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.

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.

Anti-inflammatory effects of naringenin 8-sulphonate from Parinari excelsa Sabine stem bark and its semi-synthetic derivatives.

The inflammatory response is a vital mechanism for repairing damage induced by aberrant health states or external insults; however, persistent activation can be linked to numerous chronic diseases. The nuclear factor kappa ß (NF-κB) inflammatory pathway and its associated mediators have emerged as critical targets for therapeutic interventions aimed at modulating inflammation, necessitating ongoing drug development. Previous studies have reported the inhibitory effect of a hydroethanol extract derived from Parinari excelsa Sabine (Chrysobalanaceae) on tumour necrosis factor-alpha (TNF-α), but the phytoconstituents and mechanisms of action remained elusive. The primary objective of this study was to elucidate the phytochemical composition of P. excelsa stem bark and its role in the mechanisms underpinning its biological activity. Two compounds were detected via HPLC-DAD-ESI(Ion Trap)-MS2 analysis. The predominant compound was isolated and identified as naringenin-8-sulphonate (1), while the identity of the second compound (compound 2) could not be determined. Both compound 1 and the extract were assessed for anti-inflammatory properties using a cell-based inflammation model, in which THP-1-derived macrophages were stimulated with LPS to examine the treatments' effects on various stages of the NF-κB pathway. Compound 1, whose biological activity is reported here for the first time, demonstrated inhibition of NF-κB activity, reduction in interleukin 6 (IL-6), TNF-α, and interleukin 1 beta (IL-1ß) production, as well as a decrease in p65 nuclear translocation in THP-1 cells, thus highlighting the potential role of sulphur substituents in the activity of naringenin (3). To explore the influence of sulphation on the anti-inflammatory properties of naringenin derivatives, we synthesized naringenin-4'-O-sulphate (4) and naringenin-7-O-sulphate (5) and evaluated their anti-inflammatory effects. Naringenin derivatives 4 and 5 did not display potent anti-inflammatory activities; however, compound 4 reduced IL-1ß production, and compound 5 diminished p65 translocation, with both exhibiting the capacity to inhibit TNF-α and IL-6 production. Collectively, the findings demonstrated that the P. excelsa extract was more efficacious than all tested compounds, while providing insights into the role of sulphation in the anti-inflammatory activity of naringenin derivatives.

Allophylus africanus Stem Bark Extract Modulates the Mitochondrial Apoptotic Pathway in Human Stomach Cancer Cells.

The present work aimed to detail the mechanisms elicited by Allophylus africanus P. Beauv. stem bark extract in human stomach cancer cells and to identify the bioactives underlying the cytotoxicity. MTT reduction and LDH leakage assays allowed characterizing the cytotoxic effects in AGS cells, which were further detailed by morphological analysis using phalloidin and Hoechst 33258. Proapoptotic mechanisms were elucidated through a mitochondrial membrane potential assay and by assessing the impact upon the activity of caspase-9 and -3. The extract displayed selective cytotoxicity against AGS cells. The absence of plasma membrane permeabilization, along with apoptotic body formation, suggested that pro-apoptotic effects triggered cell death. Intrinsic apoptosis pathway activation was verified, as mitochondrial membrane potential decrease and activation of caspase-9 and -3 were observed. HPLC-DAD profiling enabled the identification of two apigenin-di-C-glycosides, vicenin-2 (1) and apigenin-6-C-hexoside-8-C-pentoside (3), as well as three mono-C-glycosides-O-glycosylated derivatives, apigenin-7-O-hexoside-8-C-hexoside (2), apigenin-8-C-(2-rhamnosyl)hexoside (4) and apigenin-6-C-(2-rhamnosyl)hexoside (5). Isovitexin-2″-O-rhamnoside (5) is the main constituent, accounting for nearly 40% of the total quantifiable flavonoid content. Our results allowed us to establish the relationship between the presence of vicenin-2 and other apigenin derivatives with the contribution to the cytotoxic effects on the presented AGS cells. Our findings attest the anticancer potential of A. africanus stem bark against gastric adenocarcinoma, calling for studies to develop herbal-based products and/or the use of apigenin derivatives in chemotherapeutic drug development.

