioactive constituents of the species. Full article
Open AccessArticle
Modulation of Cytochrome P450, P-glycoprotein and Pregnane X Receptor by Selected Antimalarial Herbs—Implication for Herb-Drug Interaction
Molecules 2017, 22(12), 2049; https://doi.org/10.3390/molecules22122049 - 23 Nov 2017
Cited by 9 | Viewed by 3229
Abstract
Seven medicinal plants popularly used for treating malaria in West Africa were selected to assess herb-drug interaction potential through a series of in vitro methods. Fluorescent cytochrome P450 (CYP) assays were conducted using the recombinant CYP enzymes for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, [...] Read more.
Seven medicinal plants popularly used for treating malaria in West Africa were selected to assess herb-drug interaction potential through a series of in vitro methods. Fluorescent cytochrome P450 (CYP) assays were conducted using the recombinant CYP enzymes for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 to assess the effect of the methanolic extracts on the metabolic activity of CYPs. Secondly, the inhibitory effect of the extracts was evaluated on P-glycoproteins (P-gp) using calcein-AM, a fluorescent substrate, in MDCK-II and hMDR1-MDCK-II cells. The inhibition of P-gp activity was determined as a reflection of increase in calcein-AM uptake. Additionally, the enzyme induction potential of the extracts was assessed through the modulation of PXR activity in HepG2 cells transiently transfected with pSG5-PXR and PCR5 plasmid DNA. Significant inhibition of CYP activity (IC50 < 10 µg/mL) was observed with the following herbs: A. muricata [CYP2C9, 3A4 and CYP2D6]; M. indica [CYP2C9]; M. charantia [CYP2C9 and CYP2C19]; P. amarus [CYP2C19, CYP2C9 and CYP3A4]; T. diversifolia [CYP2C19 and CYP3A4]. Extracts of four herbs (P. amarus, M. charantia, T. diversifolia and A. muricata) exhibited significant inhibition of P-gp with IC50 values (µg/mL) of 17 ± 1, 16 ± 0.4, 26 ± 1, and 24 ± 1, respectively. In addition, four herbs (A. mexicana, M. charantia, P. amarus and T. diversifolia) showed a >two-fold increase in induction in PXR activity. These findings suggest that these herbs may be capable of eliciting herb-drug interactions if consumed in high quantities with concomitant use of conventional therapies. Full article
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Open AccessCommunication
Preparative Separation and Purification of Four Glycosides from Gentianae radix by High-Speed Counter-Current Chromatography and Comparison of Their Anti-NO Production Effects
Molecules 2017, 22(11), 2002; https://doi.org/10.3390/molecules22112002 - 17 Nov 2017
Cited by 8 | Viewed by 1850
Abstract
Secoiridoid and iridoid glycosides are the main active components of Gentianae radix. In this work, one iridoid and three secoiridoid glycosides from Gentianae radix have been purified by high-speed counter-current chromatography in two runs using different solvent systems. Ethyl acetate–n-butanol–water [...] Read more.
Secoiridoid and iridoid glycosides are the main active components of Gentianae radix. In this work, one iridoid and three secoiridoid glycosides from Gentianae radix have been purified by high-speed counter-current chromatography in two runs using different solvent systems. Ethyl acetate–n-butanol–water (2:1:3, v/v/v) was the optimum solvent system to purify ca. 4.36 mg of loganic acid, 3.05 mg of swertiamarin, and 35.66 mg of gentiopicroside with 98.1%, 97.2% and 98.6% purities, respectively, while 31.15 mg of trifloroside with 98.9% purity was separated using hexane–ethyl acetate–methanol–water (1:3:1:3, v/v/v/v). The structures of the glycosides were identified by mass spectrometry and NMR. After separation, the anti-nitric oxide production effects of the compounds on lipopolysaccharide-induced BV-2 murine microglial cells were also evaluated. All of the compounds inhibited the production of nitric oxide in lipopolysaccharide-induced BV-2 cells with high cell viabilities in a concentration-dependent manner, which demonstrated that were able to be used as a nitric oxide inhibitor. Full article
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Open AccessArticle
Sulforaphane Alters β-Naphthoflavone-Induced Changes in Activity and Expression of Drug-Metabolizing Enzymes in Rat Hepatocytes
Molecules 2017, 22(11), 1983; https://doi.org/10.3390/molecules22111983 - 16 Nov 2017
Cited by 5 | Viewed by 1530
Abstract
Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, exerts many beneficial effects on human health such as antioxidant, anti-inflammatory, and anticancer effects. The effect of SFN alone on drug-metabolizing enzymes (DMEs) has been investigated in numerous in vitro and in vivo models, but [...] Read more.
Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, exerts many beneficial effects on human health such as antioxidant, anti-inflammatory, and anticancer effects. The effect of SFN alone on drug-metabolizing enzymes (DMEs) has been investigated in numerous in vitro and in vivo models, but little is known about the effect of SFN in combination with cytochrome P450 (CYP) inducer. The aim of our study was to evaluate the effect of SFN on the activity and gene expression of selected DMEs in primary cultures of rat hepatocytes treated or non-treated with β-naphthoflavone (BNF), the model CYP1A inducer. In our study, SFN alone did not significantly alter the activity and expression of the studied DMEs, except for the glutathione S-transferase (GSTA1) mRNA level, which was significantly enhanced. Co-treatment of hepatocytes with SFN and BNF led to a substantial increase in sulfotransferase, aldoketoreductase 1C, carbonylreductase 1 and NAD(P)H:quinone oxidoreductase 1 activity and a marked decrease in cytochrome P450 (CYP) Cyp1a1, Cyp2b and Cyp3a4 expression in comparison to the treatment with BNF alone. Sulforaphane is able to modulate the activity and/or expression of DMEs, thus shifting the balance of carcinogen metabolism toward deactivation, which could represent an important mechanism of its chemopreventive activity. Full article
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Open AccessArticle
An Optimized and Sensitive Pharmacokinetic Quantitative Method of Investigating Gastrodin, Parishin, and Parishin B, C and E in Beagle Dog Plasma using LC-MS/MS after Intragastric Administration of Tall Gastrodia Capsules
Molecules 2017, 22(11), 1938; https://doi.org/10.3390/molecules22111938 - 10 Nov 2017
Cited by 4 | Viewed by 2372
Abstract
Gastrodia elata Blume, called Tianma in China, has been widely used to treat headaches, convulsions and epilepsy for thousands of years. In the present study, a series of optimizations were employed to develop a rapid, sensitive, and reliable high-performance liquid chromatography-triple quadrupole mass [...] Read more.
Gastrodia elata Blume, called Tianma in China, has been widely used to treat headaches, convulsions and epilepsy for thousands of years. In the present study, a series of optimizations were employed to develop a rapid, sensitive, and reliable high-performance liquid chromatography-triple quadrupole mass spectrometry method, which was then used for the simultaneous determination of gastrodin, parishin, parishin B, parishin C and parishin E in beagle dog plasma after intragastric administration of tall Gastrodia capsules (Tianma brand). The chromatographic separation was achieved on a C18 column with gradient elution by using a mixture of 0.4% formic acid aqueous solution and acetonitrile as the mobile phase at a flow rate of 0.15 mL/min. A tandem mass spectrometric detection was conducted using multiple-reaction monitoring (MRM) via electrospray ionization (ESI) source in negative ionization mode. Samples were pre-treated by a single-step protein precipitation with methanol, and bergenin was used as internal standard (IS). Under the optimized conditions, the lower limit of quantification (LLOQ) was 0.10 ng/mL for gastrodin, 0.40 ng/mL for parishin B, 0.02 ng/mL for parishin E and 0.20 ng/mL for parishin and parishin C, all of which previously were the highest levels of sensitivity. The methods were optimized for selectivity, calibration curves, accuracy and precision. Extraction recoveries, matrix effects and stability were within acceptable ranges. Pharmacokinetic parameters of the tested substances were also quantitatively determined. Finally, a possible metabolic pathway was induced based on correlations obtained from quantitative and qualitative data analysis in vivo. Full article
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Open AccessArticle
Ginger and Propolis Exert Neuroprotective Effects against Monosodium Glutamate-Induced Neurotoxicity in Rats
Molecules 2017, 22(11), 1928; https://doi.org/10.3390/molecules22111928 - 08 Nov 2017
Cited by 28 | Viewed by 3444
Abstract
Central nervous system cytotoxicity is linked to neurodegenerative disorders. The objective of the study was to investigate whether monosodium glutamate (MSG) neurotoxicity can be reversed by natural products, such as ginger or propolis, in male rats. Four different groups of Wistar rats were [...] Read more.
Central nervous system cytotoxicity is linked to neurodegenerative disorders. The objective of the study was to investigate whether monosodium glutamate (MSG) neurotoxicity can be reversed by natural products, such as ginger or propolis, in male rats. Four different groups of Wistar rats were utilized in the study. Group A served as a normal control, whereas group B was orally administered with MSG (100 mg/kg body weight, via oral gavage). Two additional groups, C and D, were given MSG as group B along with oral dose (500 mg/kg body weight) of either ginger or propolis (600 mg/kg body weight) once a day for two months. At the end, the rats were sacrificed, and the brain tissue was excised and levels of neurotransmitters, ß-amyloid, and DNA oxidative marker 8-OHdG were estimated in the brain homogenates. Further, formalin-fixed and paraffin-embedded brain sections were used for histopathological evaluation. The results showed that MSG increased lipid peroxidation, nitric oxide, neurotransmitters, and 8-OHdG as well as registered an accumulation of ß-amyloid peptides compared to normal control rats. Moreover, significant depletions of glutathione, superoxide dismutase, and catalase as well as histopathological alterations in the brain tissue of MSG-treated rats were noticed in comparison with the normal control. In contrast, treatment with ginger greatly attenuated the neurotoxic effects of MSG through suppression of 8-OHdG and β-amyloid accumulation as well as alteration of neurotransmitter levels. Further improvements were also noticed based on histological alterations and reduction of neurodegeneration in the brain tissue. A modest inhibition of the neurodegenerative markers was observed by propolis. The study clearly indicates a neuroprotective effect of ginger and propolis against MSG-induced neurodegenerative disorders and these beneficial effects could be attributed to the polyphenolic compounds present in these natural products. Full article
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Open AccessArticle
Enhanced Agronomic Traits and Medicinal Constituents of Autotetraploids in Anoectochilus formosanus Hayata, a Top-Grade Medicinal Orchid
Molecules 2017, 22(11), 1907; https://doi.org/10.3390/molecules22111907 - 07 Nov 2017
Cited by 10 | Viewed by 2697
Abstract
This study developed an efficient and reliable system for inducing polyploidy in Anoectochilus formosanus Hayata, a top-grade medicinal orchid. The resulting tetraploid gave a significant enhancement on various agronomic traits, including dry weight, fresh weight, shoot length, root length, leaf width, the size [...] Read more.
