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International Journal of Pharmaceutics Jun 2024Dry eye disease (DED) is a chronic multifactorial disorder of the ocular surface caused by tear film dysfunction and constitutes one of the most common ocular conditions...
Dry eye disease (DED) is a chronic multifactorial disorder of the ocular surface caused by tear film dysfunction and constitutes one of the most common ocular conditions worldwide. However, its treatment remains unsatisfactory. While artificial tears are commonly used to moisturize the ocular surface, they do not address the underlying causes of DED. Apigenin (APG) is a natural product with anti-inflammatory properties, but its low solubility and bioavailability limit its efficacy. Therefore, a novel formulation of APG loaded into biodegradable and biocompatible nanoparticles (APG-NLC) was developed to overcome the restricted APG stability, improve its therapeutic efficacy, and prolong its retention time on the ocular surface by extending its release. APG-NLC optimization, characterization, biopharmaceutical properties and therapeutic efficacy were evaluated. The optimized APG-NLC exhibited an average particle size below 200 nm, a positive surface charge, and an encapsulation efficiency over 99 %. APG-NLC exhibited sustained release of APG, and stability studies demonstrated that the formulation retained its integrity for over 25 months. In vitro and in vivo ocular tolerance studies indicated that APG-NLC did not cause any irritation, rendering them suitable for ocular topical administration. Furthermore, APG-NLC showed non-toxicity in an epithelial corneal cell line and exhibited fast cell internalization. Therapeutic benefits were demonstrated using an in vivo model of DED, where APG-NLC effectively reversed DED by reducing ocular surface cellular damage and increasing tear volume. Anti-inflammatory assays in vivo also showcased its potential to treat and prevent ocular inflammation, particularly relevant in DED patients. Hence, APG-NLC represent a promising system for the treatment and prevention of DED and its associated inflammation.
Topics: Animals; Apigenin; Drug Carriers; Dry Eye Syndromes; Humans; Rabbits; Lipids; Cell Line; Nanoparticles; Administration, Ophthalmic; Drug Liberation; Anti-Inflammatory Agents; Particle Size; Nanostructures; Male
PubMed: 38735632
DOI: 10.1016/j.ijpharm.2024.124222 -
Plants (Basel, Switzerland) Apr 2024The present study focuses on the chemical characterization of a dry extract obtained from the species (L.) Schreb, evaluating its antioxidant properties, toxicity, and...
The present study focuses on the chemical characterization of a dry extract obtained from the species (L.) Schreb, evaluating its antioxidant properties, toxicity, and in silico profile. Quantitative analysis of the dry extract revealed a notable amount of phytochemical compounds: 59.932 ± 21.167 mg rutin equivalents (mg REs)/g dry weight, 45.864 ± 4.434 mg chlorogenic acid equivalents (mg ChAEs)/g dry weight and, respectively, 83.307 ± 3.989 mg tannic acid equivalents (TAEs)/g dry weight. By UHPLC-HRMS/MS, the following were quantified as major compounds: caffeic acid (3253.8 μg/g extract) and kaempherol (3041.5 μg/g extract); more than 11 types of polyphenolic compounds were quantified (genistin 730.2 μg/g extract, naringenin 395 μg/g extract, apigenin 325.7 μg/g extract, galangin 283.3 μg/g extract, ferulic acid 254.3 μg/g extract, p-coumaric acid 198.2 μg/g extract, rutin 110.6 μg/g extract, chrysin 90.22 μg/g extract, syringic acid 84.2 μg/g extract, pinocembrin 32.7 μg/g extract, ellagic acid 18.2 μg/g extract). The antioxidant activity was in accordance with the amount of phytochemical compounds: ICDPPH = 483.6 ± 41.4 µg/mL, ICABTS = 127.4 ± 20.2 µg/mL, and ECFRAP = 491.6 ± 2 µg/mL. On the larvae of sp., it was found that the extract has a low cytotoxic action. In silico studies have highlighted the possibility of inhibiting the activity of protein kinases CDK5 and GSK-3b for apigenin, galangin, and kaempferol, with possible utility for treating neurodegenerative pathologies and neuropathic pain. Further studies are warranted to confirm the predicted molecular mechanisms of action and to further investigate the therapeutic potential in animal models of neurological disorders.
