Marine-Derived Leads as Anticancer Candidates by Disrupting Hypoxic Signaling through Hypoxia-Inducible Factors Inhibition.

The inadequate vascularization seen in fast-growing solid tumors gives rise to hypoxic areas, fostering specific changes in gene expression that bolster tumor cell survival and metastasis, ultimately leading to unfavorable clinical prognoses across different cancer types. Hypoxia-inducible factors (HIF-1 and HIF-2) emerge as druggable pivotal players orchestrating tumor metastasis and angiogenesis, thus positioning them as prime targets for cancer treatment. A range of HIF inhibitors, notably natural compounds originating from marine organisms, exhibit encouraging anticancer properties, underscoring their significance as promising therapeutic options. Bioprospection of the marine environment is now a well-settled approach to the discovery and development of anticancer agents that might have their medicinal chemistry developed into clinical candidates. However, despite the massive increase in the number of marine natural products classified as 'anticancer leads,' most of which correspond to general cytotoxic agents, and only a few have been characterized regarding their molecular targets and mechanisms of action. The current review presents a critical analysis of inhibitors of HIF-1 and HIF-2 and hypoxia-selective compounds that have been sourced from marine organisms and that might act as new chemotherapeutic candidates or serve as templates for the development of structurally similar derivatives with improved anticancer efficacy.

Onion (Allium cepa L.) Skin Waste Valorization: Unveiling the Phenolic Profile and Biological Potential for the Creation of Bioactive Agents through Subcritical Water Extraction.

Onion skin waste (OSW), the primary non-edible byproduct from onion processing, offers a renewable source of bioactive compounds. This study aims to valorize OSW through subcritical water extraction (SWE), aligning with a circular economy and biorefinery principles. SWE was carried out at 145 °C and 50 bar for 50 min in a discontinuous reactor, producing a phenolic-rich extract (32.3 ± 2.6 mg/g) dominated by protocatechuic acid (20.3 ± 2.5 mg/g), quercetin-4'-O-glucoside (7.5 ± 0.2 mg/g), and quercetin (3.2 ± 0.6 mg/g). Additionally, the extract contains sugars (207.1 ± 20.3 mg sucrose-Eq/g), proteins (22.8 ± 1.6 mg BSA-Eq/g), and free amino acids (20.4 ± 1.2 mg arginine-Eq/g). Its phenolic richness determines its scavenging activity against ●NO and O2●- radicals and its α-glucosidase and aldose-reductase inhibition without affecting α-amylase. Notably, the extract demonstrates significant α-glucosidase inhibition (IC50 = 75.6 ± 43.5 µg/mL), surpassing acarbose (IC50 = 129.5 ± 1.0 µg/mL) in both pure enzyme and cell culture tests without showing cytotoxicity to AGS, HepG2, and Caco-2 human cell lines. The extract's bioactivity and nutritional content make it suitable for developing antioxidant and antidiabetic nutraceutical/food components, highlighting SWE's potential for OSW valorization without using organic solvents.

Antifungal Activity of Guiera senegalensis: From the Chemical Composition to the Mitochondrial Toxic Effects and Tyrosinase Inhibition.

Pest resistance against fungicides is a widespread and increasing problem, with impact on crop production and public health, making the development of new fungicides an urgent need. Chemical analyses of a crude methanol extract (CME) of Guiera senegalensis leaves revealed the presence of sugars, phospholipids, phytosterols, guieranone A, porphyrin-containing compounds, and phenolics. To connect chemical composition with biological effects, solid-phase extraction was used to discard water-soluble compounds with low affinity for the C18 matrix and obtain an ethyl acetate fraction (EAF) that concentrates guieranone A and chlorophylls, and a methanol fraction (MF) dominated by phenolics. While the CME and MF exhibited poor antifungal activity against Aspergillus fumigatus, Fusarium oxysporum and Colletotrichum gloeosporioides, the EAF demonstrated antifungal activity against these filamentous fungi, particularly against C. gloeosporioides. Studies with yeasts revealed that the EAF has strong effectiveness against Saccharomyces cerevisiae, Cryptococcus neoformans and Candida krusei with MICs of 8, 8 and 16 µg/mL, respectively. A combination of in vivo and in vitro studies shows that the EAF can function as a mitochondrial toxin, compromising complexes I and II activities, and as a strong inhibitor of fungal tyrosinase (Ki = 14.40 ± 4.49 µg/mL). Thus, EAF appears to be a promising candidate for the development of new multi-target fungicides.