This study developed an efficient and reliable system for inducing polyploidy in Anoectochilus formosanus Hayata, a top-grade medicinal orchid. The resulting tetraploid gave a significant enhancement on various agronomic traits, including dry weight, fresh weight, shoot length, root length, leaf width, the size of stoma, and number of chloroplasts per stoma. A reduction of the ratio of length to width was observed in stomata and leaves of the tetraploid, and consequently, an alteration of organ shape was found. The major bioactive compounds, total flavonoid and gastrodin, were determined by the aluminum chloride colorimetric method and ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), respectively. The tetraploid produced significantly higher contents of total flavonoid and gastrodin in the leaf, the stem, and the whole plant when compared with the diploid. The resulting tetraploids in this study are proposed to be suitable raw materials in the pharmaceutical industry for enhancing productivity and reducing cost. Full article
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Open AccessArticle
Anti-HIV Activity of Ocimum labiatum Extract and Isolated Pheophytin-a
Molecules 2017, 22(11), 1763; https://doi.org/10.3390/molecules22111763 - 06 Nov 2017
Cited by 8 | Viewed by 2056
Abstract
Ocimum plants are traditionally used to manage HIV/AIDS in various African countries. The effects of Ocimum labiatum extract on HIV-1 protease (PR) and reverse transcriptase (RT) is presented here along with characterization of an identified bioactive compound, achieved through 1H- and 13 [...] Read more.
Ocimum plants are traditionally used to manage HIV/AIDS in various African countries. The effects of Ocimum labiatum extract on HIV-1 protease (PR) and reverse transcriptase (RT) is presented here along with characterization of an identified bioactive compound, achieved through 1H- and 13C-NMR. The extract’s effect on HIV-1 replication was assessed by HIV-1 p24 antigen capture. Cytotoxicity of samples was evaluated using tetrazolium dyes and real-time cell electronic sensing (RT-CES). Ocimum labiatum inhibited HIV-1 PR with an IC50 value of 49.8 ± 0.4 μg/mL and presented weak inhibition (21%) against HIV-1 RT. The extract also reduced HIV-1 replication in U1 cells at a non-cytotoxic concentration (25 μg/mL). The CC50 value of the extract in U1 cells was 42.0 ± 0.13 μg/mL. The HIV-1 PR inhibiting fraction was purified using prep-HPLC and yielded a chlorophyll derivative, pheophytin-a (phy-a). Phy-a inhibited HIV-1 PR with an IC50 value of 44.4 ± 1.5 μg/mL (51 ± 1.7 μM). The low cytotoxicity of phy-a in TZM-bl cells was detected by RT-CES and the CC50 value in U1 cells was 51.3 ± 1.0 μg/mL (58.9 ± 1.2 μM). This study provides the first in vitro evidence of anti-HIV activity of O. labiatum and isolated phy-a, supporting further investigation of O. labiatum for lead compounds against HIV-1. Full article
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Open AccessArticle
Marrubium vulgare L. Leave Extract: Phytochemical Composition, Antioxidant and Wound Healing Properties
Molecules 2017, 22(11), 1851; https://doi.org/10.3390/molecules22111851 - 28 Oct 2017
Cited by 22 | Viewed by 3522
Abstract
Several factors contribute in wound generation, e.g., accidental traumas or surgery, and in certain cases, this dermal injury may have a devastating outcome. When skin damage occurs, the human body puts in place a sophisticated choreography, which involves numerous repairing processes to restore [...] Read more.
Several factors contribute in wound generation, e.g., accidental traumas or surgery, and in certain cases, this dermal injury may have a devastating outcome. When skin damage occurs, the human body puts in place a sophisticated choreography, which involves numerous repairing processes to restore physiological conditions. Nevertheless, natural healing mechanisms are ineffective towards chronic or non-healing wounds and thus, therapeutic strategies may represent the only beneficial alternative to counteract these tissue insults. Over the years, numerous studies showed the great potential of plants in promoting wound healing, by virtue of their high contents in antioxidant species. These compounds trigger a molecular cascade that collimate into the promotion of reparative processes. In this article, we report on the potential effect on wound healing of Marrubium vulgare L., a medicinal plant well known for several pharmaceutical activities. To this aim, the methanolic extract was prepared and subjected to a phytochemical investigation, quantifying the amount of marrubiin via NMR and drawing the phytochemical fingerprint via high performance liquid chromatography—ultra violet/photodiode-array detection-electrospray/mass (HPLC-UV/PAD-ESI/MS) analysis. Lastly, the antioxidant properties and wound healing potential have been evaluated. Full article
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Open AccessArticle
Simultaneous Determination of Seven Anthraquinone Aglycones of Crude and Processed Semen Cassiae Extracts in Rat Plasma by UPLC–MS/MS and Its Application to a Comparative Pharmacokinetic Study
Molecules 2017, 22(11), 1803; https://doi.org/10.3390/molecules22111803 - 28 Oct 2017
Cited by 12 | Viewed by 2082
Abstract
Semen cassiae is the ripe seed of Cassia obtusifolia L. or Cassia tora L. of the family Leguminosae. In traditional Chinese medicine, the two forms of Semen cassiae are raw Semen cassiae (R-SC) and parched Semen cassiae (P-SC). To clarify the processing mechanism [...] Read more.
