International Journal of Molecular Sciences

2024

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10 pages, 2504 KiB

Open AccessArticle

Improved Kaempferol Solubility via Heptakis-O-(2-hydroxypropyl)-β-cyclodextrin Complexation: A Combined Spectroscopic and Theoretical Study

by Dongxu Han, Zhongbao Han, Liyan Liu, Shigang Xin and Zhan Yu

Int. J. Mol. Sci. 2024, 25(23), 12492; https://doi.org/10.3390/ijms252312492 - 21 Nov 2024

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Abstract

Four cyclodextrins (CDs) including heptakis-O-(2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), heptakis-O-(2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD), β-cyclodextrin (β-CD), and γ-cyclodextrin (γ-CD) were evaluated for their ability to enhance the aqueous solubility of kaempferol (Kae). Phase solubility studies indicated that these four CDs can form 1:1 type complexes with Kae and that [...] Read more.

Four cyclodextrins (CDs) including heptakis-O-(2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), heptakis-O-(2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD), β-cyclodextrin (β-CD), and γ-cyclodextrin (γ-CD) were evaluated for their ability to enhance the aqueous solubility of kaempferol (Kae). Phase solubility studies indicated that these four CDs can form 1:1 type complexes with Kae and that HP-β-CD demonstrated the most significant solubilizing effect on Kae. Among the CDs tested, HP-β-CD demonstrated the most significant solubilizing effect on Kae. With an HP-β-CD concentration of 5.00 × 10⁻³ mol·L⁻¹, the concentration of Kae reached 4.56 × 10⁻⁵ mol·L⁻¹, which is 12.7 times greater than its solubility in water. Characterization of the HP-β-CD/Kae complex was performed using empirical methods. Molecular docking indicated that the A and C rings of Kae fit into the hydrophobic cavity of HP-β-CD, while the B ring remained at the rim. Six hydrogen bonds were found between HP-β-CD and the -OH groups of Kae. The negative complexation energy (ΔE) suggests the complex formation was exergonic. A 30-ns molecular dynamics simulation revealed no significant structural changes, with average root-mean-square deviation RMSD values of 2.230 Å for HP-β-CD and 0.786 Å for Kae, indicating high stability of the complex. Full article

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20 pages, 3229 KiB

Open AccessArticle

Pterostilbene, a Dimethyl Derivative of Resveratrol, Exerts Cytotoxic Effects on Melanin-Producing Cells through Metabolic Activation by Tyrosinase

by Hitomi Tanaka, Tomoko Nishimaki-Mogami, Norimasa Tamehiro, Norihito Shibata, Hiroki Mandai, Shosuke Ito and Kazumasa Wakamatsu

Int. J. Mol. Sci. 2024, 25(18), 9990; https://doi.org/10.3390/ijms25189990 - 17 Sep 2024

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Abstract

Pterostilbene (PTS), which is abundant in blueberries, is a dimethyl derivative of the natural polyphenol resveratrol (RES). Several plant species, including peanuts and grapes, also produce PTS. Although RES has a wide range of health benefits, including anti-cancer properties, PTS has a robust [...] Read more.

Pterostilbene (PTS), which is abundant in blueberries, is a dimethyl derivative of the natural polyphenol resveratrol (RES). Several plant species, including peanuts and grapes, also produce PTS. Although RES has a wide range of health benefits, including anti-cancer properties, PTS has a robust pharmacological profile that includes a better intestinal absorption and an increased hepatic stability compared to RES. Indeed, PTS has a higher bioavailability and a lower toxicity compared to other stilbenes, making it an attractive drug candidate for the treatment of various diseases, including diabetes, cancer, cardiovascular disease, neurodegenerative disorders, and aging. We previously reported that RES serves as a substrate for tyrosinase, producing an o-quinone metabolite that is highly cytotoxic to melanocytes. The present study investigated whether PTS may also be metabolized by tyrosinase, similarly to RES. PTS was oxidized as a substrate by tyrosinase to form an o-quinone, which reacted with thiols, such as N-acetyl-L-cysteine, to form di- and tri-adducts. We also confirmed that PTS was taken up and metabolized by human tyrosinase-expressing 293T cells in amounts several times greater than RES. In addition, PTS showed a tyrosinase-dependent cytotoxicity against B16BL6 melanoma cells that was stronger than RES and also inhibited the formation of melanin in B16BL6 melanoma cells and in the culture medium. These results suggest that the two methyl groups of PTS, which are lipophilic, increase its membrane permeability, making it easier to bind to intracellular proteins, and may therefore be more cytotoxic to melanin-producing cells. Full article

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16 pages, 1920 KiB

Open AccessArticle

Nutraceutical Supplementation as a Potential Non-Drug Treatment for Fibromyalgia: Effects on Lipid Profile, Oxidative Status, and Quality of Life

by Salvador de la Cruz Cazorla, Santos Blanco, Alma Rus, Francisco Javier Molina-Ortega, Esther Ocaña, Raquel Hernández, Francesco Visioli and María Luisa del Moral

Int. J. Mol. Sci. 2024, 25(18), 9935; https://doi.org/10.3390/ijms25189935 - 14 Sep 2024

Viewed by 1038

Abstract

Fibromyalgia (FM) is a chronic syndrome of unknown etiology, although many studies point to inflammation, oxidative stress, and altered mitochondrial metabolism as some of the cornerstones of this disease. Despite its socioeconomic importance and due to the difficulties in diagnosis, there are no [...] Read more.

Fibromyalgia (FM) is a chronic syndrome of unknown etiology, although many studies point to inflammation, oxidative stress, and altered mitochondrial metabolism as some of the cornerstones of this disease. Despite its socioeconomic importance and due to the difficulties in diagnosis, there are no effective treatments. However, the use of non-drug treatments is increasingly becoming a recommended strategy. In this context, the effects of supplementation of FM patients with an olive (poly)phenol, vitamin C, and vitamin B preparation were investigated in this work, analyzing complete blood count, biochemical, lipid, and coagulation profiles, and inflammation and oxidation status in blood samples. To gain a better understanding of the molecular mechanisms and pathways involved in the etiology of FM, a proteomic study was also performed to investigate the mechanisms of action of the supplement. Our results show that the nutraceutical lowers the lipid profile, namely cholesterol, and improves the oxidative status of patients as well as their quality of life, suggesting that this product could be beneficial in the co-treatment of FM. ClinicalTrials.gov (ID: NCT06348537). Full article

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21 pages, 862 KiB

Open AccessReview

Wine, Polyphenols, and the Matrix Effect: Is Alcohol Always the Same?

by Elisabetta Miraldi, Giulia Baini, Marco Biagi, Giorgio Cappellucci, Alessandro Giordano, Federica Vaccaro and Alberto A. E. Bertelli

Int. J. Mol. Sci. 2024, 25(18), 9796; https://doi.org/10.3390/ijms25189796 - 10 Sep 2024

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Abstract

While the number of publications on wine and health is steadily increasing, ranging from a molecular level to epidemiological studies, often with contradictory results, little attention has been given to a holistic approach to research, starting from the molecular level to arrive at [...] Read more.

While the number of publications on wine and health is steadily increasing, ranging from a molecular level to epidemiological studies, often with contradictory results, little attention has been given to a holistic approach to research, starting from the molecular level to arrive at pharmacological and medical conclusions. In this review, some unusual concepts are considered, such as the phytocomplex, the vehicle, and the Matrix effect. The concept of the phytocomplex is discussed, specifically the biological activities of Tyrosol, Hydroxytyrosol, and Resveratrol; indeed, the interactions among different molecules in herbal matrices provide a specific response. This is often markedly different from the response evoked by single constituents in the modulation of microbial populations in the gut, in intestinal stability and bioaccessibility, and, obviously, in inducing biological responses. Among the many alcoholic beverages which contain these molecules, wine has the most peculiar Matrix effect, which can heavily influence the bioavailability of the phytocomplex obtained by the fermentation processes that produce this beverage. Wine’s Matrix effect plays an instrumental role in improving the beneficial compounds’ bioavailability and/or in inhibiting alcohol metabolites’ carcinogenicity. Underestimation of the wine Matrix effect could lead to deceiving results, as in the case of dealcoholized wine or wine-compound-based nutritional supplements; alternatively, this can occur in the emphasis of a single component’s toxic activity, in this case, alcohol, ignoring the specific molecular-level protective action of other compounds (polyphenols) that are present in the same matrix. The dark side of the Matrix effect is also discussed. This review confirms the research recommendations made by the WHO Scientific Group, which suggests it is important “to investigate the possible protective effects of ingredients other than alcohol in alcoholic beverages”, considering that most recent studies seem not only relevant but also capable of directing future research towards innovative points of view that have so far been too neglected. Full article

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20 pages, 2316 KiB

Open AccessArticle

Evaluation of Chemical Profile and Biological Properties of Extracts of Different Origanum vulgare Cultivars Growing in Poland

by Izabela Betlej, Natalia Żurek, Tomasz Cebulak, Ireneusz Kapusta, Maciej Balawejder, Anna Kiełtyka-Dadasiewicz, Sławomir Jaworski, Agata Lange, Marta Kutwin, Barbara Krochmal-Marczak, Teresa Kłosińska, Barbara Nasiłowska, Zygmunt Mierczyk and Piotr Borysiuk

Int. J. Mol. Sci. 2024, 25(17), 9417; https://doi.org/10.3390/ijms25179417 - 30 Aug 2024

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Abstract

This research studied the phenolic content compared with the antioxidant properties of various O. vulgare (Lamiaceae) cultivars grown in Poland. The research results in this paper indicate that the dominant ingredient in all oregano cultivars was rosmarinic acid, known for its strong antioxidant [...] Read more.

This research studied the phenolic content compared with the antioxidant properties of various O. vulgare (Lamiaceae) cultivars grown in Poland. The research results in this paper indicate that the dominant ingredient in all oregano cultivars was rosmarinic acid, known for its strong antioxidant properties. The highest amounts of rosmarinic acid (87.16 ± 4.03 mg/g dm) were identified in the O. vulgare spp. hirtum (Link) Ietsw. Other metabolites identified in the studied extracts include luteolin O-di-glucuronide-O-di-pentoside (30.79 ± 0.38 mg/g dm in the ‘Aureum’ cultivar), 4′-O-glucopyranosyl-3′, 4′-dihydroxy benzyl-protocatechuate (19.84 ± 0.60 mg/g dm in the ‘Margerita’ cultivar), and p-coumaroyl-triacetyl-hexoside (25.44 ± 0.18 mg/g dm in the ‘Margerita’ cultivar). ‘Hot & spicy’ and ‘Margerita’ cultivars were characterized by the highest activity in eliminating OH^• and O₂^•− radicals. Extracts from Greek oregano had the highest ability to scavenge DPPH radicals and chelate iron ions. This research has also provided new evidence that oregano has anti-migratory, cytotoxic properties and influences the viability of gastric cancer cells (the highest cytotoxicity was attributed to the ‘Hot & spicy’ cultivar, which performed the worst in antioxidant properties tests). Extracts from the tested cultivars at a concentration of 0.625% effectively inhibited the growth of S. aureus and P. aeruginosa bacteria. It seems that the oregano grown in Poland is of good quality and can be successfully grown on a large scale if the appropriate use is found. Full article

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17 pages, 1722 KiB

Open AccessArticle

Impact of Alcalase Hydrolysis and Simulated Gastrointestinal Digestion on the Release of Bioactive Peptides from Erythrina edulis (Chachafruto) Proteins

by Jessica L. Correa, José Edgar Zapata and Blanca Hernández-Ledesma

Int. J. Mol. Sci. 2024, 25(17), 9290; https://doi.org/10.3390/ijms25179290 - 27 Aug 2024

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Abstract

Amidst increasing awareness of diet-health relationships, plant-derived bioactive peptides are recognized for their dual nutritional and health benefits. This study investigates bioactive peptides released after Alcalase hydrolysis of protein from chachafruto (Erythrina edulis), a nutrient-rich South American leguminous plant, focusing on [...] Read more.

Amidst increasing awareness of diet-health relationships, plant-derived bioactive peptides are recognized for their dual nutritional and health benefits. This study investigates bioactive peptides released after Alcalase hydrolysis of protein from chachafruto (Erythrina edulis), a nutrient-rich South American leguminous plant, focusing on their behavior during simulated gastrointestinal digestion. Evaluating their ability to scavenge radicals, mitigate oxidative stress, and influence immune response biomarkers, this study underscores the importance of understanding peptide interactions in digestion. The greatest contribution to the antioxidant activity was exerted by the low molecular weight peptides with ORAC values for the <3 kDa fraction of HES, GD-HES, and GID-HES of 0.74 ± 0.03, 0.72 ± 0.004, and 0.56 ± 0.01 (μmol TE/mg protein, respectively). GD-HES and GID-HES exhibited immunomodulatory effects, promoting the release of NO up to 18.52 and 8.58 µM, respectively. The findings of this study highlighted the potential of chachafruto bioactive peptides in functional foods and nutraceuticals, supporting human health through dietary interventions. Full article

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10 pages, 1042 KiB

Open AccessArticle

Synthesis and Antioxidant Activity of N-Benzyl-2-[4-(aryl)-1H-1,2,3-triazol-1-yl]ethan-1-imine Oxides

by Dimitra Hadjipavlou-Litina, Iwona E. Głowacka, José Marco-Contelles and Dorota G. Piotrowska

Int. J. Mol. Sci. 2024, 25(11), 5908; https://doi.org/10.3390/ijms25115908 - 29 May 2024

Cited by 1 | Viewed by 854

Abstract

The synthesis, antioxidant capacity, and anti-inflammatory activity of four novel N-benzyl-2-[4-(aryl)-1H-1,2,3-triazol-1-yl]ethan-1-imine oxides 10a–d are reported herein. The nitrones 10a–d were tested for their antioxidant properties and their ability to inhibit soybean lipoxygenase (LOX). Four diverse antioxidant [...] Read more.

The synthesis, antioxidant capacity, and anti-inflammatory activity of four novel N-benzyl-2-[4-(aryl)-1H-1,2,3-triazol-1-yl]ethan-1-imine oxides 10a–d are reported herein. The nitrones 10a–d were tested for their antioxidant properties and their ability to inhibit soybean lipoxygenase (LOX). Four diverse antioxidant tests were used for in vitro antioxidant assays, namely, interaction with the stable free radical DPPH (1,1-diphenyl-2-picrylhydrazyl radical) as well as with the water-soluble azo compound AAPH (2,2′-azobis(2-amidinopropane) dihydrochloride), competition with DMSO for hydroxyl radicals, and the scavenging of cationic radical ABTS^•+ (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) radical cation). Nitrones 10b, 10c, and 10d, having the 4-fluorophenyl, 2,4-difluorophenyl, and 4-fluoro-3-methylphenyl motif, respectively, exhibited high interaction with DPPH (64.5–81% after 20 min; 79–96% after 60 min), whereas nitrone 10a with unfunctionalized phenyl group showed the lowest inhibitory potency (57% after 20 min, 78% after 60 min). Nitrones 10a and 10d, decorated with phenyl and 4-fluoro-3-methylphenyl motif, respectively, appeared the most potent inhibitors of lipid peroxidation. The results obtained from radical cation ABTS^•+ were not significant, since all tested compounds 10a–d showed negligible activity (8–46%), much lower than Trolox (91%). Nitrone 10c, bearing the 2,4-difluorophenyl motif, was found to be the most potent LOX inhibitor (IC₅₀ = 10 μM). Full article

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29 pages, 1238 KiB

Open AccessArticle

A View on the Chemical and Biological Attributes of Five Edible Fruits after Finishing Their Shelf Life: Studies on Caco-2 Cells

by Lucia Camelia Pirvu, Nicoleta Rusu, Cristina Bazdoaca, Elena Androne, Georgeta Neagu and Adrian Albulescu

Int. J. Mol. Sci. 2024, 25(9), 4848; https://doi.org/10.3390/ijms25094848 - 29 Apr 2024

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Abstract

We studied five common perishable fruits in terms of their polyphenols dynamic, minerals distribution, scavenger activity and the effects of 50% ethanolic extracts on the viability of Caco-2 cells in vitro, over a period of time between T = 0 and T = [...] Read more.

We studied five common perishable fruits in terms of their polyphenols dynamic, minerals distribution, scavenger activity and the effects of 50% ethanolic extracts on the viability of Caco-2 cells in vitro, over a period of time between T = 0 and T = 5/7 days, typically the end of their shelf life. Altogether, there were few changes found, consisting of either an increase or a decrease in their chemical and biological attributes. A slow decrease was found in the antioxidant activity in apricot (−11%), plum (−6%) and strawberry (−4%) extracts, while cherry and green seedless table grape extracts gained 7% and 2% antioxidant potency, respectively; IC₅₀ values ranged from 1.67 to 5.93 μg GAE/μL test extract. The cytotoxicity MTS assay at 24 h revealed the ability of all 50% ethanol fruit extracts to inhibit the Caco-2 cell viability; the inhibitory effects ranged from 49% to 83% and were measured at 28 µg GAE for strawberry extracts/EES, from 22 µg to 45 µg GAE for cherry extracts/EEC, from 7.58 to 15.16 µg GAE for apricot extracts/EEA, from 12.50 to 25.70 µg GAE for plum extracts/EEP and from 21.51 to 28.68 µg GAE for green table grape extracts/EEG. The MTS anti-proliferative assay (72 h) also revealed a stimulatory potency upon the Caco-2 viability, from 34% (EEA, EEG) and 48% (EEC) to 350% (EES) and 690% (EEP); therefore fruit juices can influence intestinal tumorigenesis in humans. Full article

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20 pages, 2395 KiB

Open AccessArticle

Design of Mixed Medicinal Plants, Rich in Polyphenols, Vitamins B, and Palmitoylethanolamide-Based Supplement to Help Reduce Nerve Pain: A Preclinical Study

by Simone Mulè, Giorgia Rosso, Mattia Botta, Arianna Brovero, Sara Ferrari, Rebecca Galla, Claudio Molinari and Francesca Uberti

Int. J. Mol. Sci. 2024, 25(9), 4790; https://doi.org/10.3390/ijms25094790 - 27 Apr 2024

Cited by 1 | Viewed by 1815

Abstract

Neuropathy affects 7–10% of the general population and is caused by a lesion or disease of the somatosensory system. The limitations of current therapies highlight the necessity of a new innovative approach to treating neuropathic pain (NP) based on the close correlation between [...] Read more.

Neuropathy affects 7–10% of the general population and is caused by a lesion or disease of the somatosensory system. The limitations of current therapies highlight the necessity of a new innovative approach to treating neuropathic pain (NP) based on the close correlation between oxidative stress, inflammatory process, and antioxidant action. The advantageous outcomes of a novel combination composed of Hop extract, Propolis, Ginkgo Biloba, Vitamin B, and palmitoylethanolamide (PEA) used as a treatment was evaluated in this study. To assess the absorption and biodistribution of the combination, its bioavailability was first examined in a 3D intestinal barrier model that replicated intestinal absorption. Further, a 3D nerve tissue model was developed to study the biological impacts of the combination during the essential pathways involved in NP. Our findings show that the combination could cross the intestinal barrier and reach the peripheral nervous system, where it modulates the oxidative stress, inflammation levels, and myelination mechanism (increased NRG, MPZ, ERB, and p75 levels) under Schwann cells damaging. This study proves the effectiveness of Ginkgo Biloba, Propolis, Hop extract, Vitamin B, and PEA in avoiding nerve damage and suggests a potential alternative nutraceutical treatment for NP and neuropathies. Full article

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18 pages, 1155 KiB

Open AccessArticle

The Biological Active Substances of Taraxacum officinale and Arctium lappa from the Siberian Federal District

by Anna S. Frolova, Anna D. Fokina, Irina S. Milentyeva, Lyudmila K. Asyakina, Larisa A. Proskuryakova and Alexander Y. Prosekov

Int. J. Mol. Sci. 2024, 25(6), 3263; https://doi.org/10.3390/ijms25063263 - 13 Mar 2024

Cited by 1 | Viewed by 2130

Abstract

Currently, scientists are increasingly focusing on utilizing the natural flora of the planet to search for and isolate individual bioactive substances that prevent various diseases, contribute to increased life expectancy, and affect all major life-supporting systems in the human body. This study describes [...] Read more.

