molecules-logo

Journal Browser

Journal Browser

Special Issue "Bioactive Molecules and Their Mechanisms of Action"

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

Deadline for manuscript submissions: closed (31 May 2019).

Special Issue Editors

Prof. Dr. Atanas G. Atanasov
Website
Guest Editor
1. Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, 05-552 Jastrzebiec, Poland
2. Department of Pharmacognosy, University of Vienna, Austria
3. International Natural Product Sciences Taskforce (INPST)
Interests: molecular medicine; biotechnology; digital health; open innovation; natural products
Special Issues and Collections in MDPI journals
Assoc. Prof. Dr. Karel Šmejkal
Website
Guest Editor
Department of Natural Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Czech Republic
Interests: natural products; phytochemistry; inflammation; antibacterial activity
Special Issues and Collections in MDPI journals
Assoc. Prof. Dr. Elke Heiss
Website
Guest Editor
Department of Pharmacognosy, University of Vienna, Austria
Interests: natural products; mode of action; cellular stress response; bioenergetics, metabolic and redox homeostasis
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Prompted by the strong academic and public interest in our previously-edited Special Issue for Molecules, focused on the topic "Effects of Natural Products in the Context of Cardiometabolic Disease", we will release another Special Issue. For this new issue, entitled "Bioactive Molecules and Their Mechanisms of Action", we strongly encourage the submission of works examining the mode of action of natural products in models of cardiovascular or metabolic diseases, but also extend the scope to include submissions that are related to the mechanistic characterization of compounds other than natural products, or to bioactivities beyond the cardiometabolic field, including but not limited to effects on inflammation, advanced antioxidant activity studies, or effects on gut microbiota.

Prof. Dr. Atanas G. Atanasov
Assoc. Prof. Dr. Karel Šmejkal
Assoc. Prof. Dr. Elke Heiss
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • bioactive compounds
  • small molecules
  • natural products
  • mechanisms of pharmacologic action
  • drug discovery
  • pharmacology
  • metabolism
  • inflammation

Related Special Issue

Published Papers (20 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Editorial

Jump to: Research, Review

Open AccessEditorial
Bioactive Molecules and Their Mechanisms of Action
Molecules 2019, 24(20), 3752; https://doi.org/10.3390/molecules24203752 - 18 Oct 2019
Abstract
Chronic inflammation with a wide spectrum of connected diseases (e [...] Full article
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)

Research

Jump to: Editorial, Review

Open AccessFeature PaperArticle
Octadecaneuropeptide (ODN) Induces N2a Cells Differentiation through a PKA/PLC/PKC/MEK/ERK-Dependent Pathway: Incidence on Peroxisome, Mitochondria, and Lipid Profiles
Molecules 2019, 24(18), 3310; https://doi.org/10.3390/molecules24183310 - 11 Sep 2019
Cited by 3
Abstract
Neurodegenerative diseases are characterized by oxidative stress, mitochondrial damage, and death of neuronal cells. To counteract such damage and to favor neurogenesis, neurotrophic factors could be used as therapeutic agents. Octadecaneuropeptide (ODN), produced by astrocytes, is a potent neuroprotective agent. In N2a cells, [...] Read more.
Neurodegenerative diseases are characterized by oxidative stress, mitochondrial damage, and death of neuronal cells. To counteract such damage and to favor neurogenesis, neurotrophic factors could be used as therapeutic agents. Octadecaneuropeptide (ODN), produced by astrocytes, is a potent neuroprotective agent. In N2a cells, we studied the ability of ODN to promote neuronal differentiation. This parameter was evaluated by phase contrast microscopy, staining with crystal violet, cresyl blue, and Sulforhodamine 101. The effect of ODN on cell viability and mitochondrial activity was determined with fluorescein diacetate and DiOC6(3), respectively. The impact of ODN on the topography of mitochondria and peroxisomes, two tightly connected organelles involved in nerve cell functions and lipid metabolism, was evaluated by transmission electron microscopy and fluorescence microscopy: detection of mitochondria with MitoTracker Red, and peroxisome with an antibody directed against the ABCD3 peroxisomal transporter. The profiles in fatty acids, cholesterol, and cholesterol precursors were determined by gas chromatography, in some cases coupled with mass spectrometry. Treatment of N2a cells with ODN (10−14 M, 48 h) induces neurite outgrowth. ODN-induced neuronal differentiation was associated with modification of topographical distribution of mitochondria and peroxisomes throughout the neurites and did not affect cell viability and mitochondrial activity. The inhibition of ODN-induced N2a differentiation with H89, U73122, chelerythrine and U0126 supports the activation of a PKA/PLC/PKC/MEK/ERK-dependent signaling pathway. Although there is no difference in fatty acid profile between control and ODN-treated cells, the level of cholesterol and some of its precursors (lanosterol, desmosterol, lathosterol) was increased in ODN-treated cells. The ability of ODN to induce neuronal differentiation without cytotoxicity reinforces the interest for this neuropeptide with neurotrophic properties to overcome nerve cell damage in major neurodegenerative diseases. Full article
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
Show Figures

