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New Insights in Natural Bioactive Compounds

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 38584

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Dear Colleagues, 

Natural bioactive compounds are small molecules produced naturally by several plants, including primary and secondary metabolites. Natural bioactive compounds have a wide range of possible applications and can be useful in the treatment and management of various kinds of human diseases due to their outstanding biological properties. Moreover, bioactive compounds and pharmaceuticals derived from natural products have received increasing attention due to their considerable benefits for human health. This Special Issue will shape the future research direction of important natural products, as well as related bioactives. Our purpose is to feature high-quality, advanced research and knowledge contributed by various research groups working on natural products from all around the world. We cordially invite authors to contribute original articles, as well as review papers on the functional and medicinal properties of natural products for preventing and managing human diseases.

Prof. Dr. Letteria Minutoli
Dr. Giovanni Pallio
Guest Editors

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Keywords

  • inflammation
  • cytokines
  • ROS
  • oxidative stress
  • natural products
  • flavonoids
  • cannabinoids

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Published Papers (19 papers)

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17 pages, 7230 KiB  
Article
In Vitro and In Vivo Therapeutic Potential of 6,6′-Dihydroxythiobinupharidine (DTBN) from Nuphar lutea on Cells and K18-hACE2 Mice Infected with SARS-CoV-2
by Shay Weiss, Kamran Waidha, Saravanakumar Rajendran, Daniel Benharroch, Jannat Khalilia, Haim Levy, Elad Bar-David, Avi Golan-Goldhirsh, Jacob Gopas and Amir Ben-Shmuel
Int. J. Mol. Sci. 2023, 24(9), 8327; https://doi.org/10.3390/ijms24098327 - 05 May 2023
Cited by 1 | Viewed by 1377
Abstract
We have previously published research on the anti-viral properties of an alkaloid mixture extracted from Nuphar lutea, the major components of the partially purified mixture found by NMR analysis. These are mostly dimeric sesquiterpene thioalkaloids called thiobinupharidines and thiobinuphlutidines against the negative [...] Read more.
We have previously published research on the anti-viral properties of an alkaloid mixture extracted from Nuphar lutea, the major components of the partially purified mixture found by NMR analysis. These are mostly dimeric sesquiterpene thioalkaloids called thiobinupharidines and thiobinuphlutidines against the negative strand RNA measles virus (MV). We have previously reported that this extract inhibits the MV as well as its ability to downregulate several MV proteins in persistently MV-infected cells, especially the P (phospho)-protein. Based on our observation that the Nuphar extract is effective in vitro against the MV, and the immediate need that the coronavirus disease 2019 (COVID-19) pandemic created, we tested here the ability of 6,6′-dihydroxythiobinupharidine DTBN, an active small molecule, isolated from the Nuphar lutea extract, on COVID-19. As shown here, DTBN effectively inhibits SARS-CoV-2 production in Vero E6 cells at non-cytotoxic concentrations. The short-term daily administration of DTBN to infected mice delayed the occurrence of severe clinical outcomes, lowered virus levels in the lungs and improved survival with minimal changes in lung histology. The viral load on lungs was significantly reduced in the treated mice. DTBN is a pleiotropic small molecule with multiple targets. Its anti-inflammatory properties affect a variety of pathogens including SARS-CoV-2 as shown here. Its activity appears to target both pathogen specific (as suggested by docking analysis) as well as cellular proteins, such as NF-κB, PKCs, cathepsins and topoisomerase 2, that we have previously identified in our work. Thus, this combined double action of virus inhibition and anti-inflammatory activity may enhance the overall effectivity of DTBN. The promising results from this proof-of-concept in vitro and in vivo preclinical study should encourage future studies to optimize the use of DTBN and/or its molecular derivatives against this and other related viruses. Full article
(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds)
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18 pages, 12201 KiB  
Article
Novel Strategy in Searching for Natural Compounds with Anti-Aging and Rejuvenating Potential
by Andrey Koptyug, Yurij Sukhovei, Elena Kostolomova, Irina Unger and Vladimir Kozlov
Int. J. Mol. Sci. 2023, 24(9), 8020; https://doi.org/10.3390/ijms24098020 - 28 Apr 2023
Cited by 2 | Viewed by 1995
Abstract
We suggest a novel approach for searching natural compounds with anti-aging and rejuvenation potential using cell cultures, with a high potential for the further in vivo applications. The present paper discusses ways of defining age for cell populations with large numbers of cells [...] Read more.