An Experimental Approach to Address the Functional Relationship between Antioxidant Enzymes and Mitochondrial Respiratory Complexes.

Mitochondrial dysfunction and cytosolic oxidative stress are pathological biomarkers interlinked in several chronic diseases and cellular toxicity promoted by high-energy radiation or xenobiotics. Thus, assessing the activities of the mitochondrial redox chain complexes and the cytosolic antioxidant enzymes in the same cell culture system is a valuable approach to addressing the challenge of chronic diseases or unveiling the molecular mechanisms underlying the toxicity of physical and chemical stress agents. The present article gathers the experimental procedures to obtain, from isolated cells, a mitochondria-free cytosolic fraction and a mitochondria-rich fraction. Furthermore, we describe the methodologies to evaluate the activity of the main antioxidant enzymes in the mitochondria-free cytosolic fraction (superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase), and the activity of the individual mitochondrial complexes I, II and IV, as well as the conjugated activity of complexes I-III and complexes II-III in the mitochondria-rich fraction. The protocol to test the citrate synthase activity was also considered and used to normalize complexes. The procedures were optimized within an experimental setup to allow that each condition to be tested only requires sampling of one T-25 flask of cells 2D cultured, as the typical results presented and discussed here.

Kitul, a food plant with antidiabetic-like effects: Reduction of intracellular reactive species in glucose-stimulated RIN-5F pancreatic ß-cells and mitigation of pro-inflammatory mediators in activated RAW 264.7 macrophages.

Kitul (Caryota urens L.) inflorescences are broadly used for sweet sap production in Asian countries and Kitul food products are known as being suitable for diabetic patients. Considering the strong ability to inhibit α-glucosidase, we hypothesize that kitul antidiabetic properties might also involve the modulation of inflammatory pathways and hyperglycaemia-induced oxidative damage. Hence, the effects of an inflorescence's methanol extract were investigated in glucose-stimulated pancreatic cells (RIN-5F) and LPS-stimulated RAW 264.7 macrophages. The extract reduced the overproduction of intracellular reactive species in pancreatic cells and also NO, L-citrulline and IL-6 levels in LPS-stimulated RAW 264.7 macrophages. Inhibition of 5-lipoxygenase (IC50 = 166.1 µg/mL) through an uncompetitive manner was also recorded upon treatment with C. urens inflorescences extract. The phenolic profile of the inflorescences was characterized by HPLC-DAD, six hydroxycinnamic acids being identified and quantified. Overall, our data provide additional evidence on the pleiotropic mechanisms of Kitul inflorescences as an antidiabetic agent.

An integrated in vitro approach on the enzymatic and antioxidant mechanisms of four commercially available essential oils (Copaifera officinalis, Gaultheria fragrantissima, Helichrysum italicum, and Syzygium aromaticum) traditionally used topically for their anti-inflammatory effects.