PubMed: 38732407
DOI: 10.3390/plants13091192 -
International Journal of Molecular... May 2024Neuroinflammation, a hallmark of various central nervous system disorders, is often associated with oxidative stress and neuronal or oligodendrocyte cell death. It is... (Review)
Review
Neuroinflammation, a hallmark of various central nervous system disorders, is often associated with oxidative stress and neuronal or oligodendrocyte cell death. It is therefore very interesting to target neuroinflammation pharmacologically. One therapeutic option is the use of nutraceuticals, particularly apigenin. Apigenin is present in plants: vegetables (parsley, celery, onions), fruits (oranges), herbs (chamomile, thyme, oregano, basil), and some beverages (tea, beer, and wine). This review explores the potential of apigenin as an anti-inflammatory agent across diverse neurological conditions (multiple sclerosis, Parkinson's disease, Alzheimer's disease), cancer, cardiovascular diseases, cognitive and memory disorders, and toxicity related to trace metals and other chemicals. Drawing upon major studies, we summarize apigenin's multifaceted effects and underlying mechanisms in neuroinflammation. Our review underscores apigenin's therapeutic promise and calls for further investigation into its clinical applications.
Topics: Apigenin; Humans; Animals; Neuroinflammatory Diseases; Anti-Inflammatory Agents; Oxidative Stress; Inflammation
PubMed: 38732259
DOI: 10.3390/ijms25095041 -
International Journal of Molecular... Apr 2024Flavonoid aglycones are secondary plant metabolites that exhibit a broad spectrum of pharmacological activities, including anti-inflammatory, antioxidant, anticancer,...
Flavonoid aglycones are secondary plant metabolites that exhibit a broad spectrum of pharmacological activities, including anti-inflammatory, antioxidant, anticancer, and antiplatelet effects. However, the precise molecular mechanisms underlying their inhibitory effect on platelet activation remain poorly understood. In this study, we applied flow cytometry to analyze the effects of six flavonoid aglycones (luteolin, myricetin, quercetin, eriodictyol, kaempferol, and apigenin) on platelet activation, phosphatidylserine externalization, formation of reactive oxygen species, and intracellular esterase activity. We found that these compounds significantly inhibit thrombin-induced platelet activation and decrease formation of reactive oxygen species in activated platelets. The tested aglycones did not affect platelet viability, apoptosis induction, or procoagulant platelet formation. Notably, luteolin, myricetin, quercetin, and apigenin increased thrombin-induced thromboxane synthase activity, which was analyzed by a spectrofluorimetric method. Our results obtained from Western blot analysis and liquid chromatography-tandem mass spectrometry demonstrated that the antiplatelet properties of the studied phytochemicals are mediated by activation of cyclic nucleotide-dependent signaling pathways. Specifically, we established by using Förster resonance energy transfer that the molecular mechanisms are, at least partly, associated with the inhibition of phosphodiesterases 2 and/or 5. These findings underscore the therapeutic potential of flavonoid aglycones for clinical application as antiplatelet agents.
Topics: Flavonoids; Humans; Platelet Aggregation Inhibitors; Platelet Activation; Blood Platelets; Reactive Oxygen Species; Apigenin; Quercetin; Luteolin; Signal Transduction; Kaempferols; Thrombin; Flavanones
PubMed: 38732081
DOI: 10.3390/ijms25094864 -
International Journal of Molecular... Apr 2024(PV) is one of the most commonly used nutraceuticals as it has been proven to have anti-inflammatory and antioxidant properties. The aim of this study was to evaluate...
