Background: Agri-food by-products are increasingly recognized as valuable sources of tannins, whose antioxidant properties represent the primary driver of their biological activity across human and animal health. The strong redox-modulating capacity of condensed and hydrolysable tannins provides a unifying mechanistic explanation for their effects on inflammation, metabolism, gut integrity and neuroprotection. Methods: This narrative review synthesizes evidence obtained through a structured literature search across major databases, selecting studies that investigated antioxidant mechanisms of tannin-rich matrices from plant- and processing-derived residues. Results: Condensed tannins, particularly proanthocyanidins, consistently display potent antioxidant activity through radical scavenging, metal chelation and activation of endogenous defenses, thereby underpinning their anti-inflammatory, anti-ischemic, neuroprotective and metabolic actions. Hydrolysable tannins similarly exert strong antioxidative effects that support antimicrobial activity, enzyme modulation and protection against neuroinflammation. In animals, the antioxidant capacity of tannins translates into improved oxidative balance, enhanced immune status, reduced tissue damage, better feed efficiency and mitigation of oxidative stress-linked methane emission pathways. Conclusions: Antioxidant activity emerges as the central, cross-species mechanism through which tannins mediate diverse health benefits. Tannin-rich agri-food by-products therefore represent promising sustainable antioxidant resources, although their efficacy remains influenced by tannin class, degree of polymerization and dosage, warranting further mechanistic and translational research.

Background: Edible and medicinal mushrooms have attracted growing attention as functional foods due to their rich content of bioactive compounds and their potential to modulate host physiology through microbiota-mediated mechanisms. Methods: This narrative review was conducted through a comprehensive literature search across major scientific databases, including PubMed, Scopus, ScienceDirect, Web of Science, and Google Scholar, selecting studies focused on mushroom-derived compounds, gut microbiota, short-chain fatty acids (SCFAs), and the gut–brain axis (GBA). Results: Current evidence indicates that mushroom-derived polysaccharides, particularly β-glucans, along with polyphenols, trehalose, and chitin, resist digestion and are fermented by intestinal microorganisms, promoting SCFA production. These metabolites contribute to intestinal barrier integrity, immune regulation, and metabolic homeostasis and may also influence neuroinflammation and neurotransmitter pathways via the GBA. However, significant variability in mushroom preparations and the limited availability of well-designed human clinical trials remain important limitations. Conclusions: Edible and medicinal mushrooms represent a promising source of novel prebiotic compounds with potential systemic health benefits, although further standardized studies and robust clinical trials are needed to confirm their efficacy and mechanisms of action.

Heart failure (HF) and atrial fibrillation (AF) are among the most prevalent cardiovascular diseases, often coexisting and sharing common pathophysiological pathways such as systemic inflammation, oxidative stress, mitochondrial dysfunction, and endothelial impairment. Despite substantial progress in pharmacological treatment, including renin-angiotensin-aldosterone system (RAAS) inhibitors, beta-blockers, sodium-glucose cotransporter 2 (SGLT2) inhibitors, mineralocorticoid receptor antagonists (MRAs), diuretics, and antiarrhythmic drugs, many patients continue to experience residual symptoms and drug-related adverse effects. Nutraceuticals have emerged as potential adjuncts to conventional therapy due to their ability to modulate key biological processes involved in HF and AF. Polyphenols from Olea europaea, Hibiscus sabdariffa, Camellia sinensis, and Vitis vinifera (resveratrol) exhibit antioxidant, anti-inflammatory, and vasoprotective effects. Omega-3 fatty acids and astaxanthin contribute to inflammation control and redox balance, while Orthosiphon stamineus and Taraxacum officinale show mild diuretic activity. Moreover, anthocyanins, ursolic acid, and Rhodiola crenulata may exert antifibrotic and antiarrhythmic properties. This review provides a mechanistic comparison between pharmacological agents and nutraceuticals with overlapping mechanisms of action, highlighting their potential role in integrative cardiovascular care. While nutraceuticals are not substitutes for established therapies, emerging evidence supports their complementary use in improving treatment response, reducing side effects, and enhancing patient outcomes. Future research should focus on large-scale trials, improved bioavailability, standardized formulations, and the development of personalized therapeutic strategies. Challenges related to dosage consistency, clinical validation, and regulatory oversight are also addressed to guide innovation in integrative cardiology.