Graphical abstract

Open AccessArticle
Identification of Constituents Affecting the Secretion of Pro-Inflammatory Cytokines in LPS-Induced U937 Cells by UHPLC-HRMS-Based Metabolic Profiling of the Traditional Chinese Medicine Formulation Huangqi Jianzhong Tang
Molecules 2019, 24(17), 3116; https://doi.org/10.3390/molecules24173116 - 27 Aug 2019
Cited by 2
Abstract
Within non-communicable diseases, chronic inflammatory conditions represent one of the biggest challenges for modern medicine. Traditional Chinese Medicine (TCM) has been practiced over centuries and has accumulated tremendous empirical knowledge on the treatment of such diseases. Huangqi Jianzhong Tang (HQJZT) is a famous [...] Read more.
Within non-communicable diseases, chronic inflammatory conditions represent one of the biggest challenges for modern medicine. Traditional Chinese Medicine (TCM) has been practiced over centuries and has accumulated tremendous empirical knowledge on the treatment of such diseases. Huangqi Jianzhong Tang (HQJZT) is a famous TCM herbal formula composed of Radix Astragali, Ramulus Cinnamomi, Radix et Rhizoma Glycyrrhizae Praeparata cum Melle, Radix Paeoniae Alba, Rhizoma Zingiberis Recens, Fructus Jujubae and Saccharum Granorum (maltose), which has been used for the treatment of various chronic inflammatory gastrointestinal diseases. However, there is insufficient knowledge about its active constituents and the mechanisms responsible for its effects. The present study aimed at identifying constituents contributing to the bioactivity of HQJZT by combining in vitro cytokine production assays and LC-MS metabolomics techniques. From the HQJZT decoction as well as from its single herbal components, extracts of different polarities were prepared. Phytochemical composition of the extracts was analyzed by means of UPLC-QTOF-MS/MS. The inhibitory effects of the extracts on TNF-α, IL-1β and IFN-γ production were studied in U937 cells. Phytochemical and pharmacological bioactivity data were correlated by orthogonal projection to latent structures discriminant analysis (OPLS-DA) in order to identify those HQJZT constituents which may be relevant for the observed pharmacological activities. The investigations resulted in the identification of 16 HQJZT constituents, which are likely to contribute to the activities observed in U937 cells. Seven of them, namely calycosin, formononetin, astragaloside I, liquiritigenin, 18β-glycyrrhetinic acid, paeoniflorin and albiflorin were unambiguously identified. The predicted results were verified by testing these compounds in the same pharmacological assays as for the extracts. In conclusion, the anti-inflammatory activity of HQJZT could be substantiated by in vitro pharmacological screening, and the predicted activities of the OPLS-DA hits could be partially verified. Moreover, the benefits and limitations of MVDA for prediction pharmacologically active compounds contributing to the activity of a TCM mixture could be detected. Full article
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
Show Figures

Figure 1

Open AccessArticle
Anti-Edematogenic and Anti-Granuloma Activity of a Synthetic Curcuminoid Analog, 5-(3,4-Dihydroxyphenyl)-3-hydroxy-1-(2-hydroxyphenyl)penta-2,4-dien-1-one, in Mouse Models of Inflammation
Molecules 2019, 24(14), 2614; https://doi.org/10.3390/molecules24142614 - 18 Jul 2019
Cited by 2
Abstract
Curcumin, derived from the rhizome Curcuma longa, has been scientifically proven to possess anti-inflammatory activity but is of limited clinical and veterinary use owing to its low bioavailability and poor solubility. Hence, analogs of curcuminoids with improved biological properties have been synthesized [...] Read more.
Curcumin, derived from the rhizome Curcuma longa, has been scientifically proven to possess anti-inflammatory activity but is of limited clinical and veterinary use owing to its low bioavailability and poor solubility. Hence, analogs of curcuminoids with improved biological properties have been synthesized to overcome these limitations. This study aims to provide the pharmacological basis for the use of 5-(3,4-dihydroxyphenyl)-3-hydroxy-1-(2-hydroxyphenyl)penta-2,4-dien-1-one (DHHPD), a synthetic curcuminoid analog, as an anti-edematogenic and anti-granuloma agent. The carrageenan-induced paw edema and the cotton pellet-induced granuloma assays were used to assess the anti-inflammatory activity of DHHPD in mice. The effects of DHHPD on the histaminergic, serotonergic, and bradykininergic systems were determined by the histamine-, serotonin-, and bradykinin-induced paw edema tests, respectively. DHHPD (0.1, 0.3, 1, and 3 mg/kg, intraperitoneal) evoked significant reductions (p < 0.05) in carrageenan-induced paw edema at different time intervals and granuloma formation (p < 0.0001) by 22.08, 32.57, 37.20, and 49.25%, respectively. Furthermore, DHHPD significantly reduced paw edema (p < 0.05) induced by histamine, serotonin, and bradykinin. The present study suggests that DHHPD exerts anti-edematogenic activity, possibly by inhibiting the synthesis or release of autacoid mediators of inflammation through the histaminergic, serotonergic, and bradykininergic systems. The anti-granuloma effect may be attributed to the suppression of transudative, exudative, and proliferative activities associated with inflammation. Full article
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
Show Figures