Semen cassiae is the ripe seed of Cassia obtusifolia L. or Cassia tora L. of the family Leguminosae. In traditional Chinese medicine, the two forms of Semen cassiae are raw Semen cassiae (R-SC) and parched Semen cassiae (P-SC). To clarify the processing mechanism of Semen cassiae, the pharmacokinetics of R-SC and P-SC extracts were examined. A simple, rapid, sensitive ultra-high-performance liquid chromatography–tandem mass spectroscopy (UPLC-MS/MS) method was developed and validated for the simultaneous determination of seven anthraquinone aglycones of Semen cassiae (aurantio-obtusin, obtusifolin, questin, 2-hydroxyemodin-1-methyl-ether, rhein, emodin, 1,2,7-trimethoxyl-6,8-dihydroxy-3-methylanthraquinone) to compare the pharmacokinetics of raw and parched Semen cassiae in rat plasma. Compared with the R-SC group, Cmax and AUC0-12 tended to be higher in the P-SC group. In particular, Cmax values for aurantio-obtusin, obtusifolin, questin, 2-hydroxyemodin-1-methyl-ether and rhein were significantly higher in the P-SC group (p < 0.05). Meanwhile, Tmax and MRT0-12 tended to be lower in the P-SC group. Specifically, Tmax for aurantio-obtusin and 2-hydroxyemodin-1-methyl-ether and MRT0-12 for obtusifolin and rhein were significantly higher in the P-SC group (p < 0.05). Full article
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Open AccessArticle
Spectrum-Effect Relationships between Fingerprints of Caulophyllum robustum Maxim and Inhabited Pro-Inflammation Cytokine Effects
Molecules 2017, 22(11), 1826; https://doi.org/10.3390/molecules22111826 - 26 Oct 2017
Cited by 12 | Viewed by 2089
Abstract
Caulophyllum robustum Maxim (CRM) is a Chinese folk medicine with significant effect on treatment of rheumatoid arthritis (RA). This study was designed to explore the spectrum-effect relationships between high-performance liquid chromatography (HPLC) fingerprints and the anti-inflammatory effects of CRM. Seventeen common peaks were [...] Read more.
Caulophyllum robustum Maxim (CRM) is a Chinese folk medicine with significant effect on treatment of rheumatoid arthritis (RA). This study was designed to explore the spectrum-effect relationships between high-performance liquid chromatography (HPLC) fingerprints and the anti-inflammatory effects of CRM. Seventeen common peaks were detected by fingerprint similarity evaluation software. Among them, 15 peaks were identified by Liquid Chromatography-Mass Spectrometry (LC-MS). Pharmacodynamics experiments were conducted in collagen-induced arthritis (CIA) mice to obtain the anti-inflammatory effects of different batches of CRM with four pro-inflammation cytokines (TNF-α, IL-β, IL-6, and IL-17) as indicators. These cytokines were suppressed at different levels according to the different batches of CRM treatment. The spectrum-effect relationships between chemical fingerprints and the pro-inflammation effects of CRM were established by multiple linear regression (MLR) and gray relational analysis (GRA). The spectrum-effect relationships revealed that the alkaloids (N-methylcytisine, magnoflorine), saponins (leiyemudanoside C, leiyemudanoside D, leiyemudanoside G, leiyemudanoside B, cauloside H, leonticin D, cauloside G, cauloside D, cauloside B, cauloside C, and cauloside A), sapogenins (oleanolic acid), β-sitosterols, and unknown compounds (X3, X17) together showed anti-inflammatory efficacy. The results also showed that the correlation between saponins and inflammatory factors was significantly closer than that of alkaloids, and saponins linked with less sugar may have higher inhibition effect on pro-inflammatory cytokines in CIA mice. This work provided a general model of the combination of HPLC and anti-inflammatory effects to study the spectrum-effect relationships of CRM, which can be used to discover the active substance and to control the quality of this treatment. Full article
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Open AccessArticle
Hepatotoxicity Induced by Sophora flavescens and Hepatic Accumulation of Kurarinone, a Major Hepatotoxic Constituent of Sophora flavescens in Rats
Molecules 2017, 22(11), 1809; https://doi.org/10.3390/molecules22111809 - 25 Oct 2017
Cited by 7 | Viewed by 2438
Abstract
Our previous study showed that kurarinone was the main hepatotoxic ingredient of Sophora flavescens, accumulating in the liver. This study characterized the mechanism of Sophora flavescens extract (ESF) hepatotoxicity and hepatic accumulation of kurarinone. ESF impaired hepatic function and caused fat accumulation [...] Read more.
Our previous study showed that kurarinone was the main hepatotoxic ingredient of Sophora flavescens, accumulating in the liver. This study characterized the mechanism of Sophora flavescens extract (ESF) hepatotoxicity and hepatic accumulation of kurarinone. ESF impaired hepatic function and caused fat accumulation in the liver after oral administration (1.25 and 2.5 g/kg for 14 days in rats). Serum metabolomics evaluation based on high-resolution mass spectrometry was conducted and real-time PCR was used to determine the expression levels of CPT-1, CPT-2, PPAR-α, and LCAD genes. Effects of kurarinone on triglyceride levels were evaluated in HL-7702 cells. Tissue distribution of kurarinone and kurarinone glucuronides was analyzed in rats receiving ESF (2.5 g/kg). Active uptake of kurarinone and kurarinone glucuronides was studied in OAT2-, OATP1B1-, OATP2B1-, and OATP1B3-transfected HEK293 cells. Our results revealed that after oral administration of ESF in rats, kurarinone glucuronides were actively transported into hepatocytes by OATP1B3 and hydrolyzed into kurarinone, which inhibited fatty acid β-oxidation through the reduction of l-carnitine and the inhibition of PPAR-α pathway, ultimately leading to lipid accumulation and liver injury. These findings contribute to understanding hepatotoxicity of kurarinone after oral administration of ESF. Full article
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Open AccessArticle
Triterpenoids from Ocimum labiatum Activates Latent HIV-1 Expression In Vitro: Potential for Use in Adjuvant Therapy
Molecules 2017, 22(10), 1703; https://doi.org/10.3390/molecules22101703 - 13 Oct 2017
Cited by 4 | Viewed by 2202
Abstract
Latent HIV reservoirs in infected individuals prevent current treatment from eradicating infection. Treatment strategies against latency involve adjuvants for viral reactivation which exposes viral particles to antiretroviral drugs. In this study, the effect of novel triterpenoids isolated from Ocimum labiatum on HIV-1 expression [...] Read more.