We suggest a novel approach for searching natural compounds with anti-aging and rejuvenation potential using cell cultures, with a high potential for the further in vivo applications. The present paper discusses ways of defining age for cell populations with large numbers of cells and suggests a method of assessing how young or old a cell population is based on a cell age profile approach. This approach uses experimental distributions of the cells over the cell cycle stages, acquired using flow cytometry. This paper discusses how such a profile should evolve under homeostatic maintenance of cell numbers in the proliferation niches. We describe promising results from experiments on a commercial substance claiming rejuvenating and anti-aging activity acting upon the cultures of human mononuclear cells and dermal fibroblasts. The chosen substance promotes a shift towards larger proportion of cells in synthesis and proliferation stages, and increases cell culture longevity. Further, we describe promising in vivo testing results of a selected food supplement. Based on the described concept of cell age profile and available test results, a strategy to search for natural compounds with regenerative, anti-aging and rejuvenation potential is suggested and proposed for wider and thorough testing. Proposed methodology of age assessment is rather generic and can be used for quantitative assessment of the anti-aging and rejuvenation potential of different interventions. Further research aimed at the tests of the suggested strategy using more substances and different interventions, and the thorough studies of molecular mechanisms related to the action of the substance used for testing the suggested search methodology, are needed. Full article
(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds)
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34 pages, 4681 KiB  
Article
Cheminformatics-Based Study Identifies Potential Ebola VP40 Inhibitors
by Emmanuel Broni, Carolyn Ashley, Joseph Adams, Hammond Manu, Ebenezer Aikins, Mary Okom, Whelton A. Miller III, Michael D. Wilson and Samuel K. Kwofie
Int. J. Mol. Sci. 2023, 24(7), 6298; https://doi.org/10.3390/ijms24076298 - 27 Mar 2023
Cited by 10 | Viewed by 2704
Abstract
The Ebola virus (EBOV) is still highly infectious and causes severe hemorrhagic fevers in primates. However, there are no regulatorily approved drugs against the Ebola virus disease (EVD). The highly virulent and lethal nature of EVD highlights the need to develop therapeutic agents. [...] Read more.
The Ebola virus (EBOV) is still highly infectious and causes severe hemorrhagic fevers in primates. However, there are no regulatorily approved drugs against the Ebola virus disease (EVD). The highly virulent and lethal nature of EVD highlights the need to develop therapeutic agents. Viral protein 40 kDa (VP40), the most abundantly expressed protein during infection, coordinates the assembly, budding, and release of viral particles into the host cell. It also regulates viral transcription and RNA replication. This study sought to identify small molecules that could potentially inhibit the VP40 protein by targeting the N-terminal domain using an in silico approach. The statistical quality of AutoDock Vina’s capacity to discriminate between inhibitors and decoys was determined, and an area under the curve of the receiver operating characteristic (AUC-ROC) curve of 0.791 was obtained. A total of 29,519 natural-product-derived compounds from Chinese and African sources as well as 2738 approved drugs were successfully screened against VP40. Using a threshold of −8 kcal/mol, a total of 7, 11, 163, and 30 compounds from the AfroDb, Northern African Natural Products Database (NANPDB), traditional Chinese medicine (TCM), and approved drugs libraries, respectively, were obtained after molecular docking. A biological activity prediction of the lead compounds suggested their potential antiviral properties. In addition, random-forest- and support-vector-machine-based algorithms predicted the compounds to be anti-Ebola with IC50 values in the micromolar range (less than 25 μM). A total of 42 natural-product-derived compounds were identified as potential EBOV inhibitors with desirable ADMET profiles, comprising 1, 2, and 39 compounds from NANPDB (2-hydroxyseneganolide), AfroDb (ZINC000034518176 and ZINC000095485942), and TCM, respectively. A total of 23 approved drugs, including doramectin, glecaprevir, velpatasvir, ledipasvir, avermectin B1, nafarelin acetate, danoprevir, eltrombopag, lanatoside C, and glycyrrhizin, among others, were also predicted to have potential anti-EBOV activity and can be further explored so that they may be repurposed for EVD treatment. Molecular dynamics simulations coupled with molecular mechanics Poisson–Boltzmann surface area calculations corroborated the stability and good binding affinities of the complexes (−46.97 to −118.9 kJ/mol). The potential lead compounds may have the potential to be developed as anti-EBOV drugs after experimental testing. Full article
(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds)
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17 pages, 14443 KiB  
Article
Ginger-Derived 3HDT Exerts Antiproliferative Effects on Breast Cancer Cells by Apoptosis and DNA Damage
by Chung-Yi Chen, Yan-Ning Chen, Jun-Ping Shiau, Jen-Yang Tang, Ming-Feng Hou and Hsueh-Wei Chang
Int. J. Mol. Sci. 2023, 24(6), 5741; https://doi.org/10.3390/ijms24065741 - 17 Mar 2023
Cited by 2 | Viewed by 1574
Abstract
Ginger-derived compounds are abundant sources of anticancer natural products. However, the anticancer effects of (E)-3-hydroxy-1-(4′-hydroxy-3′,5′-dimethoxyphenyl)-tetradecan-6-en-5-one (3HDT) have not been examined. This study aims to assess the antiproliferation ability of 3HDT on triple-negative breast cancer (TNBC) cells. 3HDT showed dose-responsive antiproliferation for [...] Read more.