Introduction: Despite the increasing number of essential oils being reported on their potential therapeutic effects, some remain relatively unknown on their biological properties. That is the case of the essential oils obtained from copaiba (Copaifera officinalis L.), wintergreen (Gaultheria fragrantissima Wall.), everlasting (Helichrysum italicum (Roth) G.Don) and clove (Syzygium aromaticum (L.) Merr. & L.M.Perry), commonly labelled as being useful on the amelioration of conditions with an inflammatory background. Methods: To further broaden the current knowledge on the four essential oils, commercially available samples were approached on their effects upon a series of mediators that are involved on the inflammatory and oxidative response, both through in vitro cell-free and cell-based assays (5-lipoxygenase activity, lipid peroxidation, free radical and nitric oxide radical scavenging properties or tyrosinase inhibition). Results: The four oils proved to be active at some of the concentrations tested in most of the performed assays. Significant differences were found between the essential oils, S. aromaticum proving to tbe the most active, followed by G. fragrantissima against 5-lipoxygenase (5-LOX) and linoleic acid peroxidation, proving their potential use as antioxidants and anti-inflammatory agents. In fact, the IC50 value of S. aromaticum in the 5-LOX assay was 62.30 µg mL-1. Besides S. aromaticum efficiently scavenged superoxide radicals generated by xanthine/xanthine oxidase, displaying an IC50 value of 135.26 µg mL-1. The essential oil obtained from H. italicum exhibited a significant decrease in the nitric oxide levels on BV-2 cells, showing its potential as a cytoprotective agent against toxic damage. Copaiba oil ranked first as the most potent tyrosinase inhibitor, exhibiting an IC50 98.22 µg mL-1. Conclusion: More studies are needed to describe the essential oils properties, but these results confirm the potential of these essential oils as anti-inflammatory and antioxidant agents.

Vasorelaxant Mechanism of Herbal Extracts from Mentha suaveolens, Conyza canadensis, Teucrium polium and Salvia verbenaca in the Aorta of Wistar Rats.

Mentha suaveolens (MS), Conyza canadensis (CC), Teucrium polium (TP) and Salvia verbenaca (SV) are used in Morocco to treat hypertension. Our aim was to characterize the composition and vasoreactivity of extracts of MS, CC, TP and SV. The chemical compositions of aqueous extracts of MS, SV and TP, and of a hydromethanolic extract of CC, were identified by HPLC-DAD. The vasoreactive effect was tested in rings of the thoracic aorta of female Wistar rats (8-14 weeks-old) pre-contracted with 10 µM noradrenaline, in the absence or presence of L-NAME 100 µM, indomethacin 10 µM or atropine 6 µM, to inhibit nitric oxide synthase, cyclooxygenase or muscarinic receptors, respectively. L-NAME and atropine decreased the vasorelaxant effect caused by low concentrations of MS. Atropine and indomethacin decreased the vasorelaxant effect of low concentrations of SV. High concentrations of MS or SV and the effect of SV and TP were not altered by any antagonist. The activation of muscarinic receptors and NO or the cyclooxygenase pathway underlie the vasorelaxant effect of MS and SV, respectively. Neither of those mechanisms underlines the vasorelaxant effect of CC and TP. These vasorelaxant effect might support the use of herbal teas from these plants as anti-hypertensives in folk medicine.

A Pipeline for Natural Small Molecule Inhibitors of Endoplasmic Reticulum Stress.

The homeostasis of eukaryotic cells is inseverable of that of the endoplasmic reticulum (ER). The main function of this organelle is the synthesis and folding of a significant portion of cellular proteins, while it is also the major calcium reservoir of the cell. Upon unresolved ER stress, a set of stress response signaling pathways that are collectively labeled as the unfolded protein response (UPR) is activated. Prolonged or intense activation of this molecular machinery may be deleterious. It is known that compromised ER homeostasis, and consequent UPR activation, characterizes the pathogenesis of neurodegenerative diseases. In an effort to discover new small molecules capable of countering ER stress, we subjected a panel of over 100 natural molecules to a battery of assays designed to evaluate several hallmarks of ER stress. The protective potential of these compounds against ER stress was evaluated at the levels of calcium homeostasis, key gene and protein expression, and levels of protein aggregation in fibroblasts. The most promising compounds were subsequently tested in neuronal cells. This framework resulted in the identification of several bioactive molecules capable of countering ER stress and deleterious events associated to it. Delphinidin stands out as the most promising candidate against neurodegeneration. This compound significantly inhibited the expression of UPR biomarkers, and displayed a strong potential to inhibit protein aggregation in the two aforementioned cell models. Our results indicate that natural products may be a valuable resource in the development of an effective therapeutic strategy against ER stress-related diseases.