Currently, scientists are increasingly focusing on utilizing the natural flora of the planet to search for and isolate individual bioactive substances that prevent various diseases, contribute to increased life expectancy, and affect all major life-supporting systems in the human body. This study describes the examination of the composition of plant raw materials from the Siberian Federal District. The research focuses on plant specimens from the root parts of Taraxacum officinale and Arctium lappa, collected in the Kemerovo region. The study determines the contents of the water-soluble vitamins B and C in the research subjects. The investigation includes assessing antioxidant properties, antimicrobial activity, and flavonoid content in extracts based on plant raw materials. All samples show a high percentage of antioxidant activity, with the highest antioxidant activity for T. officinale at 85.51 and that for A. lappa at 88.97. The results indicate low antimicrobial activity against Escherichia coli (growth inhibition zone up to 15.5 mm). Plant extracts contain significant amounts of B-group vitamins, with pyridoxine in T. officinale (156.40 μg/mL) and thiamine (46.20 μg/mL) and pyridoxine (357.10 μg/mL) in Arctium lappa. Flavonoids (rutin and quercetin) are identified in T. officinale and A. lappa extracts based on the study results. Full article

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14 pages, 754 KiB

Open AccessArticle

Biological Activity and Chemical Composition of Propolis Extracts with Potential Use in Vulvovaginal Candidiasis Management

by Ana Margarida Silva, Beatriz Rocha, Manuela M. Moreira, Cristina Delerue-Matos, José das Neves and Francisca Rodrigues

Int. J. Mol. Sci. 2024, 25(5), 2478; https://doi.org/10.3390/ijms25052478 - 20 Feb 2024

Cited by 3 | Viewed by 2145

Abstract

Environmental sustainability is an increasing challenge in the pharmaceutical field, leading to the search for eco-friendly active ingredients. Among natural ingredients, propolis arises as an excellent alternative, being a complex substance with pharmacological properties. This work aims to explore the potential of propolis [...] Read more.

Environmental sustainability is an increasing challenge in the pharmaceutical field, leading to the search for eco-friendly active ingredients. Among natural ingredients, propolis arises as an excellent alternative, being a complex substance with pharmacological properties. This work aims to explore the potential of propolis as a new pharmaceutical ingredient for the replacement of conventional vulvovaginal antifungals. Propolis extracts were obtained by Ultrasound-Assisted Extraction using different solvents (water, water/ethanol (50:50, v/v), and ethanol). Afterwards, the extracts were characterized regarding total phenolic content (TPC), antioxidant/antiradical activities, radical scavenging capacity, antifungal activity against strains of Candida species, and viability effect on two female genital cell lines. The aqueous extract achieved the best TPC result as well as the highest antioxidant/antiradical activities and ability to capture reactive oxygen species. A total of 38 phenolic compounds were identified and quantified by HPLC, among which ferulic acid, phloridzin and myricetin predominated. Regarding the anti-Candida spp. activity, the aqueous and the hydroalcoholic extracts achieved the best outcomes (with MIC values ranging between 128 and 512 μg/mL). The cell viability assays confirmed that the aqueous extract presented mild selectivity, while the hydroalcoholic and alcoholic extracts showed higher toxicities. These results attest that propolis has a deep potential for vulvovaginal candidiasis management, supporting its economic valorization. Full article

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27 pages, 9522 KiB

Open AccessReview

Sirtuins as Players in the Signal Transduction of Citrus Flavonoids

by Giovanni Enrico Lombardo, Caterina Russo, Alessandro Maugeri and Michele Navarra

Int. J. Mol. Sci. 2024, 25(4), 1956; https://doi.org/10.3390/ijms25041956 - 6 Feb 2024

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Abstract

Sirtuins (SIRTs) belong to the family of nicotine adenine dinucleotide (NAD⁺)-dependent class III histone deacetylases, which come into play in the regulation of epigenetic processes through the deacetylation of histones and other substrates. The human genome encodes for seven homologs (SIRT1-7), [...] Read more.

Sirtuins (SIRTs) belong to the family of nicotine adenine dinucleotide (NAD⁺)-dependent class III histone deacetylases, which come into play in the regulation of epigenetic processes through the deacetylation of histones and other substrates. The human genome encodes for seven homologs (SIRT1-7), which are localized into the nucleus, cytoplasm, and mitochondria, with different enzymatic activities and regulatory mechanisms. Indeed, SIRTs are involved in different physio-pathological processes responsible for the onset of several human illnesses, such as cardiovascular and neurodegenerative diseases, obesity and diabetes, age-related disorders, and cancer. Nowadays, it is well-known that Citrus fruits, typical of the Mediterranean diet, are an important source of bioactive compounds, such as polyphenols. Among these, flavonoids are recognized as potential agents endowed with a wide range of beneficial properties, including antioxidant, anti-inflammatory, hypolipidemic, and antitumoral ones. On these bases, we offer a comprehensive overview on biological effects exerted by Citrus flavonoids via targeting SIRTs, which acted as modulator of several signaling pathways. According to the reported studies, Citrus flavonoids appear to be promising SIRT modulators in many different pathologies, a role which might be potentially evaluated in future therapies, along with encouraging the study of those SIRT members which still lack proper evidence on their support. Full article

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32 pages, 7913 KiB

Open AccessArticle

The Potential of Plum Seed Residue: Unraveling the Effect of Processing on Phytochemical Composition and Bioactive Properties

by Sandra Rodríguez-Blázquez, Laura Pedrera-Cajas, Esther Gómez-Mejía, David Vicente-Zurdo, Noelia Rosales-Conrado, María Eugenia León-González, Juan José Rodríguez-Bencomo and Ruben Miranda

Int. J. Mol. Sci. 2024, 25(2), 1236; https://doi.org/10.3390/ijms25021236 - 19 Jan 2024

Cited by 1 | Viewed by 2543

Abstract

Bioactive compounds extracted from plum seeds were identified and quantified, aiming to establish how the brandy manufacturing process affects the properties and possible cascade valorization of seed residues. Extraction with n-hexane using Soxhlet has provided oils rich in unsaturated fatty acids (92.24–92.51%), [...] Read more.

Bioactive compounds extracted from plum seeds were identified and quantified, aiming to establish how the brandy manufacturing process affects the properties and possible cascade valorization of seed residues. Extraction with n-hexane using Soxhlet has provided oils rich in unsaturated fatty acids (92.24–92.51%), mainly oleic acid (72–75.56%), which is characterized by its heart-healthy properties. The fat extracts also contain tocopherols with antioxidant and anti-inflammatory properties. All the ethanol–water extracts of the defatted seeds contain neochlorogenic acid (90–368 µg·g⁻¹), chlorogenic acid (36.1–117 µg·g⁻¹), and protocatechuate (31.8–100 µg·g⁻¹) that have an impact on bioactive properties such as antimicrobial and antioxidant. Anti-amyloidogenic activity (25 mg·mL⁻¹) was observed in the after both fermentation and distillation extract, which may be related to high levels of caffeic acid (64 ± 10 µg·g⁻¹). The principal component analysis showed that all plum seed oils could have potential applications in the food industry as edible oils or in the cosmetic industry as an active ingredient in anti-aging and anti-stain cosmetics, among others. Furthermore, defatted seeds, after both fermentation and distillation, showed the greatest applicability in the food and nutraceutical industry as a food supplement or as an additive in the design of active packaging. Full article

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11 pages, 2478 KiB

Open AccessArticle

Impact of Sinapic Acid on Bovine Serum Albumin Thermal Stability

by Aurica Precupas and Vlad Tudor Popa

Int. J. Mol. Sci. 2024, 25(2), 936; https://doi.org/10.3390/ijms25020936 - 11 Jan 2024

Cited by 4 | Viewed by 1832

Abstract

The thermal stability of bovine serum albumin (BSA) in Tris buffer, as well as the effect of sinapic acid (SA) on protein conformation were investigated via calorimetric (differential scanning microcalorimetry—μDSC), spectroscopic (dynamic light scattering—DLS; circular dichroism—CD), and molecular docking approaches. μDSC data revealed [...] Read more.

The thermal stability of bovine serum albumin (BSA) in Tris buffer, as well as the effect of sinapic acid (SA) on protein conformation were investigated via calorimetric (differential scanning microcalorimetry—μDSC), spectroscopic (dynamic light scattering—DLS; circular dichroism—CD), and molecular docking approaches. μDSC data revealed both the denaturation (endotherm) and aggregation (exotherm) of the protein, demonstrating the dual effect of SA on protein thermal stability. With an increase in ligand concentration, (i) protein denaturation shifts to a higher temperature (indicating native form stabilization), while (ii) the aggregation process shifts to a lower temperature (indicating enhanced reactivity of the denatured form). The stabilization effect of SA on the native structure of the protein was supported by CD results. High temperature (338 K) incubation induced protein unfolding and aggregation, and increasing the concentration of SA altered the size distribution of the protein population, as DLS measurements demonstrated. Complementary information offered by molecular docking allowed for the assessment of the ligand binding within the Sudlow’s site I of the protein. The deeper insight into the SA–BSA interaction offered by the present study may serve in the clarification of ligand pharmacokinetics and pharmacodynamics, thus opening paths for future research and therapeutic applications. Full article

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2023

Jump to: 2024, 2022, 2021, 2020

18 pages, 3969 KiB

Open AccessArticle

Hydroxyl Group Acetylation of Quercetin Enhances Intracellular Absorption and Persistence to Upregulate Anticancer Activity in HepG2 Cells

by Kozue Sakao, Hanako Saruwatari, Shohei Minami and De-Xing Hou

Int. J. Mol. Sci. 2023, 24(23), 16652; https://doi.org/10.3390/ijms242316652 - 23 Nov 2023

Cited by 4 | Viewed by 1866

Abstract

Quercetin, a flavonoid compound widely distributed in many plants, is known to have potent antitumor effects on several cancer cells. Our previous study revealed that the acetylation of quercetin enhanced its antitumor effect. However, the mechanisms remain unknown. This study aimed to elucidate [...] Read more.

Quercetin, a flavonoid compound widely distributed in many plants, is known to have potent antitumor effects on several cancer cells. Our previous study revealed that the acetylation of quercetin enhanced its antitumor effect. However, the mechanisms remain unknown. This study aimed to elucidate the bioavailability of acylated quercetin in the HepG2 cell model based on its antitumor effect. The positions of quercetin 3,7,3′,4′-OH were acetylated as 3,7,3′,4′-O-tetraacetylquercetin (4Ac-Q). The inhibitory effect of 4Ac-Q on HepG2 cell proliferation was assessed by measuring cell viability. The apoptosis was characterized by apoptotic proteins and mitochondrial membrane potential shifts, as well as mitochondrial reactive oxygen species (ROS) levels. The bioavailability of 4Ac-Q was analyzed by measuring the uptake and metabolites in HepG2 cells with high performance liquid chromatography (HPLC)—photodiode array detector (PDA) and—ultraviolet/visible detector (UV/Vis). The results revealed that 4Ac-Q enhanced the inhibitory effect on HepG2 cell proliferation and induced its apoptosis significantly higher than quercetin. Protein array analysis of apoptosis-related protein indicated that 4Ac-Q increased the activation or expression of pro-apoptotic proteins, including caspase-3, -9, as well as second mitochondria-derived activator of caspases (SMAC), and suppressed the expression of apoptosis inhibiting proteins such as cellular inhibitor of apoptosis (cIAP)-1, -2, Livin, Survivin, and X-linked inhibitor of apoptosis (XIAP). Furthermore, 4Ac-Q stimulated mitochondrial cytochrome c release into the cytosol by enhancing ROS level and depolarizing the mitochondrial membrane. Finally, the analysis of uptake and metabolites of 4Ac-Q in HpG2 cells with HPLC-PDA and -UV/Vis revealed that 4Ac-Q was metabolized to quercetin and several different acetylated quercetins which caused 2.5-fold higher quercetin present in HepG2 cells than parent quercetin. These data demonstrated that acetylation of the quercetin hydroxyl group significantly increased its intracellular absorption. Taken together, our findings provide the first evidence that acetyl modification of quercetin not only substantially augments the intracellular absorption of quercetin but also bolsters its metabolic stability to elongate its intracellular persistence. Therefore, acetylation could serve as a strategic approach to enhance the ability of quercetin and analogous flavonoids to suppress cancer cell proliferation. Full article

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15 pages, 592 KiB

Open AccessOpinion

Current Challenges and Opportunities for Improved Cannabidiol Solubility

by Khondker Rufaka Hossain, Amani Alghalayini and Stella M. Valenzuela

Int. J. Mol. Sci. 2023, 24(19), 14514; https://doi.org/10.3390/ijms241914514 - 25 Sep 2023

Cited by 16 | Viewed by 3178

Abstract

Cannabidiol (CBD), derived from the cannabis plant, has gained significant attention due to its potential therapeutic benefits. However, one of the challenges associated with CBD administration is its low bioavailability, which refers to the fraction of an administered dose that reaches systemic circulation. [...] Read more.

Cannabidiol (CBD), derived from the cannabis plant, has gained significant attention due to its potential therapeutic benefits. However, one of the challenges associated with CBD administration is its low bioavailability, which refers to the fraction of an administered dose that reaches systemic circulation. This limitation necessitates the exploration of various approaches to enhance the bioavailability of CBD, thus helping to maximize its therapeutic potential. A variety of approaches are now emerging, including nanoemulsion-based systems, lipid-based formulations, prodrugs, nanocarriers, and alternative routes of administration, which hold promise for improving the bioavailability of CBD and pave the way for novel formulations that maximize the therapeutic potential of CBD in various medical conditions. This opinion piece presents the current understanding surrounding CBD bioavailability and considers strategies aimed at improving both its absorption and its bioavailability. Full article

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18 pages, 3260 KiB

Open AccessArticle

Cooking, Digestion, and In Vitro Colonic Fermentation of Nigerian Wholegrains Affect Phenolic Acid Metabolism and Gut Microbiota Composition

by Oghenerukevwe Anne Obayiuwana, Volker Behrends, Yolanda Calle-Patino, Monica Barone, Silvia Turroni, Patrizia Brigidi, Adele Costabile and Giulia Corona

Int. J. Mol. Sci. 2023, 24(18), 14111; https://doi.org/10.3390/ijms241814111 - 14 Sep 2023

Cited by 2 | Viewed by 1514

Abstract

Wholegrains contain both fibre and phenolic acids (PAs), and their gastrointestinal modifications are critical for their bioavailability and bioactivity. We evaluated the modifications on the PA profile and gut microbiota composition of selected Nigerian wholegrains, following cooking and gastrointestinal digestion. Red fonio, red [...] Read more.

Wholegrains contain both fibre and phenolic acids (PAs), and their gastrointestinal modifications are critical for their bioavailability and bioactivity. We evaluated the modifications on the PA profile and gut microbiota composition of selected Nigerian wholegrains, following cooking and gastrointestinal digestion. Red fonio, red millet, red sorghum, and white corn were cooked, digested, and fermented using an in vitro colonic model. A total of 26 PA derivatives were quantified in soluble and bound fractions using Ultraperformance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) analysis. DNA samples were analysed using 16S rRNA amplicon sequencing to profile the microbiota composition. The results show that cooking and digestion significantly affected the levels of PAs in all grains (p ≤ 0.05) compared to raw grains. Colonic fermentation resulted in a peak of total soluble PAs at 4–6 h for red sorghum and white corn and at 24 h for red millet and red fonio. Enterobacteriaceae genera were the most abundant at 24 h in all grains studied. 3-hydroxybenzaldehyde correlated positively with the relative abundance of Dorea and the mucus-degrader bacteria Akkermansia (p ≤ 0.05), whereas hydroferulic acid and isoferulic acid levels correlated negatively with Oscillospira and Ruminococcus (p ≤ 0.05), respectively. Our data indicate that cooking, digestion, and colonic fermentation affect the release of bound PAs from wholegrains and, consequently, their metabolic conversion. Furthermore, PA fermentation in the gut is associated with potentially relevant changes in the microbiota. This in vitro study provides the basis for the design of an in vivo human intervention study that can confirm the trends herein observed but also assess the impact on health outcomes. Full article

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13 pages, 974 KiB

Open AccessArticle

Relationship between the Consumption of Fermented Red Beetroot Juice and Levels of Perfluoroalkyl Substances in the Human Body’s Fluids and Blood Parameters

by Magdalena Surma, Tomasz Sawicki, Mariusz Piskuła and Wiesław Wiczkowski

Int. J. Mol. Sci. 2023, 24(18), 13956; https://doi.org/10.3390/ijms241813956 - 11 Sep 2023

Viewed by 1401

Abstract

Per- and polyfluoroalkyl substances (PFASs) are a group of fluorinated, organic, man-made chemicals; they do not occur naturally in the environment. This study aimed to determine the profile and content of PFASs in the volunteers’ blood plasma and urine after the consumption of [...] Read more.

Per- and polyfluoroalkyl substances (PFASs) are a group of fluorinated, organic, man-made chemicals; they do not occur naturally in the environment. This study aimed to determine the profile and content of PFASs in the volunteers’ blood plasma and urine after the consumption of fermented red beetroot juice and then correlated it with the blood parameters. Over 42 days, 24 healthy volunteers ingested 200 mL/60 kg of body weight of fermented red beetroot juice. PFASs were analyzed using the micro-HPLC-MS/MS method. Five perfluoroalkyl substances were found in the volunteers’ body fluids. After consuming the juice, it was discovered that regarding the perfluorocarboxylic acids, a downward trend was observed, while regarding the perfluoroalkane sulfonates, and their plasma content showed a statistically significant upward trend. Analysis of the hematology parameters indicated that the intake of fermented red beetroot juice showed a significant decrease in mean corpuscular volume (MCV), platelets concentration, mean platelet volume (MPV), platelet large cell ratio (P-LCR) at the significance level p < 0.01, and hematocrit (p < 0.05). On the other hand, the dietary intervention also indicated a significant (p < 0.01) increase in corpuscular/cellular hemoglobin concentration (MCHC). In the case of blood biochemistry, no significant change was observed in the blood samples after the intake of the fermented beetroot juice. However, a decreasing tendency of total cholesterol and low-density lipoprotein concentration (LDL-C) was observed. Based on the presented results, there is a need to analyze and monitor health-promoting food regarding undesirable substances and their impact on consumer health. Full article

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22 pages, 68441 KiB

Open AccessArticle

Pharmacological Inhibition and Genetic Deletion of Cystathionine Gamma-Lyase in Mice Protects against Organ Injury in Sepsis: A Key Role of Adhesion Molecules on Endothelial Cells

by Sumeet Manandhar, Stephen Chambers, Andrew Miller, Isao Ishii and Madhav Bhatia

Int. J. Mol. Sci. 2023, 24(17), 13650; https://doi.org/10.3390/ijms241713650 - 4 Sep 2023

Cited by 2 | Viewed by 2044

Abstract

Hydrogen sulfide (H₂S), synthesized by cystathionine gamma-lyase (Cth), contributes to the inflammatory response observed in sepsis. This study examines the effect of Cth-derived H₂S in adhesion molecules on endothelial cells of vital organs in mice in a cecal ligation [...] Read more.

Hydrogen sulfide (H₂S), synthesized by cystathionine gamma-lyase (Cth), contributes to the inflammatory response observed in sepsis. This study examines the effect of Cth-derived H₂S in adhesion molecules on endothelial cells of vital organs in mice in a cecal ligation puncture (CLP)-induced model of sepsis, using two different and complementary approaches: Cth gene deletion and pharmacological inhibition. Our findings revealed a decreased level of H₂S-synthesizing activity (via Cth) in both Cth^−/− mice and PAG-treated wild-type (WT) mice following CLP-induced sepsis. Both treatment groups had reduced MPO activity and expression of chemokines (MCP-1 and MIP-2α), adhesion molecules (ICAM-1 and VCAM-1), ERK1/2 phosphorylation, and NF-κB in the liver and lung compared with in CLP-WT mice. Additionally, we found that PAG treatment in Cth^−/− mice had no additional effect on the expression of ERK1/2 phosphorylation, NF-κB, or the production of chemokines and adhesion molecules in the liver and lung compared to Cth^−/− mice following CLP-induced sepsis. The WT group with sepsis had an increased immunoreactivity of adhesion molecules on endothelial cells in the liver and lung than the WT sham-operated control. The Cth^−/−, PAG-treated WT, and Cth^−/− groups of mice showed decreased immunoreactivity of adhesion molecules on endothelial cells in the liver and lung following sepsis. Inhibition of H₂S production via both approaches reduced adhesion molecule expression on endothelial cells and reduced liver and lung injury in mice with sepsis. In conclusion, this study demonstrates that H₂S has an important role in the pathogenesis of sepsis and validates PAG use as a suited tool for investigating the Cth/H₂S-signalling axis in sepsis. Full article

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13 pages, 3791 KiB

Open AccessArticle

Overexpression of BmJHBPd2 Repressed Silk Synthesis by Inhibiting the JH/Kr-h1 Signaling Pathway in Bombyx mori

by Jikailang Zhang, Xia Zhang, Hui Zhang, Jiaojiao Li, Wei Li and Chun Liu

Int. J. Mol. Sci. 2023, 24(16), 12650; https://doi.org/10.3390/ijms241612650 - 10 Aug 2023

Cited by 2 | Viewed by 1338

Abstract

The efficient production of silkworm silk is crucial to the silk industry. Silk protein synthesis is regulated by the juvenile hormone (JH) and 20-Hydroxyecdysone (20E). Therefore, the genetic regulation of silk production is a priority. JH binding protein (JHBP) transports JH from the [...] Read more.

