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Pharmacological Activities of Flavonoids and Their Analogues 2024

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Natural Products".

Deadline for manuscript submissions: closed (25 March 2025) | Viewed by 15928

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Dr. Fernando Calzada

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Medical Research Unit in Pharmacology, Speciality Hospital, National Medical Center Siglo XXI, Av. Cuauhtémoc 330 Col Doctores, México City CP 06725, Mexico
Interests: pharmacognosy of Mexican medicinal plants; diabetes mellitus; cancer; diarrhea; molecular docking; secondary metabolites
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Dr. Miguel Valdes

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Medical Research Unit in Pharmacology, Speciality Hospital. National Medical Center Siglo XXI, Av. Cuauhtémoc 330 Col Doctores, Mexico City CP 06725, Mexico
Interests: pharmacology; pharmacognosy; phytochemistry; medicinal plants; diabetes mellitus; cancer; diarrhea; drug development; isolation of natural compounds; terpenoids; flavonoids; molecular docking; molecular mechanism elucidation; pharmacological evaluation of natural compounds isolated from plants used in traditional Mexican medicine
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Special Issue Information

Dear Colleagues,

The development of new drugs continues to be an important point for global society. In recent years, there has been increased interest in the study of polyphenols due to the multiple pharmacological activities that they have demonstrated. Flavonoids are a class of polyphenols that have been widely studied; they are characterized as having a 15-carbon skeleton with a 2-phenylbenzopyranone core structure. They are classified as flavones, isoflavones, flavonols, anthocyanidins, flavanones, flavanols, chalcones and aurones. Within the various classes, further differentiation is possible based on the number and nature of substituent groups attached to the rings; moreover, flavonoids can exist as free aglycones or conjugated glycosidic bonds. Flavonoids are present in almost all types of nourishment, and recent studies have focused on their biological, nutritional, pharmacological and medicinal relevance. These kind of molecules, as well as their analogues, are of utmost relevance due to their multiple applications. Considering the above, we invite researchers to publish their findings on the pharmacological applications of flavonoids, as well as their analogs, while highlighting the importance of using these molecules as a basis for the development of new drugs.

Dr. Fernando Calzada
Dr. Miguel Valdes
Guest Editors

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Keywords

natural products
polyphenols
flavonoids
medicinal chemistry
traditional medicine
flavonoid isolation
flavonoid identification
flavonoid pharmacology
flavonoids as prodrugs
in vivo, in vitro and in silico studies
molecular modeling studies

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Research

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24 pages, 2863 KiB

Open AccessArticle

Soy Isoflavones Protects Against Stroke by Inhibiting Keap1/NQO1/Nrf2/HO-1 Signaling Pathway: Network Pharmacology Analysis Combined with the Experimental Validation

by Huiming Xue, Zhen Feng, Chang Jin, Yue Zhang, Yongxing Ai, Jing Wang, Meizhu Zheng and Dongfang Shi

Pharmaceuticals 2025, 18(4), 548; https://doi.org/10.3390/ph18040548 - 8 Apr 2025