New Insight on the Bioactivity of Solanum aethiopicum Linn. Growing in Basilicata Region (Italy): Phytochemical Characterization, Liposomal Incorporation, and Antioxidant Effects.

Food extract's biological effect and its improvement using nanotechnologies is one of the challenges of the last and the future decades; for this reason, the antioxidant effect of scarlet eggplant extract liposomal incorporation was investigated. Scarlet eggplant (Solanum aethiopicum L.) is a member of the Solanaceae family, and it is one of the most consumed vegetables in tropical Africa and south of Italy. This study investigated the antioxidant activity and the phytochemical composition of S. aethiopicum grown in the Basilicata Region for the first time. The whole fruit, peel, and pulp were subjected to ethanolic exhaustive maceration extraction, and all extracts were investigated. The HPLC-DAD analysis revealed the presence of ten phenolic compounds, including hydroxycinnamic acids, flavanones, flavanols, and four carotenoids (one xanthophyll and three carotenes). The peel extract was the most promising, active, and the richest in specialized metabolites; hence, it was tested on HepG2 cell lines and incorporated into liposomes. The nanoincorporation enhanced the peel extract's antioxidant activity, resulting in a reduction of the concentration used. Furthermore, the extract improved the expression of endogenous antioxidants, such as ABCG2, CAT, and NQO1, presumably through the Nrf2 pathway.

Mitochondria research and neurodegenerative diseases: On the track to understanding the biological world of high complexity.

From the simple unicellular eukaryote to the highly complex multicellular organism like Human, mitochondrion emerges as a ubiquitous player to ensure the organism's functionality. It is popularly known as "the powerhouse of the cell" by its key role in ATP generation. However, our understanding of the physiological relevance of mitochondria is being challenged by data obtained in different fields. In this review, a short history of the mitochondria research field is presented, stressing the findings and questions that allowed the knowledge advances, and put mitochondrion as the main player of safeguarding organism life as well as a key to solve the puzzle of the neurodegenerative diseases.

HPLC-DAD-ESI/MSn and UHPLC-ESI/QTOF/MSn characterization of polyphenols in the leaves of Neocarya macrophylla (Sabine) Prance ex F. White and cytotoxicity to gastric carcinoma cells.

Among several extracts from species from Guinea-Bissauan flora, the hydroethanol extract obtained from the leaves of gingerbread plum (Neocarya macrophylla (Sabine) Prance ex F. White.) revealed to be one of the most cytotoxic towards human gastric AGS carcinoma cells. Considering the increasing use of N. macrophylla in the food industry and the abundant biomass of agricultural wastes being generated, the identification of phenolic bioactives has been attained by HPLC-DAD-ESI/MSn and UHPLC-ESI/QTOF/MSn. Twenty-seven phenolic constituents were identified for the first time in the monotypic genus Neosartorya, 5-O-caffeoylquinic acid being detected as the major constituent (4.90 ± 0.20 mg g-1 dry extract). While 15 flavan-3-ols derivatives were determined, the extract is predominantly characterized by the occurrence of quercetin, kaempferol, apigenin and chrysoeriol glycosides. Typical apoptotic changes in gastric adenocarcinoma AGS cells upon exposure to N. macrophylla leaf extract were observed. The apoptotic cell death is mediated by the activation of the mitochondrial pathway, as loss of mitochondrial membrane potential was detected, as well as increased caspase-9 and -3 activities. The industrial relevance of this plant material, along with the data presented here on the potential anticancer effects of N. macrophylla and the efficient extraction of phenolic bioactives using water and ethanol (GRAS substance), calls for further research on the leaves as a potential functional food and/or ingredient.

Trichilia catigua and Turnera diffusa phyto-phospholipid nanostructures: Physicochemical characterization and bioactivity in cellular models of induced neuroinflammation and neurotoxicity.

