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Bioactive Compounds and Small Molecules with Neuroprotective and Anti-Inflammatory Functions

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

Deadline for manuscript submissions: 30 September 2026 | Viewed by 26570

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Special Issue Editor

Prof. Dr. Chiara Porro

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Department of Clinical and Experimental Medicine, University of Foggia, 71121 Foggia, Italy
Interests: extracellular vesicle; microglia; bioactive foods; neuroprotection; neurodegenera-tive diseases; ageing; anti-inflammatory molecules; curcumin; resveratrol; vita-mins
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Dear Colleagues,

Most neurodegenerative diseases are defined as complex multifactorial disorders, with genetic and environmental factors greatly contributing to their onset.

The relevance of lifestyle, including diet and exercise, has been associated with improved learning and memory capacity, delayed age-related cognitive decline, and a reduced risk of neurodegeneration.

The bioactive compounds and small molecules found in food exhibit beneficial effects, such as antioxidant, anti-inflammatory, and neuroprotective.

There is evidence that the consumption of certain food components, such as omega-3 fatty acids, carotenoids, flavonoids, polyphenols, etc., can reduce the risk of neurodegeneration and inflammatory diseases.

Supplementation with bioactive compounds is a valuable tool for strengthening neuroprotection and preventing inflammatory diseases. Therefore, there is increasing interest in identifying nutrients or dietary treatments that are neuroprotective and anti-inflammatory.

This Special Issue, entitled “Bioactive Compounds and Small Molecules with Neuroprotective and Anti-Inflammatory Functions”, welcomes the submission of both original research manuscripts and reviews concerning the in vitro and in vivo biological effects of bioactive foods and small molecules and their potential therapeutic applications in neuroprotection and inflammatory diseases.

Prof. Dr. Chiara Porro
Guest Editor

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Keywords

bioactive foods
small molecules
neuroprotection
anti-inflammatory
inflammasome
neurodegeneration

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Published Papers (9 papers)

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Research

Jump to: Review

18 pages, 1296 KB

Open AccessArticle

Metformin and Sitagliptin Impact the Brain Kynurenine Pathway: Region-Specific Modulation of Neuroactive Metabolites in Non-Diabetic Male Rats

by Kinga Bednarz, Renata Kloc, Tymoteusz Słowik and Ewa M. Urbanska

Molecules 2026, 31(4), 714; https://doi.org/10.3390/molecules31040714 - 19 Feb 2026

Viewed by 470

Abstract

An excessive activation of the tryptophan–kynurenine (TRP-KYN) pathway, frequently observed in metabolic and inflammatory disorders, leads to disturbances in the balance between neurotoxic and neuroprotective metabolites. These alterations may contribute to neuronal dysfunction and cognitive impairment, highlighting the importance of modulating this pathway in the context of neuroprotection. Metformin, apart from the AMPK activation and its broad anti-inflammatory actions, has been indicated as a drug capable of influencing the synthesis of TRP metabolites, including the neuroprotective kynurenic acid (KYNA), whereas the effects of sitagliptin in this regard are not known. Here, the effects of sub-chronic metformin or sitagliptin treatment on the brain levels of kynurenines and on functional alterations within the TRP-KYN pathway were evaluated in vivo, in adult non-diabetic Wistar male rats. A 5-day treatment with metformin decreased cortical TRP and KYNA, hippocampal KYN, and cerebellar levels of all studied kynurenines, whereas in the striatum, KYNA level increased. In contrast, sitagliptin did not alter the formation of kynurenines in the examined structures. However, both of the tested drugs had a significant impact on TRP/L-KYN or L-KYN/KYNA ratios in different parts of the brain. These findings indicate a prominent region-specific effect of metformin on brain kynurenines. In conclusion, commonly used antidiabetic agents differ in their impact on central TRP metabolism, which may have significant implications for understanding their potential neuroprotective effects and role in cognitive impairment. Full article

(This article belongs to the Special Issue Bioactive Compounds and Small Molecules with Neuroprotective and Anti-Inflammatory Functions)