Neurodegenerative diseases involve progressive neuronal loss associated with oxidative stress (OS) and inflammation. Given the limited efficacy of current therapies, natural compounds with multitarget neuroprotective potential are of growing interest. In this study, we investigated the neuroprotective effects of a standardized Magnolia officinalis (L.) bark extract (MOE) in rat brain cortical slices exposed to hydrogen peroxide-induced OS. MOE significantly recovered tissue viability and reduced ROS and malondialdehyde levels caused by OS while attenuating caspase-3, -8, and -9 activation, suggesting modulation of intrinsic and extrinsic apoptotic pathways. Shotgun proteomics using LC-HRMS/MS identified OS-induced protein expression changes reversed by MOE, with fourteen of thirty-three altered proteins rescued by MOE co-treatment. These proteins participate in several processes, including neuronal survival, OS response, and proteostasis. Bioinformatic analysis demonstrated that genes responsible for protein synthesis regulated by MOE are subjected to transcriptional regulation by factors associated with OS, including FOXO4, NRF2, and SP1. The present findings support the hypothesis that MOE exerts multitarget neuroprotective effects by modulating key proteins involved in OS responses and neuronal survival in an acute ex vivo oxidative injury model, suggesting potential relevance for mechanisms associated with NDs.

Pathogen infections, exacerbated by emerging drug resistance, remain among the most challenging health issues, for which multitargeting approaches may offer effective solutions. In this context, medicinal plants, including essential oils, provide complex mixtures of diverse molecules that can exert therapeutic effects, either alone or synergistically with established antibiotics. Although several databases comprehensively collect information on the antibacterial properties of medicinal plants, including chemical composition, bioactivity data, and ethnobotanical uses, there is a notable lack of tools to hypothesize mechanisms of action. To address this gap, we developed a computational pipeline that integrates chemoinformatics and bioinformatics, specifically designed for scenarios in which only the chemical composition of a complex mixture of natural phytocompounds is available. Beginning with an ultralarge, structure-based screening across thousands of proteins and their potential binding sites of six bacterial species, we used the predicted targets as input for bioinformatics tools commonly employed in the omics fields, such as pathway enrichment analysis and network analysis. Using this pipeline, we modeled how the essential oils of thyme, oregano, and cinnamon exert antibacterial activity against six bacterial pathogens. Applied here in the context of urinary tract infection, but extendable to other therapeutic scenarios, this pipeline provides a novel protocol for mode of action investigation and experimental prioritization, to be applied in drug discovery involving natural substances.

Lubeluzole is a neuroprotective agent displaying antimyotonic activity. Lubeluzole clinical development as an antiischemic drug was discontinued due to a lack of efficacy in human trials and possible cardiac toxicity. Since lubeluzole is a potent inhibitor of the hERG channel, involved in long QT syndromes and the potentially fatal cardiac arrhythmia Torsade de Pointes, a series of lubeluzole analogues were prepared to investigate the structural requirements to reduce the affinity for hERG channels to possibly obtain safe antimyotonic drugs. Compound 16o was identified as the less potent hERG blocker possibly endowed with lower cardiac liability in comparison with the parent compound. Antimyotonic activity of 16o was also investigated in vitro on hNav1.4 and higher use-dependence was observed in comparison to lubeluzole, thus suggesting greater selectivity toward highly excited tissues, such as the myotonic muscle. To further verify the cardiac safety of 16o, patch-clamp experiments on hNav1.5 were also carried out and a 3-fold reduction of potency in comparison with hNav1.4 in phasic block was observed. In vivo evaluation of the antimyotonic activity showed unintended effects on rat motor performance. Ex vivo studies suggested calcium channel blocking activity as a possible off-target source of the 16o unintended effects, also reinforced by possible interaction with β2 receptors, as indicated by in vitro binding assays and in silico studies. In conclusion, we think our results may support the rational design of lubeluzole analogues endowed with both antimyotonic activity and lower hERG liability.

Background: The gut–brain axis (GBA) is a complex bidirectional communication system that links the gastrointestinal tract and the central nervous system. Essential oils (EOs) have emerged as promising natural compounds capable of modulating this axis. Methods: A comprehensive analysis of the recent literature was conducted, focusing on studies investigating the effects of EOs on the GBA. Particular attention was given to the endocannabinoid system, the role of cannabis-derived EOs, and other plant-based EOs with potential neuroprotective and gut microbiota-modulating effects. Results: Among the EOs analyzed, cannabis essential oil (CEO) gained attention for its interaction with cannabinoid receptors (CBR1 and CBR2), modulating gut motility, immune responses, and neurotransmission. While acute administration of the CEO reduces inflammation and gut permeability, chronic use has been associated with alterations in gut microbiota composition, potentially impairing cognitive function. Other EOs, such as those from rosemary, lavender, eucalyptus, and oregano, demonstrated effects on neurotransmitter modulation, gut microbiota balance, and neuroinflammation, supporting their potential therapeutic applications in GBA-related disorders. Conclusions: EOs demonstrate promising potential in modulating the GBA through mechanisms including neurotransmitter regulation, gut microbiota modulation, and anti-inflammatory activity. At the same time, phytocannabinoids offer therapeutic value; their long-term use warrants caution due to potential impacts on microbiota. Future research should aim to identify EO-based interventions that can synergistically restore GBA homeostasis and mitigate neurodegenerative and gastrointestinal disorders.