Flavonoid-based therapies supported by nanotechnology are considered valuable strategies to prevent or delay age-related and chronic neurodegenerative disorders. Egg yolk phospholipids were combined with flavonoid-rich extracts obtained from Trichilia catigua A.Juss. (rich in flavan-3-ols and phenylpropanoid derivatives) or Turnera diffusa Willd. ex Schult (dominated by luteolin derivatives) to prepare nanophytosomes. The nanophytosomes showed that size and surface charge of the lipid-based vesicles are dependent of their phenolic composition. In vitro assays with SH-SY5Y cells showed that both formulations protect cells from glutamate-induced toxicity, but not from 6-hydroxydopamine/ascorbic acid. T. diffusa nanophytosomes promote a decrease of nitric oxide produced by BV-2 cells stimulated with interferon-γ. Nanophytosomes dialysed against a mannitol solution, and then lyophilised, allow to obtain freeze-dried products that after re-hydration preserve the essential physicochemical features of the original formulations, and exhibit improved colloidal stability. These results indicate that these flavonoid/phospholipid-based nanophytosomes have suitable features to be considered as tool in the development of therapeutic and food applications.

In vivo methodologies to assist preclinical development of topical fixed-dose combinations for pain management.

The combination in a fixed dose of two or more active pharmaceutical ingredients in the same pharmaceutical dosage form is an approach that has been used successfully in the treatment of several pathologies, including pain. In the preclinical development of a topical fixed-dose combination product with analgesic and anti-inflammatory activities for pain management, the main objective is to establish the nature of the interaction between the different active pharmaceutical ingredients while obtaining data on the medicinal product safety and efficacy. Despite the improvement of in vitro assays, animal models remain a fundamental strategy to characterise the interaction, efficacy and safety of active pharmaceutical ingredients at the physiological level, which cannot be reached by in vitro assays. Thus, the main goal of this review is to systematise the available animal models to evaluate the efficacy and safety of a new fixed-dose combination product for topical administration indicated for pain management. Particular emphasis is given to animal models that are accepted for regulatory purposes.

Topical fixed-dose combinations: Current in vitro methodologies for pre-clinical development.

The combination of two or more active pharmaceutical ingredients in the same dosage form - fixed-dose combination products - for topical administration represents a promising therapeutic approach for treating several pathologies, including pain. The pre-clinical development of fixed-dose combination products aims to characterize the interactions between the different APIs and ensure that the final medicinal product has the required safety characteristics. To this end, there are several regulatory accepted in vitro tests to assess the safety of medicinal products intended for cutaneous administration. In turn, the evaluation of anti-inflammatory activity should be based on models described in the scientific literature, as there are no models fully validated by competent entities. Therefore, this work presents the information regarding accepted in vitro tests to assess the safety of topical products and the most used methods to assess anti-inflammatory activity. Additionally, a new approach to select a fixed-dose combination product with the potential to enhance the therapeutic effects of the individual active pharmaceutical ingredients is rationalized by integrating the overall effects on several targets relevant for inflammation and pain management in one numeric index.

Exploring the Biotechnological Value of Marine Invertebrates: A Closer Look at the Biochemical and Antioxidant Properties of Sabella spallanzanii and Microcosmus squamiger.

Sabella spallanzanii and Microcosmus squamiger were profiled for proximate composition, minerals, amino acids, fatty acids (FA), carotenoids, radical scavenging activity on the 2,2-diphenyl-1- picrylhydrazyl (DPPH) radical, oxygen radical absorbance capacity (ORAC) and iron and copper chelating properties. Microcosmus squamiger had the highest level of moisture and crude protein, S. spallanzanii was enriched in crude fat and ash. Both species had similar levels of carbohydrates and energy. There was a prevalence of arginine and glycine in S. spallanzanii, and of taurine in M. squamiger. The most abundant minerals in both species were Na, Ca, and K. The methanol extract of S. spallanzanii had metal chelating properties towards copper and iron, while the methanol extract of M. squamiger was able to chelate copper. M. squamiger extracts had similar ORAC values. Fucoxanthinol and fucoxanthin were the major carotenoids in the M. squamiger dichloromethane extract. Saturated FA were more abundant than unsaturated ones in methanol extracts, and unsaturated FA prevailed in the dichloromethane extracts. Palmitic acid was the predominant FA in methanol extracts, whereas eicosapentaenoic (EPA) and dihomo-γ-linolenic acids were the major compounds in dichloromethane extracts. Low n-6/n-3 ratios were obtained. Our results suggests that both species could be explored as sources of bioactive ingredients with multiple applications.