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.

The burden of injury in Central, Eastern, and Western European sub-region: a systematic analysis from the Global Burden of Disease 2019 Study.

BACKGROUND: Injury remains a major concern to public health in the European region. Previous iterations of the Global Burden of Disease (GBD) study showed wide variation in injury death and disability adjusted life year (DALY) rates across Europe, indicating injury inequality gaps between sub-regions and countries. The objectives of this study were to: 1) compare GBD 2019 estimates on injury mortality and DALYs across European sub-regions and countries by cause-of-injury category and sex; 2) examine changes in injury DALY rates over a 20 year-period by cause-of-injury category, sub-region and country; and 3) assess inequalities in injury mortality and DALY rates across the countries. METHODS: We performed a secondary database descriptive study using the GBD 2019 results on injuries in 44 European countries from 2000 to 2019. Inequality in DALY rates between these countries was assessed by calculating the DALY rate ratio between the highest-ranking country and lowest-ranking country in each year. RESULTS: In 2019, in Eastern Europe 80 [95% uncertainty interval (UI): 71 to 89] people per 100,000 died from injuries; twice as high compared to Central Europe (38 injury deaths per 100,000; 95% UI 34 to 42) and three times as high compared to Western Europe (27 injury deaths per 100,000; 95%UI 25 to 28). The injury DALY rates showed less pronounced differences between Eastern (5129 DALYs per 100,000; 95% UI: 4547 to 5864), Central (2940 DALYs per 100,000; 95% UI: 2452 to 3546) and Western Europe (1782 DALYs per 100,000; 95% UI: 1523 to 2115). Injury DALY rate was lowest in Italy (1489 DALYs per 100,000) and highest in Ukraine (5553 DALYs per 100,000). The difference in injury DALY rates by country was larger for males compared to females. The DALY rate ratio was highest in 2005, with DALY rate in the lowest-ranking country (Russian Federation) 6.0 times higher compared to the highest-ranking country (Malta). After 2005, the DALY rate ratio between the lowest- and the highest-ranking country gradually decreased to 3.7 in 2019. CONCLUSIONS: Injury mortality and DALY rates were highest in Eastern Europe and lowest in Western Europe, although differences in injury DALY rates declined rapidly, particularly in the past decade. The injury DALY rate ratio of highest- and lowest-ranking country declined from 2005 onwards, indicating declining inequalities in injuries between European countries.

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.

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.

Pharmacokinetics and Pharmacodynamics of Salvinorin A and Salvia divinorum: Clinical and Forensic Aspects.

Salvia divinorum Epling and Játiva is a perennial mint from the Lamiaceae family, endemic to Mexico, predominantly from the state of Oaxaca. Due to its psychoactive properties, S. divinorum had been used for centuries by Mazatecans for divinatory, religious, and medicinal purposes. In recent years, its use for recreational purposes, especially among adolescents and young adults, has progressively increased. The main bioactive compound underlying the hallucinogenic effects, salvinorin A, is a non-nitrogenous diterpenoid with high affinity and selectivity for the k-opioid receptor. The aim of this work is to comprehensively review and discuss the toxicokinetics and toxicodynamics of S. divinorum and salvinorin A, highlighting their psychological, physiological, and toxic effects. Potential therapeutic applications and forensic aspects are also covered in this review. The leaves of S. divinorum can be chewed, drunk as an infusion, smoked, or vaporised. Absorption of salvinorin A occurs through the oral mucosa or the respiratory tract, being rapidly broken down in the gastrointestinal system to its major inactive metabolite, salvinorin B, when swallowed. Salvinorin A is rapidly distributed, with accumulation in the brain, and quickly eliminated. Its pharmacokinetic parameters parallel well with the short-lived psychoactive and physiological effects. No reports on toxicity or serious adverse outcomes were found. A variety of therapeutic applications have been proposed for S. divinorum which includes the treatment of chronic pain, gastrointestinal and mood disorders, neurological diseases, and treatment of drug dependence. Notwithstanding, there is still limited knowledge regarding the pharmacology and toxicology features of S. divinorum and salvinorin A, and this is needed due to its widespread use. Additionally, the clinical acceptance of salvinorin A has been hampered, especially due to the psychotropic side effects and misuse, turning the scientific community to the development of analogues with better pharmacological profiles.