The efficient production of silkworm silk is crucial to the silk industry. Silk protein synthesis is regulated by the juvenile hormone (JH) and 20-Hydroxyecdysone (20E). Therefore, the genetic regulation of silk production is a priority. JH binding protein (JHBP) transports JH from the hemolymph to target organs and cells and protects it. In a previous study, we identified 41 genes containing a JHBP domain in the Bombyx mori genome. Only one JHBP gene, BmJHBPd2, is highly expressed in the posterior silk gland (PSG), and its function remains unknown. In the present study, we investigated the expression levels of BmJHBPd2 and the major silk protein genes in the high-silk-producing practical strain 872 (S872) and the low-silk-producing local strain Dazao. We found that BmJHBPd2 was more highly expressed in S872 than in the Dazao strain, which is consistent with the expression pattern of fibroin genes. A subcellular localization assay indicated that BmJHBPd2 is located in the cytoplasm. In vitro hormone induction experiments showed that BmJHBPd2 was upregulated by juvenile hormone analogue (JHA) treatment. BmKr-h1 upregulation was significantly inhibited by the overexpression of BmJHBPd2 (BmJHBPd2OE) at the cell level when induced by JHA. However, overexpression of BmJHBPd2 in the PSG by transgenic methods led to the inhibition of silk fibroin gene expression, resulting in a reduction in silk yield. Further investigation showed that in the transgenic BmJHBPd2OE silkworm, the key transcription factor of the JH signaling pathway, Krüppel homolog 1 (Kr-h1), was inhibited, and 20E signaling pathway genes, such as broad complex (Brc), E74A, and ultraspiracle protein (USP), were upregulated. Our results indicate that BmJHBPd2 plays an important role in the JH signaling pathway and is important for silk protein synthesis. Furthermore, our findings help to elucidate the mechanisms by which JH regulates silk protein synthesis. Full article

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20 pages, 3066 KiB

Open AccessArticle

Quercetins, Chlorogenic Acids and Their Colon Metabolites Inhibit Colon Cancer Cell Proliferation at Physiologically Relevant Concentrations

by Alice Cattivelli, Angela Conte and Davide Tagliazucchi

Int. J. Mol. Sci. 2023, 24(15), 12265; https://doi.org/10.3390/ijms241512265 - 31 Jul 2023

Cited by 3 | Viewed by 1431

Abstract

Several studies have suggested that a phenolic-rich diet may be protective against colon cancer. Most phenolic compounds are not absorbed in the small intestine and reach the colon where they are metabolized by gut microbiota in simple phenolic acids. In this study, the [...] Read more.

Several studies have suggested that a phenolic-rich diet may be protective against colon cancer. Most phenolic compounds are not absorbed in the small intestine and reach the colon where they are metabolized by gut microbiota in simple phenolic acids. In this study, the anti-proliferative activity of quercetins, chlorogenic acids, their colon metabolites and mixtures of parent compounds/metabolites was assessed by using two colon cancer cell lines (Caco-2 and SW480) at physiologically relevant concentrations. Chlorogenic acids, quercetin and the metabolite 3-(3′,4′-dihydroxyphenyl)acetic acid exerted remarkable anti-proliferative activity against Caco-2, whereas quercetin derivatives and metabolites were the most active against SW480. Tested compounds arrested the cell cycle at the S phase in both the cell lines. The mixtures of parent compounds/metabolites, which mimic the colon human metabotypes that slowly or rapidly metabolize the parent compounds, similarly inhibited cell growth. SW480 cells metabolized parent phenolic compounds more rapidly and extensively than Caco-2, whereas colon metabolites were more stable. These results suggest that dietary phenolic compounds exert an anti-proliferative effect against human colon cancer cells that can be further sustained by the colon metabolites. Therefore, gut microbiota metabolism of phenolic compounds may be of paramount importance in explaining the protective effect of phenolic-rich foods against colon cancer. Full article

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11 pages, 2391 KiB

Open AccessArticle

Equol and Resveratrol Improve Bone Turnover Biomarkers in Postmenopausal Women: A Clinical Trial

by Graziamaria Corbi, Vincenzo Nobile, Valeria Conti, Alessandro Cannavo, Vincenzo Sorrenti, Alessandro Medoro, Giovanni Scapagnini and Sergio Davinelli

Int. J. Mol. Sci. 2023, 24(15), 12063; https://doi.org/10.3390/ijms241512063 - 27 Jul 2023

Cited by 12 | Viewed by 3104

Abstract

Estrogen deficiency is a major cause of loss of postmenopausal bone mineral density (BMD). This study aimed to evaluate the effects of equol and resveratrol on bone turnover biomarkers in postmenopausal women. Sixty healthy postmenopausal women were randomly assigned to receive 200 mg [...] Read more.

Estrogen deficiency is a major cause of loss of postmenopausal bone mineral density (BMD). This study aimed to evaluate the effects of equol and resveratrol on bone turnover biomarkers in postmenopausal women. Sixty healthy postmenopausal women were randomly assigned to receive 200 mg fermented soy containing 10 mg equol and 25 mg resveratrol or a placebo for 12 months. Whole-body BMD and bone turnover biomarkers, such as deoxypyridinoline (DPD), tartrate-resistant acid phosphatase 5b (TRACP-5b), osteocalcin, and bone-specific alkaline phosphatase (BAP), were measured at baseline and after 12 months of treatment. At the end of treatment, DPD, osteocalcin, and BAP significantly improved in the active group (p < 0.0001 for all) compared to the placebo group. Conversely, TRACP-5b levels were unaffected by supplementation (p = 0.051). Statistically significant changes in the concentrations of DPD (p < 0.0001), osteocalcin (p = 0.0001), and BAP (p < 0.0001) compared to baseline were also identified. Overall, the intervention significantly increased BMD measured in the whole body (p = 0.0220) compared with the placebo. These data indicate that the combination of equol and resveratrol may positively modulate bone turnover biomarkers and BMD, representing a potential approach to prevent age-related bone loss in postmenopausal women. Full article

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45 pages, 3121 KiB

Open AccessReview

Biological and Catalytic Properties of Selenoproteins

by Jean Chaudière

Int. J. Mol. Sci. 2023, 24(12), 10109; https://doi.org/10.3390/ijms241210109 - 14 Jun 2023

Cited by 15 | Viewed by 2615

Abstract

Selenocysteine is a catalytic residue at the active site of all selenoenzymes in bacteria and mammals, and it is incorporated into the polypeptide backbone by a co-translational process that relies on the recoding of a UGA termination codon into a serine/selenocysteine codon. The [...] Read more.

Selenocysteine is a catalytic residue at the active site of all selenoenzymes in bacteria and mammals, and it is incorporated into the polypeptide backbone by a co-translational process that relies on the recoding of a UGA termination codon into a serine/selenocysteine codon. The best-characterized selenoproteins from mammalian species and bacteria are discussed with emphasis on their biological function and catalytic mechanisms. A total of 25 genes coding for selenoproteins have been identified in the genome of mammals. Unlike the selenoenzymes of anaerobic bacteria, most mammalian selenoenzymes work as antioxidants and as redox regulators of cell metabolism and functions. Selenoprotein P contains several selenocysteine residues and serves as a selenocysteine reservoir for other selenoproteins in mammals. Although extensively studied, glutathione peroxidases are incompletely understood in terms of local and time-dependent distribution, and regulatory functions. Selenoenzymes take advantage of the nucleophilic reactivity of the selenolate form of selenocysteine. It is used with peroxides and their by-products such as disulfides and sulfoxides, but also with iodine in iodinated phenolic substrates. This results in the formation of Se-X bonds (X = O, S, N, or I) from which a selenenylsulfide intermediate is invariably produced. The initial selenolate group is then recycled by thiol addition. In bacterial glycine reductase and D-proline reductase, an unusual catalytic rupture of selenium–carbon bonds is observed. The exchange of selenium for sulfur in selenoproteins, and information obtained from model reactions, suggest that a generic advantage of selenium compared with sulfur relies on faster kinetics and better reversibility of its oxidation reactions. Full article

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25 pages, 630 KiB

Open AccessReview

Exploring the Impact of Cyanidin-3-Glucoside on Inflammatory Bowel Diseases: Investigating New Mechanisms for Emerging Interventions

by Maximos Frountzas, Eva Karanikki, Orsalia Toutouza, Demosthenis Sotirakis, Dimitrios Schizas, Panagiotis Theofilis, Dimitris Tousoulis and Konstantinos G. Toutouzas

Int. J. Mol. Sci. 2023, 24(11), 9399; https://doi.org/10.3390/ijms24119399 - 28 May 2023

Cited by 7 | Viewed by 5875

Abstract

Cyanidin-3-O-glucoside (C3G), the most widely distributed anthocyanin (ACN) in edible fruits, has been proposed for several bioactivities, including anti-inflammatory, neuro-protective, antimicrobial, anti-viral, anti-thrombotic and epigenetic actions. However, habitual intake of ACNs and C3G may vary widely among populations, regions, and seasons, among individuals [...] Read more.

Cyanidin-3-O-glucoside (C3G), the most widely distributed anthocyanin (ACN) in edible fruits, has been proposed for several bioactivities, including anti-inflammatory, neuro-protective, antimicrobial, anti-viral, anti-thrombotic and epigenetic actions. However, habitual intake of ACNs and C3G may vary widely among populations, regions, and seasons, among individuals with different education and financial status. The main point of C3G absorption occurs in the small and large bowel. Therefore, it has been supposed that the treating properties of C3G might affect inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn’s disease (CD). IBDs develop through complex inflammatory pathways and sometimes may be resistant to conventional treatment strategies. C3G presents antioxidative, anti-inflammatory, cytoprotective, and antimicrobial effects useful for IBD management. In particular, different studies have demonstrated that C3G inhibits NF-κB pathway activation. In addition, C3G activates the Nrf2 pathway. On the other hand, it modulates the expression of antioxidant enzymes and cytoprotective proteins, such as NAD(P)H, superoxide dismutase, heme-oxygenase (HO-1), thioredoxin, quinone reductase-oxide 1 (NQO1), catalase, glutathione S-transferase and glutathione peroxidase. Interferon I and II pathways are downregulated by C3G inhibiting interferon-mediating inflammatory cascades. Moreover, C3G reduces reactive species and pro-inflammatory cytokines, such as C reactive protein, interferon-γ, tumor necrosis factor-α, interleukin (IL)-5, IL-9, IL-10, IL-12p70, and IL-17A in UC and CD patients. Finally, C3G modulates gut microbiota by inducing an increase in beneficial gut bacteria and increasing microbial abundances, thus mitigating dysbiosis. Thus, C3G presents activities that may have potential therapeutic and protective actions against IBD. Still, in the future, clinical trials should be designed to investigate the bioavailability of C3G in IBD patients and the proper therapeutic doses through different sources, aiming to the standardization of the exact clinical outcome and efficacy of C3G. Full article

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15 pages, 2698 KiB

Open AccessArticle

Bioactive Constituents of Verbena officinalis Alleviate Inflammation and Enhance Killing Efficiency of Natural Killer Cells

by Xiangdong Dai, Xiangda Zhou, Rui Shao, Renping Zhao, Archana K. Yanamandra, Zhimei Xing, Mingyu Ding, Junhong Wang, Tao Liu, Qi Zheng, Peng Zhang, Han Zhang, Yi Wang, Bin Qu and Yu Wang

Int. J. Mol. Sci. 2023, 24(8), 7144; https://doi.org/10.3390/ijms24087144 - 12 Apr 2023

Cited by 3 | Viewed by 2970

Abstract

Natural killer (NK) cells play key roles in eliminating pathogen-infected cells. Verbena officinalis (V. officinalis) has been used as a medical plant in traditional and modern medicine for its anti-tumor and anti-inflammatory activities, but its effects on immune responses remain largely [...] Read more.

Natural killer (NK) cells play key roles in eliminating pathogen-infected cells. Verbena officinalis (V. officinalis) has been used as a medical plant in traditional and modern medicine for its anti-tumor and anti-inflammatory activities, but its effects on immune responses remain largely elusive. This study aimed to investigate the potential of V. officinalis extract (VO extract) to regulate inflammation and NK cell functions. We examined the effects of VO extract on lung injury in a mouse model of influenza virus infection. We also investigated the impact of five bioactive components of VO extract on NK killing functions using primary human NK cells. Our results showed that oral administration of VO extract reduced lung injury, promoted the maturation and activation of NK cells in the lung, and decreased the levels of inflammatory cytokines (IL-6, TNF-α and IL-1β) in the serum. Among five bioactive components of VO extract, Verbenalin significantly enhanced NK killing efficiency in vitro, as determined by real-time killing assays based on plate-reader or high-content live-cell imaging in 3D using primary human NK cells. Further investigation showed that treatment of Verbenalin accelerated the killing process by reducing the contact time of NK cells with their target cells without affecting NK cell proliferation, expression of cytotoxic proteins, or lytic granule degranulation. Together, our findings suggest that VO extract has a satisfactory anti-inflammatory effect against viral infection in vivo, and regulates the activation, maturation, and killing functions of NK cells. Verbenalin from V. officinalis enhances NK killing efficiency, suggesting its potential as a promising therapeutic to fight viral infection. Full article

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11 pages, 328 KiB

Open AccessArticle

Hepatic, Muscle and Intestinal Oxidative Status and Plasmatic Parameters of Greater Amberjack (Seriola dumerili, Risso, 1810) Fed Diets with Fish Oil Replacement and Probiotic Addition

by Maria Consolación Milián-Sorribes, Helena Peres, Ana Tomás-Vidal, Sara Moutinho, David S. Peñaranda, Miguel Jover-Cerdá, Aires Oliva-Teles and Silvia Martínez-Llorens

Int. J. Mol. Sci. 2023, 24(7), 6768; https://doi.org/10.3390/ijms24076768 - 5 Apr 2023

Cited by 1 | Viewed by 2059

Abstract

The present study was conducted to investigate the effects of dietary fish oil replacement with a mixture of vegetable oils and probiotic supplementation on plasma biochemical parameters, oxidative stress, and antioxidant ability of Seriola dumerili. Specimens with an initial weight of 175 [...] Read more.

The present study was conducted to investigate the effects of dietary fish oil replacement with a mixture of vegetable oils and probiotic supplementation on plasma biochemical parameters, oxidative stress, and antioxidant ability of Seriola dumerili. Specimens with an initial weight of 175 g were used. Four feeds were formulated with 0% (FO-100), 75% (FO-25), and 100% (FO-0 and FO-0+ with the addition of Lactobacillus probiotics) substitution of fish oil with a mixture of linseed, sunflower, and palm oils. After 109 days, no significant differences were observed in the activity of antioxidant enzymes in the liver, foregut, and hindgut, only glucose-6-phosphate dehydrogenase activity in the liver was higher in the fish fed the FO-100 diet than in those fed the FO-0 diet. No significant differences were observed in the total, reduced, and oxidized glutathione and the oxidative stress index in the liver. In addition, lipid peroxidation in the liver and red muscle values were higher in the fish fed the FO-100 diet than in the fish fed the FO-0+ diet, however, the foregut of the fish fed the FO-100 diet presented lower values than that of the fish fed the FO replacement diet, with and without probiotics. There were significant differences in cholesterol levels in the FO-100 group; they were significantly higher than those observed with the fish diets without fish oil. To sum up, fish oil can be replaced by up to 25% with vegetable oils in diets for Seriola dumerili juveniles, but total fish oil substitution is not feasible because it causes poor survival. The inclusion of probiotics in the FO-0+ diet had no effects on the parameters measured. Full article

16 pages, 4162 KiB

Open AccessArticle

Biofilm-Based Biocatalysis for Galactooligosaccharides Production by the Surface Display of β-Galactosidase in Pichia pastoris

by Tianpeng Chen, Shimeng Wang, Huanqing Niu, Guanjia Yang, Sinan Wang, Yuqi Wang, Chaowei Zhou, Bin Yu, Pengpeng Yang, Wenjun Sun, Dong Liu, Hanjie Ying and Yong Chen

Int. J. Mol. Sci. 2023, 24(7), 6507; https://doi.org/10.3390/ijms24076507 - 30 Mar 2023

Cited by 3 | Viewed by 2515

Abstract

Galactooligosaccharides (GOS) are one of the most important functional oligosaccharide prebiotics. The surface display of enzymes was considered one of the most excellent strategies to obtain these products. However, a rough industrial environment would affect the biocatalytic process. The catalytic process could be [...] Read more.

Galactooligosaccharides (GOS) are one of the most important functional oligosaccharide prebiotics. The surface display of enzymes was considered one of the most excellent strategies to obtain these products. However, a rough industrial environment would affect the biocatalytic process. The catalytic process could be efficiently improved using biofilm-based fermentation with high resistance and activity. Therefore, the combination of the surface display of β-galactosidase and biofilm formation in Pichia pastoris was constructed. The results showed that the catalytic conversion rate of GOS was up to 50.3% with the maximum enzyme activity of 5125 U/g by screening the anchorin, and the number of the continuous catalysis batches was up to 23 times. Thus, surface display based on biofilm-immobilized fermentation integrated catalysis and growth was a co-culture system, such that a dynamic equilibrium in the consolidated integrative process was achieved. This study provides the basis for developing biofilm-based surface display methods in P. pastoris during biochemical production processes. Full article

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19 pages, 3473 KiB

Open AccessArticle

Isolation and NMR Scaling Factors for the Structure Determination of Lobatolide H, a Flexible Sesquiterpene from Neurolaena lobata

by Tibor Kovács, Ildikó Lajter, Norbert Kúsz, Zsuzsanna Schelz, Noémi Bózsity-Faragó, Anikó Borbás, István Zupkó, Georg Krupitza, Richard Frisch, Judit Hohmann, Andrea Vasas and Attila Mándi

Int. J. Mol. Sci. 2023, 24(6), 5841; https://doi.org/10.3390/ijms24065841 - 19 Mar 2023

Cited by 3 | Viewed by 2425

Abstract

A new flexible germacranolide (1, lobatolide H) was isolated from the aerial parts of Neurolaena lobata. The structure elucidation was performed by classical NMR experiments and DFT NMR calculations. Altogether, 80 theoretical level combinations with existing ¹³C NMR scaling [...] Read more.

A new flexible germacranolide (1, lobatolide H) was isolated from the aerial parts of Neurolaena lobata. The structure elucidation was performed by classical NMR experiments and DFT NMR calculations. Altogether, 80 theoretical level combinations with existing ¹³C NMR scaling factors were tested, and the best performing ones were applied on 1. ¹H and ¹³C NMR scaling factors were also developed for two combinations utilizing known exomethylene containing derivatives, and the results were complemented by homonuclear coupling constant (J_HH) and TDDFT-ECD calculations to elucidate the stereochemistry of 1. Lobatolide H possessed remarkable antiproliferative activity against human cervical tumor cell lines with different HPV status (SiHa and C33A), induced cell cycle disturbance and exhibited a substantial antimigratory effect in SiHa cells. Full article

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17 pages, 2345 KiB

Open AccessCommunication

Cornelian Cherry (Cornus mas L.) Iridoid and Anthocyanin-Rich Extract Reduces Various Oxidation, Inflammation, and Adhesion Markers in a Cholesterol-Rich Diet Rabbit Model

by Maciej Danielewski, Agnieszka Gomułkiewicz, Alicja Z. Kucharska, Agnieszka Matuszewska, Beata Nowak, Narcyz Piórecki, Małgorzata Trocha, Marta Szandruk-Bender, Paulina Jawień, Adam Szeląg, Piotr Dzięgiel and Tomasz Sozański

Int. J. Mol. Sci. 2023, 24(4), 3890; https://doi.org/10.3390/ijms24043890 - 15 Feb 2023

Cited by 8 | Viewed by 2317

Abstract

Atherogenesis leads to the development of atherosclerosis, a progressive chronic disease characterized by subendothelial lipoprotein retention and endothelial impairment in the arterial wall. It develops mainly as a result of inflammation and also many other complex processes, which arise from, among others, oxidation [...] Read more.