Ginger-derived compounds are abundant sources of anticancer natural products. However, the anticancer effects of (E)-3-hydroxy-1-(4′-hydroxy-3′,5′-dimethoxyphenyl)-tetradecan-6-en-5-one (3HDT) have not been examined. This study aims to assess the antiproliferation ability of 3HDT on triple-negative breast cancer (TNBC) cells. 3HDT showed dose-responsive antiproliferation for TNBC cells (HCC1937 and Hs578T). Moreover, 3HDT exerted higher antiproliferation and apoptosis on TNBC cells than on normal cells (H184B5F5/M10). By examining reactive oxygen species, mitochondrial membrane potential, and glutathione, we found that 3HDT provided higher inductions for oxidative stress in TNBC cells compared with normal cells. Antiproliferation, oxidative stress, antioxidant signaling, and apoptosis were recovered by N-acetylcysteine, indicating that 3HDT preferentially induced oxidative-stress-mediated antiproliferation in TNBC cells but not in normal cells. Moreover, by examining γH2A histone family member X (γH2AX) and 8-hydroxy-2-deoxyguanosine, we found that 3HDT provided higher inductions for DNA damage, which was also reverted by N-acetylcysteine. In conclusion, 3HDT is an effective anticancer drug with preferential antiproliferation, oxidative stress, apoptosis, and DNA damage effects on TNBC cells. Full article
(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds)
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17 pages, 3023 KiB  
Article
Catechin versus MoS2 Nanoflakes Functionalized with Catechin: Improving the Sperm Fertilizing Ability—An In Vitro Study in a Swine Model
by Costanza Cimini, Marina Ramal-Sanchez, Angela Taraschi, Flavio Della Pelle, Annalisa Scroccarello, Ramses Belda-Perez, Luca Valbonetti, Paola Lanuti, Marco Marchisio, Mario D’Atri, Claudio Ortolani, Stefano Papa, Giulia Capacchietti, Nicola Bernabò, Dario Compagnone and Barbara Barboni
Int. J. Mol. Sci. 2023, 24(5), 4788; https://doi.org/10.3390/ijms24054788 - 01 Mar 2023
Cited by 1 | Viewed by 1219
Abstract
Nowadays, the adoption of In Vitro Fertilization (IVF) techniques is undergoing an impressive increase. In light of this, one of the most promising strategies is the novel use of non-physiological materials and naturally derived compounds for advanced sperm preparation methods. Here, sperm cells [...] Read more.
Nowadays, the adoption of In Vitro Fertilization (IVF) techniques is undergoing an impressive increase. In light of this, one of the most promising strategies is the novel use of non-physiological materials and naturally derived compounds for advanced sperm preparation methods. Here, sperm cells were exposed during capacitation to MoS2/Catechin nanoflakes and catechin (CT), a flavonoid with antioxidant properties, at concentrations of 10, 1, 0.1 ppm. The results showed no significant differences in terms of sperm membrane modifications or biochemical pathways among the groups, allowing the hypothesis that MoS2/CT nanoflakes do not induce any negative effect on the parameters evaluated related to sperm capacitation. Moreover, the addition of CT alone at a specific concentration (0.1 ppm) increased the spermatozoa fertilizing ability in an IVF assay by increasing the number of fertilized oocytes with respect to the control group. Our findings open interesting new perspectives regarding the use of catechins and new materials obtained using natural or bio compounds, which could be used to implement the current strategies for sperm capacitation. Full article
(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds)
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18 pages, 3246 KiB  
Article
Inhibition of Melanogenesis by Essential Oils from the Citrus Cultivars Peels
by Jiyoon Yang, Su-Yeon Lee, Soo-Kyeong Jang, Ki-Joong Kim and Mi-Jin Park
Int. J. Mol. Sci. 2023, 24(4), 4207; https://doi.org/10.3390/ijms24044207 - 20 Feb 2023
Cited by 4 | Viewed by 2253
Abstract
Citrus is one of the most popular and widely grown fruit crops in the world. However, the bioactivity of only certain species of citrus cultivars is studied. In this study, the effects of essential oils from 21 citrus cultivars on melanogenesis were investigated [...] Read more.
Citrus is one of the most popular and widely grown fruit crops in the world. However, the bioactivity of only certain species of citrus cultivars is studied. In this study, the effects of essential oils from 21 citrus cultivars on melanogenesis were investigated in an effort to identify active anti-melanogenesis constituents. The essential oils from the peels of 21 citrus cultivars obtained by hydro-distillation were analyzed using gas chromatography–mass spectrometry. Mouse melanoma B16BL6 cells were used in all assays conducted in this study. The tyrosinase activity and melanin content were determined using the lysate of α-Melanocyte-stimulated B16BL6 cells. In addition, the melanogenic gene expression was determined by quantitative reverse transcription-polymerase chain reaction. Overall, the essential oils of (Citrus unshiu X Citrus sinensis) X Citrus reticulata, Citrus reticulata, and ((Citrus unshiu X Citrus sinensis) X Citrus reticulata) X Citrus reticulata provided the best bioactivity and comprised five distinct constituents compared to other essential oils such as limonene, farnesene, β-elemene, terpinen-4-ol, and sabinene. The anti-melanogenesis activities of the five individual compounds were evaluated. Among the five essential oils, β-elemene, farnesene, and limonene showed dominating properties. The experimental results indicated that (Citrus unshiu X Citrus sinensis) X Citrus reticulata, Citrus reticulata, and ((Citrus unshiu X Citrus sinensis) X Citrus reticulata) X Citrus reticulara are potential candidates with anti-melanogenesis activity for use as cosmetics and pharmaceutical agents against skin hyperpigmentation. Full article
(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds)
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16 pages, 16758 KiB  
Article
Untargeted Metabolomics Based Prediction of Therapeutic Potential for Apigenin and Chrysin
by Cole Cochran, Katelyn Martin, Daniel Rafferty, Jennifer Choi, Angela Leontyev, Akanksh Shetty, Sonali Kurup and Prasanth Puthanveetil
Int. J. Mol. Sci. 2023, 24(4), 4066; https://doi.org/10.3390/ijms24044066 - 17 Feb 2023
Viewed by 1336
Abstract
The prominent flavonoids apigenin and chrysin have been demonstrated to have systemic benefits. Our previous work was first to establish the impact of apigenin and chrysin on cellular transcriptome. In the current study, we have revealed the ability of apigenin and chrysin to [...] Read more.