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.

Cassia sieberiana DC. leaves modulate LPS-induced inflammatory response in THP-1 cells and inhibit eicosanoid-metabolizing enzymes.

ETHNOPHARMACOLOGICAL RELEVANCE: According to ethnobotanical surveys, Cassia sieberiana DC. (1825) is a particularly reputed species in African folk Medicine, namely due to the application of its leaves and roots for the treatment of diseases and symptomatology that appear to be related with an inflammatory background. In contrast with the roots of the plant, the leaves remain to be investigated, which prompted us to further detail mechanisms underlying their anti-inflammatory properties, by using in vitro models of disease. AIM OF THE STUDY: Considering its use in the amelioration and treatment of conditions that frequently underlie an inflammatory response, C. sieberiana leaves extract was prioritized amongst a collection of extracts obtained from plants collected in Guinea-Bissau. As such, this work aims to deliver experimental data on the anti-inflammatory properties of C. sieberiana leaf and to establish possible associations with its chemical composition, thus providing a rationale on its use in folk Medicine. MATERIALS AND METHODS: The chemical profile of an hydroethanol extract obtained from the leaves of the plant was established by HPLC-DAD-ESI/MSn in order to identify bioactives. The extract and its main compound were tested towards a series of inflammatory mediators, both in enzymatic and cell-based models. The capacity to interfere with the eicosanoid-metabolizing enzymes 5-lipoxygenase (5-LOX), cyclooxygenase-1 (COX-1) and -2 (COX-2) was evaluated in cell-free systems, while the effects in interleukin 6 (IL-6) and tumour necrosis factor-α (TNF-α) levels produced by THP-1 derived macrophages were assessed through ELISA. RESULTS: HPLC-DAD-ESI/MSn analysis of the extract elucidated a chemical profile qualitatively characterized by a series of anthraquinones, particularly rhein derivatives, and nine flavonols, most of which 3-O-glycosylated. Considering the concentrations of the identified compounds, quercetin was detached as the main component. Effects of the hydroethanol extract obtained from C. sieberiana leaves against key enzymes of the arachidonic acid cascade were recorded, namely a concentration-dependent inhibition against 5-LOX, at concentrations ranging from 16 to 250 µg mL-1 and a selective inhibitory action upon COX-2 (IC50 = 3.58 µg mL-1) in comparison with the isoform COX-1 (IC50 = 9.10 µg mL-1). Impact on inflammatory cytokines was also noted, C. sieberiana leaf extract significantly decreasing IL-6 levels in THP-1 derived macrophages at 250 and 500 µg mL-1. In contrast, TNF-α levels were found to be increased in the same model. Quercetin appears to partially account for the observed effects, namely due to the significant inhibitory effects on the activity of the arachidonic acid metabolizing enzymes COX-2 and 5-LOX. CONCLUSIONS: The anti-inflammatory effects herein reported provide a rationale for the use of C. sieberiana leaves in African folk practices, such as in the treatment of arthritis, rheumatism and body aches. Considering the occurrence of flavonoidic and anthraquinonic constituents, as well as the observed anti-inflammatory properties of quercetin, recorded effects must be related with the presence of several bioactives.

Gustavia gracillima Miers. flowers effects on enzymatic targets underlying metabolic disorders and characterization of its polyphenolic content by HPLC-DAD-ESI/MSn.