Graphical abstract

Open AccessArticle
Benzimidazoles Downregulate Mdm2 and MdmX and Activate p53 in MdmX Overexpressing Tumor Cells
Molecules 2019, 24(11), 2152; https://doi.org/10.3390/molecules24112152 - 07 Jun 2019
Cited by 3
Abstract
Tumor suppressor p53 is mutated in about 50% of cancers. Most malignant melanomas carry wild-type p53, but p53 activity is often inhibited due to overexpression of its negative regulators Mdm2 or MdmX. We performed high throughput screening of 2448 compounds on A375 cells [...] Read more.
Tumor suppressor p53 is mutated in about 50% of cancers. Most malignant melanomas carry wild-type p53, but p53 activity is often inhibited due to overexpression of its negative regulators Mdm2 or MdmX. We performed high throughput screening of 2448 compounds on A375 cells carrying p53 activity luciferase reporter construct to reveal compounds that promote p53 activity in melanoma. Albendazole and fenbendazole, two approved and commonly used benzimidazole anthelmintics, stimulated p53 activity and were selected for further studies. The protein levels of p53 and p21 increased upon the treatment with albendazole and fenbendazole, indicating activation of the p53–p21 pathway, while the levels of Mdm2 and MdmX decreased in melanoma and breast cancer cells overexpressing these proteins. We also observed a reduction of cell viability and changes of cellular morphology corresponding to mitotic catastrophe, i.e., G2/M cell cycle arrest of large multinucleated cells with disrupted microtubules. In summary, we established a new tool for testing the impact of small molecule compounds on the activity of p53 and used it to identify the action of benzimidazoles in melanoma cells. The drugs promoted the stability and transcriptional activity of wild-type p53 via downregulation of its negative regulators Mdm2 and MdmX in cells overexpressing these proteins. The results indicate the potential for repurposing the benzimidazole anthelmintics for the treatment of cancers overexpressing p53 negative regulators. Full article
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
Show Figures

Graphical abstract

Open AccessArticle
Epigallocatechin-3-Gallate Prevents Acute Gout by Suppressing NLRP3 Inflammasome Activation and Mitochondrial DNA Synthesis
Molecules 2019, 24(11), 2138; https://doi.org/10.3390/molecules24112138 - 06 Jun 2019
Cited by 4
Abstract
Gout is a chronic inflammatory disease evoked by the deposition of monosodium urate (MSU) crystals in joint tissues. The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is responsible for the gout inflammatory symptoms induced by MSU crystals. [...] Read more.
Gout is a chronic inflammatory disease evoked by the deposition of monosodium urate (MSU) crystals in joint tissues. The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is responsible for the gout inflammatory symptoms induced by MSU crystals. We investigated whether epigallocatechin-3-gallate (EGCG) suppresses the activation of the NLRP3 inflammasome, thereby effectively preventing gouty inflammation. EGCG blocked MSU crystal-induced production of caspase-1(p10) and interleukin-1β in primary mouse macrophages, indicating its suppressive effect on the NLRP3 inflammasome. In an acute gout mouse model, oral administration of EGCG to mice effectively alleviated gout inflammatory symptoms in mouse foot tissue injected with MSU crystals. The in vivo suppressive effects of EGCG correlated well with the suppression of the NLRP3 inflammasome in mouse foot tissue. EGCG inhibited the de novo synthesis of mitochondrial DNA as well as the production of reactive oxygen species in primary mouse macrophages, contributing to the suppression of the NLRP3 inflammasome. These results show that EGCG suppresses the activation of the NLRP3 inflammasome in macrophages via the blockade of mitochondrial DNA synthesis, contributing to the prevention of gouty inflammation. The inhibitory effects of EGCG on the NLRP3 inflammasome make EGCG a promising therapeutic option for NLRP3-dependent diseases such as gout. Full article
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
Show Figures

Figure 1

Open AccessArticle
Astragalus Polysaccharide RAP Induces Macrophage Phenotype Polarization to M1 via the Notch Signaling Pathway
Molecules 2019, 24(10), 2016; https://doi.org/10.3390/molecules24102016 - 27 May 2019
Cited by 5
Abstract
Macrophages occur in polarized phenotypes, whose characteristics determine the role they play in tumor growth. The M1 phenotype macrophages promote tumoricidal responses and suppress tumor growth. Our previous study showed that a polysaccharide isolated from Radix Astragali, named RAP, was itself non-cytotoxic but [...] Read more.
Macrophages occur in polarized phenotypes, whose characteristics determine the role they play in tumor growth. The M1 phenotype macrophages promote tumoricidal responses and suppress tumor growth. Our previous study showed that a polysaccharide isolated from Radix Astragali, named RAP, was itself non-cytotoxic but induced RAW264.7 cells’ cytotoxicity against cancer cells. The current study was undertaken to determine its mechanism. Series studies was conducted to show that RAP is able to induce much higher gene expression of M1 markers, including iNOS, IL-6, TNF-a, and CXCL10, compared with the control group. When RAP-induced BMDMs were transplanted together with 4T1 tumor cells in BALB/c mice, both tumor volume and tumor weight decreased. Further studies indicated that RAP induces the Notch signaling pathway in RAW264.7 cells. The function of Notch signaling in macrophage polarization was confirmed by using γ-secretase inhibitor. These results suggested that Astragalus polysaccharide RAP induces macrophage’s polarization to M1 phenotype via the Notch signaling pathway. Full article
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
Show Figures