Viewed by 779

Abstract

Objectives: Ischemic stroke is a severe neurological disorder with high morbidity, mortality, and disability rates, posing a substantial burden on patients, families, and healthcare systems. Soy isoflavone (SI), a naturally occurring phytoestrogen, has demonstrated promising neuroprotective effects. This study aimed to evaluate the anti-stroke efficacy of SI and elucidate its underlying mechanisms through integrated phytochemical profiling, network pharmacology, and both in vitro and in vivo experimental validation. Methods: Active constituents of SI were extracted via reflux and identified using liquid chromatography–mass spectrometry (LC-MS). Network pharmacology was employed to predict therapeutic targets and signaling pathways. The neuroprotective effects of SI were first assessed in PC12 cells subjected to oxygen–glucose deprivation/reoxygenation (OGD/R) injury in vitro. For in vivo evaluation, transient cerebral ischemia–reperfusion injury was induced using the bilateral common carotid artery occlusion (BCCAO) model in adult male ICR rats (27.3 ± 1.8 g; 6–8 weeks old), obtained from the Shanghai Experimental Animal Center, Chinese Academy of Sciences. Forty-eight rats were randomly assigned into four groups (n = 12): sham, model (BCCAO), SI-treated (100 mg/kg, oral gavage for 5 days), and edaravone (EDA)-treated (10 mg/kg, i.p., positive control). All procedures were approved by the Institutional Animal Care and Use Committee of Changchun Normal University (Approval No. 2024003, 13 March 2024) and conducted in accordance with the NIH guidelines and ARRIVE 2.0 reporting standards. Results: In vitro, SI significantly enhanced PC12 cell viability from 57.23 ± 2.88% to 80.76 ± 4.43% following OGD/R. It also reduced intracellular Ca²⁺ by 58.42%, lactate dehydrogenase (LDH) release by 37.67%, caspase-3 activity by 55.05%, and reactive oxygen species (ROS) levels by 74.13% (p < 0.05). A flow cytometry analysis revealed that OGD/R increased the apoptosis rate from 5.34% (control) to 30.85% (model group), which was significantly attenuated by SI treatment, especially in the 560 µg/mL group (20.00%), followed by the 140 and 280 µg/mL groups. In vivo, SI improved neurological scores from 8.3 ± 1.09 to 6.8 ± 1.68, reduced cerebral infarction volume by 18.49%, and alleviated brain edema by 10.42% (p < 0.05). SI also decreased malondialdehyde (MDA) and LDH levels by 31.15% and 39.46%, respectively, while increasing the activity of antioxidant enzymes: superoxide dismutase (SOD) by 11.70%, catalase (CAT) by 26.09%, and glutathione peroxidase (GSH-px) by 27.55% (p < 0.01). Scratch assay results showed that SI restored the impaired migratory ability of the OGD/R-treated PC12 cells, further supporting its role in cellular repair. A Western blot analysis demonstrated the upregulation of nuclear factor erythroid 2–related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H:quinone oxidoreductase 1 (NQO1) and the downregulation of Kelch-like, ECH-associated protein 1 (Keap1) in the cerebral ischemia–reperfusion model. Conclusions: These findings indicate that soy isoflavone confers significant neuroprotective effects against cerebral ischemia–reperfusion injury by enhancing endogenous antioxidant defense mechanisms, reducing oxidative stress, inhibiting apoptosis, and promoting cell migration. The protective effects are likely mediated through the activation of the Nrf2/Keap1 signaling pathway, supporting the therapeutic potential of SI in ischemic stroke treatment. Full article

(This article belongs to the Special Issue Pharmacological Activities of Flavonoids and Their Analogues 2024)

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30 pages, 5575 KiB

Open AccessArticle

Regulation of Intestinal Barrier Function and Gut Microbiota by Hot Melt Extrusion-Drug Delivery System-Prepared Mulberry Anthocyanin in an Inflammatory Bowel Disease Model

by Eun-Ji Go, Byeong Ryeol Ryu, Gyeong Ju Gim, Ye Rim Shin, Min Ji Kang, Min Jun Kim, Jong-Suep Baek and Jung Dae Lim

Pharmaceuticals 2025, 18(4), 475; https://doi.org/10.3390/ph18040475 - 27 Mar 2025