Notwithstanding Gustavia gracillima Miers widespread distribution in neotropical regions, its chemical profile and biological properties remain uninvestigated. A methanol extract obtained from the flowers was characterized through HPLC-DAD-ESI/MSn, nine ellagic acid derivatives and twelve kaempferol 3-O-glycosides being identified and quantitated for the first time at the species and genus. Preliminary cytotoxicity screening did not reveal noticeable effects upon gastrointestinal representative cell lines (AGS, Caco-2 and Hep G2), which further prompted us to evaluate the impact in a series of targets involved in metabolic disorders and associated complications. Despite of the moderate inhibition towards 5-lipoxygense activity, G. gracillima methanol extract displayed significant effects on carbohydrates-hydrolysing enzymes. In contrast with the antidiabetic reference drug acarbose, the extract was able to selectively inhibit yeast α-glucosidase activity (IC50 = 4.72 µg/mL), with negligible inhibitory effects upon α-amylase. Kinetic studies pointed to a model of mixed inhibition with a great binding activity, characterized by an inhibitory constant of 2.91 µg/mL. The notable inhibitory activity was also confirmed in α-glucosidase homogenates isolated from human intestinal cells (IC50 = 34.03 µg/mL). Moreover, the extract obtained from the flowers of G. gracillima displayed significant aldose reductase inhibition (IC50 = 61.88 µg/mL), as well as O2- and NO scavenging properties. A moderate inhibitory effect was also recorded against pancreatic lipase (IC50 = 362.17 µg/mL) through a mixed inhibition mode. Recorded data supports the potential incorporation of G. gracillima flowers on antidiabetic herbal formulations and/or supplements, with not only straight action on carbohydrates digestion, but also direct interference with targets involved on subsequent diabetes events, such as triglycerides metabolism, inflammation and radical-mediated stress.

Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids N,N-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact.

Ayahuasca is a hallucinogenic botanical beverage originally used by indigenous Amazonian tribes in religious ceremonies and therapeutic practices. While ethnobotanical surveys still indicate its spiritual and medicinal uses, consumption of ayahuasca has been progressively related with a recreational purpose, particularly in Western societies. The ayahuasca aqueous concoction is typically prepared from the leaves of the N,N-dimethyltryptamine (DMT)-containing Psychotria viridis, and the stem and bark of Banisteriopsis caapi, the plant source of harmala alkaloids. Herein, the toxicokinetics and toxicodynamics of the psychoactive DMT and harmala alkaloids harmine, harmaline and tetrahydroharmine, are comprehensively covered, particularly emphasizing the psychological, physiological, and toxic effects deriving from their concomitant intake. Potential therapeutic utility, particularly in mental and psychiatric disorders, and forensic aspects of DMT and ayahuasca are also reviewed and discussed. Following administration of ayahuasca, DMT is rapidly absorbed and distributed. Harmala alkaloids act as potent inhibitors of monoamine oxidase A (MAO-A), preventing extensive first-pass degradation of DMT into 3-indole-acetic acid (3-IAA), and enabling sufficient amounts of DMT to reach the brain. DMT has affinity for a variety of serotonergic and non-serotonergic receptors, though its psychotropic effects are mainly related with the activation of serotonin receptors type 2A (5-HT2A). Mildly to rarely severe psychedelic adverse effects are reported for ayahuasca or its alkaloids individually, but abuse does not lead to dependence or tolerance. For a long time, the evidence has pointed to potential psychotherapeutic benefits in the treatment of depression, anxiety, and substance abuse disorders; and although misuse of ayahuasca has been diverting attention away from such clinical potential, research onto its therapeutic effects has now strongly resurged.