Latent HIV reservoirs in infected individuals prevent current treatment from eradicating infection. Treatment strategies against latency involve adjuvants for viral reactivation which exposes viral particles to antiretroviral drugs. In this study, the effect of novel triterpenoids isolated from Ocimum labiatum on HIV-1 expression was measured through HIV-1 p24 antigen capture in the U1 latency model of HIV-1 infection and in peripheral blood mononuclear cells (PBMCs) of infected patients on combination antiretroviral therapy (cART). The mechanism of viral reactivation was determined through the compound’s effect on cytokine production, histone deacetylase (HDAC) inhibition, and protein kinase C (PKC) activation. Cytotoxicity of the triterpenoids was determined using a tetrazolium dye and flow cytometry. The isolated triterpene isomers, 3-hydroxy-4,6a,6b,11,12,14b-hexamethyl-1,2,3,4,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecahydropicene-4,8a-dicarboxylic acid (HHODC), significantly (p < 0.05) induced HIV-1 expression in a dose-dependent manner in U1 cells at non-cytotoxic concentrations. HHODC also induced viral expression in PBMCs of HIV-1 infected patients on cART. In addition, the compound up-regulated the production of interleukin (IL)-2, IL-6, tumour necrosis factor (TNF)-α, and interferon (IFN)-γ but had no effect on HDAC and PKC activity, suggesting cytokine upregulation as being involved in latency activation. The observed in vitro reactivation of HIV-1 introduces the adjuvant potential of HHODC for the first time here. Full article
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Open AccessReview
Chemical and Biological Research on Herbal Medicines Rich in Xanthones
Molecules 2017, 22(10), 1698; https://doi.org/10.3390/molecules22101698 - 11 Oct 2017
Cited by 22 | Viewed by 3213
Abstract
Xanthones, as some of the most active components and widely distributed in various herb medicines, have drawn more and more attention in recent years. So far, 168 species of herbal plants belong to 58 genera, 24 families have been reported to contain xanthones. [...] Read more.
Xanthones, as some of the most active components and widely distributed in various herb medicines, have drawn more and more attention in recent years. So far, 168 species of herbal plants belong to 58 genera, 24 families have been reported to contain xanthones. Among them, Calophyllum, Cratoxylum, Cudrania, Garcinia, Gentiana, Hypericum and Swertia genera are plant resources with great development prospect. This paper summarizes the plant resources, bioactivity and the structure-activity relationships (SARs) of xanthones from references published over the last few decades, which may be useful for new drug research and development on xanthones. Full article
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Open AccessArticle
Influence of Plant Growth Retardants on Quality of Codonopsis Radix
Molecules 2017, 22(10), 1655; https://doi.org/10.3390/molecules22101655 - 09 Oct 2017
Cited by 5 | Viewed by 2303
Abstract
Plant growth retardant (PGR) refers to organics that can inhibit the cell division of plant stem tip sub-apical meristem cells or primordial meristem cell. They are widely used in the cultivation of rhizomatous functional plants; such as Codonopsis Radix, that is a famous [...] Read more.
Plant growth retardant (PGR) refers to organics that can inhibit the cell division of plant stem tip sub-apical meristem cells or primordial meristem cell. They are widely used in the cultivation of rhizomatous functional plants; such as Codonopsis Radix, that is a famous Chinese traditional herb. However, it is still unclear whether PGR affects the medicinal quality of C. Radix. In the present study, amino acid analyses, targeted and non-targeted analyses by ultra-performance liquid chromatography combined with time-of-flight mass spectrometry (UPLC-TOF-MS) and gas chromatography-MS were used to analyze and compare the composition of untreated C. Radix and C. Radix treated with PGR. The contents of two key bioactive compounds, lobetyolin and atractylenolide III, were not affected by PGR treatment. The amounts of polysaccharides and some internal volatiles were significantly decreased by PGR treatment; while the free amino acids content was generally increased. Fifteen metabolites whose abundance were affected by PGR treatment were identified by UPLC-TOF-MS. Five of the up-regulated compounds have been reported to show immune activity, which might contribute to the healing efficacy (“buqi”) of C. Radix. The results of this study showed that treatment of C. Radix with PGR during cultivation has economic benefits and affected some main bioactive compounds in C. Radix. Full article
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Open AccessArticle
Intestinal Absorption of Triterpenoids and Flavonoids from Glycyrrhizae radix et rhizoma in the Human Caco-2 Monolayer Cell Model
Molecules 2017, 22(10), 1627; https://doi.org/10.3390/molecules22101627 - 29 Sep 2017
Cited by 16 | Viewed by 2282
Abstract
Glycyrrhizae radix et rhizoma has been used as a traditional Chinese medicine for the treatment of various diseases. Triterpenoids and flavonoids from the plant have many beneficial effects and their chemical structures are modified in the gastrointestinal tract after oral administration. However, absorption [...] Read more.