The correct evaluation of the effects of a new drug or molecule on the tissues it interacts with is essential for fully understanding its benefits and side effects. To date, there is a lack of accurate biomechanical characterization of gastrointestinal tissues, with the effects of active ingredients primarily assessed based on clinical outcomes. While we know a drug is effective, we often fail to understand the underlying mechanisms. Investigating the effects of these substances at the tissue level would improve our understanding of their biochemical and biomechanical properties, allowing the development of more effective drugs or identifying natural molecules with similar benefits but reduced side effects and costs. This study aims to characterize the biomechanical properties of gastrointestinal tissues from small animals. It presents a methodological overview and application using guinea pigs. The research involves biological sample preparation, assessment of spontaneous and induced motility, and evaluation of passive elastic behavior. The study focuses on tissues extracted ex vivo from the ileum and colon of healthy guinea pigs, analyzing their behavior in longitudinal and circular directions. Stress–strain curves were generated for circular samples. Our findings demonstrate the reliability of the proposed method for predicting the activity of compounds and extracts. The clinical efficacy of Otilonium Bromide (OB), tested in our models, highlights the method’s validity. This evidence supports biomechanical characterization as a complementary approach to clinical outcomes, enhancing our understanding of how active ingredients affect gastrointestinal function.

Background/Objectives: This study investigates the pharmacological potential of 1,4-dihydropyridine derivatives, functionalized with an imidazo[2,1-b]thiazole scaffold, as selective modulators of intestinal motility. Given their structural similarity to both L-type calcium channel blockers and spasmolytics such as Otilonium Bromide (OB), we explored their repurposing for the treatment of gut motility disorders. Methods: A focused library of 83 1,4-dihydropyridine derivatives was screened for spasmolytic activity on potassium (80 mM)-induced depolarization in isolated guinea pig ileal and colonic tissues. Compounds showing pharmacodynamic profiles similar to OB and nifedipine were further evaluated for their effects on the spontaneous contractility of longitudinal and circular smooth muscle layers. Additional functional assays assessed intestinal transit, visceral nociception, and mixing/fragmentation efficiency. Microbiota safety was preliminarily tested on mixed cultures of Bifidobacterium and Lactobacillus species. Results: Compounds 62 and 65 selectively relaxed intestinal smooth muscle, primarily targeting the longitudinal layer without affecting vascular contractility. Ex vivo testing highlights that compounds 62 and 65 could both modulate gut transit and mixing without causing functional constipation or pain. Microbiota analyses showed no detrimental effects on “good” bacterial species Bifidobacterium and Lactobacillus spp. Conclusions: The favorable gastrointestinal and microbiological profiles of compounds 62 and 65, combined with their structural versatility, support their potential repurposing for functional bowel disorders. Their selective activity suggests a promising role in therapies targeting intestinal motility while preserving microbiota homeostasis, supporting the need for extended pharmacological characterization.

Nitric oxide (NO) has been defined as the “miracle molecule” due to its essential pleiotropic role in living systems. Besides its implications in physiologic functions, it is also involved in the development of several disease states, and understanding this ambivalence is crucial for medicinal chemists to develop therapeutic strategies that regulate NO production without compromising its beneficial functions in cell physiology. Although nitric oxide synthase (NOS), i.e., the enzyme deputed to the NO biosynthesis, is a well-recognized druggable target to regulate NO bioavailability, some issues have emerged during the past decades, limiting the progress of NOS modulators in clinical trials. In the present review, we discuss the most promising advancements in the research of small molecules that are able to regulate NOS activity with improved pharmacodynamic and pharmacokinetic profiles, providing an updated framework of this research field that could be useful for the design and development of new NOS modulators.