Medicinal plants utilized in Thai Traditional Medicine for diabetes treatment: Ethnobotanical surveys, scientific evidence and phytochemicals.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetes mellitus remains the most lethal metabolic disease of contemporaneous times and despite the therapeutic arsenal currently available, research on new antidiabetic agents remains a priority. In recent years, the revitalization of Thai Traditional Medicine (TTM) became a clear priority for the Thai government, and many efforts have been undertaken to accelerate research on herbal medicines and their use in medical services in various hospitals. Additionally, and particularly in rural areas, treatment of diabetes and associated symptomatology frequently relies on herbal preparations recommended by practitioners of TTM. In the current work, medicinal plants used in Thailand for treating diabetes, as well as their hypoglycaemic pharmacological evidences and potential therapeutic use for diabetes-related complications were reviewed. MATERIALS AND METHODS: Ethnopharmacological information on the plant materials used in TTM for diabetes treatment was collected through literature search in a range of scientific databases using the search terms: diabetes, folk medicine, Thailand medicinal plants, traditional medicine. Information regarding scientific evidence on the antidiabetic effects of surveyed species was obtained considering not only the most common taxonomic designation, but also taxonomic synonyms, and including the keywords 'diabetes' and 'hypoglycaemic effect'. RESULTS: A total of 183 species known to be used for diabetes management in TTM were reviewed, with 30% of them still lacking experimental evidences to support claims regarding the mechanisms and phytochemicals underlying their antidiabetic properties. Moreover, a total of 46 bioactives displaying effective antidiabetic effects have been isolated from 24 species, their underlying mechanism(s) of action being fully or partially disclosed. CONCLUSIONS: We deliver the most extensive survey dealing with the ethnomedicinal knowledge of Thai medicinal plants utilized on diabetes management. We are certain that the current review will spark further research on Thai plants for the development of new standardized phytomedicines through drug discovery programmes.

Inhibition of Proinflammatory Enzymes and Attenuation of IL-6 in LPS-Challenged RAW 264.7 Macrophages Substantiates the Ethnomedicinal Use of the Herbal Drug Homalium bhamoense Cubitt & W.W.Sm.

Commonly used to treat skin injuries in Asia, several Homalium spp. have been found to promote skin regeneration and wound healing. While ethnobotanical surveys report the use of H. bhamoense trunk bark as a wound salve, there are no studies covering bioactive properties. As impaired cutaneous healing is characterized by excessive inflammation, a series of inflammatory mediators involved in wound healing were targeted with a methanol extract obtained from H. bhamoense trunk bark. Results showed concentration-dependent inhibition of hyaluronidase and 5-lipoxygenase upon exposure to the extract, with IC50 values of 396.9 ± 25.7 and 29.0 ± 2.3 µg mL-1, respectively. H. bhamoense trunk bark extract also exerted anti-inflammatory activity by significantly suppressing the overproduction of interleukin 6 (IL-6) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages at concentrations ranging from 125 to 1000 µg mL-1, while leading to a biphasic effect on nitric oxide (NO) and tumor necrosis factor alpha (TNF-α) levels. The phenolic profile was elucidated by HPLC-DAD, being characterized by the occurrence of ellagic acid as the main constituent, in addition to a series of methylated derivatives, which might underlie the observed anti-inflammatory effects. Our findings provide in vitro data on anti-inflammatory ability of H. bhamoense trunk bark, disclosing also potential cutaneous toxicity as assessed in HaCaT keratinocytes.

Anti-inflammatory properties of Xylopia aethiopica leaves: Interference with pro-inflammatory cytokines in THP-1-derived macrophages and flavonoid profiling.