Atherogenesis leads to the development of atherosclerosis, a progressive chronic disease characterized by subendothelial lipoprotein retention and endothelial impairment in the arterial wall. It develops mainly as a result of inflammation and also many other complex processes, which arise from, among others, oxidation and adhesion. Cornelian cherry (Cornus mas L.) fruits are abundant in iridoids and anthocyanins—compounds with potent antioxidant and anti-inflammatory activity. This study aimed to determine the effect of two different doses (10 mg and 50 mg per kg of body weight, respectively) of iridoid and anthocyanin-rich resin-purified Cornelian cherry extract on the markers that are important in the progress of inflammation, cell proliferation and adhesion, immune system cell infiltration, and atherosclerotic lesion development in a cholesterol-rich diet rabbit model. We used biobank blood and liver samples that were collected during the previous original experiment. We assessed the mRNA expression of MMP-1, MMP-9, IL-6, NOX, and VCAM-1 in the aorta, and the serum levels of VCAM-1, ICAM-1, CRP, PON-1, MCP-1, and PCT. The application of the Cornelian cherry extract at a dose of 50 mg/kg bw resulted in a significant reduction in MMP-1, IL-6, and NOX mRNA expression in the aorta and a decrease in VCAM-1, ICAM-1, PON-1, and PCT serum levels. The administration of a 10 mg/kg bw dose caused a significant decrease in serum ICAM-1, PON-1, and MCP-1. The results indicate the potential usefulness of the Cornelian cherry extract in the prevention or treatment of atherogenesis-related cardiovascular diseases, such as atherosclerosis or metabolic syndrome. Full article

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15 pages, 11185 KiB

Open AccessArticle

Differential Roles of Cystathionine Gamma-Lyase and Mercaptopyruvate Sulfurtransferase in Hapten-Induced Colitis and Contact Dermatitis in Mice

by Noriyuki Akahoshi, Ryoka Hasegawa, Shingo Yamamoto, Rintaro Takemoto, Toshiki Yoshizawa, Waka Kamichatani and Isao Ishii

Int. J. Mol. Sci. 2023, 24(3), 2659; https://doi.org/10.3390/ijms24032659 - 31 Jan 2023

Cited by 3 | Viewed by 2476

Abstract

Hydrogen sulfide (H₂S) has been shown to act as both anti-inflammatory and pro-inflammatory mediators. Application of H₂S donors generally protects against inflammation; however, experimental results using mice lacking endogenous H₂S-producing enzymes, such as cystathionine γ-lyase (CTH) and [...] Read more.

Hydrogen sulfide (H₂S) has been shown to act as both anti-inflammatory and pro-inflammatory mediators. Application of H₂S donors generally protects against inflammation; however, experimental results using mice lacking endogenous H₂S-producing enzymes, such as cystathionine γ-lyase (CTH) and mercaptopyruvate sulfurtransferase (MPST), are often contradictory. We herein examined two types of model hapten-induced inflammation models, colitis (an inflammatory bowel disease model of mucosal immunity) and contact dermatitis (a type IV allergic model of systemic immunity), in CTH-deficient (Cth^–/–) and MPST-deficient (Mpst^–/–) mice. Both mice exhibited no significant alteration from wild-type mice in trinitrobenzene sulfonic acid (Th1-type hapten)-induced colitis (a Crohn’s disease model) and oxazolone (Th1/Th2 mix-type; Th2 dominant)-induced colitis (an ulcerative colitis model). However, Cth^–/– (not Mpst^–/–) mice displayed more exacerbated phenotypes in trinitrochlorobenzene (TNCB; Th1-type)-induced contact dermatitis, but not oxazolone, at the delayed phase (24 h post-administration) of inflammation. CTH mRNA expression was upregulated in the TNCB-treated ears of both wild-type and Mpst^–/– mice. Although mRNA expression of pro-inflammatory cytokines (IL-1β and IL-6) was upregulated in both early (2 h) and delayed phases of TNCB-triggered dermatitis in all genotypes, that of Th2 (IL-4) and Treg cytokines (IL-10) was upregulated only in Cth^–/– mice, when that of Th1 cytokines (IFNγ and IL-2) was upregulated in wild-type and Mpst^–/– mice at the delayed phase. These results suggest that (upregulated) CTH or H₂S produced by it helps maintain Th1/Th2 balance to protect against contact dermatitis. Full article

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19 pages, 4082 KiB

Open AccessReview

Biological Activity of Selenium and Its Impact on Human Health

by Giuseppe Genchi, Graziantonio Lauria, Alessia Catalano, Maria Stefania Sinicropi and Alessia Carocci

Int. J. Mol. Sci. 2023, 24(3), 2633; https://doi.org/10.3390/ijms24032633 - 30 Jan 2023

Cited by 120 | Viewed by 11536

Abstract

Selenium (Se) is a naturally occurring metalloid element essential to human and animal health in trace amounts but it is harmful in excess. Se plays a substantial role in the functioning of the human organism. It is incorporated into selenoproteins, thus supporting antioxidant [...] Read more.

Selenium (Se) is a naturally occurring metalloid element essential to human and animal health in trace amounts but it is harmful in excess. Se plays a substantial role in the functioning of the human organism. It is incorporated into selenoproteins, thus supporting antioxidant defense systems. Selenoproteins participate in the metabolism of thyroid hormones, control reproductive functions and exert neuroprotective effects. Among the elements, Se has one of the narrowest ranges between dietary deficiency and toxic levels. Its level of toxicity may depend on chemical form, as inorganic and organic species have distinct biological properties. Over the last decades, optimization of population Se intake for the prevention of diseases related to Se deficiency or excess has been recognized as a pressing issue in modern healthcare worldwide. Low selenium status has been associated with an increased risk of mortality, poor immune function, cognitive decline, and thyroid dysfunction. On the other hand, Se concentrations slightly above its nutritional levels have been shown to have adverse effects on a broad spectrum of neurological functions and to increase the risk of type-2 diabetes. Comprehension of the selenium biochemical pathways under normal physiological conditions is therefore an important issue to elucidate its effect on human diseases. This review gives an overview of the role of Se in human health highlighting the effects of its deficiency and excess in the body. The biological activity of Se, mainly performed through selenoproteins, and its epigenetic effect is discussed. Moreover, a brief overview of selenium phytoremediation and rhizofiltration approaches is reported. Full article

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11 pages, 2285 KiB

Open AccessArticle

A Mixture of Dietary Plant Sterols at Nutritional Relevant Serum Concentration Inhibits Extrinsic Pathway of Eryptosis Induced by Cigarette Smoke Extract

by Ignazio Restivo, Alessandro Attanzio, Luisa Tesoriere, Mario Allegra, Guadalupe Garcia-Llatas and Antonio Cilla

Int. J. Mol. Sci. 2023, 24(2), 1264; https://doi.org/10.3390/ijms24021264 - 9 Jan 2023

Cited by 3 | Viewed by 2235

Abstract

Cell death program of red blood cells (RBCs), called eryptosis, is characterized by activation of caspases and scrambling of membrane phospholipids with externalization of phosphatidylserine (PS). Excessive eryptosis confers a procoagulant phenotype and is implicated in impairment of microcirculation and increased prothrombotic risk. [...] Read more.

Cell death program of red blood cells (RBCs), called eryptosis, is characterized by activation of caspases and scrambling of membrane phospholipids with externalization of phosphatidylserine (PS). Excessive eryptosis confers a procoagulant phenotype and is implicated in impairment of microcirculation and increased prothrombotic risk. It has recently been reported that cigarette smokers have high levels of circulating eryptotic erythrocytes, and a possible contribution of eryptosis to the vaso-occlusive complications associated to cigarette smoke has been postulated. In this study, we demonstrate how a mixture of plant sterols (MPtS) consisting of β-sitosterol, campesterol and stigmasterol, at serum concentration reached after ingestion of a drink enriched with plant sterols, inhibits eryptosis induced by cigarette smoke extract (CSE). Isolated RBCs were exposed for 4 h to CSE (10–20% v/v). When RBCs were co-treated with CSE in the presence of 22 µM MPtS, a significant reduction of the measured hallmarks of apoptotic death like assembly of the death-inducing signaling complex (DISC), PS outsourced, ceramide production, cleaved forms of caspase 8/caspase 3, and phosphorylated p38 MAPK, was evident. The new beneficial properties of plant sterols on CSE-induced eryptosis presented in this work open new perspectives to prevent the negative physio-pathological events caused by the eryptotic red blood cells circulating in smokers. Full article

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22 pages, 8529 KiB

Open AccessArticle

Hyperforin Elicits Cytostatic/Cytotoxic Activity in Human Melanoma Cell Lines, Inhibiting Pro-Survival NF-κB, STAT3, AP1 Transcription Factors and the Expression of Functional Proteins Involved in Mitochondrial and Cytosolic Metabolism

by Alessia Cardile, Valentina Zanrè, Rachele Campagnari, Francesca Asson, Solomon Saforo Addo, Elisa Orlandi and Marta Menegazzi

Int. J. Mol. Sci. 2023, 24(2), 1263; https://doi.org/10.3390/ijms24021263 - 9 Jan 2023

Cited by 10 | Viewed by 3169

Abstract

Hyperforin (HPF), the main component responsible for the antidepressant action of Hypericum perforatum, displays additional beneficial properties including anti-inflammatory, antimicrobic, and antitumor activities. Among its antitumor effects, HPF activity on melanoma is poorly documented. Melanoma, especially BRAF-mutated melanoma, is still a high-mortality [...] Read more.

Hyperforin (HPF), the main component responsible for the antidepressant action of Hypericum perforatum, displays additional beneficial properties including anti-inflammatory, antimicrobic, and antitumor activities. Among its antitumor effects, HPF activity on melanoma is poorly documented. Melanoma, especially BRAF-mutated melanoma, is still a high-mortality tumor type and the currently available therapies do not provide solutions. We investigated HPF’s antimelanoma effectiveness in A375, FO1 and SK-Mel-28 human BRAF-mutated cell lines. Cell viability assays documented that all melanoma cells were affected by low HPF concentrations (EC50% 2–4 µM) in a time-dependent manner. A Br-deoxy-uridine incorporation assay attested a significant reduction of cell proliferation accompanied by decreased expression of cyclin D1 and A2, CDK4 and of the Rb protein phosphorylation, as assessed by immunoblots. In addition, the expression of P21/waf1 and the activated form of P53 were increased in A375 and SK-Mel-28 cells. Furthermore, HPF exerts cytotoxic effects. Apoptosis is induced 24 h after HPF administration, documented by an increase of cleaved-PARP1 and a decrease of both Bcl2 and Bcl-xL expression levels. Autophagy is induced, attested by an augmented LC3B expression and augmentation of the activated form of AMPK. Moreover, HPF lowers GPX4 enzyme expression, suggesting ferroptosis induction. HPF has been reported to activate the TRPC6 Ca⁺⁺ channel and/or Ca⁺⁺ and Zn⁺⁺ release from mitochondria stores, increasing cytosolic Ca⁺⁺ and Zn⁺⁺ concentrations. Our data highlighted that HPF affects many cell-signaling pathways, including signaling induced by Ca⁺⁺, such as FRA1, pcJun and pCREB, the expression or activity of which are increased shortly after treatment. However, the blockage of the TRPC6 Ca⁺⁺ channel or the use of Ca⁺⁺ and Zn⁺⁺ chelators do not hinder HPF cytostatic/cytotoxic activity, suggesting that damages induced in melanoma cells may pass through other pathways. Remarkably, 24 h after HPF treatment, the expression of activated forms of the transcription factors NF-κB P65 subunit and STAT3 are significantly lowered. Several cytosolic (PGM2, LDHA and pPKM2) and mitochondrial (UQCRC1, COX4 and ATP5B) enzymes are downregulated by HPF treatment, suggesting a generalized reduction of vital functions in melanoma cells. In line with these results is the recognized ability of HPF to affect mitochondrial membrane potential by acting as a protonophore. Finally, HPF can hinder both melanoma cell migration and colony formation in soft agar. In conclusion, we provide evidence of the pleiotropic antitumor effects induced by HPF in melanoma cells. Full article

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20 pages, 4174 KiB

Open AccessArticle

Differential Effects of Oligosaccharides, Antioxidants, Amino Acids and PUFAs on Heat/Hypoxia-Induced Epithelial Injury in a Caco-2/HT-29 Co-Culture Model

by Puqiao Lian, Paul A. J. Henricks, Harry J. Wichers, Gert Folkerts and Saskia Braber

Int. J. Mol. Sci. 2023, 24(2), 1111; https://doi.org/10.3390/ijms24021111 - 6 Jan 2023

Cited by 5 | Viewed by 2837

Abstract

(1) Exposure of intestinal epithelial cells to heat and hypoxia causes a (heat) stress response, resulting in the breakdown of epithelial integrity. There are indications that several categories of nutritional components have beneficial effects on maintaining the intestinal epithelial integrity under stress conditions. [...] Read more.

(1) Exposure of intestinal epithelial cells to heat and hypoxia causes a (heat) stress response, resulting in the breakdown of epithelial integrity. There are indications that several categories of nutritional components have beneficial effects on maintaining the intestinal epithelial integrity under stress conditions. This study evaluated the effect of nine nutritional components, including non-digestible oligosaccharides (galacto-oligosaccharides (GOS), fructo-oligosaccharides (FOS), chitosan oligosaccharides (COS)), antioxidants (α-lipoic acid (ALA), resveratrol (RES)), amino acids (l-glutamine (Glu), l-arginine (Arg)) and polyunsaturated fatty acids (PUFAs) (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)), on heat/hypoxia-induced epithelial injury. (2) Two human colonic cell lines, Caco-2 and HT-29, were co-cultured and pre-treated with the nutritional components for 48 h. After pre-treatment, the cells were exposed to heat/hypoxia (42 °C, 5% O₂) for 2 h. Epithelial integrity was evaluated by measuring trans-epithelial electrical resistance (TEER), paracellular Lucifer Yellow (LY) permeability, and tight junction (TJ) protein expression. Heat stress and oxidative stress levels were evaluated by determining heat-shock protein-70 (HSP-70) expression and the concentration of the lipid peroxidation product malondialdehyde (MDA). (3) GOS, FOS, COS, ALA, RES, Arg, and EPA presented protective effects on epithelial damage in heat/hypoxia-exposed Caco-2/HT-29 cells by preventing the decrease in TEER, the increase in LY permeability, and/or decrease in TJ proteins zonula occludens-1 (ZO-1) and claudin-3 expression. COS, RES, and EPA demonstrated anti-oxidative stress effects by suppressing the heat/hypoxia-induced MDA production, while Arg further elevated the heat/hypoxia-induced increase in HSP-70 expression. (4) This study indicates that various nutritional components have the potential to counteract heat/hypoxia-induced intestinal injury and might be interesting candidates for future in vivo studies and clinical trials in gastrointestinal disorders related to heat stress and hypoxia. Full article

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2022

Jump to: 2024, 2023, 2021, 2020

16 pages, 1915 KiB

Open AccessArticle

Cannabidiol and Nano-Selenium Increase Microvascularization and Reduce Degenerative Changes in Superficial Breast Muscle in C. perfringens-Infected Chickens

by Paweł Konieczka, Dominika Szkopek, Misza Kinsner, Paweł Kowalczyk, Monika Michalczuk, Damian Bień, Joanna Banach, Paulius Matusevičius and Joanna Bogucka

Int. J. Mol. Sci. 2023, 24(1), 237; https://doi.org/10.3390/ijms24010237 - 23 Dec 2022

Cited by 5 | Viewed by 3058

Abstract

Here, we demonstrated the potential of Cannabis-derived cannabidiol (CBD) and nanosized selenium (nano-Se) for the modulation of microvascularization and muscle fiber lesions in superficial breast muscle in C. perfringens-challenged chickens. The administration of CBD resulted in a decreased number of atrophic [...] Read more.

Here, we demonstrated the potential of Cannabis-derived cannabidiol (CBD) and nanosized selenium (nano-Se) for the modulation of microvascularization and muscle fiber lesions in superficial breast muscle in C. perfringens-challenged chickens. The administration of CBD resulted in a decreased number of atrophic fibers (3.13 vs. 1.13/1.5 mm²) compared with the control, whereas nano-Se or both substances resulted in a decreased split fiber number (4.13 vs. 1.55/1.5 mm²) and in a lower number of necrotic myofibers (2.38 vs. 0.69/1.5 mm²) in breast muscle than the positive control. There was a significantly higher number of capillary vessels in chickens in the CBD+Nano-Se group than in the control and positive control groups (1.31 vs. 0.97 and 0.98, respectively). Feeding birds experimental diets lowered the activity of DNA damage repair enzymes, including 3,N4-ethenodeoxycytosine (by 39.6%), 1,N6-ethenodeoxyadenosine (by 37.5%), 8-oxo-guanine (by 36.2%), formamidopyrimidine (fapy)-DNA glycosylase (by 56.2%) and human alkyl adenine DNA glycosylase (by 40.2%) in the ileal mucosa, but it did not compromise the blood mitochondrial oxygen consumption rate (−2.67 OD/min on average). These findings indicate a potential link between gut mucosa condition and histopathological changes in superficial pectoral muscle under induced inflammation and show the ameliorative effect of CBD and nano-Se in this cross-talk due to their protection from mucosal DNA damage. Full article

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12 pages, 3694 KiB

Open AccessArticle

Ivermectin Attenuates CCl₄-Induced Liver Fibrosis in Mice by Suppressing Hepatic Stellate Cell Activation

by Hanglu Ying, Long Li, Yufen Zhao and Feng Ni

Int. J. Mol. Sci. 2022, 23(24), 16043; https://doi.org/10.3390/ijms232416043 - 16 Dec 2022

Cited by 4 | Viewed by 7206

Abstract

Liver fibrosis, a common liver dysfunction with high morbidity and mortality rates, is the leading cause of cirrhosis and hepatocellular carcinoma, for which there are no effective therapies. Ivermectin is an antiparasitic drug that also has been showing therapeutic actions in many other [...] Read more.

Liver fibrosis, a common liver dysfunction with high morbidity and mortality rates, is the leading cause of cirrhosis and hepatocellular carcinoma, for which there are no effective therapies. Ivermectin is an antiparasitic drug that also has been showing therapeutic actions in many other diseases, including antiviral and anticancer actions, as well as treating metabolic diseases. Herein, we evaluated the function of ivermectin in regulating liver fibrosis. Firstly, carbon tetrachloride (CCl₄)-injected Balb/c mice were used to assess the antifibrosis effects of ivermectin in vivo. Further, CFSC, a rat hepatic stellate cell (HSC) line, was used to explore the function of ivermectin in HSC activation in vitro. The in vivo data showed that ivermectin administration alleviated histopathological changes, improved liver function, reduced collagen deposition, and downregulated the expression of profibrotic genes. Mechanistically, the ivermectin treatment inhibited intrahepatic macrophage accumulation and suppressed the production of proinflammatory factors. Importantly, the ivermectin administration significantly decreased the protein levels of α-smooth muscle actin (α-SMA) both in vivo and in vitro, suggesting that the antifibrotic effects of ivermectin are mainly due to the promotion of HSC deactivation. The present study demonstrates that ivermectin may be a potential therapeutic agent for the prevention of hepatic fibrosis. Full article

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16 pages, 1237 KiB

Open AccessReview

Crosstalk between Resveratrol and Gut Barrier: A Review

by Natalia Drabińska and Elżbieta Jarocka-Cyrta

Int. J. Mol. Sci. 2022, 23(23), 15279; https://doi.org/10.3390/ijms232315279 - 3 Dec 2022

Cited by 10 | Viewed by 2714

Abstract

The plant-based nutraceuticals are receiving increasing interest in recent time. The high attraction to the phytochemicals is associated with their anti-inflammatory and antioxidant activities, which can lead to reduced risk of the development of cardiovascular and other non-communicable diseases. One of the most [...] Read more.