Graphical abstract

Open AccessArticle
An Improved Method for the Synthesis of Butein Using SOCl2/EtOH as Catalyst and Deciphering Its Inhibition Mechanism on Xanthine Oxidase
Molecules 2019, 24(10), 1948; https://doi.org/10.3390/molecules24101948 - 21 May 2019
Cited by 3
Abstract
Butein (3,4,2′,4′-tetrahydroxychalcone) belongs to the chalcone family of flavonoids and possesses various biological activities. In this study, butein was synthesized through aldol condensation catalyzed by thionyl chloride (SOCl2)/ethyl alcohol (EtOH) for the first time. The optimal reaction conditions including the molar [...] Read more.
Butein (3,4,2′,4′-tetrahydroxychalcone) belongs to the chalcone family of flavonoids and possesses various biological activities. In this study, butein was synthesized through aldol condensation catalyzed by thionyl chloride (SOCl2)/ethyl alcohol (EtOH) for the first time. The optimal reaction conditions including the molar ratio of reactants, the dosage of catalyst, and the reaction time on the yield of product were investigated, and the straightforward strategy assembles the yield of butein up to 88%. Butein has been found to inhibit xanthine oxidase (XO) activity. Herein, the inhibitory mechanism of butein against XO was discussed in aspects of inhibition kinetic, fluorescence titration, synchronous fluorescence spectroscopy, and molecular docking. The inhibition kinetic analysis showed that butein possessed a stronger inhibition on XO in an irreversible competitive manner with IC50 value of 2.93 × 10−6 mol L−1. The results of fluorescence titrations and synchronous fluorescence spectroscopy indicated that butein was able to interact with XO at one binding site, and the fluorophores of XO were placed in a more hydrophobic environment with the addition of butein. Subsequently, the result of molecular docking between butein and XO protein revealed that butein formed hydrogen bonding with the amino acid residues located in the hydrophobic cavity of XO. All the results suggested that the inhibitory mechanism of butein on XO may be the insertion of butein into the active site occupying the catalytic center of XO to avoid the entrance of xanthine and inducing conformational changes in XO. Full article
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
Show Figures

Figure 1

Open AccessArticle
Curcumin: Total-Scale Analysis of the Scientific Literature
Molecules 2019, 24(7), 1393; https://doi.org/10.3390/molecules24071393 - 09 Apr 2019
Cited by 8
Abstract
The current study aimed to provide a comprehensive bibliometric overview of the literature on curcumin, complementing the previous reviews and meta-analyses on its potential health benefits. Bibliometric data for the current analysis were extracted from the Web of Science Core Collection database, using [...] Read more.
The current study aimed to provide a comprehensive bibliometric overview of the literature on curcumin, complementing the previous reviews and meta-analyses on its potential health benefits. Bibliometric data for the current analysis were extracted from the Web of Science Core Collection database, using the search string TOPIC=(“curcumin*”), and analyzed by the VOSviewer software. The search yielded 18,036 manuscripts. The ratio of original articles to reviews was 10.4:1. More than half of the papers have been published since 2014. The major contributing countries were the United States, China, India, Japan, and South Korea. These publications were mainly published in journals representing the following scientific disciplines: biochemistry, chemistry, oncology, and pharmacology. There was a significant positive correlation between the total publication count and averaged citations per manuscript for affiliations, but not for countries/regions and journals. Chemicals that were frequently mentioned in the keywords of evaluated curcumin publications included curcuminoids, resveratrol, chitosan, flavonoids, quercetin, and polyphenols. The literature mainly focused on curcumin’s effects against cancer, inflammation, and oxidative stress. Cancer types most frequently investigated were breast, colon, colorectal, pancreatic, and prostate cancers. Full article
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
Show Figures

Figure 1

Open AccessCommunication
Co-Existence of Hypertensive and Anti-Hypertensive Constituents, Synephrine, and Nobiletin in Citrus unshiu Peel
Molecules 2019, 24(7), 1197; https://doi.org/10.3390/molecules24071197 - 27 Mar 2019
Cited by 2
Abstract
A single herb can contain multiple constituents with diverse bioactivities. We found that the extract of Citrus unshiu peel (CUP), induced abnormal vasoconstriction responses on the freshly isolated rat aortic rings in vitro. CUP stimulated the vasoconstriction alone, and it suppressed the phenylephrine-stimulated [...] Read more.
A single herb can contain multiple constituents with diverse bioactivities. We found that the extract of Citrus unshiu peel (CUP), induced abnormal vasoconstriction responses on the freshly isolated rat aortic rings in vitro. CUP stimulated the vasoconstriction alone, and it suppressed the phenylephrine-stimulated vasoconstriction. We studied the reasons behind this abnormal vasoconstriction pattern. Major constituents of CUP were determined and evaluated for their vaso-activities. Notably, synephrine, a contractile agonist, and nobiletin, newly identified to have anti-contractile activity co-existed in CUP. Synephrine and nobiletin competitively blocked or activated the same contractile targets resulting in contradicting and abnormal vasoconstriction responses. Accordingly, the vasoconstriction pattern varies significantly depending on the relative contents of synephrine and nobiletin in CUP. Interestingly, this response pattern could be observed with another plant extract, Acorus gramineus Sol. Collectively, we demonstrated that active ingredients with contradicting bioactivities could co-exist in a single plant extract, interact and produce abnormal response patterns in bioassay, which would give an important insight into the interpretation of unusual activity patterns induced by plant extracts. Full article
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
Show Figures