The prominent flavonoids apigenin and chrysin have been demonstrated to have systemic benefits. Our previous work was first to establish the impact of apigenin and chrysin on cellular transcriptome. In the current study, we have revealed the ability of apigenin and chrysin to alter the cellular metabolome based on our untargeted metabolomics. Based on our metabolomics data, both these structurally related flavonoids demonstrate diverging and converging properties. Apigenin demonstrated the potential to possess anti-inflammatory and vasorelaxant properties through the upregulation of intermediate metabolites of alpha-linolenic acid and linoleic acid pathways. Chrysin, on the other hand, exhibited abilities to inhibit protein and pyrimidine synthesis along with downregulation of gluconeogenesis pathways based on the altered metabolites detected. Chrysin-mediated metabolite changes are mostly due to its ability to modulate L-alanine metabolism and the urea cycle. On the other hand, both the flavonoids also demonstrated converging properties. Apigenin and chrysin were able to downregulate metabolites involved in cholesterol biosynthesis and uric acid synthesis, namely 7-dehydrocholesterol and xanthosine, respectively. This work will provide understanding regarding the diverse therapeutic potential of these naturally occurring flavonoids and help us in curbing an array of metabolic complications. Full article
(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds)
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15 pages, 4407 KiB  
Article
Structure-Function Studies of Sponge-Derived Compounds on the Cardiac CaV3.1 Channel
by Anne-Sophie Depuydt, Piyush A. Patel, Žan Toplak, Chinmaya Bhat, Manuela Voráčová, Irene Eteläinen, Fiammetta Vitulano, Tanja Bruun, Antti Lempinen, Nives Hribernik, Eero Mäki-Lohiluoma, Louise Hendrickx, Ernesto Lopes Pinheiro-Junior, Tihomir Tomašič, Lucija Peterlin Mašič, Jari Yli-Kauhaluoma, Paula Kiuru, Jan Tytgat and Steve Peigneur
Int. J. Mol. Sci. 2023, 24(4), 3429; https://doi.org/10.3390/ijms24043429 - 08 Feb 2023
Viewed by 1307
Abstract
T-type calcium (CaV3) channels are involved in cardiac automaticity, development, and excitation–contraction coupling in normal cardiac myocytes. Their functional role becomes more pronounced in the process of pathological cardiac hypertrophy and heart failure. Currently, no CaV3 channel inhibitors are [...] Read more.
T-type calcium (CaV3) channels are involved in cardiac automaticity, development, and excitation–contraction coupling in normal cardiac myocytes. Their functional role becomes more pronounced in the process of pathological cardiac hypertrophy and heart failure. Currently, no CaV3 channel inhibitors are used in clinical settings. To identify novel T-type calcium channel ligands, purpurealidin analogs were electrophysiologically investigated. These compounds are alkaloids produced as secondary metabolites by marine sponges, and they exhibit a broad range of biological activities. In this study, we identified the inhibitory effect of purpurealidin I (1) on the rat CaV3.1 channel and conducted structure–activity relationship studies by characterizing the interaction of 119 purpurealidin analogs. Next, the mechanism of action of the four most potent analogs was investigated. Analogs 74, 76, 79, and 99 showed a potent inhibition on the CaV3.1 channel with IC50’s at approximately 3 μM. No shift of the activation curve could be observed, suggesting that these compounds act like a pore blocker obstructing the ion flow by binding in the pore region of the CaV3.1 channel. A selectivity screening showed that these analogs are also active on hERG channels. Collectively, a new class of CaV3 channel inhibitors has been discovered and the structure–function studies provide new insights into the synthetic design of drugs and the mechanism of interaction with T-type CaV channels. Full article
(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds)
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17 pages, 5889 KiB  
Article
The SlDOG1 Affect Biosynthesis of Steroidal Glycoalkaloids by Regulating GAME Expression in Tomato
by Xuecheng Zhao, Yueran Zhang, Jun Lai, Yuan Deng, Yingchen Hao, Shouchuang Wang and Jun Yang
Int. J. Mol. Sci. 2023, 24(4), 3360; https://doi.org/10.3390/ijms24043360 - 08 Feb 2023
Cited by 5 | Viewed by 1672
Abstract
Steroidal alkaloids (SAs) and steroidal glycoalkaloids (SGAs) are common constituents of plant species belonging to the Solanaceae family. However, the molecular mechanism regulating the formation of SAs and SGAs remains unknown. Here, genome-wide association mapping was used to elucidate SA and SGA regulation [...] Read more.
Steroidal alkaloids (SAs) and steroidal glycoalkaloids (SGAs) are common constituents of plant species belonging to the Solanaceae family. However, the molecular mechanism regulating the formation of SAs and SGAs remains unknown. Here, genome-wide association mapping was used to elucidate SA and SGA regulation in tomatoes: a SlGAME5-like glycosyltransferase (Solyc10g085240) and the transcription factor SlDOG1 (Solyc10g085210) were significantly associated with steroidal alkaloid composition. In this study, it was found that rSlGAME5-like can catalyze a variety of substrates for glycosidation and can catalyze SA and flavonol pathways to form O-glucoside and O-galactoside in vitro. The overexpression of SlGAME5-like promoted α-tomatine, hydroxytomatine, and flavonol glycoside accumulation in tomatoes. Furthermore, assessments of natural variation combined with functional analyses identified SlDOG1 as a major determinant of tomato SGA content, which also promoted SA and SGA accumulation via the regulation of GAME gene expression. This study provides new insights into the regulatory mechanisms underlying SGA production in tomatoes. Full article
(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds)
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18 pages, 15593 KiB  
Article
Targeting Energy Protection as a Novel Strategy to Disclose Di’ao Xinxuekang against the Cardiotoxicity Caused by Doxorubicin
by Tao Wang, Chuqiao Yuan, Jia Liu, Liangyan Deng, Wei Li, Junling He, Honglin Liu, Liping Qu, Jianming Wu and Wenjun Zou
Int. J. Mol. Sci. 2023, 24(2), 897; https://doi.org/10.3390/ijms24020897 - 04 Jan 2023
Cited by 4 | Viewed by 2478
Abstract
Doxorubicin (DOX) can induce myocardial energy metabolism disorder and further worsen heart failure. “Energy protection” is proposed as a new cardiac protection strategy. Previous studies have found that Di’ao Xinxuekang (DXXK) can improve doxorubicin-induced cardiotoxicity in mice by inhibiting ferroptosis. However, there are [...] Read more.