The plant-based nutraceuticals are receiving increasing interest in recent time. The high attraction to the phytochemicals is associated with their anti-inflammatory and antioxidant activities, which can lead to reduced risk of the development of cardiovascular and other non-communicable diseases. One of the most disseminated groups of plant bioactives are phenolic compounds. It was recently hypothesized that phenolic compounds can have the ability to improve the functioning of the gut barrier. The available studies showed that one of the polyphenols, resveratrol, has great potential to improve the integrity of the gut barrier. Very promising results have been obtained with in vitro and animal models. Still, more clinical trials must be performed to evaluate the effect of resveratrol on the gut barrier, especially in individuals with increased intestinal permeability. Moreover, the interplay between phenolic compounds, intestinal microbiota and gut barrier should be carefully evaluated in the future. Therefore, this review offers an overview of the current knowledge about the interaction between polyphenols with a special emphasis on resveratrol and the gut barrier, summarizes the available methods to evaluate the intestinal permeability, discusses the current research gaps and proposes the directions for future studies in this research area. Full article

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18 pages, 1827 KiB

Open AccessArticle

Selectively Halogenated Flavonolignans—Preparation and Antibacterial Activity

by Martina Hurtová, Kristýna Káňová, Simona Dobiasová, Kateřina Holasová, Denisa Čáková, Lan Hoang, David Biedermann, Marek Kuzma, Josef Cvačka, Vladimír Křen, Jitka Viktorová and Kateřina Valentová

Int. J. Mol. Sci. 2022, 23(23), 15121; https://doi.org/10.3390/ijms232315121 - 1 Dec 2022

Cited by 10 | Viewed by 2360

Abstract

A library of previously unknown halogenated derivatives of flavonolignans (silybins A and B, 2,3-dehydrosilybin, silychristin A, and 2,3-dehydrosilychristin A) was prepared. The effect of halogenation on the biological activity of flavonolignans was investigated. Halogenated derivatives had a significant effect on bacteria. All prepared [...] Read more.

A library of previously unknown halogenated derivatives of flavonolignans (silybins A and B, 2,3-dehydrosilybin, silychristin A, and 2,3-dehydrosilychristin A) was prepared. The effect of halogenation on the biological activity of flavonolignans was investigated. Halogenated derivatives had a significant effect on bacteria. All prepared derivatives inhibited the AI-2 type of bacterial communication (quorum sensing) at concentrations below 10 µM. All prepared compounds also inhibited the adhesion of bacteria (Staphyloccocus aureus and Pseudomonas aeruginosa) to the surface, preventing biofilm formation. These two effects indicate that the halogenated derivatives are promising antibacterial agents. Moreover, these derivatives acted synergistically with antibiotics and reduced the viability of antibiotic-resistant S. aureus. Some flavonolignans were able to reverse the resistant phenotype to a sensitive one, implying that they modulate antibiotic resistance. Full article

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17 pages, 1364 KiB

Open AccessArticle

Effect of the Production Parameters and In Vitro Digestion on the Content of Polyphenolic Compounds, Phenolic Acids, and Antiradical Properties of Innovative Snacks Enriched with Wild Garlic (Allium ursinum L.) Leaves

by Kamila Kasprzak-Drozd, Tomasz Oniszczuk, Iwona Kowalska, Jarosław Mołdoch, Maciej Combrzyński, Marek Gancarz, Bohdan Dobrzański, Jr., Adrianna Kondracka and Anna Oniszczuk

Int. J. Mol. Sci. 2022, 23(22), 14458; https://doi.org/10.3390/ijms232214458 - 21 Nov 2022

Cited by 10 | Viewed by 2042

Abstract

A new type of corn snack has been created containing additions of wild garlic (Allium ursinum L.). This medicinal and dietary plant has a long tradition of use in folk medicine. However, studies on wild garlic composition and activity are fairly recent [...] Read more.

A new type of corn snack has been created containing additions of wild garlic (Allium ursinum L.). This medicinal and dietary plant has a long tradition of use in folk medicine. However, studies on wild garlic composition and activity are fairly recent and scarce. This research aimed to investigate the influence of the screw speed and A. ursinum amounts on the antiradical properties as well as the content of polyphenolic compounds and individual phenolic acids of innovative snacks enriched with wild garlic leaves. The highest radical scavenging activity and content of polyphenols and phenolic acids were found in the snacks enriched with 4% wild garlic produced using screw speed 120 rpm. The obtained findings demonstrated that snacks enriched with wild garlic are a rich source of polyphenolic compounds. Since the concentration of such compounds is affected by many factors, e.g., plant material, presence of other compounds, and digestion, the second aim of this study was to determine radical scavenging activity, the content of polyphenols, and individual phenolic acids of snacks after in vitro simulated gastrointestinal digestion. Using an in vitro two-stage model, authors noted a significant difference between the concentration of polyphenolic compounds and the polyphenol content of the plant material before digestion. Full article

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12 pages, 1386 KiB

Open AccessArticle

DPP-IV Inhibitory Peptides GPF, IGL, and GGGW Obtained from Chicken Blood Hydrolysates

by Gisela Carrera-Alvarado, Fidel Toldrá and Leticia Mora

Int. J. Mol. Sci. 2022, 23(22), 14140; https://doi.org/10.3390/ijms232214140 - 16 Nov 2022

Cited by 9 | Viewed by 2679

Abstract

Blood is a meat by-product rich in proteins with properties that can be improved after hydrolysis, making it a sustainable alternative for use in the generation of bioactive peptides. The objective of this study was to identify dipeptidyl peptidase IV (DPP-IV) inhibitory peptides [...] Read more.

Blood is a meat by-product rich in proteins with properties that can be improved after hydrolysis, making it a sustainable alternative for use in the generation of bioactive peptides. The objective of this study was to identify dipeptidyl peptidase IV (DPP-IV) inhibitory peptides obtained from different chicken blood hydrolysates prepared using combinations of four different enzymes. Best results were observed for AP (2% Alcalase + 5% Protana Prime) and APP (2% Alcalase + 5% Protana Prime + 3% Protana UBoost) hydrolysates obtaining inhibition values of 60.55 and 53.61%, respectively, assayed at a concentration of 10 mg/mL. Free amino acids were determined to establish the impact of exopeptidase activity in the samples. A total of 79 and 12 sequences of peptides were identified by liquid chromatography and mass spectrometry in tandem (LC-MS/MS) in AP and APP samples, respectively. Nine of the identified peptides were established as potential DPP-IV inhibitory using in silico approaches and later synthesized for confirmation. Thus, peptides GPF, IGL, and GGGW showed good DPP-IV inhibitory activity with IC₅₀ values of 0.94, 2.22, and 2.73 mM, respectively. This study confirmed the potential of peptides obtained from chicken blood hydrolysates to be used as DPP-IV inhibitors and, therefore, in the control or modulation of type 2 diabetes. Full article

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22 pages, 7586 KiB

Open AccessArticle

Nontoxic and Naturally Occurring Active Compounds as Potential Inhibitors of Biological Targets in Liriomyza trifolii

by Israa M. Shamkh, Mohammed Al-Majidi, Ahmed Hassen Shntaif, Peter Tan Deng Kai, Ngoc Nh-Pham, Ishrat Rahman, Dalia Hamza, Mohammad Shahbaz Khan, Maii S. Elsharayidi, Eman T. Salah, Abdullah Haikal, Modupe Akintomiwa Omoniyi, Mahmoud A. Abdalrahman and Tomasz M. Karpinski

Int. J. Mol. Sci. 2022, 23(21), 12791; https://doi.org/10.3390/ijms232112791 - 24 Oct 2022

Cited by 6 | Viewed by 3072

Abstract

In recent years, novel strategies to control insects have been based on protease inhibitors (PIs). In this regard, molecular docking and molecular dynamics simulations have been extensively used to investigate insect gut proteases and the interactions of PIs for the development of resistance [...] Read more.

In recent years, novel strategies to control insects have been based on protease inhibitors (PIs). In this regard, molecular docking and molecular dynamics simulations have been extensively used to investigate insect gut proteases and the interactions of PIs for the development of resistance against insects. We, herein, report an in silico study of (disodium 5′-inosinate and petunidin 3-glucoside), (calcium 5′-guanylate and chlorogenic acid), chlorogenic acid alone, (kaempferol-3,7-di-O-glucoside with hyperoside and delphinidin 3-glucoside), and (myricetin 3′-glucoside and hyperoside) as potential inhibitors of acetylcholinesterase receptors, actin, α-tubulin, arginine kinase, and histone receptor III subtypes, respectively. The study demonstrated that the inhibitors are capable of forming stable complexes with the corresponding proteins while also showing great potential for inhibitory activity in the proposed protein-inhibitor combinations. Full article

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16 pages, 3819 KiB

Open AccessArticle

Anti-Inflammatory and Analgesic Effects of Curcumin Nanoparticles Associated with Diclofenac Sodium in Experimental Acute Inflammation

by Ioana Boarescu, Raluca Maria Pop, Paul-Mihai Boarescu, Ioana Corina Bocșan, Dan Gheban, Ruxandra-Mioara Râjnoveanu, Armand Râjnoveanu, Adriana Elena Bulboacă, Anca Dana Buzoianu and Sorana D. Bolboacă

Int. J. Mol. Sci. 2022, 23(19), 11737; https://doi.org/10.3390/ijms231911737 - 3 Oct 2022

Cited by 17 | Viewed by 3810

Abstract

The present study evaluated the anti-inflammatory and analgesic effects of conventional curcumin (cC) and curcumin nanoparticles (nC) associated with diclofenac sodium (D) in experimental acute inflammation (AI) induced by carrageenan administration. Seven groups of eight randomly selected Wistar-Bratislava white rats were evaluated. One [...] Read more.

The present study evaluated the anti-inflammatory and analgesic effects of conventional curcumin (cC) and curcumin nanoparticles (nC) associated with diclofenac sodium (D) in experimental acute inflammation (AI) induced by carrageenan administration. Seven groups of eight randomly selected Wistar-Bratislava white rats were evaluated. One group was the control (C), and AI was induced in the other six groups. The AI group was treated with saline solution, the AID group was treated with D, the AIcC200 and AInC200 groups were treated with cC and nC, respectively, while AIcC200D and AInC200D were treated with cC and nC, respectively, both associated with D. Conventional curcumin, nC, and D were administered in a single dose of 200 mg/kg b.w. for cC and nC and 5 mg/kg b.w. for D. Association of cC or nC to D resulted in significant antinociceptive activity, and improved mechanical pressure stimulation and heat thresholds at 3, 5, 7 and 24 h (p < 0.03). The association of cC and nC with D (AIcC200D and AInC200D groups) showed significantly lower plasma and tissue levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) up to 2.5 times, with the best results in the group who received nC. Moreover, AInC200D presented the least severe histopathological changes with a reduced level of inflammation in the dermis and hypodermis. The combination of nC to D showed efficiency in reducing pain, inflammatory cytokines, and histological changes in acute inflammation. Full article

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42 pages, 3840 KiB

Open AccessReview

Biologically Active Diterpenoids in the Clerodendrum Genus—A Review

by Łukasz Kuźma and Jan Gomulski

Int. J. Mol. Sci. 2022, 23(19), 11001; https://doi.org/10.3390/ijms231911001 - 20 Sep 2022

Cited by 10 | Viewed by 2913

Abstract

One of the key areas of interest in pharmacognosy is that of the diterpenoids; many studies have been performed to identify new sources, their optimal isolation and biological properties. An important source of abietane-, pimarane-, clerodane-type diterpenoids and their derivatives are the members [...] Read more.

One of the key areas of interest in pharmacognosy is that of the diterpenoids; many studies have been performed to identify new sources, their optimal isolation and biological properties. An important source of abietane-, pimarane-, clerodane-type diterpenoids and their derivatives are the members of the genus Clerodendrum, of the Lamiaceae. Due to their diverse chemical nature, and the type of plant material, a range of extraction techniques are needed with various temperatures, solvent types and extraction times, as well as the use of an ultrasound bath. The diterpenoids isolated from Clerodendrum demonstrate a range of cytotoxic, anti-proliferative, antibacterial, anti-parasitic and anti-inflammatory activities. This review describes the various biological activities of the diterpenoids isolated so far from species of Clerodendrum with the indication of the most active ones, as well as those from other plant sources, taking into account their structure in terms of their activity, and summarises the methods for their extraction. Full article

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18 pages, 2685 KiB

Open AccessArticle

Synthesis and NLRP3-Inflammasome Inhibitory Activity of the Naturally Occurring Velutone F and of Its Non-Natural Regioisomeric Chalconoids

by Tiziano De Ventura, Mariasole Perrone, Sonia Missiroli, Paolo Pinton, Paolo Marchetti, Giovanni Strazzabosco, Giulia Turrin, Davide Illuminati, Virginia Cristofori, Anna Fantinati, Martina Fabbri, Carlotta Giorgi, Claudio Trapella and Vinicio Zanirato

Int. J. Mol. Sci. 2022, 23(16), 8957; https://doi.org/10.3390/ijms23168957 - 11 Aug 2022

Cited by 3 | Viewed by 2399

Abstract

Plant-derived remedies rich in chalcone-based compounds have been known for centuries in the treatment of specific diseases, and nowadays, the fascinating chalcone framework is considered a useful and, above all, abundant natural chemotype. Velutone F, a new chalconoid from Millettia velutina, exhibits [...] Read more.

Plant-derived remedies rich in chalcone-based compounds have been known for centuries in the treatment of specific diseases, and nowadays, the fascinating chalcone framework is considered a useful and, above all, abundant natural chemotype. Velutone F, a new chalconoid from Millettia velutina, exhibits a potent effect as an NLRP3-inflammasome inhibitor; the search for new natural/non-natural lead compounds as NLRP3 inhibitors is a current topical subject in medicinal chemistry. The details of our work toward the synthesis of velutone F and the unknown non-natural regioisomers are herein reported. We used different synthetic strategies both for the construction of the distinctive benzofuran nucleus (BF) and for the key phenylpropenone system (PhP). Importantly, we have disclosed a facile entry to the velutone F via synthetic routes that can also be useful for preparing non-natural analogs, a prerequisite for extensive SAR studies on the new flavonoid class of NLRP3-inhibitors. Full article

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12 pages, 13965 KiB

Open AccessArticle

Viability of Glioblastoma Cells and Fibroblasts in the Presence of Imidazole-Containing Compounds

by Elisabeth Christiane Seidel, Claudia Birkemeyer, Rainer Baran-Schmidt, Jürgen Meixensberger, Henry Oppermann and Frank Gaunitz

Int. J. Mol. Sci. 2022, 23(10), 5834; https://doi.org/10.3390/ijms23105834 - 23 May 2022

Cited by 5 | Viewed by 2521

Abstract

The naturally occurring dipeptide carnosine (β-alanyl-L-histidine) specifically attenuates tumor growth. Here, we ask whether other small imidazole-containing compounds also affect the viability of tumor cells without affecting non-malignant cells and whether the formation of histamine is involved. Patient-derived fibroblasts and glioblastoma [...] Read more.

The naturally occurring dipeptide carnosine (β-alanyl-L-histidine) specifically attenuates tumor growth. Here, we ask whether other small imidazole-containing compounds also affect the viability of tumor cells without affecting non-malignant cells and whether the formation of histamine is involved. Patient-derived fibroblasts and glioblastoma cells were treated with carnosine, L-alanyl-L-histidine (LA-LH), β-alanyl-L-alanine, L-histidine, histamine, imidazole, β-alanine, and L-alanine. Cell viability was assessed by cell-based assays and microscopy. The intracellular release of L-histidine and formation of histamine was investigated by high-performance liquid chromatography coupled to mass spectrometry. Carnosine and LA-LH inhibited tumor cell growth with minor effects on fibroblasts, and L-histidine, histamine, and imidazole affected viability in both cell types. Compounds without the imidazole moiety did not diminish viability. In the presence of LA-LH but not in the presence of carnosine, a significant rise in intracellular amounts of histidine was detected in all cells. The formation of histamine was not detectable in the presence of carnosine, LA-LH, or histidine. In conclusion, the imidazole moiety of carnosine contributes to its anti-neoplastic effect, which is also seen in the presence of histidine and LA-LH. Despite the fact that histamine has a strong effect on cell viability, the formation of histamine is not responsible for the effects on the cell viability of carnosine, LA-LH, and histidine. Full article

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17 pages, 1614 KiB

Open AccessArticle

Sulfated Phenolic Substances: Preparation and Optimized HPLC Analysis

by Lucie Petrásková, Kristýna Káňová, Katerina Brodsky, Anastasiia Hetman, Barbora Petránková, Helena Pelantová, Vladimír Křen and Kateřina Valentová

Int. J. Mol. Sci. 2022, 23(10), 5743; https://doi.org/10.3390/ijms23105743 - 20 May 2022

Cited by 3 | Viewed by 2772

Abstract

Sulfation is an important reaction in nature, and sulfated phenolic compounds are of interest as standards of mammalian phase II metabolites or pro-drugs. Such standards can be prepared using chemoenzymatic methods with aryl sulfotransferases. The aim of the present work was to obtain [...] Read more.

Sulfation is an important reaction in nature, and sulfated phenolic compounds are of interest as standards of mammalian phase II metabolites or pro-drugs. Such standards can be prepared using chemoenzymatic methods with aryl sulfotransferases. The aim of the present work was to obtain a large library of sulfated phenols, phenolic acids, flavonoids, and flavonolignans and optimize their HPLC (high performance liquid chromatography) analysis. Four new sulfates of 2,3,4-trihydroxybenzoic acid, catechol, 4-methylcatechol, and phloroglucinol were prepared and fully characterized using MS (mass spectrometry), ¹H, and ¹³C NMR. The separation was investigated using HPLC with PDA (photodiode-array) detection and a total of 38 standards of phenolics and their sulfates. Different stationary (monolithic C18, C18 Polar, pentafluorophenyl, ZICpHILIC) and mobile phases with or without ammonium acetate buffer were compared. The separation results were strongly dependent on the pH and buffer capacity of the mobile phase. The developed robust HPLC method is suitable for the separation of enzymatic sulfation reaction mixtures of flavonoids, flavonolignans, 2,3-dehydroflavonolignans, phenolic acids, and phenols with PDA detection. Moreover, the method is directly applicable in conjunction with mass detection due to the low flow rate and the absence of phosphate buffer and/or ion-pairing reagents in the mobile phase. Full article

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18 pages, 21142 KiB

Open AccessArticle

Effects of Hypocalcemic Vitamin D Analogs in the Expression of DNA Damage Induced in Minilungs from hESCs: Implications for Lung Fibrosis

by Esmeralda Magro-Lopez, Irene Chamorro-Herrero and Alberto Zambrano

Int. J. Mol. Sci. 2022, 23(9), 4921; https://doi.org/10.3390/ijms23094921 - 28 Apr 2022

Cited by 3 | Viewed by 3213

Abstract

In our previous work, we evaluated the therapeutic effects of 1α,25-Dihydroxyvitamin D₃, the biologically active form of vitamin D, in the context of bleomycin-induced lung fibrosis. Contrary to the expected, vitamin D supplementation increased the DNA damage expression and cellular senescence [...] Read more.

In our previous work, we evaluated the therapeutic effects of 1α,25-Dihydroxyvitamin D₃, the biologically active form of vitamin D, in the context of bleomycin-induced lung fibrosis. Contrary to the expected, vitamin D supplementation increased the DNA damage expression and cellular senescence in alveolar epithelial type II cells and aggravated the overall lung pathology induced in mice by bleomycin. These effects were probably due to an alteration in the cellular DNA double-strand breaks’ repair capability. In the present work, we have evaluated the effects of two hypocalcemic vitamin D analogs (calcipotriol and paricalcitol) in the expression of DNA damage in the context of minilungs derived from human embryonic stem cells and in the cell line A549. Full article

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15 pages, 3720 KiB

Open AccessArticle

Urolithin A Inactivation of TLR3/TRIF Signaling to Block the NF-κB/STAT1 Axis Reduces Inflammation and Enhances Antioxidant Defense in Poly(I:C)-Induced RAW264.7 Cells

by Wen-Chung Huang, Chian-Jiun Liou, Szu-Chuan Shen, Sindy Hu, Jane C-J Chao, Chien-Yu Hsiao and Shu-Ju Wu

Int. J. Mol. Sci. 2022, 23(9), 4697; https://doi.org/10.3390/ijms23094697 - 23 Apr 2022

Cited by 21 | Viewed by 3995

Abstract

Urolithin A is an active compound of gut-microbiota-derived metabolites of polyphenol ellagic acid that has anti-aging, antioxidative, and anti-inflammatory effects. However, the effects of urolithin A on polyinosinic acid-polycytidylic acid (poly(I:C))-induced inflammation remain unclear. Poly(I:C) is a double-stranded RNA (dsRNA) similar to a [...] Read more.