Graphical abstract

Open AccessArticle
Physalis peruviana-Derived 4β-Hydroxywithanolide E, a Novel Antagonist of Wnt Signaling, Inhibits Colorectal Cancer In Vitro and In Vivo
Molecules 2019, 24(6), 1146; https://doi.org/10.3390/molecules24061146 - 22 Mar 2019
Cited by 3
Abstract
Deregulation of the Wnt signaling pathway leads to colorectal cancer progression. Natural dietary compounds serve as promising candidates for development as chemopreventive agents by suppressing the Wnt/β-catenin signaling pathway. Physalis peruviana-derived 4βHWE showed a significant inhibitory activity with a calculated IC50 [...] Read more.
Deregulation of the Wnt signaling pathway leads to colorectal cancer progression. Natural dietary compounds serve as promising candidates for development as chemopreventive agents by suppressing the Wnt/β-catenin signaling pathway. Physalis peruviana-derived 4βHWE showed a significant inhibitory activity with a calculated IC50 of 0.09 μΜ in a screening of novel inhibitors of Wnt signaling with the dual-luciferase reporter assay. This study investigated the anti-tumor effect of 4βHWE and the potential Wnt signaling inhibitory mechanism. Both the western blot analysis and immunofluorescence assay showed that 4βHWE promoted the phosphorylation and degradation of β-catenin and the subsequent inhibition of its nuclear translocation to attenuate the endogenous Wnt target gene expression in colorectal cancer (CRC) cells. The cell viability assay indicated that 4βHWE preferentially inhibited the proliferation of CRC compared with CCD-841-CoN, a normal human colonic epithelial cell line. 4βHWE-mediated G0/G1 cell cycle arrest and apoptosis induction contributed to the suppression of the proliferation of CRC in the cell cycle and Annexin V-FITC/Propidium Iodide apoptosis analysis. Moreover, in vivo, 4βHWE dramatically inhibited tumor growth in HCT116 xenografts by attenuating the Wnt/β-catenin signaling pathway. In conclusion, our study suggested that 4βHWE could be of potential use in anti-tumor agent development as a novel Wnt signaling inhibitor. Full article
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
Show Figures

Graphical abstract

Open AccessArticle
The Ethanol Extract of Holotrichia diomphalia Larvae, Containing Fatty acids and Amino acids, Exerts Anti-Asthmatic Effects through Inhibition of the GATA-3/Th2 Signaling Pathway in Asthmatic Mice
Molecules 2019, 24(5), 852; https://doi.org/10.3390/molecules24050852 - 28 Feb 2019
Cited by 2
Abstract
Holotrichia diomphalia larvae (HD), a natural product from an insect resource, possesses many pharmacological properties, including anticoagulant, antitumor, anti-inflammatory, and analgesic activity. The major bioactive ingredients include oleic acid, palmitic acid, palmitoleic acid, linoleic acid, proline, and glutamic acid. Although HD is associated [...] Read more.
Holotrichia diomphalia larvae (HD), a natural product from an insect resource, possesses many pharmacological properties, including anticoagulant, antitumor, anti-inflammatory, and analgesic activity. The major bioactive ingredients include oleic acid, palmitic acid, palmitoleic acid, linoleic acid, proline, and glutamic acid. Although HD is associated with immunoregulatory activities in allergic diseases, the therapeutic mechanisms of the action of HD in allergic diseases have not been investigated. The aim of this study was to evaluate the anti-asthmatic potential of HD in an ovalbumin (OVA)-induced mouse model of allergic asthma. Moreover, the anti-inflammatory potential of HD was examined to identify a plausible mechanism of action of HD in vitro. HD strongly reduced goblet cell hyperplasia, eosinophil infiltration, and reactive oxygen species (ROS), which reduced airway hyperresponsiveness (AHR), inflammation, and the expression of Th2 cytokines (IL-5 and IL-13) in bronchoalveolar lavage fluid (BALF). The expression of IL-5, IL-4, eotaxin-2, lysyl oxidase-like 2 (loxl2), and GATA-binding protein 3 (GATA-3) was attenuated in the lungs. In an in vitro assay, HD exerted immunomodulatory effects through the suppression of Th2 cytokines (IL-5, IL-13), IL-17, and tumor necrosis factor (TNF)-α production through downregulation of GATA-3 expression in EL-4 T cells. These findings suggest that the anti-asthmatic activity of HD may occur through the suppression of Th2 cytokines and total Immunoglobulin E (IgE) production by inhibition of the GATA-3 transcription pathway. Our results suggest that HD may be a potential alternative therapy, or a novel therapeutic traditional medicine, for the treatment of allergic asthma. Full article
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
Show Figures