Doxorubicin (DOX) can induce myocardial energy metabolism disorder and further worsen heart failure. “Energy protection” is proposed as a new cardiac protection strategy. Previous studies have found that Di’ao Xinxuekang (DXXK) can improve doxorubicin-induced cardiotoxicity in mice by inhibiting ferroptosis. However, there are very few studies associating DXXK and energy protection. This study aims to explore the “energy protection” effect of DXXK on cardiotoxicity induced by DOX. A DOX-induced cardiotoxicity model established in rats and H9c2 cells are used to analyze the therapeutic effects of DXXK on serum indexes, cardiac function indexes and cardiac histopathology. The metabonomic methods were used to explore the potential mechanism of DXXK in treating DOX-induced cardiotoxicity. In addition, we also observed the mitochondrial- and autophagy-related indicators of myocardial cells and the mRNA expression level of the core target regulating energy-metabolism-related pathways. Our results indicated that DXXK can improve cardiac function, reduce myocardial enzymes and alleviate the histological damage of heart tissue caused by DOX. In addition, DXXK can improve mitochondrial damage induced by DOX and inhibit excessive autophagy. Metabonomics analysis showed that DOX can significantly affects the pathways related to energy metabolism of myocardial cells, which are involved in the therapeutic mechanism of DXXK. In conclusion, DXXK can treat DOX-induced cardiotoxicity through the AMPK-mediated energy protection pathway. Full article
(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds)
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13 pages, 1985 KiB  
Article
The Ethanol Extract of Evodiae Fructus and Its Ingredient, Rutaecarpine, Inhibit Infection of SARS-CoV-2 and Inflammatory Responses
by Shengying Lin, Xiaoyang Wang, Hongsheng Guo, Niyu Dai, Roy Wai-Lun Tang, Hung Chun Lee, Ka Wing Leung, Tina Ting-Xia Dong, Sarah E. Webb, Andrew L. Miller and Karl Wah-Keung Tsim
Int. J. Mol. Sci. 2023, 24(1), 762; https://doi.org/10.3390/ijms24010762 - 01 Jan 2023
Cited by 1 | Viewed by 2170
Abstract
COVID-19, derived from SARS-CoV-2, has resulted in millions of deaths and caused unprecedented socioeconomic damage since its outbreak in 2019. Although the vaccines developed against SARS-CoV-2 provide some protection, they have unexpected side effects in some people. Furthermore, new viral mutations reduce the [...] Read more.
COVID-19, derived from SARS-CoV-2, has resulted in millions of deaths and caused unprecedented socioeconomic damage since its outbreak in 2019. Although the vaccines developed against SARS-CoV-2 provide some protection, they have unexpected side effects in some people. Furthermore, new viral mutations reduce the effectiveness of the current vaccines. Thus, there is still an urgent need to develop potent non-vaccine therapeutics against this infectious disease. We recently established a series of detecting platforms to screen a large library of Chinese medicinal herbs and phytochemicals. Here, we reveal that the ethanolic extract of Evodiae Fructus and one of its components, rutaecarpine, showed promising potency in inhibiting the activity of 3C-like (3CL) protease, blocking the entry of the pseudo-typed SARS-CoV-2 (including wild-type and omicron) into cultured cells. In addition, inflammatory responses induced by pseudo-typed SARS-CoV-2 were markedly reduced by Evodiae Fructus extract and rutaecarpine. Together our data indicate that the herbal extract of Evodiae Fructus and rutaecarpine are potent anti-SARS-CoV-2 agents, which might be considered as a treatment against COVID-19 in clinical applications. Full article
(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds)
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24 pages, 5841 KiB  
Article
Targeting TLR2/Rac1/cdc42/JNK Pathway to Reveal That Ruxolitinib Promotes Thrombocytopoiesis
by Shuo Yang, Xiaoqin Tang, Long Wang, Chengyang Ni, Yuesong Wu, Ling Zhou, Yueying Zeng, Chunling Zhao, Anguo Wu, Qiaozhi Wang, Xiyan Xu, Yiwei Wang, Rong Chen, Xiao Zhang, Lile Zou, Xinwu Huang and Jianming Wu
Int. J. Mol. Sci. 2022, 23(24), 16137; https://doi.org/10.3390/ijms232416137 - 17 Dec 2022
Cited by 1 | Viewed by 1976
Abstract
Background: Thrombocytopenia has long been considered an important complication of chemotherapy and radiotherapy, which severely limits the effectiveness of cancer treatment and the overall survival of patients. However, clinical treatment options are extremely limited so far. Ruxolitinib is a potential candidate. Methods: The [...] Read more.