Viewed by 550

Abstract

Background/Objectives: Anthocyanins (ACNs) derived from mulberry (Morus alba L.) exhibit potent antioxidant and anti-inflammatory activities. However, their low stability and bioavailability in physiological environments limit their therapeutic potential. This study aimed to enhance the stability and controlled release ACNs using a hot-melt extrusion drug delivery system (HME-DDS) formulation, HME-MUL-F2, and evaluate its effects on gut barrier function and microbiota composition in a DSS-induced colitis model. Methods: The anthocyanin content of HME-MUL-F2 was quantified and compared with that of raw mulberry extract. The formulation’s protective effects were assessed in Caco-2 and RAW 264.7 cells, confirming its biocompatibility and anti-inflammatory properties. The therapeutic efficacy was further evaluated in a dextran sulfate sodium (DSS)-induced inflammatory bowel disease (IBD) model, focusing on gut barrier integrity, inflammatory cytokine modulation, and gut microbiota composition. Results: HME-MUL-F2 significantly improved gut barrier function by upregulating tight junction proteins and reducing inflammatory cytokine levels in the colitis model. Moreover, the formulation modulated gut microbiota composition, promoting beneficial bacteria while suppressing pathogenic strains. HME-MUL-F2 administration led to a significant increase in the Bacteroidetes-to-Firmicutes ratio, which is associated with improved gut health. These results indicate that HME-MUL-F2 significantly enhances anthocyanin bioavailability, leading to improved gut health and potential therapeutic applications for inflammatory conditions. Conclusions: This study highlights the potential of HME technology for improving the stability, bioavailability, and therapeutic efficacy of anthocyanins. HME-MUL-F2 is a sustained-release formulation that enhances gut barrier function and modulates intestinal microbial balance in a DSS-induced inflammatory bowel disease model. These findings strongly suggest that the observed therapeutic effects of HME-MUL-F2 are primarily due to enhanced anthocyanin bioavailability and targeted delivery to the colon, although further clinical studies will provide more definitive confirmation. Full article

(This article belongs to the Special Issue Pharmacological Activities of Flavonoids and Their Analogues 2024)

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11 pages, 2557 KiB

Open AccessArticle

Effects of Hispidulin on the Osteo/Odontogenic and Endothelial Differentiation of Dental Pulp Stem Cells

by Yeon Kim, Hyun-Joo Park, Mi-Kyoung Kim, Hyung Joon Kim, Yong-Il Kim, Soo-Kyung Bae and Moon-Kyoung Bae

Pharmaceuticals 2024, 17(12), 1740; https://doi.org/10.3390/ph17121740 - 23 Dec 2024

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Abstract

Background: Human dental pulp stem cells (HDPSCs) with multi-lineage differentiation potential and migration ability are required for HDPSC-based bone and dental regeneration. Hispidulin is a naturally occurring flavonoid with diverse pharmacological activities, but its effects on biological properties of HDPSCs remain unknown. Therefore, we investigated the effects of hispidulin on the differentiation potential and migration ability of HDPSCs and elucidated their underlying mechanisms. Methods: The osteo/odontogenic capacity of HDPSCs was assessed using the alkaline phosphatase (ALP) and Alizarin Red S (ARS) staining. The migration ability of HDPSCs was evaluated using a scratch wound assay. Furthermore, the endothelial differentiation of HDPSCs was examined by using a capillary sprouting assay and by assessing CD31 expression. Results: Hispidulin significantly enhanced the osteo/odontogenic differentiation of HDPSCs with increased expression of osteo/odontogenic differentiation markers. Hispidulin increased the migration of HDPSCs, which was mediated by the upregulation of C-X-C chemokine receptor type 4 (CXCR4). The treatment of HDPSCs with hispidulin enhanced the differentiation of HDPSCs into endothelial cells, as evidenced by increased capillary sprouting and endothelial marker expression. In addition, we demonstrated that hispidulin activated the ERK1/2 signaling, and its inhibition by U0126 significantly suppressed the hispidulin-induced endothelial differentiation of HDPSCs. Conclusions: These findings demonstrate that hispidulin effectively promotes the osteo/odontogenic and endothelial differentiation, and migration of HDPSCs. These results suggest that hispidulin may have potential therapeutic applications in dental pulp regeneration and tissue engineering. Full article

(This article belongs to the Special Issue Pharmacological Activities of Flavonoids and Their Analogues 2024)

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11 pages, 3689 KiB

Open AccessArticle

Isoorientin Improves Excisional Skin Wound Healing in Mice

by Aline B. Hora, Laiza S. Biano, Ana Carla S. Nascimento, Zaine T. Camargo, Greice I. Heiden, Ricardo L. C. Albulquerque-Júnior, Renata Grespan, Jessica M. D. A. Aragão and Enilton A. Camargo

Pharmaceuticals 2024, 17(10), 1368; https://doi.org/10.3390/ph17101368 - 14 Oct 2024