(PV) is one of the most commonly used nutraceuticals as it has been proven to have anti-inflammatory and antioxidant properties. The aim of this study was to evaluate the phytochemical composition of PV and its in vivo antioxidant properties. A phytochemical analysis measuring the total phenolic content (TPC), the identification of phenolic compounds by HPLC-DAD-ESI, and the evaluation of the in vitro antioxidant activity by the DPPH assay of the extract were performed. The antioxidant effects on inflammation induced by turpentine oil were experimentally tested in rats. Seven groups with six animals each were used: a control group, the experimental inflammation treatment group, the experimental inflammation and diclofenac sodium (DS) treatment group, and four groups with their inflammation treated using different dilutions of the extract. Serum redox balance was assessed based on total oxidative status (TOS), nitric oxide (NO), malondialdehyde (MDA), total antioxidant capacity (TAC), total thiols, and an oxidative stress index (OSI) contents. The TPC was 0.28 mg gallic acid equivalents (GAE)/mL extract, while specific representatives were represented by caffeic acid, -coumaric acid, dihydroxybenzoic acid, gentisic acid, protocatechuic acid, rosmarinic acid, vanillic acid, apigenin-glucuronide, hesperidin, kaempferol-glucuronide. The highest amount (370.45 μg/mL) was reported for hesperidin, which is a phenolic compound belonging to the flavanone subclass. The antioxidant activity of the extracts, determined using the DPPH assay, was 27.52 mmol Trolox/mL extract. The PV treatment reduced the oxidative stress by lowering the TOS, OSI, NO, and MDA and by increasing the TAC and thiols. In acute inflammation, treatment with the PV extract reduced oxidative stress, with lower concentrations being more efficient and having a better effect than DS.
Topics: Animals; Antioxidants; Rats; Prunella; Plant Extracts; Phytochemicals; Inflammation; Oxidative Stress; Male; Anti-Inflammatory Agents; Phenols; Rats, Wistar
PubMed: 38732062
DOI: 10.3390/ijms25094843 -
Cancers Apr 2024Plant-derived polyphenols are bioactive compounds with potential health-promoting properties including antioxidant, anti-inflammatory, and anticancer activity. However,...
Plant-derived polyphenols are bioactive compounds with potential health-promoting properties including antioxidant, anti-inflammatory, and anticancer activity. However, their beneficial effects and biomedical applications may be limited due to their low bioavailability. In the present study, we have considered a microencapsulation-based drug delivery system to investigate the anticancer effects of polyphenol-rich (apigenin, caffeic acid, and luteolin) fractions, extracted from a cereal crop pearl millet (), using three phenotypically different cellular models of breast cancer in vitro, namely triple negative HCC1806, ER-positive HCC1428, and HER2-positive AU565 cells. Encapsulated polyphenolic extract induced apoptotic cell death in breast cancer cells with different receptor status, whereas it was ineffective against non-tumorigenic MCF10F cells. Encapsulated polyphenolic extract was also found to be cytotoxic against drug-resistant doxorubicin-induced senescent breast cancer cells that were accompanied by increased levels of apoptotic and necrotic markers, cell cycle inhibitor p21 and proinflammatory cytokine IL8. Furthermore, diverse responses to the stimulation with encapsulated polyphenolic extract in senescent breast cancer cells were observed, as in the encapsulated polyphenolic extract-treated non-proliferating AU565 cells, the autophagic pathway, here cytotoxic autophagy, was also induced, as judged by elevated levels of beclin-1 and LC3b. We show for the first time the anti-breast cancer activity of encapsulated polyphenolic extract of pearl millet and postulate that microencapsulation may be a useful approach for potentiating the anticancer effects of phytochemicals with limited bioavailability.