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21 pages, 10742 KB

Open AccessArticle

Anti-Inflammatory Effects of Bisacurone Isolated from Curcuma longa (Ryudai Gold): An In Vivo and In Silico Study

by Mahir Anjum, Md. Amzad Hossain, Jesmin Akter, Atsushi Miyamoto and Md. Zahorul Islam

Molecules 2026, 31(3), 548; https://doi.org/10.3390/molecules31030548 - 4 Feb 2026

Cited by 1 | Viewed by 724

Abstract

Bisacurone is a sesquiterpenoid constituent of Curcuma longa that has received considerably less attention than curcuminoids despite emerging evidence of its biological activity. In this study, the anti-inflammatory potential of bisacurone isolated from the Ryudai gold variety of Curcuma longa was evaluated using an integrated in vivo and in silico approach. Acute inflammation was assessed in rats using a carrageenan-induced paw edema model, supported by histopathological examination of paw tissues. Bisacurone significantly reduced paw edema during the peak inflammatory phase and markedly attenuated dermal thickening and inflammatory cell infiltration, indicating effective suppression of acute inflammatory responses. The effects of bisacurone were comparable to that of indomethacin. To elucidate the underlying molecular basis, density functional theory calculations, molecular docking, molecular dynamics simulations, and pharmacokinetic and toxicity predictions were performed. In silico analyses revealed favorable electronic properties, drug-likeness, and stable interactions of bisacurone with key inflammatory regulators, particularly IKKβ and COX-1, along with moderate interactions with MAPKs and iNOS. Molecular dynamics simulations confirmed the stability of the protein–ligand complexes. Collectively, these findings demonstrate that bisacurone exerts anti-inflammatory effects through multi-target modulation of inflammatory signaling pathways and highlight its potential as a bioactive functional food component and a lead compound for anti-inflammatory drug development. Full article

(This article belongs to the Special Issue Bioactive Compounds and Small Molecules with Neuroprotective and Anti-Inflammatory Functions)

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15 pages, 785 KB

Open AccessArticle

In Vitro Biological Activities and Phytochemical Analyses of Mespilus germanica L.

by Ekin Kurtul, Şükran Öztürk, Selen Tekin, Özge Yılmaz and Özlem Bahadır-Acıkara

Molecules 2026, 31(1), 50; https://doi.org/10.3390/molecules31010050 - 23 Dec 2025

Cited by 1 | Viewed by 631

Abstract

Mespilus germanica L. is one of the two species of the genus Mespilus L., and is distributed in several regions, including Southeastern Europe, Anatolia, the Caucasus, and parts of the Middle East. The fruits of the plant are consumed as food, and the fruits, leaves, and stem bark are traditionally used for various systemic disorders, including gastrointestinal, respiratory, urinary tract, and skin conditions, as well as menstrual irregularities. In our study, the anti-inflammatory potential and antimicrobial activities of aqueous-methanolic extracts prepared from ripe (MGRF) and unripe fruits (MGUF), leaves (MGL), and stem bark (MGB) of M. germanica were evaluated in vitro. Quercetin, catechin, epicatechin, ellagic acid, chlorogenic acid, and caffeic acid were analyzed using high-performance liquid chromatography. MGL exhibited the strongest activity against Staphylococcus aureus (MIC = 8 µg/mL), while MGB was most active against Enterococcus faecalis (MIC = 4 µg/mL), and fruit extracts were effective against resistant Acinetobacter baumannii (MIC = 16–32 µg/mL). Membrane-protective effects were more pronounced in MGUF and MGB, whereas MGL demonstrated the highest protein stabilization activity. Leaves also contained the highest levels of chlorogenic acid and epicatechin. These findings support the traditional use of M. germanica, though further studies are required to explore its therapeutic potential. Full article

(This article belongs to the Special Issue Bioactive Compounds and Small Molecules with Neuroprotective and Anti-Inflammatory Functions)

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19 pages, 1553 KB

Open AccessArticle

Chrysin-Loaded Extracellular Vesicles Attenuate LPS-Induced Neuroinflammation in BV2 Microglial Cells In Vitro: A Novel Neuroprotective Strategy

by Francesca Martina Filannino, Raffaella Soleti, Melania Ruggiero, Maria Ida de Stefano, Maria Antonietta Panaro, Dario Domenico Lofrumento, Teresa Trotta, Angela Bruna Maffione, Tarek Benameur, Antonia Cianciulli, Rosa Calvello, Federico Zoila and Chiara Porro