Urolithin A is an active compound of gut-microbiota-derived metabolites of polyphenol ellagic acid that has anti-aging, antioxidative, and anti-inflammatory effects. However, the effects of urolithin A on polyinosinic acid-polycytidylic acid (poly(I:C))-induced inflammation remain unclear. Poly(I:C) is a double-stranded RNA (dsRNA) similar to a virus and is recognized by Toll-like receptor-3 (TLR3), inducing an inflammatory response in immune cells, such as macrophages. Inflammation is a natural defense process of the innate immune system. Therefore, we used poly(I:C)-induced RAW264.7 cells and attenuated the inflammation induced by urolithin A. First, our data suggested that 1–30 μM urolithin A does not reduce RAW264.7 cell viability, whereas 1 μM urolithin A is sufficient for antioxidation and the decreased production of tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and C-C chemokine ligand 5. The inflammation-related proteins cyclooxygenase-2 and inducible nitric oxide synthase were also downregulated by urolithin A. Next, 1 μM urolithin A inhibited the levels of interferon (INF)-α and INF-β. Urolithin A was applied to investigate the blockade of the TLR3 signaling pathway in poly(I:C)-induced RAW264.7 cells. Moreover, the TLR3 signaling pathway, subsequent inflammatory-related pathways, and antioxidation pathways showed changes in nuclear factor-κB (NF-κB) signaling and blocked ERK/mitogen-activated protein kinase (MAPK) signaling. Urolithin A enhanced catalase (CAT) and superoxide dismutase (SOD) activities, but decreased malondialdehyde (MDA) levels in poly(I:C)-induced RAW264.7 cells. Thus, our results suggest that urolithin A inhibits TLR3-activated inflammatory and oxidative-associated pathways in macrophages, and that this inhibition is induced by poly(I:C). Therefore, urolithin A may have antiviral effects and could be used to treat viral-infection-related diseases. Full article

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13 pages, 2692 KiB

Open AccessArticle

Overexpression of Neuregulin-1 Type III Has Impact on Visual Function in Mice

by Nan Su, Weiqi Zhang, Nicole Eter, Peter Heiduschka and Mingyue Zhang

Int. J. Mol. Sci. 2022, 23(9), 4489; https://doi.org/10.3390/ijms23094489 - 19 Apr 2022

Cited by 3 | Viewed by 2551

Abstract

Schizophrenia is associated with several brain deficits, including abnormalities in visual processes. Neuregulin-1 (Nrg1) is a family of trophic factors containing an epidermal growth factor (EGF)-like domain. It is thought to play a role in neural development and has been linked to neuropsychiatric [...] Read more.

Schizophrenia is associated with several brain deficits, including abnormalities in visual processes. Neuregulin-1 (Nrg1) is a family of trophic factors containing an epidermal growth factor (EGF)-like domain. It is thought to play a role in neural development and has been linked to neuropsychiatric disorders. Abnormal Nrg1 expression has been observed in schizophrenia in clinical studies. Moreover, in schizophrenia, there is more and more evidence found about pathological changes of the retina regarding structural, neurochemical and physiological parameters. However, mechanisms of these changes are not well known. To investigate this, we analysed the function of the visual system using electroretinography (ERG) and the measurement of visual evoked potentials (VEP) in transgenic mice overexpressing Nrg1 type III of three different ages (12 weeks, 24 weeks and 55 weeks). ERG amplitudes tended to be higher in transgenic mice than in control mice in 12-week old mice, whereas the amplitudes were almost similar in older mice. VEP amplitudes were larger in transgenic mice at all ages, with significant differences at 12 and 55 weeks (p values between 0.003 and 0.036). Latencies in ERG and VEP measurements did not differ considerably between control mice and transgenic mice at any age. Our data show for the first time that overexpression of Nrg1 type III changed visual function in transgenic mice. Overall, this investigation of visual function in transgenic mice may be helpful to understand corresponding changes that occur in schizophrenia, as they may find use as biomarkers for psychiatric disorders as well as a potential tool for diagnosis in psychiatry. Full article

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16 pages, 4077 KiB

Open AccessArticle

S-Acetyl-Glutathione Attenuates Carbon Tetrachloride-Induced Liver Injury by Modulating Oxidative Imbalance and Inflammation

by Rosanna Di Paola, Sergio Modafferi, Rosalba Siracusa, Marika Cordaro, Ramona D’Amico, Maria Laura Ontario, Livia Interdonato, Angela Trovato Salinaro, Roberta Fusco, Daniela Impellizzeri, Vittorio Calabrese and Salvatore Cuzzocrea

Int. J. Mol. Sci. 2022, 23(8), 4429; https://doi.org/10.3390/ijms23084429 - 17 Apr 2022

Cited by 20 | Viewed by 4935

Abstract

Liver fibrosis, depending on the stage of the disease, could lead to organ dysfunction and cirrhosis, and no effective treatment is actually available. Emergent proof supports a link between oxidative stress, liver fibrogenesis and mitochondrial dysfunction as molecular bases of the pathology. A [...] Read more.

Liver fibrosis, depending on the stage of the disease, could lead to organ dysfunction and cirrhosis, and no effective treatment is actually available. Emergent proof supports a link between oxidative stress, liver fibrogenesis and mitochondrial dysfunction as molecular bases of the pathology. A valid approach to protect against the disease would be to replenish the endogenous antioxidants; thus, we investigated the protective mechanisms of the S-acetyl-glutathione (SAG), a glutathione (GSH) prodrug. Preliminary in vitro analyses were conducted on primary hepatic cells. SAG pre-treatment significantly protected against cytotoxicity induced by CCl4. Additionally, CCl4 induced a marked increase in AST and ALT levels, whereas SAG significantly reduced these levels, reaching values found in the control group. For the in vivo analyses, mice were administered twice a week with eight consecutive intraperitoneal injections of 1 mL/kg CCl4 (diluted at 1:10 in olive oil) to induce oxidative imbalance and liver inflammation. SAG (30 mg/kg) was administered orally for 8 weeks. SAG significantly restored SOD activity, GSH levels and GPx activity, while it strongly reduced GSSG levels, lipid peroxidation and H₂O₂ and ROS levels in the liver. Additionally, CCl4 induced a decrease in anti-oxidants, including Nrf2, HO-1 and NQO-1, which were restored by treatment with SAG. The increased oxidative stress characteristic on liver disfunction causes the impairment of mitophagy and accumulation of dysfunctional and damaged mitochondria. Our results showed the protective effect of SAG administration in restoring mitophagy, as shown by the increased PINK1 and Parkin expressions in livers exposed to CCl4 intoxication. Thus, the SAG administration showed anti-inflammatory effects decreasing pro-inflammatory cytokines TNF-α, IL-6, MCP-1 and IL-1β in both serum and liver, and suppressing the TLR4/NFkB pathway. SAG attenuated reduced fibrosis, collagen deposition, hepatocellular damage and organ dysfunction. In conclusion, our results suggest that SAG administration protects the liver from CCl4 intoxication by restoring the oxidative balance, ameliorating the impairment of mitophagy and leading to reduced inflammation. Full article

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15 pages, 1090 KiB

Open AccessReview

COVID-19 and One-Carbon Metabolism

by Joanna Perła-Kaján and Hieronim Jakubowski

Int. J. Mol. Sci. 2022, 23(8), 4181; https://doi.org/10.3390/ijms23084181 - 10 Apr 2022

Cited by 16 | Viewed by 7078

Abstract

Dysregulation of one-carbon metabolism affects a wide range of biological processes and is associated with a number of diseases, including cardiovascular disease, dementia, neural tube defects, and cancer. Accumulating evidence suggests that one-carbon metabolism plays an important role in COVID-19. The symptoms of [...] Read more.

Dysregulation of one-carbon metabolism affects a wide range of biological processes and is associated with a number of diseases, including cardiovascular disease, dementia, neural tube defects, and cancer. Accumulating evidence suggests that one-carbon metabolism plays an important role in COVID-19. The symptoms of long COVID-19 are similar to those presented by subjects suffering from vitamin B₁₂ deficiency (pernicious anemia). The metabolism of a cell infected by the SARS-CoV-2 virus is reshaped to fulfill the need for massive viral RNA synthesis, which requires de novo purine biosynthesis involving folate and one-carbon metabolism. Many aspects of host sulfur amino acid metabolism, particularly glutathione metabolism underlying antioxidant defenses, are also taken over by the SARS-CoV-2 virus. The purpose of this review is to summarize recent findings related to one-carbon metabolism and sulfur metabolites in COVID-19 and discuss how they inform strategies to combat the disease. Full article

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15 pages, 5111 KiB

Open AccessArticle

Neferine, an Alkaloid from Lotus Seed Embryos, Exerts Antiseizure and Neuroprotective Effects in a Kainic Acid-Induced Seizure Model in Rats

by Tzu-Yu Lin, Chih-Yu Hung, Kuan-Ming Chiu, Ming-Yi Lee, Cheng-Wei Lu and Su-Jane Wang

Int. J. Mol. Sci. 2022, 23(8), 4130; https://doi.org/10.3390/ijms23084130 - 8 Apr 2022

Cited by 19 | Viewed by 3313

Abstract

Current anti-seizure drugs fail to control approximately 30% of epilepsies. Therefore, there is a need to develop more effective anti-seizure drugs, and medicinal plants provide an attractive source for new compounds. This study aimed to evaluate the possible anti-seizure and neuroprotective effects of [...] Read more.

Current anti-seizure drugs fail to control approximately 30% of epilepsies. Therefore, there is a need to develop more effective anti-seizure drugs, and medicinal plants provide an attractive source for new compounds. This study aimed to evaluate the possible anti-seizure and neuroprotective effects of neferine, an alkaloid from the lotus seed embryos of Nelumbo nucifera, in a kainic acid (KA)-induced seizure rat model and its underlying mechanisms. Rats were intraperitoneally (i.p.) administrated neferine (10 and 50 mg/kg) 30 min before KA injection (15 mg/kg, i.p.). Neferine pretreatment increased seizure latency and reduced seizure scores, prevented glutamate elevation and neuronal loss, and increased presynaptic protein synaptophysin and postsynaptic density protein 95 expression in the hippocampi of rats with KA. Neferine pretreatment also decreased glial cell activation and proinflammatory cytokine (interleukin-1β, interleukin-6, tumor necrosis factor-α) expression in the hippocampi of rats with KA. In addition, NOD-like receptor 3 (NLRP3) inflammasome, caspase-1, and interleukin-18 expression levels were decreased in the hippocampi of seizure rats pretreated with neferine. These results indicated that neferine reduced seizure severity, exerted neuroprotective effects, and ameliorated neuroinflammation in the hippocampi of KA-treated rats, possibly by inhibiting NLRP3 inflammasome activation and decreasing inflammatory cytokine secretion. Our findings highlight the potential of neferine as a therapeutic option in the treatment of epilepsy. Full article

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47 pages, 6249 KiB

Open AccessReview

Nutraceutical Concepts and Dextrin-Based Delivery Systems

by Gjylije Hoti, Adrián Matencio, Alberto Rubin Pedrazzo, Claudio Cecone, Silvia Lucia Appleton, Yousef Khazaei Monfared, Fabrizio Caldera and Francesco Trotta

Int. J. Mol. Sci. 2022, 23(8), 4102; https://doi.org/10.3390/ijms23084102 - 7 Apr 2022

Cited by 27 | Viewed by 7949

Abstract

Nutraceuticals are bioactive or chemical compounds acclaimed for their valuable biological activities and health-promoting effects. The global community is faced with many health concerns such as cancers, cardiovascular and neurodegenerative diseases, diabetes, arthritis, osteoporosis, etc. The effect of nutraceuticals is similar to pharmaceuticals, [...] Read more.

Nutraceuticals are bioactive or chemical compounds acclaimed for their valuable biological activities and health-promoting effects. The global community is faced with many health concerns such as cancers, cardiovascular and neurodegenerative diseases, diabetes, arthritis, osteoporosis, etc. The effect of nutraceuticals is similar to pharmaceuticals, even though the term nutraceutical has no regulatory definition. The usage of nutraceuticals, to prevent and treat the aforementioned diseases, is limited by several features such as poor water solubility, low bioavailability, low stability, low permeability, low efficacy, etc. These downsides can be overcome by the application of the field of nanotechnology manipulating the properties and structures of materials at the nanometer scale. In this review, the linear and cyclic dextrin, formed during the enzymatic degradation of starch, are highlighted as highly promising nanomaterials- based drug delivery systems. The modified cyclic dextrin, cyclodextrin (CD)-based nanosponges (NSs), are well-known delivery systems of several nutraceuticals such as quercetin, curcumin, resveratrol, thyme essential oil, melatonin, and appear as a more advanced drug delivery system than modified linear dextrin. CD-based NSs prolong and control the nutraceuticals release, and display higher biocompatibility, stability, and solubility of poorly water-soluble nutraceuticals than the CD-inclusion complexes, or uncomplexed nutraceuticals. In addition, the well-explored CD-based NSs pathways, as drug delivery systems, are described. Although important progress is made in drug delivery, all the findings will serve as a source for the use of CD-based nanosystems for nutraceutical delivery. To sum up, our review introduces the extensive literature about the nutraceutical concepts, synthesis, characterization, and applications of the CD-based nano delivery systems that will further contribute to the nutraceutical delivery with more potent nanosystems based on linear dextrins. Full article

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19 pages, 1413 KiB

Open AccessReview

Gases in Sepsis: Novel Mediators and Therapeutic Targets

by Zhixing Zhu, Stephen Chambers, Yiming Zeng and Madhav Bhatia

Int. J. Mol. Sci. 2022, 23(7), 3669; https://doi.org/10.3390/ijms23073669 - 27 Mar 2022

Cited by 18 | Viewed by 3983

Abstract

Sepsis, a potentially lethal condition resulting from failure to control the initial infection, is associated with a dysregulated host defense response to pathogens and their toxins. Sepsis remains a leading cause of morbidity, mortality and disability worldwide. The pathophysiology of sepsis is very [...] Read more.

Sepsis, a potentially lethal condition resulting from failure to control the initial infection, is associated with a dysregulated host defense response to pathogens and their toxins. Sepsis remains a leading cause of morbidity, mortality and disability worldwide. The pathophysiology of sepsis is very complicated and is not yet fully understood. Worse still, the development of effective therapeutic agents is still an unmet need and a great challenge. Gases, including nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H₂S), are small-molecule biological mediators that are endogenously produced, mainly by enzyme-catalyzed reactions. Accumulating evidence suggests that these gaseous mediators are widely involved in the pathophysiology of sepsis. Many sepsis-associated alterations, such as the elimination of invasive pathogens, the resolution of disorganized inflammation and the preservation of the function of multiple organs and systems, are shaped by them. Increasing attention has been paid to developing therapeutic approaches targeting these molecules for sepsis/septic shock, taking advantage of the multiple actions played by NO, CO and H₂S. Several preliminary studies have identified promising therapeutic strategies for gaseous-mediator-based treatments for sepsis. In this review article, we summarize the state-of-the-art knowledge on the pathophysiology of sepsis; the metabolism and physiological function of NO, CO and H₂S; the crosstalk among these gaseous mediators; and their crucial effects on the development and progression of sepsis. In addition, we also briefly discuss the prospect of developing therapeutic interventions targeting these gaseous mediators for sepsis. Full article

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16 pages, 978 KiB

Open AccessReview

Diet and Male Fertility: The Impact of Nutrients and Antioxidants on Sperm Energetic Metabolism

by Alessandra Ferramosca and Vincenzo Zara

Int. J. Mol. Sci. 2022, 23(5), 2542; https://doi.org/10.3390/ijms23052542 - 25 Feb 2022

Cited by 63 | Viewed by 20844

Abstract

Diet might affect male reproductive potential, but the biochemical mechanisms involved in the modulation of sperm quality remain poorly understood. While a Western diet is considered a risk factor for male infertility, the Mediterranean diet seems to protect against male infertility; moreover, the [...] Read more.

Diet might affect male reproductive potential, but the biochemical mechanisms involved in the modulation of sperm quality remain poorly understood. While a Western diet is considered a risk factor for male infertility, the Mediterranean diet seems to protect against male infertility; moreover, the role of a vegetarian habitus in the preservation of sperm quality is controversial. The aim of this review is to analyze the molecular effects of single nutrients on sperm quality, focusing on their involvement in biochemical mechanisms related to sperm bioenergetics. It appears that diets rich in saturated fatty acids (SFA) and low in polyunsaturated fatty acids (PUFA) negatively affect sperm quality, whereas unsaturated fatty acids supplementation ameliorates sperm quality. In fact, the administration of PUFA, especially omega-3 PUFA, determined an increase in mitochondrial energetic metabolism and a reduction in oxidative damage. Carbohydrates and proteins are also nutritional modulators of oxidative stress and testosterone levels, which are strictly linked to sperm mitochondrial function, a key element for sperm quality. Moreover, many dietary natural polyphenols differentially affect (positively or negatively) the mitochondrial function, depending on their concentration. We believe that an understanding of the biochemical mechanisms responsible for sperm quality will lead to more targeted and effective therapeutics for male infertility. Full article

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21 pages, 7246 KiB

Open AccessArticle

Theophylline Extracted from Fu Brick Tea Affects the Metabolism of Preadipocytes and Body Fat in Mice as a Pancreatic Lipase Inhibitor

by Tian-Tian Liu, Xiao-Tian Liu, Gui-Li Huang, Long Liu, Qing-Xi Chen and Qin Wang

Int. J. Mol. Sci. 2022, 23(5), 2525; https://doi.org/10.3390/ijms23052525 - 25 Feb 2022

Cited by 11 | Viewed by 3315

Abstract

The dramatic increase in obesity is putting people under increasing pressure. Lipase inhibitors, as a kind of effective anti-obesity drug, have attracted more and more researchers’ attention in recent years because of their advantages of acting on the intestinal tract and having no [...] Read more.

The dramatic increase in obesity is putting people under increasing pressure. Lipase inhibitors, as a kind of effective anti-obesity drug, have attracted more and more researchers’ attention in recent years because of their advantages of acting on the intestinal tract and having no side effects on the central nervous system. In this study, lipase inhibitor Fu Brick Theophylline (FBT) was screened based on enzyme molecular dynamics, and the inhibition mechanism of lipase inhibitors on obesity was analyzed and discussed at the cellular level and animal model level. We found that FBT had high inhibition effects of lipase with an IC₅₀ of 1.02~0.03 μg/mL. Firstly, the laboratory used 3T3-L1 proadipocytes as models, flow cytometry was used to detect the effects of FBT on the cycle, apoptosis and intracellular ROS activity of proadipocytes. To study the contents of triglyceride, total cholesterol, related metabolites and related gene and protein expression in adipocytes. The results showed that FBT could reduce ROS production and inflammatory factor mRNA expression during cell differentiation. Secondly, by establishing the animal model of high-fat feed ob nutritional obese mice, the morphological observation and gene expression analysis of body weight, fat rate, adipocyte and hepatocyte metabolism of FBT obese mice were further discussed. It was proven that FBT can effectively reduce the degree of fatty liver, prevent liver fibrosis and fat accumulation, and improve the damage of mitochondrial membrane structure. This study provides a theoretical basis for the screening and clinical treatment of lipase inhibitors. Full article

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16 pages, 1226 KiB

Open AccessReview

The Role of Nutrients in Maintaining Hematopoietic Stem Cells and Healthy Hematopoiesis for Life

by Yuko Tadokoro and Atsushi Hirao

Int. J. Mol. Sci. 2022, 23(3), 1574; https://doi.org/10.3390/ijms23031574 - 29 Jan 2022

Cited by 2 | Viewed by 4417

Abstract

Nutrients are converted by the body to smaller molecules, which are utilized for both anabolic and catabolic metabolic reactions. Cooperative regulation of these processes is critical for life-sustaining activities. In this review, we focus on how the regulation of nutrient-driven metabolism maintains healthy [...] Read more.

Nutrients are converted by the body to smaller molecules, which are utilized for both anabolic and catabolic metabolic reactions. Cooperative regulation of these processes is critical for life-sustaining activities. In this review, we focus on how the regulation of nutrient-driven metabolism maintains healthy hematopoietic stem cells (HSCs). For this purpose, we have examined the metabolic regulation of HSCs from two perspectives: (1) the control of intracellular metabolism by the balance of anabolic and catabolic reactions; and (2) the control of organismal metabolic status and hematopoiesis by dietary intake of nutrients. Critical roles of catabolic regulators in stem cell homeostasis are conserved in several types of tissues, including hematopoiesis. These catabolic signals are also major regulators of organismal lifespan in multiple species. In parallel, changes to nutrients via alterations to dietary intake affect not only an organism’s metabolic state but also the behavior of its stem cells. While the molecular mechanisms involved in these two aspects of nutrient function may not necessarily overlap, a deeper understanding of these phenomena will point to new avenues of medical research and may furnish new agents for improving human health care. Full article

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19 pages, 782 KiB

Open AccessReview

Exogenous Bioactive Peptides Have a Potential Therapeutic Role in Delaying Aging in Rodent Models

by Jianqiang Wang, Yixin Wu, Zhongxu Chen, Yajuan Chen, Qinlu Lin and Ying Liang

Int. J. Mol. Sci. 2022, 23(3), 1421; https://doi.org/10.3390/ijms23031421 - 26 Jan 2022

Cited by 13 | Viewed by 5435

Abstract

In recent years, some exogenous bioactive peptides have been shown to have promising anti-aging effects. These exogenous peptides may have a mechanism similar to endogenous peptides, and some can even regulate the release of endogenous active peptides and play a synergistic role with [...] Read more.