PubMed: 38730703
DOI: 10.3390/cancers16091750 -
Food Science & Nutrition May 2024In the middle of an ever-changing landscape of diabetes care, precision medicine, and lifestyle therapies are becoming increasingly important. Dietary polyphenols are... (Review)
Review
In the middle of an ever-changing landscape of diabetes care, precision medicine, and lifestyle therapies are becoming increasingly important. Dietary polyphenols are like hidden allies found in our everyday meals. These biomolecules, found commonly in fruits, vegetables, and various plant-based sources, hold revolutionary potential within their molecular structure in the way we approach diabetes and its intimidating consequences. There are currently numerous types of diabetes medications, but they are not appropriate for all patients due to limitations in dosages, side effects, drug resistance, a lack of efficacy, and ethnicity. Currently, there has been increased interest in practicing herbal remedies to manage diabetes and its related complications. This article aims to summarize the potential of dietary polyphenols as a foundation in the treatment of diabetes and its associated consequences. We found that most polyphenols inhibit enzymes linked to diabetes. This review outlines the potential benefits of selected molecules, including kaempferol, catechins, rosmarinic acid, apigenin, chlorogenic acid, and caffeic acid, in managing diabetes mellitus as these compounds have exhibited promising results in in vitro, in vivo, in silico, and some preclinical trials study. This encompassing exploration reveals the multifaceted impact of polyphenols not only in mitigating diabetes but also in addressing associated conditions like inflammation, obesity, and even cancer. Their mechanisms involve antioxidant functions, immune modulation, and proinflammatory enzyme regulation. Furthermore, these molecules exhibit anti-tumor activities, influence cellular pathways, and activate AMPK pathways, offering a less toxic, cost-effective, and sustainable approach to addressing diabetes and its complications.
PubMed: 38726403
DOI: 10.1002/fsn3.3983 -
Identification of potent inhibitors of kynurenine-3-monooxygenase from natural products: approaches.Heliyon May 2024Existing inhibitors of kynurenine-3-monooxygenase (KMO) have side effects and poorly cross the blood-brain barrier. Therefore, the discovery of new molecules targeting...
Existing inhibitors of kynurenine-3-monooxygenase (KMO) have side effects and poorly cross the blood-brain barrier. Therefore, the discovery of new molecules targeting KMO isnecessary.This study aims to develop a novel therapeutic drug targeting KMO using computational methods and experimental validation of natural compounds.The results of our study show that the top four compounds, namely, 3'-Hydroxy-alpha-naphthoflavone exhibited the best docking scores with KMO (-10.0 kcal/mol), followed by 3'-Hydroxy-ss-naphthoflavone (-9.9 kcal/mol), genkwanin (-9.2 kcal/mol) and apigenin(-9.1 kcal/mol) respectively. Molecular dynamics was used to assess the stability of the primary target, KMO, and inhibitor complexes. We found stable interactions of 3'-Hydroxy-ss-naphthoflavone and apigenin with KMO up to 100 ns. Further, kinetic measurements showed that 3'-Hydroxy-alpha-naphthoflavone and 3'-Hydroxy-ss-naphthoflavone induce competitive inhibition with a good IC activity (15.85 ± 0.98 μM and 18.71 ± 0.78, respectively), while Genkwanin and Apigenin exhibit non-competitive inhibition mechanism (21.61 ± 0.97 μM and 24.14 ± 1.00 μM, respectively).Drug-likeness features and ADME analysis features also showed that the top four compounds could be used as potential candidates to replace the synthetic KMO inhibitor drugs with known side effects and poor brain-blood barrier penetration.
PubMed: 38726174
DOI: 10.1016/j.heliyon.2024.e30287 -
Biomedicine & Pharmacotherapy =... Jun 2024The growth of antibiotic resistance to antifungal drugs contributes to the search for new ways to enhance their effectiveness and reduce toxicity. The undeniable...