The significant number of individuals impacted by the pandemic makes prolonged symptoms after COVID-19 a matter of considerable concern. These are numerous and affect multiple organ systems. According to the World Health Organization (WHO), prolonged gastrointestinal issues are a crucial part of post-COVID-19 syndrome. The resulting disruption of homeostasis underscores the need for a therapeutic approach based on compounds that can simultaneously affect more than one target/node. The present review aimed to check for nutraceuticals possessing multiple molecular mechanisms helpful in relieving Long COVID-19-specific gastrointestinal symptoms. Specific plants used in Keywords Chinese Medicine (TCM) expected to be included in the WHO Global Medical Compendium were selected based on the following criteria: (1) they are widely used in the Western world as natural remedies and complementary medicine adjuvants; (2) their import and trade are regulated by specific laws that ensure quality and safety (3) have the potential to be beneficial in alleviating intestinal issues associated with Long COVID-19. Searches were performed in PubMed, Elsevier, Google Scholar, Scopus, Science Direct, and ResearchGate up to 2023. Cinnamomum cassia, Glycyrrhiza uralensis, Magnolia officinalis, Poria cocos, Salvia miltiorrhiza, Scutellaria baicalensis, and Zingiber officinalis were identified as the most promising for their potential impact on inflammation and oxidative stress. Based on the molecular mechanisms of the phytocomplexes and isolated compounds of the considered plants, their clinical use may lead to benefits in gastrointestinal diseases associated with Long COVID-19, thanks to a multiorgan and multitarget approach.

Waste from the agri-food chain represents a valuable reservoir of organic compounds with health-promoting properties. Momast Plus 30 Bio (MP30B) is a derivative obtained from olive-oil wastewater. Its enrichment in hydroxytyrosol (HT) via a patented technique has paved the way for its potential application as a dietary supplement in preventing cardiovascular diseases. MP30B demonstrates no significant alteration in cardiac and vascular parameters in “ex vivo” studies. However, it exhibits a strong ability to remove reactive oxygen species and exerts anti-inflammatory effects, notably reducing the concentration of iNOS and mitigating heart infections in “in vitro” experiments. Furthermore, MP30B slightly decreases the stiffness of the “ex vivo” thoracic aorta, potentially resulting in lowered arterial pressure and enhanced energy transfer to a normal ventricle. Based on these findings, we posit MP30B as a promising extract for cardiovascular disease prevention, and its specific antibacterial properties suggest its utility in preventing cardiac infections.

Background: Three herbal extracts (Asparagus racemosus Willd., Tabebuia avellanedae Lorentz, and Glycyrrhiza glabra L.) were mixed with three essential oils (Foeniculum vulgare Mill., Mentha piperita L., and Pimpinella anisum L.) to formulate a product (HEMEO) whose active compounds include saponins and steroids in Asparagus racemosus, known for their anti-inflammatory properties; glycyrrhizin and flavonoids in Glycyrrhiza glabra, which exhibit gastroprotective and antispasmodic effects; menthol in Mentha piperita, contributing with antispasmodic and antimicrobial properties; and anethole and polyphenols in Pimpinella anisum, which modulate intestinal motility and offer antimicrobial activity. Objective: HEMEO was formulated for applications in intestinal motility disorders. Methods: HEMEO was evaluated for spontaneous and induced motility effects in isolated guinea pig ileum, colon, and stomach. Ex vivo experiments were conducted using LabChart software v7.0, and the product’s antibacterial action against Helicobacter pylori and its antioxidant effects were assessed through disc diffusion and FRAP assays. The presence of the volatile compounds in the formulation was confirmed by GC-MS analysis; the TPC of HEMEO, determined using the Folin–Ciocalteu method, was 9.925 ± 0.42 mg GAE/g. Conclusions: HEMEO showed a phenolic content correlated with its antioxidant potential and in addition inhibited H. pylori growth and demonstrated notable antioxidant properties, suggesting its role as a supportive agent in digestive processes and in managing motility disorders.

Background/Objectives: In the contest of agro-industrial waste valorization, we focused our attention on lentil seed coats as a source of health-promoting phytochemicals possibly useful in managing inflammatory bowel diseases (IBDs), usually characterized by inflammation and altered intestinal motility. Methods: Both traditional (maceration) and innovative microwave-assisted extractions were performed using green solvents, and the anti-inflammatory and spasmolytic activities of the so-obtained extracts were determined through in vitro and ex vivo assays, respectively. Results: The extract obtained through the microwave-assisted procedure using ethyl acetate as the extraction solvent (BEVa) proved to be the most useful in inflammation and intestinal motility management. In LPS-activated Caco-2 cells, BEVa down-regulated TLR4 expression, reduced iNOS expression and the pro-inflammatory cytokine IL-1 production, and upregulated the anti-inflammatory cytokine IL-10 production, thus positively affecting cell inflammatory responses. Moreover, a significant decrease in the longitudinal and circular tones of the guinea pig ileum, with a reduction of transit speed and pain at the ileum level, together with reduced transit speed, pain, and muscular tone at the colon level, was observed with BEVa. HPLC separation combined with an Orbitrap-based high-resolution mass spectrometry (HRMS) technique indicated that 7% of all the identified metabolites were endowed with proven anti-inflammatory and antispasmodic activities, among which niacinamide, apocynin, and p-coumaric acid were the most abundant. Conclusions: Our results suggest that lentil hull extract consumption could contribute to overall intestinal health maintenance, with BEVa possibly representing a dietary supplementation and a promising approach to treating intestinal barrier dysfunction.