Molecules 2025, 30(15), 3131; https://doi.org/10.3390/molecules30153131 - 25 Jul 2025

Cited by 4 | Viewed by 3937

Abstract

Neuroinflammation, driven by activated microglia, contributes to the progression of neurodegenerative diseases. Extracellular vesicles mediate intercellular communication and influence immune responses. Chrysin, a natural flavone found in fruits and propolis, has demonstrated anti-inflammatory effects. This study explored the immunomodulatory potential of chrysin-loaded EVs (EVs-Chry) derived from BV2 microglial cells. BV2 cells were treated with chrysin for 24 h to assess cytotoxicity and proliferation. EVs were isolated from treated and untreated cells, characterized by nanoparticle tracking analysis, and applied to naïve BV2 cells prior to LPS stimulation. Effects on cell morphology, migration, cytokine expression (IL-1β, IL-6), inflammasome activity (caspase-1), and apoptosis-related protein Bcl-xL were investigated. Our results show that EVs-Chry significantly reduced LPS-induced cell proliferation, restored resting microglial morphology, and reduced migratory capacity. Furthermore, co-treatment with EVs-Chry and LPS reduced pro-inflammatory cytokines such as IL-1β, IL-6, and caspase-1 expression while enhancing anti-apoptotic Bcl-xL levels, indicating a shift toward an anti-inflammatory, neuroprotective micro-glial phenotype. Together, our results demonstrated that EVs-Chry have neuroprotective effects on LPS-induced microglial activation and modulate microglial responses to inflammatory stimuli, attenuating pro-inflammatory signaling and promoting cellular homeostasis. These findings support the therapeutic potential of EVs-Chry in the context of neuroinflammatory and neurodegenerative disorders. Full article

(This article belongs to the Special Issue Bioactive Compounds and Small Molecules with Neuroprotective and Anti-Inflammatory Functions)

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18 pages, 2563 KB

Open AccessArticle

The Potential Anti-Cancer Effects of Polish Ethanolic Extract of Propolis and Quercetin on Glioma Cells Under Hypoxic Conditions

by Małgorzata Kłósek, Anna Kurek-Górecka, Radosław Balwierz, Grażyna Pietsz and Zenon P. Czuba

Molecules 2025, 30(14), 3008; https://doi.org/10.3390/molecules30143008 - 17 Jul 2025

Cited by 2 | Viewed by 1837

Abstract

Tissue hypoxia is commonly observed in head cancers and contributes to both molecular and functional changes in tumour cells. It is known to stimulate erythropoiesis, angiogenesis, and metabolic alterations within tumour cells. Glioblastoma, a type of brain tumour, is characterized by rapid proliferation and aggressive growth. Recent studies have indicated that natural products may hold potential as components of cancer therapy. Among these, Polish propolis and its active compound, quercetin, have demonstrated promising anti-cancer properties. The aim of this study was to evaluate the concentrations of selected cytokines—specifically IL-6, IL-9, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF-BB), interferon gamma-induced protein 10 (IP-10), and monocyte chemoattractant protein-1 (MCP-1)—produced by astrocytes of the CCF-STTG1 cell line. The cytotoxic effects of ethanolic extract of propolis (EEP) and quercetin were assessed using the MTT assay. Astrocytes were stimulated with lipopolysaccharide (LPS, 200 ng/mL) and/or IFN-α (100 U/mL), followed by treatment with EEP or quercetin (25–50 µg/mL) under hypoxic conditions for two hours. Cytokine concentrations were measured using the xMAP Luminex Multiplex Immunoassay and the Multiplex Bead-Based Cytokine Kit. Our study demonstrated that Polish propolis and its component quercetin modulate the tumour microenvironment in vitro, primarily by altering the levels of specific cytokines. The HCA analysis revealed that IL-6 and MCP-1 formed a distinct cluster at the highest linkage distance (approximately 100% of Dmax), suggesting that their expression patterns are significantly different from those of the other cytokines and that they are more similar to each other than to the rest. PCA analysis showed that EEP-PL (50 μg/mL) with IFN-α and EEP-PL (50 μg/mL) with LPS exert similar activities on cytokine secretion by astrocytes. Similar effects were demonstrated for EEP-PL 50 μg/mL + LPS + IFN-α, EEP-PL 25 μg/mL + IFN-α and EEP-PL 25 μg/mL + LPS + IFN-α. Our findings suggest that Polish propolis and quercetin may serve as promising natural agents to support the treatment of stage IV malignant astrocytoma. Nonetheless, further research is needed to confirm these results. Full article