The growth of antibiotic resistance to antifungal drugs contributes to the search for new ways to enhance their effectiveness and reduce toxicity. The undeniable advantage of polyene macrolide antibiotic amphotericin B (AmB) which ensures low pathogen resistance is its mechanism of action related to the formation of transmembrane pores in target lipid membranes. Here, we investigated the effects of plant flavones, chrysin, wogonin, baicalein, apigenin, scutellarein, luteolin, morin and fisetin on the pore-forming activity of AmB in the sterol-enriched membranes by electrophysiological assays. Сhrysin, wogonin, baicalein, apigenin, scutellarein, and luteolin were shown to decrease the AmB pore-forming activity in the bilayers composed of palmitoyloleylphosphocholine independently of their sterol composition. Morin and fisetin led to the increase and decrease in the AmB pore-forming activity in the ergosterol- and cholesterol-containing bilayers respectively. Differential scanning microcalorimetry of the gel-to-liquid crystalline phase transition of membrane forming lipids, molecular dynamics simulations, and absorbance spectroscopy revealed the possibility of direct interactions between AmB and some flavones in the water and/or in the lipid bilayer. The influence of these interactions on the antibiotic partitioning between aqueous solution and membrane and/or its transition between different states in the bilayer was discussed.
Topics: Amphotericin B; Flavones; Lipid Bilayers; Molecular Dynamics Simulation; Antifungal Agents; Phase Transition
PubMed: 38723514
DOI: 10.1016/j.biopha.2024.116723 -
Frontiers in Immunology 2024Chronic inflammation is a hallmark of chronic wounds and inflammatory skin diseases. Due to a hyperactive and prolonged inflammation triggered by proinflammatory immune... (Comparative Study)
Comparative Study
INTRODUCTION
Chronic inflammation is a hallmark of chronic wounds and inflammatory skin diseases. Due to a hyperactive and prolonged inflammation triggered by proinflammatory immune cells, transitioning to the repair and healing phase is halted. T cells may exacerbate the proinflammatory milieu by secreting proinflammatory cytokines. L. (chamomile) has been suggested for use in several inflammatory diseases, implying a capability to modulate T cells. Here, we have characterized and compared the effects of differently prepared chamomile extracts and characteristic pure compounds on the T cell redox milieu as well as on the migration, activation, proliferation, and cytokine production of primary human T cells.
METHODS
Phytochemical analysis of the extracts was carried out by LC-MS/MS. Primary human T cells from peripheral blood (PBTs) were pretreated with aqueous or hydroethanolic chamomile extracts or pure compounds. Subsequently, the effects on intracellular ROS levels, SDF-1α induced T cell migration, T cell activation, proliferation, and cytokine production after TCR/CD3 and CD28 costimulation were determined. Gene expression profiling was performed using nCounter analysis, followed by ingenuity pathway analysis, and validation at protein levels.
RESULTS
The tested chamomile extracts and pure compounds differentially affected intracellular ROS levels, migration, and activation of T cells. Three out of five differently prepared extracts and two out of three pure compounds diminished T cell proliferation. In line with these findings, LC-MS/MS analysis revealed high heterogeneity of phytochemicals among the different extracts. nCounter based gene expression profiling identified several genes related to T cell functions associated with activation and differentiation to be downregulated. Most prominently, apigenin significantly reduced granzyme B induction and cytotoxic T cell activity.
CONCLUSION
Our results demonstrate an anti-inflammatory effect of chamomile- derived products on primary human T cells. These findings provide molecular explanations for the observed anti-inflammatory action of chamomile and imply a broader use of chamomile extracts in T cell driven chronic inflammatory diseases such as chronic wounds and inflammatory skin diseases. Importantly, the mode of extract preparation needs to be considered as the resulting different phytochemicals can result in differential effects on T cells.
Topics: Humans; Plant Extracts; T-Lymphocytes; Matricaria; Anti-Inflammatory Agents; Cytokines; Flowers; Lymphocyte Activation; Plant Roots; Cells, Cultured; Cell Proliferation; Cell Movement
PubMed: 38720895
DOI: 10.3389/fimmu.2024.1388962