In recent years, some exogenous bioactive peptides have been shown to have promising anti-aging effects. These exogenous peptides may have a mechanism similar to endogenous peptides, and some can even regulate the release of endogenous active peptides and play a synergistic role with endogenous active peptides. Most aging studies use rodents that are easy to maintain in the laboratory and have relatively homogenous genotypes. Moreover, many of the anti-aging studies using bioactive peptides in rodent models only focus on the activity of single endogenous or exogenous active peptides, while the regulatory effects of exogenous active peptides on endogenous active peptides remain largely under-investigated. Furthermore, the anti-aging activity studies only focus on the effects of these bioactive peptides in individual organs or systems. However, the pathological changes of one organ can usually lead to multi-organ complications. Some anti-aging bioactive peptides could be used for rescuing the multi-organ damage associated with aging. In this paper, we review recent reports on the anti-aging effects of bioactive peptides in rodents and summarize the mechanism of action for these peptides, as well as discuss the regulation of exogenous active peptides on endogenous active peptides. Full article

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36 pages, 8018 KiB

Open AccessReview

The Versatility in the Applications of Dithiocarbamates

by Timothy O. Ajiboye, Titilope T. Ajiboye, Riadh Marzouki and Damian C. Onwudiwe

Int. J. Mol. Sci. 2022, 23(3), 1317; https://doi.org/10.3390/ijms23031317 - 24 Jan 2022

Cited by 68 | Viewed by 8957

Abstract

Dithiocarbamate ligands have the ability to form stable complexes with transition metals, and this chelating ability has been utilized in numerous applications. The complexes have also been used to synthesize other useful compounds. Here, the up-to-date applications of dithiocarbamate ligands and complexes are [...] Read more.

Dithiocarbamate ligands have the ability to form stable complexes with transition metals, and this chelating ability has been utilized in numerous applications. The complexes have also been used to synthesize other useful compounds. Here, the up-to-date applications of dithiocarbamate ligands and complexes are extensively discussed. Some of these are their use as enzyme inhibitor and treatment of HIV and other diseases. The application as anticancer, antimicrobial, medical imaging and anti-inflammatory agents is examined. Moreover, the application in the industry as vulcanization accelerator, froth flotation collector, antifouling, coatings, lubricant additives and sensors is discussed. The various ways in which they have been employed in synthesis of other compounds are highlighted. Finally, the agricultural uses and remediation of heavy metals via dithiocarbamate compounds are comprehensively discussed. Full article

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2021

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11 pages, 555 KiB

Open AccessReview

Natural Dibenzo-α-Pyrones: Friends or Foes?

by Georg Aichinger

Int. J. Mol. Sci. 2021, 22(23), 13063; https://doi.org/10.3390/ijms222313063 - 2 Dec 2021

Cited by 11 | Viewed by 4515

Abstract

Natural dibenzo-α-pyrones (DAPs) can be viewed from two opposite angles. From one angle, the gastrointestinal metabolites urolithins are regarded as beneficial, while from the other, the emerging mycotoxin alternariol and related fungal metabolites are evaluated critically with regards to potential hazardous effects. Thus, [...] Read more.

Natural dibenzo-α-pyrones (DAPs) can be viewed from two opposite angles. From one angle, the gastrointestinal metabolites urolithins are regarded as beneficial, while from the other, the emerging mycotoxin alternariol and related fungal metabolites are evaluated critically with regards to potential hazardous effects. Thus, the important question is: can the structural characteristics of DAP subgroups be held responsible for distinct bioactivity patterns? If not, certain toxicological and/or pharmacological aspects of natural DAPs might yet await elucidation. Thus, this review focuses on comparing published data on the two groups of natural DAPs regarding both adverse and beneficial effects on human health. Literature on genotoxic, estrogenic, endocrine-disruptive effects, as well as on the induction of the cellular anti-oxidative defense system, anti-inflammatory properties, the inhibition of kinases, the activation of mitophagy and the induction of autophagy, is gathered and critically reviewed. Indeed, comparing published data suggests similar bioactivity profiles of alternariol and urolithin A. Thus, the current stratification into hazardous Alternaria toxins and healthy urolithins seems debatable. An extrapolation of bioactivities to the other DAP sub-class could serve as a promising base for further research. Conclusively, urolithins should be further evaluated toward high-dose toxicity, while alternariol derivatives could be promising chemicals for the development of therapeutics. Full article

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16 pages, 2871 KiB

Open AccessArticle

Dityrosine Crosslinking of Collagen and Amyloid-β Peptides Is Formed by Vitamin B₁₂ Deficiency-Generated Oxidative Stress in Caenorhabditis elegans

by Kyohei Koseki, Aoi Yamamoto, Keisuke Tanimoto, Naho Okamoto, Fei Teng, Tomohiro Bito, Yukinori Yabuta, Tsuyoshi Kawano and Fumio Watanabe

Int. J. Mol. Sci. 2021, 22(23), 12959; https://doi.org/10.3390/ijms222312959 - 30 Nov 2021

Cited by 5 | Viewed by 3602

Abstract

(1) Background: Vitamin B₁₂ deficiency in Caenorhabditis elegans results in severe oxidative stress and induces morphological abnormality in mutants due to disordered cuticle collagen biosynthesis. We clarified the underlying mechanism leading to such mutant worms due to vitamin B₁₂ deficiency. (2) [...] Read more.

(1) Background: Vitamin B₁₂ deficiency in Caenorhabditis elegans results in severe oxidative stress and induces morphological abnormality in mutants due to disordered cuticle collagen biosynthesis. We clarified the underlying mechanism leading to such mutant worms due to vitamin B₁₂ deficiency. (2) Results: The deficient worms exhibited decreased collagen levels of up to approximately 59% compared with the control. Although vitamin B₁₂ deficiency did not affect the mRNA expression of prolyl 4-hydroxylase, which catalyzes the formation of 4-hydroxyproline involved in intercellular collagen biosynthesis, the level of ascorbic acid, a prolyl 4-hydroxylase coenzyme, was markedly decreased. Dityrosine crosslinking is involved in the extracellular maturation of worm collagen. The dityrosine level of collagen significantly increased in the deficient worms compared with the control. However, vitamin B₁₂ deficiency hardly affected the mRNA expression levels of bli-3 and mlt-7, which are encoding crosslinking-related enzymes, suggesting that deficiency-induced oxidative stress leads to dityrosine crosslinking. Moreover, using GMC101 mutant worms that express the full-length human amyloid β, we found that vitamin B₁₂ deficiency did not affect the gene and protein expressions of amyloid β but increased the formation of dityrosine crosslinking in the amyloid β protein. (3) Conclusions: Vitamin B₁₂-deficient wild-type worms showed motility dysfunction due to decreased collagen levels and the formation of highly tyrosine-crosslinked collagen, potentially reducing their flexibility. In GMC101 mutant worms, vitamin B₁₂ deficiency-induced oxidative stress triggers dityrosine-crosslinked amyloid β formation, which might promote its stabilization and toxic oligomerization. Full article

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19 pages, 4119 KiB

Open AccessArticle

Transcriptomic Characterization of Cow, Donkey and Goat Milk Extracellular Vesicles Reveals Their Anti-Inflammatory and Immunomodulatory Potential

by Samanta Mecocci, Daniele Pietrucci, Marco Milanesi, Luisa Pascucci, Silvia Filippi, Vittorio Rosato, Giovanni Chillemi, Stefano Capomaccio and Katia Cappelli

Int. J. Mol. Sci. 2021, 22(23), 12759; https://doi.org/10.3390/ijms222312759 - 25 Nov 2021

Cited by 40 | Viewed by 4771

Abstract

Milk extracellular vesicles (mEVs) seem to be one of the main maternal messages delivery systems. Extracellular vesicles (EVs) are micro/nano-sized membrane-bound structures enclosing signaling molecules and thus acting as signal mediators between distant cells and/or tissues, exerting biological effects such as immune modulation [...] Read more.

Milk extracellular vesicles (mEVs) seem to be one of the main maternal messages delivery systems. Extracellular vesicles (EVs) are micro/nano-sized membrane-bound structures enclosing signaling molecules and thus acting as signal mediators between distant cells and/or tissues, exerting biological effects such as immune modulation and pro-regenerative activity. Milk is also a unique, scalable, and reliable source of EVs. Our aim was to characterize the RNA content of cow, donkey, and goat mEVs through transcriptomic analysis of mRNA and small RNA libraries. Over 10,000 transcripts and 2000 small RNAs were expressed in mEVs of each species. Among the most represented transcripts, 110 mRNAs were common between the species with cow acting as the most divergent. The most represented small RNA class was miRNA in all the species, with 10 shared miRNAs having high impact on the immune regulatory function. Functional analysis for the most abundant mRNAs shows epigenetic functions such as histone modification, telomere maintenance, and chromatin remodeling for cow; lipid catabolism, oxidative stress, and vitamin metabolism for donkey; and terms related to chemokine receptor interaction, leukocytes migration, and transcriptional regulation in response to stress for goat. For miRNA targets, shared terms emerged as the main functions for all the species: immunity modulation, protein synthesis, cellular cycle regulation, transmembrane exchanges, and ion channels. Moreover, donkey and goat showed additional terms related to epigenetic modification and DNA maintenance. Our results showed a potential mEVs immune regulatory purpose through their RNA cargo, although in vivo validation studies are necessary. Full article

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15 pages, 3320 KiB

Open AccessArticle

Oleanolic Acid Alleviates Atopic Dermatitis-like Responses In Vivo and In Vitro

by Yun-Mi Kang, Hye-Min Kim, Minho Lee and Hyo-Jin An

Int. J. Mol. Sci. 2021, 22(21), 12000; https://doi.org/10.3390/ijms222112000 - 5 Nov 2021

Cited by 18 | Viewed by 4149

Abstract

Oleanolic acid (OA) is a pentacyclic triterpenoid, abundantly found in plants of the Oleaceae family, and is well known for its beneficial pharmacological activities. Previously, we reported the inhibitory effect of OA on mast cell-mediated allergic inflammation. In this study, we investigated the [...] Read more.

Oleanolic acid (OA) is a pentacyclic triterpenoid, abundantly found in plants of the Oleaceae family, and is well known for its beneficial pharmacological activities. Previously, we reported the inhibitory effect of OA on mast cell-mediated allergic inflammation. In this study, we investigated the effects of OA on atopic dermatitis (AD)-like skin lesions and its underlying mechanism of action. We evaluated the inhibitory effect of OA on AD-like responses and the possible mechanisms using a 1-chloro-2,4-dinitrochlorobenzene (DNCB)-induced AD animal model and tumor necrosis factor (TNF)-α/interferon (IFN)-γ-stimulated HaCaT keratinocytes. We found that OA has anti-atopic effects, including histological alterations, on DNCB-induced AD-like lesions in mice. Moreover, it suppressed the expression of Th2 type cytokines and chemokines in the AD mouse model and TNF-α/IFN-γ-induced HaCaT keratinocytes by blocking the activation of serine-threonine kinase Akt, nuclear factor-κB, and the signal transducer and activator of transcription 1. The results demonstrate that OA inhibits AD-like symptoms and regulates the inflammatory mediators; therefore, it may be used as an effective and attractive therapeutic agent for allergic disorders, such as AD. Moreover, the findings of this study provide novel insights into the potential pharmacological targets of OA for treating AD. Full article

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25 pages, 2101 KiB

Open AccessReview

Targeting Mammalian 5-Lipoxygenase by Dietary Phenolics as an Anti-Inflammatory Mechanism: A Systematic Review

by Juan Antonio Giménez-Bastida, Antonio González-Sarrías, José Moisés Laparra-Llopis, Claus Schneider and Juan Carlos Espín

Int. J. Mol. Sci. 2021, 22(15), 7937; https://doi.org/10.3390/ijms22157937 - 25 Jul 2021

Cited by 35 | Viewed by 5661

Abstract

5-Lipoxygenase (5-LOX) plays a key role in inflammation through the biosynthesis of leukotrienes and other lipid mediators. Current evidence suggests that dietary (poly)phenols exert a beneficial impact on human health through anti-inflammatory activities. Their mechanisms of action have mostly been associated with the [...] Read more.

5-Lipoxygenase (5-LOX) plays a key role in inflammation through the biosynthesis of leukotrienes and other lipid mediators. Current evidence suggests that dietary (poly)phenols exert a beneficial impact on human health through anti-inflammatory activities. Their mechanisms of action have mostly been associated with the modulation of pro-inflammatory cytokines (TNF-α, IL-1β), prostaglandins (PGE₂), and the interaction with NF-κB and cyclooxygenase 2 (COX-2) pathways. Much less is known about the 5-lipoxygenase (5-LOX) pathway as a target of dietary (poly)phenols. This systematic review aimed to summarize how dietary (poly)phenols target the 5-LOX pathway in preclinical and human studies. The number of studies identified is low (5, 24, and 127 human, animal, and cellular studies, respectively) compared to the thousands of studies focusing on the COX-2 pathway. Some (poly)phenolics such as caffeic acid, hydroxytyrosol, resveratrol, curcumin, nordihydroguaiaretic acid (NDGA), and quercetin have been reported to reduce the formation of 5-LOX eicosanoids in vitro. However, the in vivo evidence is inconclusive because of the low number of studies and the difficulty of attributing effects to (poly)phenols. Therefore, increasing the number of studies targeting the 5-LOX pathway would largely expand our knowledge on the anti-inflammatory mechanisms of (poly)phenols. Full article

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17 pages, 2571 KiB

Open AccessArticle

Glycyrrhizin Attenuates Portal Hypertension and Collateral Shunting via Inhibition of Extrahepatic Angiogenesis in Cirrhotic Rats

by Chon Kit Pun, Hui-Chun Huang, Ching-Chih Chang, Chiao-Lin Chuang, Chun-Hsien Yen, Shao-Jung Hsu, Fa-Yauh Lee, Ming-Chih Hou and Yi-Hsiang Huang

Int. J. Mol. Sci. 2021, 22(14), 7662; https://doi.org/10.3390/ijms22147662 - 17 Jul 2021

Cited by 8 | Viewed by 3233

Abstract

Portal hypertension develops along with liver cirrhosis then induces the formation of portal-systemic collaterals and lethal complications. Extrahepatic angiogenesis plays an important role. Glycyrrhizin has been found to exhibit anti-angiogenic features, which leads to its extensive use. However, the relevant effects of glycyrrhizin [...] Read more.

Portal hypertension develops along with liver cirrhosis then induces the formation of portal-systemic collaterals and lethal complications. Extrahepatic angiogenesis plays an important role. Glycyrrhizin has been found to exhibit anti-angiogenic features, which leads to its extensive use. However, the relevant effects of glycyrrhizin on liver cirrhosis and portal hypertension have not been evaluated. This study thus aimed to investigate the impact of glycyrrhizin on portal hypertension-related derangements in cirrhotic rats. Male Sprague-Dawley rats received bile duct ligation (BDL) to induce cirrhosis or sham operation as control. The rats were subdivided to receive glycyrrhizin (150 mg/kg/day, oral gavage) or vehicle beginning on the 15th day post operation, when BDL-induced liver fibrosis developed. The effects of glycyrrhizin were determined on the 28th day, the typical timing of BDL-induced cirrhosis. Glycyrrhizin significantly reduced portal pressure (p = 0.004). The splanchnic inflow as measured by superior mesenteric arterial flow decreased by 22% (p = 0.029). The portal-systemic collateral shunting degree reduced by 30% (p = 0.024). The mesenteric angiogenesis and phospho-VEGFR2 protein expression were also downregulated (p = 0.038 and 0.031, respectively). Glycyrrhizin did not significantly influence the liver biochemistry data. Although glycyrrhizin tended to reverse liver fibrosis, statistical significance was not reached (p = 0.069). Consistently, hepatic inflow from portal side, hepatic vascular resistance, and liver fibrosis-related protein expressions were not affected. Glycyrrhizin treatment at the stage of hepatic fibrosis still effectively attenuated portal hypertension and portosystemic collateral shunting. These beneficial effects were attributed to, at least in part, the suppression of mesenteric angiogenesis by VEGF signaling pathway downregulation. Full article

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14 pages, 2682 KiB

Open AccessArticle

Influence of the Anthocyanin and Cofactor Structure on the Formation Efficiency of Naturally Derived Pyranoanthocyanins

by Gonzalo Miyagusuku-Cruzado, Danielle M. Voss and M. Monica Giusti

Int. J. Mol. Sci. 2021, 22(13), 6708; https://doi.org/10.3390/ijms22136708 - 23 Jun 2021

Cited by 13 | Viewed by 3005

Abstract

Pyranoanthocyanins are anthocyanin-derived pigments with higher stability to pH and storage. However, their slow formation and scarcity in nature hinder their industrial application. Pyranoanthocyanin formation can be accelerated by selecting anthocyanin substitutions, cofactor concentrations, and temperature. Limited information is available on the impacts [...] Read more.

Pyranoanthocyanins are anthocyanin-derived pigments with higher stability to pH and storage. However, their slow formation and scarcity in nature hinder their industrial application. Pyranoanthocyanin formation can be accelerated by selecting anthocyanin substitutions, cofactor concentrations, and temperature. Limited information is available on the impacts of the chemical structure of the cofactor and anthocyanin; therefore, we evaluated their impacts on pyranoanthocyanin formation efficiency under conditions reported as favorable for the reaction. Different cofactors were evaluated including pyruvic acid, acetone, and hydroxycinnamic acids (p-coumaric, caffeic, ferulic, and sinapic acid) by incubating them with anthocyanins in a molar ratio of 1:30 (anthocyanin:cofactor), pH 3.1, and 45 °C. The impact of the anthocyanin aglycone was evaluated by incubating delphinidin, cyanidin, petunidin, or malvidin derivatives with the most efficient cofactor (caffeic acid) under identical conditions. Pigments were identified using UHPLC-PDA and tandem mass spectrometry, and pyranoanthocyanin formation was monitored for up to 72 h. Pyranoanthocyanin yields were the highest with caffeic acid (~17% at 72 h, p < 0.05). When comparing anthocyanins, malvidin-3-O-glycosides yielded twice as many pyranoanthocyanins after 24 h (~20%, p < 0.01) as cyanidin-3-O-glycosides. Petunidin- and delphinidin-3-O-glycosides yielded <2% pyranoanthocyanins. This study demonstrated the importance of anthocyanin and cofactor selection in pyranoanthocyanin production. Full article

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15 pages, 1872 KiB

Open AccessArticle

Carnosic Acid Attenuates an Early Increase in ROS Levels during Adipocyte Differentiation by Suppressing Translation of Nox4 and Inducing Translation of Antioxidant Enzymes

by Dae-Kun Lee and Hae-Dong Jang

Int. J. Mol. Sci. 2021, 22(11), 6096; https://doi.org/10.3390/ijms22116096 - 5 Jun 2021

Cited by 22 | Viewed by 3688

Abstract

The objective of this study was to investigate molecular mechanisms underlying the ability of carnosic acid to attenuate an early increase in reactive oxygen species (ROS) levels during MDI-induced adipocyte differentiation. The levels of superoxide anion and ROS were determined using dihydroethidium (DHE) [...] Read more.