Glycyrrhizae radix et rhizoma has been used as a traditional Chinese medicine for the treatment of various diseases. Triterpenoids and flavonoids from the plant have many beneficial effects and their chemical structures are modified in the gastrointestinal tract after oral administration. However, absorption of these triterpenoids and flavonoids still needs to be defined. Here, the uptake and transepithelial transport of the selected major triterpenoids, glycyrrhizin (1), glycyrrhetic acid-3-O-mono-β-d-glucuronide (2), and glycyrrhetinic acid (3); and the selected major flavonoids, licochalcone A (4), licochalcone B (5), licochalcone C (6), echinatin (7), isoliquiritin apioside (8), liquiritigenin (9), liquiritin apioside (10) isolated from Glycyrrhizae radix et rhizoma, were investigated in the human intestinal epithelium-like Caco-2 cell monolayer model. Compounds 3, 57, and 9 were designated as well-absorbed compounds, 2 and 4 were designated as moderately absorbed ones, and 1, 8, and 10 were assigned for the poorly absorbed ones. The absorption mechanism of well and moderately absorbed compound was mainly passive diffusion to pass through the human intestinal Caco-2 cell monolayer. These findings provided useful information for predicting their oral bioavailability and the clinical application. Full article
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Open AccessArticle
Diuretic Activity of Compatible Triterpene Components of Alismatis rhizoma
Molecules 2017, 22(9), 1459; https://doi.org/10.3390/molecules22091459 - 06 Sep 2017
Cited by 24 | Viewed by 2479
Abstract
Alismatis rhizoma (AR), the dried rhizoma of Alisma orientale Juzepzuk (Alismataceae), is a traditional Chinese medicine. AR is an important part of many prescriptions and is commonly used as a diuretic agent in Asia. This study aimed to evaluate the diuretic effects of [...] Read more.
Alismatis rhizoma (AR), the dried rhizoma of Alisma orientale Juzepzuk (Alismataceae), is a traditional Chinese medicine. AR is an important part of many prescriptions and is commonly used as a diuretic agent in Asia. This study aimed to evaluate the diuretic effects of total triterpene extract (TTE) and triterpene component compatibility (TCC, the mixture of alisol B 23-acetate, alisol B, alisol A 24-acetate, alisol A, and alisol C 23-acetate) of AR in saline-loaded rats. The optimal diuretic TCC of AR was optimized using a uniform design. Different doses (5, 20, and 40 mg/kg) of TTE and TCC groups (N1–N8) were orally administered to rats. Urinary excretion rate, pH, and electrolyte excretion were measured in the urine of saline-loaded rats. Results showed that TTE doses increased urine volume and electrolyte excretion compared with the control group. All uniformly designed groups of TCC also increased urine excretion. In addition, optimal diuretic TCC was calculated (alisol B 23-acetate: alisol B: alisol A 24-acetate: alisol A: alisol C 23-acetate 7.2:0.6:2.8:3.0:6.4) and further validated by saline-loaded rats. This study demonstrated that TTE presented a notable diuretic effect by increasing Na+, K+, and Cl displacements. The most suitable TTC compatible proportion of alisol B 23-acetate: alisol B: alisol A 24-acetate: alisol A: alisol C 23-acetate for diuretic activity was validated, and triterpenes were the material basis for the diuretic activity of AR. Full article
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Open AccessArticle
Identification of a Quality Marker (Q-Marker) of Danhong Injection by the Zebrafish Thrombosis Model
Molecules 2017, 22(9), 1443; https://doi.org/10.3390/molecules22091443 - 31 Aug 2017
Cited by 11 | Viewed by 2866
Abstract
Quality-marker (Q-marker) is an emerging concept to ensure the quality and batch-to-batch consistency of Chinese medicine (CM). However, significant difficulties remain in the identification of Q-markers due to the unclear relationship between complex chemical compositions and the pharmacological efficacy of CM. In the [...] Read more.
Quality-marker (Q-marker) is an emerging concept to ensure the quality and batch-to-batch consistency of Chinese medicine (CM). However, significant difficulties remain in the identification of Q-markers due to the unclear relationship between complex chemical compositions and the pharmacological efficacy of CM. In the present study, we proposed a novel strategy to identify the potential Q-marker of danhong injection (DHI) by an in vivo zebrafish thrombosis model. The anti-thrombotic effects of DHI and its major constituents were evaluated by the zebrafish model of arachidonic acid (AA)-induced thrombosis. The results indicated that DHI can attenuate tail venous thrombus and recover the decrease of heart red blood cell (RBC) intensity in a dose-dependent manner. The result that DHI prevented the formulation of thrombosis in zebrafish was also validated in the zebrafish thrombosis model with green fluorescence protein (GFP)-labeled hemoglobin. The major components of DHI, namely danshen (DS) and honghua (HH), as well as the major chemical constituents of DHI, also exerted anti-thrombotic effects, among which rosmarinic acid (RA) and p-coumaric acid (pCA) showed moderate anti-thrombotic effects. This is the first time that pCA from HH has been found as an active compound exerting an anti-thrombotic effect in a dose-dependent manner, whose IC50 value is approximately 147 μg/mL. By analyzing 10 batches of normal DHI samples and five abnormal samples by high-performance liquid chromatography (HPLC), we found the contents of pCA and RA can be positively correlated to the anti-thrombotic effect of DHI, suggesting that pCA and RA could be potential Q-markers of DHI to ensure batch-to-batch consistency. Our findings illustrated that discovering major active compounds from CM by in vivo pharmacological models can be a useful approach to identifying Q-markers of CM, and in vivo pharmacological models can be a potential tool to evaluate batch-to-batch consistency of CMs. Full article
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Open AccessArticle
Alkaloid Constituents of the Amaryllidaceae Plant Amaryllis belladonna L
Molecules 2017, 22(9), 1437; https://doi.org/10.3390/molecules22091437 - 31 Aug 2017
Cited by 17 | Viewed by 2956
Abstract
The plant family Amaryllidaceae is well-known for its unique alkaloid constituents, which exhibit a wide range of biological activities. Its representative, Amaryllis belladonna, has a geographical distribution covering mainly southern Africa, where it has significant usage in the traditional medicine of the [...] Read more.