Cited by 1 | Viewed by 1479

Abstract

Background/Objectives: Wound healing relies on a coordinated process with the participation of different mediators. Natural products are a source of active compounds with healing potential. Isoorientin is a natural flavone recognized as having several pharmacological properties, such as anti-inflammatory effects, making it a potential treatment for wounds. We investigated the effect of isoorientin on the healing of excisional skin wounds. Methods: Male Swiss mice were subjected to the induction of excisional skin wounds (6 mm diameter) and treated with a vehicle (2% dimethyl sulfoxide in propylene glycol) or 2.5% isoorientin applied topically once a day for 14 days. The wound area was measured on days 0, 3, 7, and 14. Histopathological analyses were performed on the cicatricial tissue after 14 days. The myeloperoxidase activity and the interleukin-1β, tumoral necrosis factor (TNF)-α, and interleukin-6 concentrations were determined on the third day. Results: We observed that 3 days after the topical application of isoorientin, the lesion area was significantly smaller when compared to those of the vehicle (p < 0.01) and control (p < 0.05) groups. No difference was observed after 7 and 14 days of induction. Despite this, on day 14, histological analysis of cicatricial tissue from the animals treated with isoorientin showed reduced epidermal thickness (p < 0.001) and increased collagen deposition (p < 0.001). These effects were accompanied by decreased myeloperoxidase activity and interleukin-1β concentration on the third day of induction, without alteration in TNF-α and interleukin-6. Conclusions: The treatment with isoorientin promoted better tissue repair in excisional wounds in mice, which may be linked to the modulation of the early inflammatory response. Full article

(This article belongs to the Special Issue Pharmacological Activities of Flavonoids and Their Analogues 2024)

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21 pages, 4435 KiB

Open AccessArticle

Anti-Alzheimer’s Potency of Rich Phenylethanoid Glycosides Extract from Marrubium vulgare L.: In Vitro and In Silico Studies

by Mahmoud Emam, Samah A. El-Newary, Hanan Y. Aati, Bin Wei, Mohamed Seif and Abeer Y. Ibrahim

Pharmaceuticals 2024, 17(10), 1282; https://doi.org/10.3390/ph17101282 - 27 Sep 2024

Cited by 3 | Viewed by 1569

Abstract

Background/Objectives: Marrubium vulgare L. (M. vulgare), the white horehound, is well known for treating inflammation-related diseases. Methods: In this context, we investigated the efficacy of M. vulgare ingredients in treating Alzheimer’s disease using various in vitro and in silico antioxidant, anti-inflammatory, anti-cholinesterase, and anti-tyrosinase mechanisms. Results: In our results, sixty-one components were tentatively identified using gas and liquid chromatography (GC-MS and LC-MSⁿ) and categorized as hydrocarbons, fatty acids, and polyphenolics. The extract inhibited linoleic oxidation with an IC₅₀ value of 114.72 µg/mL, captured iron (Fe²⁺) ions with an IC₅₀ value of 164.19 µg/mL, and displayed reducing power. In addition, the extract showed radical-scavenging ability towards DPPH^•, NO^•, ABTS^•+, and H₂O₂ assays compared to L-ascorbic acid and butylated hydroxytoluene. The DPPH^• was scavenged by 77.62% at 100 µg/mL, and NO^•, ABTS^•+, and H₂O₂ were scavenged with IC₅₀ values of 531.66, 117.51, and 143.10 µg/mL, respectively. M. vulgare also exhibited discriminating anti-inflammatory potency against cyclooxygenase (COX-2) with IC₅₀ values of 619.15 µg/mL compared to celecoxib (p > 0.05). Notably, three Alzheimer’s biomarkers, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and tyrosinase were significantly inhibited. The molecular docking study supposed that the phenylethanoid glycosides of samioside and forsythoside B inhibited AChE and tyrosinase enzymes with low binding affinities of −9.969 and −8.804 kcal/mol, respectively. Marruboside was a proper inhibitor of COX and BChE enzymes with a binding score of −10.218 and −10.306 kcal/mol, respectively. Conclusions: M. vulgare extract showed significant inhibitory actions, which suggest that it could have a promising potential as an anti-Alzheimer agent. Full article