Homarine Alkyl Ester Derivatives as Promising Acetylcholinesterase Inhibitors.

Reversible acetylcholinesterase (AChE) inhibitors are key therapeutic tools to modulate the cholinergic connectivity compromised in several degenerative pathologies. In this work, four alkyl esters of homarine were synthesized and screened by using Electrophorus electricus AChE and rat brain AChE-rich fraction. Results showed that all homarine alkyl esters are able to inhibit AChE by a competitive inhibition mode. The effectiveness of AChE inhibition increases with the alkyl side chain length of the homarine esters, being HO-C16 (IC50 =7.57±3.32 µM and Ki =18.96±2.28 µM) the most potent inhibitor. The fluorescence quenching studies confirmed that HO-C16 is the compound with higher selectivity and affinity for the tryptophan residues in the catalytic active site of AChE. Preliminary cell viability studies showed that homarine esters display no toxicity for human neuronal SH-SY5Y cells. Thus, the long-chain homarine esters emerge as new anti-cholinesterase agents, with potential to be considered for therapeutic applications development.

Biosynthetic versatility of marine-derived fungi on the delivery of novel antibacterial agents against priority pathogens.

Despite the increasing number of novel marine natural products being reported from fungi in the last three decades, to date only the broad-spectrum cephalosporin C can be tracked back as marine fungal-derived drug. Cephalosporins were isolated in the early 1940s from a strain of Acremonium chrysogenum obtained in a sample collected in sewage water in the Sardinian coast, preliminary findings allowing the discovery of cephalosporin C. Since then, bioprospection of marine fungi has been enabling the identification of several metabolites with antibacterial effects, many of which proving to be active against multi-drug resistant strains, available data suggesting also that some might fuel the pharmaceutical firepower towards some of the bacterial pathogens classified as a priority by the World Health Organization. Considering the success of their terrestrial counterparts on the discovery and development of several antibiotics that are nowadays used in the clinical setting, marine fungi obviously come into mind as producers of new prototypes to counteract antibiotic-resistant bacteria that are no longer responding to available treatments. We mainly aim to provide a snapshot on those metabolites that are likely to proceed to advanced preclinical development, not only based on their antibacterial potency, but also considering their targets and modes of action, and activity against priority pathogens.

Activation of caspase-3 in gastric adenocarcinoma AGS cells by Xylopia aethiopica (Dunal) A. Rich. fruit and characterization of its phenolic fingerprint by HPLC-DAD-ESI(Ion Trap)-MSn and UPLC-ESI-QTOF-MS2.

While the fruits of Xylopia aethiopica (Dunal) A. Rich. are important in African countries as a local trade product, their composition remains scarcely investigated. Phenolic fingerprint is herein delivered through HPLC-DAD-ESI(Ion Trap)-MSn and UPLC-ESI-QTOF-MS2 analysis, six cinnamoylquinic acid derivatives and twenty-four flavonoid glycosides being determined, chrysoeriol-7-O-glycosides being the main constituents. A cytotoxicity screening of twenty-eight hydroethanol extracts, obtained from a collection of Guinea-Bissauan plants, against A549 and AGS carcinoma cells, revealed the selective and potent effect towards AGS cells (IC50 = 151 × 10-3 g L-1), upon exposure to the extract from X. aethiopica fruits. Additional experiments demonstrated insignificant effect on LDH release at 151 × 10-3 g L-1, morphological analysis further suggesting induction of apoptosis. Pro-apoptotic effects were confirmed, as the extract enabled the activation of the effector caspase-3, broadening the knowledge on the anticancer mechanisms elicited by the fruits of X. aethiopica. Phenolic constituents might contribute to the cytotoxic effects, particularly via caspase-3 activation. Considering that X. aethiopica fruit is very often referred as an anticancer ingredient in Africa, but mainly the potent cytotoxicity herein recorded, our results call for additional research aiming to identify non-phenolic constituents contributing to the effects and also to further detail the anticancer mechanisms.