The plant family Amaryllidaceae is well-known for its unique alkaloid constituents, which exhibit a wide range of biological activities. Its representative, Amaryllis belladonna, has a geographical distribution covering mainly southern Africa, where it has significant usage in the traditional medicine of the native people. In this study, A. belladonna samples collected in Brazil were examined for alkaloid content. Alkaloid profiles of A. belladonna bulbs were generated by a combination of chromatographic, spectroscopic and spectrometric methods, including GC–MS and 2D NMR. In vitro screening against four different parasitic protozoa (Trypanosoma cruzi, T. brucei rhodesiense, Leishmania donovani and Plasmodium falciparum) was carried out using the A. belladonna crude methanol extract, as well as three of its alkaloid isolates. Twenty-six different Amaryllidaceae alkaloids were identified in the A. belladonna bulb samples, and three of them were isolated. Evidence for their respective biosynthetic pathways was afforded via their mass-spectral fragmentation data. Improved data for 1-O-acetylcaranine was provided by 2D NMR experiments, together with new 1H-NMR data for buphanamine. The crude extract and 3-O-acetylhamayne exhibited good antiprotozoal activity in vitro, although both with a high cytotoxic index. Full article
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Open AccessArticle
Anti-Anxiety Effect of (−)-Syringaresnol-4-O-β-d-apiofuranosyl-(1→2)-β-d-glucopyranoside from Albizzia julibrissin Durazz (Leguminosae)
Molecules 2017, 22(8), 1331; https://doi.org/10.3390/molecules22081331 - 11 Aug 2017
Cited by 10 | Viewed by 2014
Abstract
Albizzia julibrissin Durazz, a Chinese Medicine, is commonly used for its anti-anxiety effects. (−)-syringaresnol-4-O-β-d-apiofuranosyl-(1→2)-β-d-glucopyranoside (SAG) is the main ingredient of Albizzia julibrissin Durazz. The present study investigated the anxiolytic effect and potential mechanisms on the HPA axis [...] Read more.
Albizzia julibrissin Durazz, a Chinese Medicine, is commonly used for its anti-anxiety effects. (−)-syringaresnol-4-O-β-d-apiofuranosyl-(1→2)-β-d-glucopyranoside (SAG) is the main ingredient of Albizzia julibrissin Durazz. The present study investigated the anxiolytic effect and potential mechanisms on the HPA axis and monoaminergic systems of SAG on acute restraint-stressed rats. The anxiolytic effect of SAG was examined through an open field test and an elevated plus maze test. The concentration of CRF, ACTH, and CORT in plasma was examined by an enzyme-linked immune sorbent assay (ELISA) kit while neurotransmitters in the cerebral cortex and hippocampus of the brain were examined by High Performance Liquid Chromatography (HPLC). We show that repeated treatment with SAG (3.6 mg/kg, p.o.) significantly increased the number and time spent on the central entries in the open-field test when compared to the vehicle/stressed group. In the elevated plus maze test, 3.6 mg/kg SAG could increase the percentage of entries into and time spent on the open arms of the elevated plus maze. In addition, the concentration of CRF, ACTH, and CORT in plasma and neurotransmitters (NE, 5-HT, DA and their metabolites 5-HIAA, DOPAC, and HVA) in the cerebral cortex and hippocampus of the brain were decreased after SAG treatment, as compared to the repeated acute restraint-stressed rats. These results suggest that SAG is a potential anti-anxiety drug candidate. Full article
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Open AccessArticle
Time- and NADPH-Dependent Inhibition on CYP3A by Gomisin A and the Pharmacokinetic Interactions between Gomisin A and Cyclophosphamide in Rats
Molecules 2017, 22(8), 1298; https://doi.org/10.3390/molecules22081298 - 08 Aug 2017
Cited by 6 | Viewed by 1902
Abstract
The traditional Chinese medicine Schisandra chinensis has remarkable protective effects against chemical-induced toxicity. Cyclophosphamide (CTX), in spite advances in chemotherapy and immunosuppressive regimes, is prone to cause severe toxicity due to its chloroacetaldehyde (CAA) metabolite produced by CYP3A. Our previous study identified that [...] Read more.