Graphical abstract

Open AccessArticle
Inhibitory Effects of Berberine Hydrochloride on Trichophyton mentagrophytes and the Underlying Mechanisms
Molecules 2019, 24(4), 742; https://doi.org/10.3390/molecules24040742 - 19 Feb 2019
Cited by 3
Abstract
Background: T. mentagrophytes can infect all mammals, including rabbits, causing serious infections with remarkable economic losses for rabbit farmers. Berberine is an alkaloid that is effective against a variety of microbial infections such as T. mentagrophytes. Growth curve by dry weight determination [...] Read more.
Background: T. mentagrophytes can infect all mammals, including rabbits, causing serious infections with remarkable economic losses for rabbit farmers. Berberine is an alkaloid that is effective against a variety of microbial infections such as T. mentagrophytes. Growth curve by dry weight determination and in-vivo antifungal assay were carried out to clarify the inhibitory effect of berberine hydrochloride against T. mentagrophytes. Transcriptomics analyses were also carried out for better understanding of the underlying mechanisms. Results: The growth rate of T. mentagrophytes was significantly higher in control condition than under berberine hydrochloride or clotrimazole for 60 h. The growth rate of T. mentagrophytes was significantly slighter higher in berberine condition (1 mg) than under clotrimazole for 46 h. T. mentagrophytes seriously shrunk after berberine or clotrimazole treatment, as observed by TEM and in SEM. Significant recovery was evident in three berberine groups on day 6 compared with the DMSO group. Results from transcriptomics analyses showed 18,881 identified unigenes, including 18,754 and 12,127 in the NT and SwissProt databases. Among these, 12,011, 9174, and 11,679 unigenes belonged to 3 Gene Ontology (GO), 43 KEGG, and 25 KOG categories, respectively. Interestingly, we found that down-regulation of 14α-demethylase exposed to various medicines was slightly different, i.e., berberine hydrochloride (fold change −3.4956) and clotrimazole (fold change −2.1283) caused various degrees of alteration. Conclusions: Berberine hydrochloride could inhibit the growth of T. mentagrophytes. Berberine hydrochloride could also cure dermatosis induced by T. mentagrophytes. Down-regulation of 14α-demethylase exposed to various medicines was slightly different and might be one of the anti-resistance mechanisms of berberine hydrochloride in T. mentagrophytes. The present investigation provides considerable transcript sequence data that would help further assess the antifungal mechanisms against T. mentagrophytes, for antifungal medicine development. Full article
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
Show Figures

Figure 1

Open AccessArticle
Structure Identification of ViceninII Extracted from Dendrobium officinale and the Reversal of TGF-β1-Induced Epithelial–Mesenchymal Transition in Lung Adenocarcinoma Cells through TGF-β/Smad and PI3K/Akt/mTOR Signaling Pathways
Molecules 2019, 24(1), 144; https://doi.org/10.3390/molecules24010144 - 02 Jan 2019
Cited by 6
Abstract
ViceninII is a naturally flavonoid glycoside extracted from Dendrobium officinale, a precious Chinese traditional herb, has been proven to be valuable for cancer treatment. Transforming growth factor-β1 (TGF-β1), promotes the induction of epithelial–mesenchymal transition (EMT), a process involved in the metastasis of [...] Read more.
ViceninII is a naturally flavonoid glycoside extracted from Dendrobium officinale, a precious Chinese traditional herb, has been proven to be valuable for cancer treatment. Transforming growth factor-β1 (TGF-β1), promotes the induction of epithelial–mesenchymal transition (EMT), a process involved in the metastasis of cells that leads to enhanced migration and invasion. However, there is no previously evidence that ViceninII has an inhibitory effect on cancer metastasis, specifically on the TGF-β1-induced EMT process in lung adenocarcinoma cells. In this experiment, we used UV, ESIMS, and NMR to identify the structure of ViceninII.A549 and H1299 cells were treated with TGF-β1 in the absence and presence of ViceninII, and subsequent migration and invasion were measured by wound-healing and transwell assays. The protein localization and expressions were detected by immunofluorescence and Western blotting. The results indicated that TGF-β1 induced spindle-shaped changes, increased migration and invasion, and upregulated or downregulated the relative expression of EMT biomarkers. Meanwhile, these alterations were significantly inhibited when co-treated with ViceninII and inhibitors LY294002 and SB431542. In conclusion, ViceninII inhibited TGF-β1-induced EMT via the deactivation of TGF-β/Smad and PI3K/Akt/mTOR signaling pathways.This is the first time that the anti-metastatic effects of ViceninII have been demonstrated, and their molecular mechanisms provided. Full article
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
Show Figures