(This article belongs to the Special Issue Bioactive Compounds and Small Molecules with Neuroprotective and Anti-Inflammatory Functions)

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Review

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16 pages, 2741 KB

Open AccessReview

Recent Advances in Erinacine A: Preparation, Biological Activities, and Biosynthetic Pathway

by Jingyuan Wang, Huan Liu, Chunlei Wang and Chengwei Liu

Molecules 2026, 31(2), 219; https://doi.org/10.3390/molecules31020219 - 8 Jan 2026

Cited by 1 | Viewed by 1187

Abstract

Erinacine A, a cyathane diterpenoid derived from the medicinal and edible fungus Hericium erinaceus, is increasingly recognized for its potent neurotrophic and neuroprotective properties. It demonstrates significant therapeutic promise for neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease, primarily by stimulating the synthesis of nerve growth factor (NGF). However, the clinical applicability of erinacine A is currently restricted by its low yield from natural sources and high production costs. This challenge has spurred significant research focused on optimizing its production. This review provides a comprehensive overview of the current advancements in the fermentation-based preparation of erinacine A, including both liquid and solid-state cultivation techniques. Furthermore, we summarize its diverse biological activities, spanning neuroprotection, anticancer, and anti-inflammatory effects, and detail the recent discoveries elucidating its complex biosynthetic pathway. This consolidated overview offers insights into strategies for enhancing its production and supports its ongoing development as a therapeutic agent. Full article

(This article belongs to the Special Issue Bioactive Compounds and Small Molecules with Neuroprotective and Anti-Inflammatory Functions)

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21 pages, 1452 KB

Open AccessReview

Ergothioneine: An Antioxidative, Neuroprotective and Anti-Inflammatory Compound from Mushroom Residuals

by Joanna Harasym, Alona Tiupova and Ewa Pejcz

Molecules 2025, 30(23), 4621; https://doi.org/10.3390/molecules30234621 - 1 Dec 2025

Viewed by 3700

Abstract

In vitro and in vivo evidence demonstrates that EGT exerts neuroprotective effects through multiple mechanisms: scavenging reactive oxygen species, suppressing neuroinflammatory cytokines (TNF-α, IL-1β, IL-6), activating Nrf2 antioxidant pathways, and preserving mitochondrial integrity. Low blood EGT levels correlate with cognitive decline and dementia, supporting its role as a conditionally essential micronutrient for healthy aging. Mushroom by-products retain EGT concentrations comparable to commercial fruiting bodies, making them viable sources for dietary supplements and functional foods. Mushroom processing generates substantial residual biomass—including stems, culls, and spent substrate—that represents an underexploited dietary source of ergothioneine (EGT), a naturally occurring antioxidant with exceptional neuroprotective and anti-inflammatory properties. Since humans cannot synthesize EGT endogenously, dietary intake is essential for maintaining neuroprotection against neurodegenerative diseases. This review examines sustainable extraction strategies—including hot-water, ultrasound-assisted, and high-hydrostatic-pressure methods—enabling integration into circular biorefinery systems. Applications in nutraceuticals and pharmaceuticals targeting oxidative stress-related neurodegeneration are highlighted. Despite challenges in standardization and regulatory approval, valorizing mushroom residuals offers a sustainable pathway to increase dietary availability of this neuroprotective antioxidant, supporting both environmental sustainability and therapeutic innovation for neurodegenerative disease prevention. Full article

(This article belongs to the Special Issue Bioactive Compounds and Small Molecules with Neuroprotective and Anti-Inflammatory Functions)