The traditional Chinese medicine Schisandra chinensis has remarkable protective effects against chemical-induced toxicity. Cyclophosphamide (CTX), in spite advances in chemotherapy and immunosuppressive regimes, is prone to cause severe toxicity due to its chloroacetaldehyde (CAA) metabolite produced by CYP3A. Our previous study identified that S. chinensis extract (SCE) co-administration potently decreased CAA production and attenuated liver, kidney and brain injuries in CTX-treated rats. Gomisin A (Gom A) is proved to be one of the most abundant bioactive lignans in S. chinensis with a significant CYP3A inhibitory effect. To find out whether and how Gom A participated in the chemoprevention of SCE against CTX toxicity, the Gom A-caused CYP3A inhibition in vitro as well as the pharmacokinetic interactions between Gom A and CTX in vivo were examined in this study. Using human liver microsomes, a reversible inhibition assay revealed that Gom A was a competitive inhibitor with a KI value of 1.10 µM, and the time- and NADPH-dependent CYP3A inhibition of Gom A was observed in a time-dependent inhibition assay (KI = 0.35 µM, kinact = 1.96 min−1). Hepatic CYP3A mRNA expression experienced a significant increase in our rat model with Gom A administration. This explained why CAA production decreased in the 0.5 h- and 6 h-pretreatment rat groups while it increased in the 24 h- and 72 h-pretreatment groups, indicating a bidirectional effect of Gom A on CYP3A-mediated CTX metabolism. The present study suggested that Gom A participates like SCE in the pharmacokinetic intervention of CTX by blocking CYP3A-mediated metabolism and reducing CAA production, and thus plays an important role in the chemopreventive activity of S. chinensis against CTX toxicity, in addition to the previously recognized protective effects. Also, the combined use of S. chinensis preparation or other drugs containing Gom A as the main component with CTX needed to be addressed for better clinical intervention. Full article
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Open AccessArticle
A Novel and Practical Chromatographic “Fingerprint-ROC-SVM” Strategy Applied to Quality Analysis of Traditional Chinese Medicine Injections: Using KuDieZi Injection as a Case Study
Molecules 2017, 22(7), 1237; https://doi.org/10.3390/molecules22071237 - 23 Jul 2017
Cited by 13 | Viewed by 2658
Abstract
Fingerprinting is widely and commonly used in the quality control of traditional Chinese medicine (TCM) injections. However, current studies informed that the fingerprint similarity evaluation was less sensitive and easily generated false positive results. For this reason, a novel and practical chromatographic “Fingerprint-ROC-SVM” [...] Read more.
Fingerprinting is widely and commonly used in the quality control of traditional Chinese medicine (TCM) injections. However, current studies informed that the fingerprint similarity evaluation was less sensitive and easily generated false positive results. For this reason, a novel and practical chromatographic “Fingerprint-ROC-SVM” strategy was established by using KuDieZi (KDZ) injection as a case study in the present article. Firstly, the chromatographic fingerprints of KDZ injection were obtained by UPLC and the common characteristic peaks were identified with UPLC/Q-TOF-MS under the same chromatographic conditions. Then, the receiver operating characteristic (ROC) curve was used to optimize common characteristic peaks by the AUCs value greater than 0.7. Finally, a support vector machine (SVM) model, with the accuracy of 97.06%, was established by the optimized characteristic peaks and applied to monitor the quality of KDZ injection. As a result, the established model could sensitively and accurately distinguish the qualified products (QPs) with the unqualified products (UPs), high-temperature processed samples (HTPs) and high-illumination processed samples (HIPs) of KDZ injection, and the prediction accuracy was 100.00%, 93.75% and 100.00%, respectively. Furthermore, through the comparison with other chemometrics methods, the superiority of the novel analytical strategy was more prominent. It indicated that the novel and practical chromatographic “Fingerprint-ROC-SVM” strategy could be further applied to facilitate the development of the quality analysis of TCM injections. Full article
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Open AccessArticle
Spectrum Effect Relationship and Component Knock-Out in Angelica Dahurica Radix by High Performance Liquid Chromatography-Q Exactive Hybrid Quadrupole-Orbitrap Mass Spectrometer
Molecules 2017, 22(7), 1231; https://doi.org/10.3390/molecules22071231 - 21 Jul 2017
Cited by 12 | Viewed by 3004
Abstract
Different extracts of Angelica dahuricae were available for whitening or treating vitiligo clinically. They showed inhibitory or activating effects on tyrosinase, a rate-limiting enzyme of melanogenesis. This study aimed to identify active compounds on tyrosinase in water extract of Angelica dahurica Radix. We [...] Read more.
Different extracts of Angelica dahuricae were available for whitening or treating vitiligo clinically. They showed inhibitory or activating effects on tyrosinase, a rate-limiting enzyme of melanogenesis. This study aimed to identify active compounds on tyrosinase in water extract of Angelica dahurica Radix. We applied spectrum-effect relationship and component knock-out methods to make it clear. HPLC was used to obtain the specific chromatograms. The effects on tyrosinase activity were examined by measuring the oxidation rate of levodopa in vitro. Partial least squares method was used to examine the spectrum-effect relationships. The knocked-out samples were prepared by HPLC method, and the identification of knocked-out compounds was conducted by the high performance liquid chromatography-four stage rod-electrostatic field orbit trap high resolution mass spectrometry. Results showed that S6, S14, S18, S21, S35, S36, S37, S40, and S41 were positively correlated to inhibitory activity of Angelica dahuricae on tyrosinase whereas S9, S11, S8, S12, S22, and S30 were negatively correlated. When the concentration of each sample was 1 g·mL−1, equal to the amount of raw medicinal herbs, oxypeucedanin hydrate, imperatorin, cnidilin, and isoimperatorin had inhibitory effects on tyrosinase activity whereas byakangelicin and bergapten had activating effects. Full article
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