Background: Thrombocytopenia has long been considered an important complication of chemotherapy and radiotherapy, which severely limits the effectiveness of cancer treatment and the overall survival of patients. However, clinical treatment options are extremely limited so far. Ruxolitinib is a potential candidate. Methods: The impact of ruxolitinib on the differentiation and maturation of K562 and Meg-01 cells megakaryocytes (MKs) was examined by flow cytometry, Giemsa and Phalloidin staining. A mouse model of radiation-injured thrombocytopenia (RIT) was employed to evaluate the action of ruxolitinib on thrombocytopoiesis. Network pharmacology, molecular docking, drug affinity responsive target stability assay (DARTS), RNA sequencing, protein blotting and immunofluorescence analysis were applied to explore the targets and mechanisms of action of ruxolitinib. Results: Ruxolitinib can stimulate MK differentiation and maturation in a dose-dependent manner and accelerates recovery of MKs and thrombocytopoiesis in RIT mice. Biological targeting analysis showed that ruxolitinib binds directly to Toll Like Receptor 2 (TLR2) to activate Rac1/cdc42/JNK, and this action was shown to be blocked by C29, a specific inhibitor of TLR2. Conclusions: Ruxolitinib was first identified to facilitate MK differentiation and thrombocytopoiesis, which may alleviate RIT. The potential mechanism of ruxolitinib was to promote MK differentiation via activating the Rac1/cdc42/JNK pathway through binding to TLR2. Full article
(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds)
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16 pages, 2989 KiB  
Article
Dual Inhibition of BRAF-MAPK and STAT3 Signaling Pathways in Resveratrol-Suppressed Anaplastic Thyroid Cancer Cells with BRAF Mutations
by Meng-Di Lu, Hong Li, Jun-Hua Nie, Sheng Li, Hai-Shan Ye, Ting-Ting Li, Mo-Li Wu and Jia Liu
Int. J. Mol. Sci. 2022, 23(22), 14385; https://doi.org/10.3390/ijms232214385 - 19 Nov 2022
Cited by 8 | Viewed by 1877
Abstract
Anaplastic thyroid cancer is an extremely lethal malignancy without reliable treatment. BRAFV600E point mutation is common in ATCs, which leads to MAPK signaling activation and is regarded as a therapeutic target. Resveratrol inhibits ATC cell growth, while its impact on BRAF-MAPK signaling remains [...] Read more.
Anaplastic thyroid cancer is an extremely lethal malignancy without reliable treatment. BRAFV600E point mutation is common in ATCs, which leads to MAPK signaling activation and is regarded as a therapeutic target. Resveratrol inhibits ATC cell growth, while its impact on BRAF-MAPK signaling remains unknown. This study aims to address this issue by elucidating the statuses of BRAF-MAPK and STAT3 signaling activities in resveratrol-treated THJ-11T, THJ-16T, and THJ-21T ATC cells and Nthyori 3-1 thyroid epithelial cells. RT-PCR and Sanger sequencing revealed MKRN1-BRAF fusion mutation in THJ-16T, BRAF V600E point mutation in THJ-21T, and wild-type BRAF genes in THJ-11T and Nthyori 3-1 cells. Western blotting and immunocytochemical staining showed elevated pBRAF, pMEK, and pERK levels in THJ-16T and THJ-21T, but not in THJ-11T or Nthyori 3-1 cells. Calcein/PI, EdU, and TUNEL assays showed that compared with docetaxel and doxorubicin and MAPK-targeting dabrafenib and trametinib, resveratrol exerted more powerful inhibitory effects on mutant BRAF-harboring THJ-16T and THJ-21T cells, accompanied by reduced levels of MAPK pathway-associated proteins and pSTAT3. Trametinib- and dabrafenib-enhanced STAT3 activation was efficiently suppressed by resveratrol. In conclusion, resveratrol acts as dual BRAF-MAPK and STAT3 signaling inhibitor and a promising agent against ATCs with BRAF mutation. Full article
(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds)
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19 pages, 22674 KiB  
Article
Methyl Gallate Alleviates Acute Ulcerative Colitis by Modulating Gut Microbiota and Inhibiting TLR4/NF-κB Pathway
by Ping Zhou, Jia Lai, Yueyue Li, Junzhu Deng, Chunling Zhao, Qianqian Huang, Fei Yang, Shuo Yang, Yuesong Wu, Xiaoqin Tang, Feihong Huang, Long Wang, Xinwu Huang, Wenjun Zou and Jianming Wu
Int. J. Mol. Sci. 2022, 23(22), 14024; https://doi.org/10.3390/ijms232214024 - 14 Nov 2022
Cited by 8 | Viewed by 1667
Abstract
Ulcerative colitis (UC) is a complex immune-mediated inflammatory disease. In recent years, the incidence of UC has increased rapidly, however, its exact etiology and mechanism are still unclear. Based on the definite anti-inflammatory and antibacterial activities of Sanguisorba officinalis L., we studied its [...] Read more.