Graphical abstract

Open AccessArticle
Polysaccharide-Enriched Fraction from Amillariella Mellea Fruiting Body Improves Insulin Resistance
Molecules 2019, 24(1), 46; https://doi.org/10.3390/molecules24010046 - 22 Dec 2018
Cited by 3
Abstract
Despite the edible fungus Amillariella mellea possessing a variety of biological activities, its effects on diabetes are still unclear. Polysaccharides are the main bioactive ingredients. In order to destroy the cell wall to obtain more polysaccharides, we used NaOH solution to extract Amillariella [...] Read more.
Despite the edible fungus Amillariella mellea possessing a variety of biological activities, its effects on diabetes are still unclear. Polysaccharides are the main bioactive ingredients. In order to destroy the cell wall to obtain more polysaccharides, we used NaOH solution to extract Amillariella mellea fruiting bodies. The alkali extraction (AAMP) was identified as a polysaccharide-enriched fraction. Using type 2 diabetic rats induced by co-treatment of a high fat diet (HFD) and dexamethasone (DEX), we evaluated the hypoglycemic effects of AAMP. The results showed that oral administration of a high dose of AAMP markedly lowered fasting blood glucose, improving glucose intolerance and insulin resistance. AAMP also enhanced the level of LPL and the expressions of two critical lipases ATGL and HSL, leading to a decrease of serum triglyceride. In addition, AAMP specifically suppressed the expression of SREBP-1c, resulting in AAMP observably inhibiting lipid accumulation in the liver. These findings demonstrated that the improvement of AAMP on HFD/DEX-induced insulin resistance was correlated with its regulation of lipid metabolism. Our results indicated that AAMP could be a novel natural drug or health food used for the treatment of diabetes. Full article
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
Show Figures

Figure 1

Open AccessArticle
l-Quebrachitol Promotes the Proliferation, Differentiation, and Mineralization of MC3T3-E1 Cells: Involvement of the BMP-2/Runx2/MAPK/Wnt/β-Catenin Signaling Pathway
Molecules 2018, 23(12), 3086; https://doi.org/10.3390/molecules23123086 - 26 Nov 2018
Cited by 9
Abstract
Osteoporosis is widely recognized as a major health problem caused by an inappropriate rate of bone resorption compared to bone formation. Previously we showed that d-pinitol inhibits osteoclastogenesis but has no effect on osteoblastogenesis. However, the effect on osteoblast differentiation of its [...] Read more.
Osteoporosis is widely recognized as a major health problem caused by an inappropriate rate of bone resorption compared to bone formation. Previously we showed that d-pinitol inhibits osteoclastogenesis but has no effect on osteoblastogenesis. However, the effect on osteoblast differentiation of its isomer, l-quebrachitol, has not yet been reported. The purpose of this study was, therefore, to investigate whether l-quebrachitol promotes the osteoblastogenesis of pre-osteoblastic MC3T3-E1 cells. Moreover, the molecular mechanism of action of l-quebrachitol was further explored. Here, it is shown for the first time that l-quebrachitol significantly promotes proliferation and cell DNA synthesis. It also enhances mineralization accompanied by increases in mRNA expression of bone matrix proteins including alkaline phosphatase (ALP), collagen type I (ColI), osteocalcin (OCN), and osteopontin (OPN). In addition, l-quebrachitol upregulates the mRNA and protein expression of bone morphogenetic protein-2 (BMP-2) and runt-related transcription factor-2 (Runx2), while down-regulating the receptor activator of the nuclear factor-κB ligand (RANKL) mRNA level. Moreover, the expression of regulatory genes associated with the mitogen-activated protein kinase (MAPK) and wingless-type MMTV integration site (Wnt)/β-catenin signaling pathways are also upregulated. These findings indicate that l-quebrachitol may promote osteoblastogenesis by triggering the BMP-2-response as well as the Runx2, MAPK, and Wnt/β-catenin signaling pathway. Full article
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
Show Figures

Graphical abstract

Open AccessArticle
Tetrahydroxystilbene Glucoside Regulates Proliferation, Differentiation, and OPG/RANKL/M-CSF Expression in MC3T3-E1 Cells via the PI3K/Akt Pathway
Molecules 2018, 23(9), 2306; https://doi.org/10.3390/molecules23092306 - 10 Sep 2018
Cited by 6
Abstract
Tetrahydroxystilbene glucoside (TSG) is a unique component of the bone-reinforcing herb Radix Polygoni Multiflori Preparata (RPMP). It has the ability to promote bone formation and protect osteoblasts. However, the underlying mechanism remains unclear. To better understand its biological function, we determined TSG’s effect [...] Read more.
Tetrahydroxystilbene glucoside (TSG) is a unique component of the bone-reinforcing herb Radix Polygoni Multiflori Preparata (RPMP). It has the ability to promote bone formation and protect osteoblasts. However, the underlying mechanism remains unclear. To better understand its biological function, we determined TSG’s effect on murine pre-osteoblastic MC3T3-E1 cells by the MTT assay, flow cytometry, FQ-PCR, Western blot, and ELISA. The results showed that TSG caused an elevation of the MC3T3-E1 cell number, the number of cells in the S phase, and the mRNA levels of the runt-related transcription factor-2 (Runx2), osterix (Osx), and collagen type I α1 (Col1a1). In addition, the osteoprotegerin (OPG) mRNA level was up-regulated, while the nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) mRNA levels were down-regulated by TSG. Furthermore, TSG activated the phosphoinosmde-3-kinase/protein kinase B (also known as PI3K/Akt) pathway, and blocking this pathway by the inhibitor LY-294002 could impair TSG’s functions in relation to the MC3T3-E1 cells. In conclusion, TSG could activate the PI3K/Akt pathway and thus promote MC3T3-E1 cell proliferation and differentiation, and influence OPG/RANKL/M-CSF expression. TSG merits further investigation as a potential therapeutic agent for osteoporosis treatment. Full article
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
Show Figures