The objective of this study was to investigate molecular mechanisms underlying the ability of carnosic acid to attenuate an early increase in reactive oxygen species (ROS) levels during MDI-induced adipocyte differentiation. The levels of superoxide anion and ROS were determined using dihydroethidium (DHE) and 2′-7′-dichlorofluorescin diacetate (DCFH-DA), respectively. Both superoxide anion and ROS levels peaked on the second day of differentiation. They were suppressed by carnosic acid. Carnosic acid attenuates the translation of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase 4 (Nox4), p47^phox, and p22^phox, and the phosphorylation of nuclear factor-kappa B (NF-κB) and NF-κB inhibitor (IkBa). The translocation of NF-κB into the nucleus was also decreased by carnosic acid. In addition, carnosic acid increased the translation of heme oxygenase-1 (HO-1), γ–glutamylcysteine synthetase (γ-GCSc), and glutathione S-transferase (GST) and both the translation and nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Taken together, these results indicate that carnosic acid could down-regulate ROS level in an early stage of MPI-induced adipocyte differentiation by attenuating ROS generation through suppression of NF-κB-mediated translation of Nox4 enzyme and increasing ROS neutralization through induction of Nrf2-mediated translation of phase II antioxidant enzymes such as HO-1, γ-GCS, and GST, leading to its anti-adipogenetic effect. Full article

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22 pages, 2100 KiB

Open AccessArticle

Prenylated Flavonoids with Potential Antimicrobial Activity: Synthesis, Biological Activity, and In Silico Study

by Mauricio Osorio, Marcela Carvajal, Alejandra Vergara, Estefania Butassi, Susana Zacchino, Carolina Mascayano, Margarita Montoya, Sophia Mejías, Marcelo Cortez-San Martín and Yesseny Vásquez-Martínez

Int. J. Mol. Sci. 2021, 22(11), 5472; https://doi.org/10.3390/ijms22115472 - 22 May 2021

Cited by 16 | Viewed by 4301

Abstract

Prenylated flavonoids are an important class of naturally occurring flavonoids with important biological activity, but their low abundance in nature limits their application in medicines. Here, we showed the hemisynthesis and the determination of various biological activities of seven prenylated flavonoids, named 7–13 [...] Read more.

Prenylated flavonoids are an important class of naturally occurring flavonoids with important biological activity, but their low abundance in nature limits their application in medicines. Here, we showed the hemisynthesis and the determination of various biological activities of seven prenylated flavonoids, named 7–13, with an emphasis on antimicrobial ones. Compounds 9, 11, and 12 showed inhibitory activity against human pathogenic fungi. Compounds 11, 12 (flavanones) and 13 (isoflavone) were the most active against clinical isolated Staphylococcus aureus MRSA, showing that structural requirements as prenylation at position C-6 or C-8 and OH at positions C-5, 7, and 4′ are key to the antibacterial activity. The combination of 11 or 12 with commercial antibiotics synergistically enhanced the antibacterial activity of vancomycin, ciprofloxacin, and methicillin in a factor of 10 to 100 times against drug-resistant bacteria. Compound 11 combined with ciprofloxacin was able to decrease the levels of ROS generated by ciprofloxacin. According to docking results of S enantiomer of 11 with ATP-binding cassette transporter showed the most favorable binding energy; however, more studies are needed to support this result. Full article

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16 pages, 2348 KiB

Open AccessArticle

A Phenylacetamide Resveratrol Derivative Exerts Inhibitory Effects on Breast Cancer Cell Growth

by Adele Chimento, Anna Santarsiero, Domenico Iacopetta, Jessica Ceramella, Arianna De Luca, Vittoria Infantino, Ortensia Ilaria Parisi, Paola Avena, Maria Grazia Bonomo, Carmela Saturnino, Maria Stefania Sinicropi and Vincenzo Pezzi

Int. J. Mol. Sci. 2021, 22(10), 5255; https://doi.org/10.3390/ijms22105255 - 17 May 2021

Cited by 18 | Viewed by 2939

Abstract

Resveratrol (RSV) is a natural compound that displays several pharmacological properties, including anti-cancer actions. However, its clinical application is limited because of its low solubility and bioavailability. Here, the antiproliferative and anti-inflammatory activity of a series of phenylacetamide RSV derivatives has been evaluated [...] Read more.

Resveratrol (RSV) is a natural compound that displays several pharmacological properties, including anti-cancer actions. However, its clinical application is limited because of its low solubility and bioavailability. Here, the antiproliferative and anti-inflammatory activity of a series of phenylacetamide RSV derivatives has been evaluated in several cancer cell lines. These derivatives contain a monosubstituted aromatic ring that could mimic the RSV phenolic nucleus and a longer flexible chain that could confer a better stability and bioavailability than RSV. Using MTT assay, we demonstrated that most derivatives exerted antiproliferative effects in almost all of the cancer cell lines tested. Among them, derivative 2, that showed greater bioavailability than RSV, was the most active, particularly against estrogen receptor positive (ER+) MCF7 and estrogen receptor negative (ER-) MDA-MB231 breast cancer cell lines. Moreover, we demonstrated that these derivatives, particularly derivative 2, were able to inhibit NO and ROS synthesis and PGE2 secretion in lipopolysaccharide (LPS)-activated U937 human monocytic cells (derived from a histiocytoma). In order to define the molecular mechanisms underlying the antiproliferative effects of derivative 2, we found that it determined cell cycle arrest at the G1 phase, modified the expression of cell cycle regulatory proteins, and ultimately triggered apoptotic cell death in both breast cancer cell lines. Taken together, these results highlight the studied RSV derivatives, particularly derivative 2, as promising tools for the development of new and more bioavailable derivatives useful in the treatment of breast cancer. Full article

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17 pages, 31205 KiB

Open AccessReview

Immunological Aspects of SARS-CoV-2 Infection and the Putative Beneficial Role of Vitamin-D

by Ming-Yieh Peng, Wen-Chih Liu, Jing-Quan Zheng, Chien-Lin Lu, Yi-Chou Hou, Cai-Mei Zheng, Jenn-Yeu Song, Kuo-Cheng Lu and You-Chen Chao

Int. J. Mol. Sci. 2021, 22(10), 5251; https://doi.org/10.3390/ijms22105251 - 16 May 2021

Cited by 48 | Viewed by 9954

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is still an ongoing global health crisis. Immediately after the inhalation of SARS-CoV-2 viral particles, alveolar type II epithelial cells harbor and initiate local innate immunity. These particles can infect circulating [...] Read more.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is still an ongoing global health crisis. Immediately after the inhalation of SARS-CoV-2 viral particles, alveolar type II epithelial cells harbor and initiate local innate immunity. These particles can infect circulating macrophages, which then present the coronavirus antigens to T cells. Subsequently, the activation and differentiation of various types of T cells, as well as uncontrollable cytokine release (also known as cytokine storms), result in tissue destruction and amplification of the immune response. Vitamin D enhances the innate immunity required for combating COVID-19 by activating toll-like receptor 2. It also enhances antimicrobial peptide synthesis, such as through the promotion of the expression and secretion of cathelicidin and β-defensin; promotes autophagy through autophagosome formation; and increases the synthesis of lysosomal degradation enzymes within macrophages. Regarding adaptive immunity, vitamin D enhances CD4⁺ T cells, suppresses T helper 17 cells, and promotes the production of virus-specific antibodies by activating T cell-dependent B cells. Moreover, vitamin D attenuates the release of pro-inflammatory cytokines by CD4⁺ T cells through nuclear factor κB signaling, thereby inhibiting the development of a cytokine storm. SARS-CoV-2 enters cells after its spike proteins are bound to angiotensin-converting enzyme 2 (ACE2) receptors. Vitamin D increases the bioavailability and expression of ACE2, which may be responsible for trapping and inactivating the virus. Activation of the renin–angiotensin–aldosterone system (RAS) is responsible for tissue destruction, inflammation, and organ failure related to SARS-CoV-2. Vitamin D inhibits renin expression and serves as a negative RAS regulator. In conclusion, vitamin D defends the body against SARS-CoV-2 through a novel complex mechanism that operates through interactions between the activation of both innate and adaptive immunity, ACE2 expression, and inhibition of the RAS system. Multiple observation studies have shown that serum concentrations of 25 hydroxyvitamin D are inversely correlated with the incidence or severity of COVID-19. The evidence gathered thus far, generally meets Hill’s causality criteria in a biological system, although experimental verification is not sufficient. We speculated that adequate vitamin D supplementation may be essential for mitigating the progression and severity of COVID-19. Future studies are warranted to determine the dosage and effectiveness of vitamin D supplementation among different populations of individuals with COVID-19. Full article

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21 pages, 3391 KiB

Open AccessArticle

Active Components from Cassia abbreviata Prevent HIV-1 Entry by Distinct Mechanisms of Action

by Yue Zheng, Xian-Wen Yang, Dominique Schols, Mattia Mori, Bruno Botta, Andy Chevigné, Martin Mulinge, André Steinmetz, Jean-Claude Schmit and Carole Seguin-Devaux

Int. J. Mol. Sci. 2021, 22(9), 5052; https://doi.org/10.3390/ijms22095052 - 10 May 2021

Cited by 8 | Viewed by 3757

Abstract

Cassia abbreviata is widely used in Sub-Saharan Africa for treating many diseases, including HIV-1 infection. We have recently described the chemical structures of 28 compounds isolated from an alcoholic crude extract of barks and roots of C. abbreviata, and showed that six [...] Read more.

Cassia abbreviata is widely used in Sub-Saharan Africa for treating many diseases, including HIV-1 infection. We have recently described the chemical structures of 28 compounds isolated from an alcoholic crude extract of barks and roots of C. abbreviata, and showed that six bioactive compounds inhibit HIV-1 infection. In the present study, we demonstrate that the six compounds block HIV-1 entry into cells: oleanolic acid, palmitic acid, taxifolin, piceatannol, guibourtinidol-(4α→8)-epiafzelechin, and a novel compound named as cassiabrevone. We report, for the first time, that guibourtinidol-(4α→8)-epiafzelechin and cassiabrevone inhibit HIV-1 entry (IC₅₀ of 42.47 µM and 30.96 µM, respectively), as well as that piceatannol interacts with cellular membranes. Piceatannol inhibits HIV-1 infection in a dual-chamber assay mimicking the female genital tract, as well as HSV infection, emphasizing its potential as a microbicide. Structure-activity relationships (SAR) showed that pharmacophoric groups of piceatannol are strictly required to inhibit HIV-1 entry. By a ligand-based in silico study, we speculated that piceatannol and norartocarpetin may have a very similar mechanism of action and efficacy because of the highly comparable pharmacophoric and 3D space, while guibourtinidol-(4α→8)-epiafzelechin and cassiabrevone may display a different mechanism. We finally show that cassiabrevone plays a major role of the crude extract of CA by blocking the binding activity of HIV-1 gp120 and CD4. Full article

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18 pages, 3832 KiB

Open AccessArticle

Chrysin Inhibits TNFα-Induced TSLP Expression through Downregulation of EGR1 Expression in Keratinocytes

by Hyunjin Yeo, Young Han Lee, Sung Shin Ahn, Euitaek Jung, Yoongho Lim and Soon Young Shin

Int. J. Mol. Sci. 2021, 22(9), 4350; https://doi.org/10.3390/ijms22094350 - 21 Apr 2021

Cited by 14 | Viewed by 3568

Abstract

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that acts as a critical mediator in the pathogenesis of atopic dermatitis (AD). Various therapeutic agents that prevent TSLP function can efficiently relieve the clinical symptoms of AD. However, the downregulation of TSLP expression [...] Read more.

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that acts as a critical mediator in the pathogenesis of atopic dermatitis (AD). Various therapeutic agents that prevent TSLP function can efficiently relieve the clinical symptoms of AD. However, the downregulation of TSLP expression by therapeutic agents remains poorly understood. In this study, we investigated the mode of action of chrysin in TSLP suppression in an AD-like inflammatory environment. We observed that the transcription factor early growth response (EGR1) contributed to the tumor necrosis factor alpha (TNFα)-induced transcription of TSLP. Chrysin attenuated TNFα-induced TSLP expression by downregulating EGR1 expression in HaCaT keratinocytes. We also showed that the oral administration of chrysin improved AD-like skin lesions in the ear and neck of BALB/c mice challenged with 2,4-dinitrochlorobenzene. We also showed that chrysin suppressed the expression of EGR1 and TSLP by inhibiting the extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1/2 mitogen-activated protein kinase pathways. Collectively, the findings of this study suggest that chrysin improves AD-like skin lesions, at least in part, through the downregulation of the ERK1/2 or JNK1/2-EGR1-TSLP signaling axis in keratinocytes. Full article

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27 pages, 5484 KiB

Open AccessArticle

The Biochemical Pathways of Nicotinamide-Derived Pyridones

by Faisal Hayat, Manoj Sonavane, Mikhail V. Makarov, Samuel A. J. Trammell, Pamela McPherson, Natalie R. Gassman and Marie E. Migaud

Int. J. Mol. Sci. 2021, 22(3), 1145; https://doi.org/10.3390/ijms22031145 - 24 Jan 2021

Cited by 16 | Viewed by 5148

Abstract

As catabolites of nicotinamide possess physiological relevance, pyridones are often included in metabolomics measurements and associated with pathological outcomes in acute kidney injury (AKI). Pyridones are oxidation products of nicotinamide, its methylated form, and its ribosylated form. While they are viewed as markers [...] Read more.

As catabolites of nicotinamide possess physiological relevance, pyridones are often included in metabolomics measurements and associated with pathological outcomes in acute kidney injury (AKI). Pyridones are oxidation products of nicotinamide, its methylated form, and its ribosylated form. While they are viewed as markers of over-oxidation, they are often wrongly reported or mislabeled. To address this, we provide a comprehensive characterization of these catabolites of vitamin B3, justify their nomenclature, and differentiate between the biochemical pathways that lead to their generation. Furthermore, we identify an enzymatic and a chemical process that accounts for the formation of the ribosylated form of these pyridones, known to be cytotoxic. Finally, we demonstrate that the ribosylated form of one of the pyridones, the 4-pyridone-3-carboxamide riboside (4PYR), causes HepG3 cells to die by autophagy; a process that occurs at concentrations that are comparable to physiological concentrations of this species in the plasma in AKI patients. Full article

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2020

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16 pages, 20573 KiB

Open AccessArticle

Double Gamers—Can Modified Natural Regulators of Higher Plants Act as Antagonists against Phytopathogens? The Case of Jasmonic Acid Derivatives

by Nicolò Orsoni, Francesca Degola, Luca Nerva, Franco Bisceglie, Giorgio Spadola, Walter Chitarra, Valeria Terzi, Stefano Delbono, Roberta Ghizzoni, Caterina Morcia, Agnieszka Jamiołkowska, Elżbieta Mielniczuk, Francesco M. Restivo and Giorgio Pelosi

Int. J. Mol. Sci. 2020, 21(22), 8681; https://doi.org/10.3390/ijms21228681 - 17 Nov 2020

Cited by 13 | Viewed by 2912

Abstract

As key players in biotic stress response of plants, jasmonic acid (JA) and its derivatives cover a specific and prominent role in pathogens-mediated signaling and hence are promising candidates for a sustainable management of phytopathogenic fungi. Recently, JA directed antimicrobial effects on plant [...] Read more.

As key players in biotic stress response of plants, jasmonic acid (JA) and its derivatives cover a specific and prominent role in pathogens-mediated signaling and hence are promising candidates for a sustainable management of phytopathogenic fungi. Recently, JA directed antimicrobial effects on plant pathogens has been suggested, supporting the theory of oxylipins as double gamers in plant-pathogen interaction. Based on these premises, six derivatives (dihydrojasmone and cis-jasmone, two thiosemicarbazonic derivatives and their corresponding complexes with copper) have been evaluated against 13 fungal species affecting various economically important herbaceous and woody crops, such as cereals, grapes and horticultural crops: Phaeoacremonium minimum, Neofusicoccum parvum, Phaeomoniella chlamydospora, Fomitiporia mediterranea, Fusarium poae, F. culmorum, F. graminearum, F. oxysporum f. sp. lactucae,F. sporotrichioides, Aspergillus flavus, Rhizoctonia solani,Sclerotinia spp. and Verticillium dahliae. The biological activity of these compounds was assessed in terms of growth inhibition and, for the two mycotoxigenic species A. flavus and F. sporotrichioides, also in terms of toxin containment. As expected, the inhibitory effect of molecules greatly varied amongst both genera and species; cis-jasmone thiosemicarbazone in particular has shown the wider range of effectiveness. However, our results show that thiosemicarbazones derivatives are more effective than the parent ketones in limiting fungal growth and mycotoxins production, supporting possible applications for the control of pathogenic fungi. Full article

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18 pages, 1198 KiB

Open AccessReview

The Beneficial Effects of Morusin, an Isoprene Flavonoid Isolated from the Root Bark of Morus

by Dong Wook Choi, Sang Woo Cho, Seok-Geun Lee and Cheol Yong Choi

Int. J. Mol. Sci. 2020, 21(18), 6541; https://doi.org/10.3390/ijms21186541 - 7 Sep 2020

Cited by 25 | Viewed by 4462

Abstract

The root bark of Morus has long been appreciated as an antiphlogistic, diuretic and expectorant drug in Chinese herbal medicine, albeit with barely known targets and mechanisms of action. In the 1970s, the development of analytic chemistry allowed for the discovery of morusin [...] Read more.

The root bark of Morus has long been appreciated as an antiphlogistic, diuretic and expectorant drug in Chinese herbal medicine, albeit with barely known targets and mechanisms of action. In the 1970s, the development of analytic chemistry allowed for the discovery of morusin as one of 7 different isoprene flavonoid derivatives in the root bark of Morus. However, the remarkable antioxidant capacity of morusin with the unexpected potential for health benefits over the other flavonoid derivatives has recently sparked scientific interest in the biochemical identification of target proteins and signaling pathways and further clinical relevance. In this review, we discuss recent advances in the understanding of the functional roles of morusin in multiple biological processes such as inflammation, apoptosis, metabolism and autophagy. We also highlight recent in vivo and in vitro evidence on the clinical potential of morusin treatment for multiple human pathologies including inflammatory diseases, neurological disorders, diabetes, cancer and the underlying mechanisms. Full article

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20 pages, 4375 KiB

Open AccessArticle

New Methodology for the Identification of Metabolites of Saccharides and Cyclitols by Off-Line EC-MALDI-TOF-MS

by Gulyaim Sagandykova, Justyna Walczak-Skierska, Fernanda Monedeiro, Paweł Pomastowski and Bogusław Buszewski

Int. J. Mol. Sci. 2020, 21(15), 5265; https://doi.org/10.3390/ijms21155265 - 24 Jul 2020

Cited by 6 | Viewed by 3879

Abstract

A combination of electrochemistry (EC) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (off-line EC-MALDI-TOF-MS) was applied for determination of the studied biologically active compounds (D-glucose, D-fructose, D-galactose, D-pinitol, L-chiro-inositol, and myo-inositol) and their possible electrochemical metabolites. In this work, [...] Read more.

A combination of electrochemistry (EC) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (off-line EC-MALDI-TOF-MS) was applied for determination of the studied biologically active compounds (D-glucose, D-fructose, D-galactose, D-pinitol, L-chiro-inositol, and myo-inositol) and their possible electrochemical metabolites. In this work, boron-doped diamond electrode (BDD) was used as a working electrode. MALDI-TOF-MS experiments were carried out (both in positive and negative ion modes and using two matrices) to identify the structures of electrochemical products. This was one of the first applications of the EC system for the generation of electrochemical products produced from saccharides and cyclitols. Moreover, exploratory data analysis approaches (correlation networks, hierarchical cluster analysis, weighted plots) were used in order to present differences/similarities between the obtained spectra, regarding the class of analyzed compounds, ionization modes, and used matrices. This work presents the investigation and comparison of fragmentation patterns of sugars, cyclitols, and their respective products generated through the electrochemistry (EC) process. Full article

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26 pages, 1150 KiB

Open AccessReview

Interactions of Whey Proteins with Metal Ions

by Agnieszka Rodzik, Paweł Pomastowski, Gulyaim N. Sagandykova and Bogusław Buszewski

Int. J. Mol. Sci. 2020, 21(6), 2156; https://doi.org/10.3390/ijms21062156 - 20 Mar 2020

Cited by 55 | Viewed by 7632

Abstract

Whey proteins tend to interact with metal ions, which have implications in different fields related to human life quality. There are two impacts of such interactions: they can provide opportunities for applications in food and nutraceuticals, but may lead to analytical challenges related [...] Read more.

Whey proteins tend to interact with metal ions, which have implications in different fields related to human life quality. There are two impacts of such interactions: they can provide opportunities for applications in food and nutraceuticals, but may lead to analytical challenges related to their study and outcomes for food processing, storage, and food interactions. Moreover, interactions of whey proteins with metal ions are complicated, requiring deep understanding, leading to consequences, such as metalloproteins, metallocomplexes, nanoparticles, or aggregates, creating a biologically active system. To understand the phenomena of metal–protein interactions, it is important to develop analytical approaches combined with studies of changes in the biological activity and to analyze the impact of such interactions on different fields. The aim of this review was to discuss chemistry of β-lactoglobulin, α-lactalbumin, and lactotransferrin, their interactions with different metal ions, analytical techniques used to study them and the implications for food and nutraceuticals. Full article

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