Trichilia catigua and Turnera diffusa extracts: In vitro inhibition of tyrosinase, antiglycation activity and effects on enzymes and pathways engaged in the neuroinflammatory process.

ETHNOPHARMACOLOGICAL RELEVANCE: Flavonoids interact with multiple targets in Central Nervous System resulting in a broad neuroprotection mediated by complementary processes and synergic interactions. Therefore, flavonoid-based therapies may input positive outcomes in the prevention and early management of neurodegenerative diseases. In Brazilian folk medicine Trichilia catigua is used for its neuroactive properties, such as neurostimulant, antioxidant and anti-neuroinflammatory, while Turnera diffusa is traditionally used as a tonic in neurasthenia. Both species are known to be rich in flavonoids. AIM OF THE STUDY: To study aqueous extracts of T. catigua and T. diffusa in terms of their antioxidant and antiglycation effects, inhibition of tyrosinase activity, and interaction with enzymes and pathways engaged in neuroinflammation. Moreover, whenever possible, to establish a relationship between the studied activities and the traditional usage of the species. MATERIALS AND METHODS: The phenolic profiles of the aqueous extracts were validated by HPLC-DAD. The effect of the extracts over mushroom tyrosinase and 5-lipoxygenase activities, as well as their capacity to impair bovine serum albumin glycation, were assessed by in vitro assays. The anti-neuroinflammatory potential of the same extracts was evaluated by their capacity to mitigate the pro-inflammatory stimulus induced in BV-2 microglia cells by interferon-gamma. RESULTS: T. catigua extract, a rich mixture of phenolic acids, catechins and flavonolignans, excels by its ability to decrease lipid peroxidation (EC50 = 227.18 ±â€¯9.04 µg/mL), and to work as anti-glycation agent, and inhibitor of both tyrosinase and 5-lipoxigenase (IC50 = 358.84 ±â€¯19.05 and 56.25 ±â€¯14.53 µg/mL, respectively). However, only T. diffusa extract, mainly composed by luteolin derivatives, is able to lower NO production by BV-2 microglia cells stimulated with interferon-gamma, despite its lower activities in the other assays. CONCLUSIONS: Overall, this work highlights the value of medicinal plant extracts as sources of bioactive flavonoid-rich extracts with neuroactive effects. Furthermore, these results support their application as alternative strategies to develop functional foods and therapeutics to fight chronic neurodegenerative disorders.

Valorisation of kitul, an overlooked food plant: Phenolic profiling of fruits and inflorescences and assessment of their effects on diabetes-related targets.

Caryota urens L. has long been valued as a traditional food, the edible fruits being eaten raw and the inflorescences commonly used on sweet sap and flour production. In the current work, the phenolic profile of methanol extracts obtained from the inflorescences and fruits was unveiled for the first time, nine caffeic acid derivatives being identified and quantified. Since kitul products have been reported for their antidiabetic properties, extracts radical scavenging activity and α-amylase, α-glucosidase and aldose reductase inhibitory activity were assessed. The inflorescences' extract was particularly active against yeast α-glucosidase (IC50 = 1.53 µg/mL), acting through a non-competitive inhibitory mechanism. This activity was also observed in enzyme-enriched homogenates obtained from human Caco-2 cells (IC50 = 64.75 µg/mL). Additionally, the extract obtained from the inflorescences showed no cytotoxicity on HepG2, AGS and Caco-2 cell lines. Our data suggest that C. urens inflorescences can support the development of new functional foods with α-glucosidase inhibitory activity.