Ulcerative colitis (UC) is a complex immune-mediated inflammatory disease. In recent years, the incidence of UC has increased rapidly, however, its exact etiology and mechanism are still unclear. Based on the definite anti-inflammatory and antibacterial activities of Sanguisorba officinalis L., we studied its monomer, methyl gallate (MG). In this study, we employed flow cytometry and detected nitric oxide production, finding MG regulated macrophage polarization and inhibited the expression of proinflammatory cytokines in vitro. MG also exhibited anti-inflammatory activity accompanying with ameliorating body weight loss, improving colon length and histological damage in dextran sulfate sodium-induced UC mice. Meanwhile, transcription sequencing and 16S rRNA sequencing analyzed the key signaling pathways and changes in the gut microbiota of MG for UC treatment, proving that MG could alleviate inflammation by regulating the TLR4/NF-κB pathway in vivo and in vitro. Additionally, MG altered the diversity and composition of the gut microbiota and changed the abundance of metabolic products. In conclusion, our results are the first to demonstrate that MG has obvious therapeutic effects against acute UC, which is related to macrophage polarization, improved intestinal flora dysbiosis and inhibition of TLR4/NF-κB signaling pathway, and MG may be a promising therapeutic agent for UC treatment. Full article
(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds)
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16 pages, 8223 KiB  
Article
Polyphyllin II Induces Protective Autophagy and Apoptosis via Inhibiting PI3K/AKT/mTOR and STAT3 Signaling in Colorectal Cancer Cells
by Jun-Kui Li, Hai-Tao Sun, Xiao-Li Jiang, Yi-Fei Chen, Zhu Zhang, Ying Wang, Wen-Qing Chen, Zhang Zhang, Stephen Cho Wing Sze, Pei-Li Zhu and Ken Kin Lam Yung
Int. J. Mol. Sci. 2022, 23(19), 11890; https://doi.org/10.3390/ijms231911890 - 06 Oct 2022
Cited by 12 | Viewed by 1983
Abstract
Polyphyllin II (PPII) is a natural steroidal saponin occurring in Rhizoma Paridis. It has been demonstrated to exhibit anti-cancer activity against a variety of cancer cells. However, the anti-colorectal cancer (CRC) effects and mechanism of action of PPII are rarely reported. In [...] Read more.
Polyphyllin II (PPII) is a natural steroidal saponin occurring in Rhizoma Paridis. It has been demonstrated to exhibit anti-cancer activity against a variety of cancer cells. However, the anti-colorectal cancer (CRC) effects and mechanism of action of PPII are rarely reported. In the present study, we showed that PPII inhibited the proliferation of HCT116 and SW620 cells. Moreover, PPII induced G2/M-phase cell cycle arrest and apoptosis, as well as protective autophagy, in CRC cells. We found that PPII-induced autophagy was associated with the inhibition of PI3K/AKT/mTOR signaling. Western blotting results further revealed that PPII lowered the protein levels of phospho-Src (Tyr416), phospho-JAK2 (Tyr1007/1008), phospho-STAT3 (Tyr705), and STAT3-targeted molecules in CRC cells. The overactivation of STAT3 attenuated the cytotoxicity of PPII against HCT116 cells, indicating the involvement of STAT3 inhibition in the anti-CRC effects of PPII. PPII (0.5 mg/kg or 1 mg/kg, i.p. once every 3 days) suppressed HCT116 tumor growth in nude mice. In alignment with the in vitro results, PPII inhibited proliferation, induced apoptosis, and lowered the protein levels of phospho-STAT3, phospho-AKT, and phospho-mTOR in xenografts. These data suggest that PPII could be a potent therapeutic agent for the treatment of CRC. Full article
(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds)
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Review

Jump to: Research

14 pages, 1097 KiB  
Review
Attention Deficit Hyperactivity Disorder (ADHD) and Polyphenols: A Systematic Review
by Fabrizio Turiaco, Chiara Cullotta, Federica Mannino, Antonio Bruno, Francesco Squadrito, Giovanni Pallio and Natasha Irrera
Int. J. Mol. Sci. 2024, 25(3), 1536; https://doi.org/10.3390/ijms25031536 - 26 Jan 2024
Viewed by 1183
Abstract
Polyphenols are natural compounds also contained in daily consumed foods that show their efficacy in different clinical fields. Both pre-clinical and clinical studies demonstrated that polyphenols may manage neuroinflammation and oxidative stress processes tightly connected to neurodegenerative diseases and mental disorders. Thus, a [...] Read more.
Polyphenols are natural compounds also contained in daily consumed foods that show their efficacy in different clinical fields. Both pre-clinical and clinical studies demonstrated that polyphenols may manage neuroinflammation and oxidative stress processes tightly connected to neurodegenerative diseases and mental disorders. Thus, a neuroinflammatory state may influence the neurotransmitters pathways, such as the noradrenergic, glutamatergic, serotoninergic, and, in particular, dopaminergic ones, whose impairment is strongly associated with attention deficit hyperactivity disorder (ADHD). Therefore, the aim of the present systematic review is to provide an overview of the clinical outcomes’ changes following ADHD treatment with polyphenols alone and in combination with the traditional drugs. This review was conducted according to PRISMA guidelines and recorded on PROSPERO with the number CRD42023438491; PubMed, Scopus, and Web of Science were used as search-engines to lead our research until June 2023. The inclusion criteria were articles written in English, including clinical, placebo-controlled, and case-control trials. We excluded reviews, metanalyses, background articles, and papers published in other languages. To avoid any bias, Rayyan software (COPYRIGHT © 2022 RAYYAN) was used to organize the work and manage the literature review. After screening, 10 studies were included, with a total of 556 patients that met the established inclusion criteria. The data obtained from these studies showed that polyphenols rebalanced oxidative stress pathways through different mechanisms, are effective for the treatment of ADHD both alone and in combination with traditional drugs, and are able to reduce symptoms as well as the side effects related to the use of conventional therapies. Finally, a positive effect of using polyphenols for ADHD prevention could be hypothesized. Full article
(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds)
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23 pages, 2338 KiB  
Review
The Application of Ethnomedicine in Modulating Megakaryocyte Differentiation and Platelet Counts
by Fei Yang, Jia Lai, Junzhu Deng, Jun Du, Xi Du, Xiaoqin Zhang, Yiwei Wang, Qianqian Huang, Qian Xu, Gang Yang, Yanjun Zhang, Xilan Zhou, Xiao Zhang, Yuan Yuan, Chunxiang Zhang and Jianming Wu
Int. J. Mol. Sci. 2023, 24(4), 3168; https://doi.org/10.3390/ijms24043168 - 05 Feb 2023
Cited by 1 | Viewed by 2157
Abstract
Megakaryocytes (MKs), a kind of functional hematopoietic stem cell, form platelets to maintain platelet balance through cell differentiation and maturation. In recent years, the incidence of blood diseases such as thrombocytopenia has increased, but these diseases cannot be fundamentally solved. The platelets produced [...] Read more.