(This article belongs to the Special Issue Pharmacological Activities of Flavonoids and Their Analogues 2024)

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15 pages, 3691 KiB

Open AccessArticle

Antibacterial Activity and Mechanisms of Plant Flavonoids against Gram-Negative Bacteria Based on the Antibacterial Statistical Model

by Yu Yan, Xuexue Xia, Aiman Fatima, Li Zhang, Ganjun Yuan, Fengxian Lian and Yu Wang

Pharmaceuticals 2024, 17(3), 292; https://doi.org/10.3390/ph17030292 - 24 Feb 2024

Cited by 27 | Viewed by 7591

Abstract

The antimicrobial quantitative structure–activity relationship of plant flavonoids against Gram-positive bacteria was established in our previous works, and the cell membrane was confirmed as a major site of action. To investigate whether plant flavonoids have similar antibacterial effects and mechanisms against both Gram-negative and Gram-positive bacteria, here, the minimum inhibitory concentrations (MICs) of 37 plant flavonoids against Escherichia coli were determined using the microdilution broth method, and then the correlation between their lipophilic parameter ACD/LogP or LogD_7.40 value and their MIC was analyzed. Simultaneously, the correlation between the ACD/LogP or LogD_7.40 value and the MIC of 46 plant flavonoids reported in the literature against E. coli was also analyzed. Both sets of results showed that there is a significant correlation between the LogP value and the MIC of plant flavonoids against Gram-negative bacteria. However, it is difficult to effectively predict the MIC of plant flavonoids against Gram-negative bacteria from their lipophilic parameters. By comparing two regression curves derived from plant flavonoids against Gram-negative and Gram-positive bacteria, it was further discovered that the antibacterial activities of most plant flavonoids against Gram-negative bacteria are stronger than those against Gram-positive bacteria when their LogP values are less than approximately 3.0, but the opposite is true when their LogP values are more than approximately 3.6. Moreover, this comparison also suggests that unlike mainly acting on the cell membrane of Gram-positive bacteria, plant flavonoids have multiple mechanisms against Gram-negative species, while the cell membrane is also an important action site among them. Combined with the correlation analyses between the enzyme inhibitory activity and the LogP value of the reported flavonoids, it was further suggested that DNA gyrase is another important target of plant flavonoids against Gram-negative bacteria. Full article

(This article belongs to the Special Issue Pharmacological Activities of Flavonoids and Their Analogues 2024)

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Review

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25 pages, 4861 KiB

Open AccessReview

Role of Polyphenols in Dermatological Diseases: Exploring Pharmacotherapeutic Mechanisms and Clinical Implications

by Juan Salazar, Ángel Ortega, José Luis Pérez, Bermary Garrido, Raquel Santeliz, Néstor Galbán, Maria Paula Díaz, Raquel Cano, Gabriel Cano, Julio Cesar Contreras-Velasquez and Maricarmen Chacín

Pharmaceuticals 2025, 18(2), 247; https://doi.org/10.3390/ph18020247 - 12 Feb 2025

Viewed by 1697

Abstract

Although not frequently lethal, dermatological diseases represent a common cause of consultation worldwide. Due to the natural and non-invasive approach of phytotherapy, research for novel alternatives, such as polyphenols, to treat skin disorders is a subject of interest in modern medicine. Polyphenols, in particular, have been considered because of their anti-inflammatory, antitumoral, antimicrobial, and antioxidant properties, low molecular weight, and lipophilic nature that enables the passage of these compounds through the skin barrier. This review discusses the treatment of common dermatological diseases such as acne vulgaris, fungal infections, dermatitis, alopecia, and skin cancer, using polyphenols as therapeutic and prophylactic options. The specific molecules considered for each disorder, mechanisms of action, current clinical trials, and proposed applications are also reviewed. Full article

(This article belongs to the Special Issue Pharmacological Activities of Flavonoids and Their Analogues 2024)

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