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19 pages, 753 KB

Open AccessReview

Neuroprotective Role of Omega-3 Fatty Acids: Fighting Alzheimer’s Disease

by Mervin Chávez-Castillo, María Paula Gotera, Pablo Duran, María P. Díaz, Manuel Nava, Clímaco Cano, Edgar Díaz-Camargo, Gabriel Cano, Raquel Cano, Diego Rivera-Porras and Valmore Bermúdez

Molecules 2025, 30(15), 3057; https://doi.org/10.3390/molecules30153057 - 22 Jul 2025

Cited by 10 | Viewed by 6435

Abstract

Alzheimer’s disease (AD) is one of the main causes of dementia, with an exponential increment in its incidence as years go by. However, since pathophysiological mechanisms are complex and multifactorial, therapeutic strategies remain inconclusive and only provide symptomatic relief to patients. In order to solve this problem, new strategies have been investigated over recent years for AD treatment. This field has been reborn due to epidemiological and preclinical findings that demonstrate the fact that omega-3 polyunsaturated fatty acids (ω-3 PUFAs) can be promising therapeutic agents because of their anti-inflammatory, antioxidant, and neurogenic-promoting activities, thus allowing us to classify these molecules as neuroprotectors. Similarly, ω-3 PUFAs perform important actions in the formation of characteristic AD lesions, amyloid-β plaques (Aβ) and neurofibrillary tangles, reducing the development of these structures. Altogether, the aforementioned actions hinder cognitive decline and possibly reduce AD development. In addition, ω-3 PUFAs modulate the inflammatory response by inhibiting the production of pro-inflammatory molecules and promoting the synthesis of specialised pro-resolving mediators. Consequently, the present review assesses the mechanisms by which ω-3 PUFAs can act as therapeutic molecules and the effectiveness of their use in patients. Clinical evidence so far has shown promising results on ω-3 PUFA effects, both in animal and epidemiological studies, but remains contradictory in clinical trials. More research on these molecules and their neuroprotective effects in AD is needed, as well as the establishment of future guidelines to obtain more reproducible results on this matter. Full article

(This article belongs to the Special Issue Bioactive Compounds and Small Molecules with Neuroprotective and Anti-Inflammatory Functions)

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29 pages, 1368 KB

Open AccessReview

Specialized Pro-Resolving Lipid Mediators in Pulmonary Diseases: Molecular and Therapeutic Implications

by Ángel Ortega, Pablo Duran, Bermary Garrido, Alexander Manzano, Carolina Navarro, Aljadis Silva, Milagros Rojas, Juan Bautista De Sanctis, Danuta Radzioch, Diego Rivera-Porras, Carlos Silva Paredes and Valmore Bermúdez

Molecules 2025, 30(10), 2212; https://doi.org/10.3390/molecules30102212 - 19 May 2025

Cited by 7 | Viewed by 6785

Abstract

Inflammatory lung diseases (ILDs) represent a global public health crisis characterized by escalating prevalence, significant morbidity, and substantial mortality. In response to the complex immunopathogenic mechanisms driving these conditions, novel pharmacological strategies targeting resolution pathways have emerged throughout the discovery of specialized pro-resolving lipid mediator (SPM; resolvins, maresins, and protectins) dysregulation across the ILD spectra, positioning these endogenous molecules as promising therapeutic candidates for modulating maladaptive inflammation and promoting tissue repair. Over the past decade, this paradigm has catalyzed extensive translational research into SPM-based interventions as precision therapeutics for respiratory inflammation. In asthma, they reduce mucus hypersecretion, bronchial hyperreactivity, and airway inflammation, with prenatal SPM exposure potentially lowering offspring disease risk. In COPD, SPMs attenuate amyloid A-driven inflammation, normalizing cytokine/chemokine imbalances and oxidative stress and mitigating COVID-19-associated cytokine storm, enhancing survival. This review synthesizes SPMs’ pharmacotherapeutic mechanisms in ILDs and evaluates current preclinical and clinical evidence. Full article

(This article belongs to the Special Issue Bioactive Compounds and Small Molecules with Neuroprotective and Anti-Inflammatory Functions)

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