Megakaryocytes (MKs), a kind of functional hematopoietic stem cell, form platelets to maintain platelet balance through cell differentiation and maturation. In recent years, the incidence of blood diseases such as thrombocytopenia has increased, but these diseases cannot be fundamentally solved. The platelets produced by MKs can treat thrombocytopenia-associated diseases in the body, and myeloid differentiation induced by MKs has the potential to improve myelosuppression and erythroleukemia. Currently, ethnomedicine is extensively used in the clinical treatment of blood diseases, and the recent literature has reported that many phytomedicines can improve the disease status through MK differentiation. This paper reviewed the effects of botanical drugs on megakaryocytic differentiation covering the period 1994–2022, and information was obtained from PubMed, Web of Science and Google Scholar. In conclusions, we summarized the role and molecular mechanism of many typical botanical drugs in promoting megakaryocyte differentiation in vivo, providing evidence as much as possible for botanical drugs treating thrombocytopenia and other related diseases in the future. Full article
(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds)
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26 pages, 3461 KiB  
Review
Toll-like Receptors and Thrombopoiesis
by Xiaoqin Tang, Qian Xu, Shuo Yang, Xinwu Huang, Long Wang, Feihong Huang, Jiesi Luo, Xiaogang Zhou, Anguo Wu, Qibing Mei, Chunling Zhao and Jianming Wu
Int. J. Mol. Sci. 2023, 24(2), 1010; https://doi.org/10.3390/ijms24021010 - 05 Jan 2023
Cited by 5 | Viewed by 2607
Abstract
Platelets are the second most abundant blood component after red blood cells and can participate in a variety of physiological and pathological functions. Beyond its traditional role in hemostasis and thrombosis, it also plays an indispensable role in inflammatory diseases. However, thrombocytopenia is [...] Read more.
Platelets are the second most abundant blood component after red blood cells and can participate in a variety of physiological and pathological functions. Beyond its traditional role in hemostasis and thrombosis, it also plays an indispensable role in inflammatory diseases. However, thrombocytopenia is a common hematologic problem in the clinic, and it presents a proportional relationship with the fatality of many diseases. Therefore, the prevention and treatment of thrombocytopenia is of great importance. The expression of Toll-like receptors (TLRs) is one of the most relevant characteristics of thrombopoiesis and the platelet inflammatory function. We know that the TLR family is found on the surface or inside almost all cells, where they perform many immune functions. Of those, TLR2 and TLR4 are the main stress-inducing members and play an integral role in inflammatory diseases and platelet production and function. Therefore, the aim of this review is to present and discuss the relationship between platelets, inflammation and the TLR family and extend recent research on the influence of the TLR2 and TLR4 pathways and the regulation of platelet production and function. Reviewing the interaction between TLRs and platelets in inflammation may be a research direction or program for the treatment of thrombocytopenia-related and inflammatory-related diseases. Full article
(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds)
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34 pages, 1261 KiB  
Review
Phytochemical Constituents and Derivatives of Cannabis sativa; Bridging the Gap in Melanoma Treatment
by Ellen Schanknecht, Ava Bachari, Nazim Nassar, Terrence Piva and Nitin Mantri
Int. J. Mol. Sci. 2023, 24(1), 859; https://doi.org/10.3390/ijms24010859 - 03 Jan 2023
Cited by 9 | Viewed by 3366
Abstract
Melanoma is deadly, physically impairing, and has ongoing treatment deficiencies. Current treatment regimens include surgery, targeted kinase inhibitors, immunotherapy, and combined approaches. Each of these treatments face pitfalls, with diminutive five-year survival in patients with advanced metastatic invasion of lymph and secondary organ [...] Read more.
Melanoma is deadly, physically impairing, and has ongoing treatment deficiencies. Current treatment regimens include surgery, targeted kinase inhibitors, immunotherapy, and combined approaches. Each of these treatments face pitfalls, with diminutive five-year survival in patients with advanced metastatic invasion of lymph and secondary organ tissues. Polyphenolic compounds, including cannabinoids, terpenoids, and flavonoids; both natural and synthetic, have emerging evidence of nutraceutical, cosmetic and pharmacological potential, including specific anti-cancer, anti-inflammatory, and palliative utility. Cannabis sativa is a wellspring of medicinal compounds whose direct and adjunctive application may offer considerable relief for melanoma suffers worldwide. This review aims to address the diverse applications of C. sativa’s biocompounds in the scope of melanoma and suggest it as a strong candidate for ongoing pharmacological evaluation. Full article
(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds)
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