The understanding of the use of Magnolia officinalis L. (Magnoliaceae) as a possible dietary supplement for supporting the treatment of airway pathologies might be of clinical interest. Two commercially available bark extracts (M. officinalis extract [MOE]) were characterized by quantitation in honokiol and magnolol content by means of high-performance liquid chromatography with UV detection. MOE effects, as well as those of the reference compounds per se, on some targets connected to airway pathologies (antibacterial- and lung and trachea relaxing- activities) were investigated. Results showed that MOE possessed interesting antibacterial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Streptococcus pneumoniae. This was accompanied by a spasmolytic and antispasmodic activity, possibly owing to its ability to concurrently modulate different targets such as H1 -, β2 - and muscarinic receptors and l-type calcium channels involved in bronchodilation. All these effects were directly related to the MOE content in honokiol and magnolol. In conclusion, the properties of MOE highlighted here strongly encourage its application as dietary supplement in the treatment of airway diseases.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Fourteen quinolizidine derivatives, structurally related to the alkaloids lupinine and cytisine and previously studied for other pharmacological purposes, were presently tested for antiarrhythmic, and other cardiovascular effects on isolated guinea pig heart tissues in comparison to well-established reference drugs. According to their structures, the tested compounds are assembled into three subsets: (a) N-(quinolizidinyl-alkyl)-benzamides; (b) 2-(benzotriazol-2-yl)methyl-1-(quinolizidinyl)alkyl-benzimidazoles; (c) N-substituted cytisines. All compounds but two displayed antiarrhythmic activity that was potent for compounds 4, 1, 6, and 5 (in ascending order). The last compound (N-(3,4,5-trimethoxybenzoyl)aminohomolupinane) was outstanding, exhibiting a nanomolar potency (EC50 = 0.017 µM) for the increase in the threshold of ac-arrhythmia. The tested compounds shared strong negative inotropic activity; however, this does not compromise the value of their antiarrhythmic action. On the other hand, only moderate or modest negative chronotropic and vasorelaxant activities were commonly observed. Compound 5, which has high antiarrhythmic potency, a favorable cardiovascular profile, and is devoid of antihypertensive activity in spontaneously hypertensive rats, represents a lead worthy of further investigation.

The impossibility of using drugs for the health of farm animals leads to the search for alternative strategies with two purposes: to maintain animal health and safeguard human health. In this perspective, tannins have shown great promises. These phytocomplexes obtained from natural matrices with multiple health properties may be used as a feed supplement in chicken farms. In this work, we studied two tannin-based extracts (from Castanea sativa Mill. wood and from Schinopsis balansae Engl. Quebracho Colorado hardwood) with different chemical compositions on the spontaneous contractility on the isolated intestinal tissues of healthy chicken. The results showed that the chemical composition of the two phytocomplexes influenced the spontaneous intestinal contractility in different ways by regulating the tone and consequent progression of the food bolus. The chemical analysis of the two extracts revealed that Castanea sativa Mill. wood mainly contains hydrolysable tannins, while Schinopsis balansae Engl. hardwood mainly contains condensed tannins. The two phytocomplexes showed different effects towards gastrointestinal smooth muscle contractility, with Castanea sativa Mill. wood providing a better activity profile than Schinopsis balansae Engl. hardwood.

Long QT syndrome (LQTS) is a disorder of cardiac electrophysiology resulting in life-threatening arrhythmias; nowadays, only a few drugs are available for the management of LQTS. Focusing our attention on LQT2, one of the most common subtypes of LQTS caused by mutations in the human ether-à-go-go-related gene (hERG), in the present work, the stereoselectivity of the recently discovered mexiletine-derived urea 8 was investigated on the hERG potassium channel. According to preliminary in silico predictions, in vitro studies revealed a stereoselective behavior, with the meso form showing the greatest hERG opening activity. In addition, functional studies on guinea pig isolated left atria, aorta, and ileum demonstrated that 8 does not present any cardiac or intestinal liability in our ex vivo studies. Due to its overall profile, (R,S)-8 paves the way for the design and development of a new series of compounds potentially useful in the treatment of both congenital and drug-induced forms of LQTS.