Figure 1

Open AccessArticle
Pseudopterosin Inhibits Proliferation and 3D Invasion in Triple-Negative Breast Cancer by Agonizing Glucocorticoid Receptor Alpha
Molecules 2018, 23(8), 1992; https://doi.org/10.3390/molecules23081992 - 10 Aug 2018
Cited by 4
Abstract
Pseudopterosin, produced by the sea whip of the genus Antillogorgia, possesses a variety of promising biological activities, including potent anti-inflammatory effects. However, few studies examined pseudopterosin in the treatment of cancer cells and, to our knowledge, the ability to inhibit triple-negative breast [...] Read more.
Pseudopterosin, produced by the sea whip of the genus Antillogorgia, possesses a variety of promising biological activities, including potent anti-inflammatory effects. However, few studies examined pseudopterosin in the treatment of cancer cells and, to our knowledge, the ability to inhibit triple-negative breast cancer (TNBC) proliferation or invasion has not been explored. Thus, we evaluated the as-yet unknown mechanism of action of pseudopterosin: Pseudopterosin was able to inhibit proliferation of TNBC. Interestingly, analyzing breast cancer cell proliferation after knocking down glucocorticoid receptor α (GRα) revealed that the antiproliferative effects of pseudopterosin were significantly inhibited when GRα expression was reduced. Furthermore, pseudopterosin inhibited the invasion of MDA-MB-231 3D tumor spheroids embedded in an extracellular-like matrix. Remarkably, the knockdown of GRα in 3D tumor spheroids revealed increased ability of cells to invade the surrounding matrix. In a coculture, encompassing peripheral blood mononuclear cells (PBMC) and MDA-MB-231 cells, and the production of interleukin 6 (IL-6) and interleukin 8 (IL-8) significantly increased compared to a monoculture. Notably, pseudopterosin indicated to block cytokine elevation, representing key players in tumor progression in the coculture. Thus, our results reveal pseudopterosin treatment as a potential novel approach in TNBC therapy. Full article
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
Show Figures

Figure 1

Review

Jump to: Editorial, Research

Open AccessReview
Maytenus macrocarpa (Ruiz & Pav.) Briq.: Phytochemistry and Pharmacological Activity
Molecules 2019, 24(12), 2288; https://doi.org/10.3390/molecules24122288 - 20 Jun 2019
Cited by 1
Abstract
Maytenus macrocarpa (Celastraceae) is a tree native to Amazonia. Its roots, leaves, bark, and combinations of these are used in traditional medicine mainly to treat rheumatism and, to a lesser extent, to heal wounds and to combat bronchitis and diarrhea. To date, mainly [...] Read more.
Maytenus macrocarpa (Celastraceae) is a tree native to Amazonia. Its roots, leaves, bark, and combinations of these are used in traditional medicine mainly to treat rheumatism and, to a lesser extent, to heal wounds and to combat bronchitis and diarrhea. To date, mainly triterpenes and dihydro-β-agarofuran sesquiterpenes were isolated from M. macrocarpa. Extracts and selected pure compounds isolated from the leaves, roots, and stem bark showed antibacterial, antiviral, antiparasitic, anti-inflammatory, and cytotoxic activities in vitro. The aim of this review is to summarize the available ethnobotanical, phytochemical, and pharmacological information about this traditional Amazonian medicinal tree, as well as to attract the attention of phytochemists and pharmacognosists to this potentially interesting source of ethnopharmaceuticals. Full article
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
Open AccessReview
Recent Advances in Degradable Hybrids of Biomolecules and NGs for Targeted Delivery
Molecules 2019, 24(10), 1873; https://doi.org/10.3390/molecules24101873 - 15 May 2019
Cited by 2
Abstract
Recently, the fast development of hybrid nanogels dedicated to various applications has been seen. In this context, nanogels incorporating biomolecules into their nanonetworks are promising innovative carriers that gain great potential in biomedical applications. Hybrid nanogels containing various types of biomolecules are exclusively [...] Read more.
Recently, the fast development of hybrid nanogels dedicated to various applications has been seen. In this context, nanogels incorporating biomolecules into their nanonetworks are promising innovative carriers that gain great potential in biomedical applications. Hybrid nanogels containing various types of biomolecules are exclusively designed for: improved and controlled release of drugs, targeted delivery, improvement of biocompatibility, and overcoming of immunological response and cell self-defense. This review provides recent advances in this rapidly developing field and concentrates on: (1) the key physical consequences of using hybrid nanogels and introduction of biomolecules; (2) the construction and functionalization of degradable hybrid nanogels; (3) the advantages of hybrid nanogels in controlled and targeted delivery; and (4) the analysis of the specificity of drug release mechanisms in hybrid nanogels. The limitations and future directions of hybrid nanogels in targeted specific- and real-time delivery are also discussed. Full article
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
Show Figures

Graphical abstract

Back to TopTop