ETHNOPHARMACOLOGICAL RELEVANCE: Ethnopharmacological surveys on Guinea-Bissauan flora reveal that several species are used to treat or ameliorate the symptomatology of conditions with an inflammatory background. As such, extracts obtained from a series of plants recorded in those surveys were screened for their anti-inflammatory properties, a hydroethanolic extract obtained from the leaves of Xylopia aethiopica (Dunal) A. Rich, (Annonaceae), used on the treatment of headache, muscular pain and rheumatic pain, scoring positively and being further investigated. AIM OF THE STUDY: In order to identify species with anti-inflammatory properties, extracts were screened for their ability to interfere with LPS-induced TNF-α levels. Since significant effects were recorded upon treatment with the extract of the leaves obtained from X. aethiopica, further assays were conducted to elucidate additional mechanisms underlying its anti-inflammatory potential. Since little is known on the chemical composition of the plant, we also aimed to characterise its phenolic profile. MATERIALS AND METHODS: Interference with cytokines was evaluated by ELISA assay, through the quantification of TNF-α and IL-6 levels in the culture medium collected from LPS-activated THP-1-derived-macrophages. Inhibition of 5-lipoxygenase was assessed based on the oxidation of linoleic acid to 13-hydroperoxylinoleic acid. Characterization of the phenolic profile was attained by HPLC-DAD. RESULTS: Evaluation of TNF-α levels in LPS-challenged THP-1 macrophages evidenced a significant inhibition (>90%) upon treatment with the hydroethanolic extract obtained from X. aethiopica leaves at a concentration of 500 µg/mL. Additional anti-inflammatory effects were recorded, including a significant decrease on IL-6 levels at 250 and 500 µg/mL. The extract proved to be active towards 5-LOX, leading to significant inhibition at concentrations ranging from 16 to 250 µg/mL (IC50 = 85 µg/mL). Phenolic profiling allowed the identification and quantitation of eight constituents, including caffeoylquinic acids (1-3), mono-O-glycosylated flavonols (5-8), and the mono-O-glycosyl flavone luteolin-7-O-glucoside (4). The main phenolic constituent, kaempferol-3-O-rutinoside (8), was found to significantly contribute to the anti-inflammatory effects, namely through the inhibition of 5-LOX. However, no effects on the decrease of TNF-α and IL-6 levels caused by this phenolic compound were found. CONCLUSION: The anti-inflammatory effects of X. aethiopica leaves are demonstrated experimentally, thus substantiating its use in folk Medicine. Relevantly, the observed anti-inflammatory properties can stimulate further studies in order to fully unveil the therapeutic potential of the plant, namely as a source of phenolic compounds with a significant ability to interfere with conventional inflammatory targets.

Double the Chemistry, Double the Fun: Structural Diversity and Biological Activity of Marine-Derived Diketopiperazine Dimers.

While several marine natural products bearing the 2,5-diketopiperazine ring have been reported to date, the unique chemistry of dimeric frameworks appears to remain neglected. Frequently reported from marine-derived strains of fungi, many naturally occurring diketopiperazine dimers have been shown to display a wide spectrum of pharmacological properties, particularly within the field of cancer and antimicrobial therapy. While their structures illustrate the unmatched power of marine biosynthetic machinery, often exhibiting unsymmetrical connections with rare linkage frameworks, enhanced binding ability to a variety of pharmacologically relevant receptors has been also witnessed. The existence of a bifunctional linker to anchor two substrates, resulting in a higher concentration of pharmacophores in proximity to recognition sites of several receptors involved in human diseases, portrays this group of metabolites as privileged lead structures for advanced pre-clinical and clinical studies. Despite the structural novelty of various marine diketopiperazine dimers and their relevant bioactive properties in several models of disease, to our knowledge, this attractive subclass of compounds is reviewed here for the first time.

Phenolic Profiling and Biological Potential of Ficus curtipes Corner Leaves and Stem Bark: 5-Lipoxygenase Inhibition and Interference with NO Levels in LPS-Stimulated RAW 264.7 Macrophages.

The economic value of fig trees has been globally acknowledged due to their utilization in the food industry, being also frequently used in traditional medicine. While ubiquitously distributed in Southeast Asia, Ficus curtipes Corner remains uninvestigated concerning its biological properties and chemical profile. HPLC-DAD-ESI/MSn characterization of methanol extracts obtained from the stem bark and leaves allowed the identification and quantitation of 21 phenolic compounds for the first time; the stem bark was predominantly rich in flavan-3-ols and apigenin derivatives, while solely apigenin-di-glycosides have been identified and quantitated on the leaf extract. Both extracts inhibited 5-lipoxygenase (5-LOX) activity in a concentration-dependent manner, the one obtained from the stem bark being significantly more active (IC50 = 10.75 µg/mL). The effect of both extracts on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages was evaluated, and while the stem bark extract did not lead to a noticeable interference on nitric oxide (NO) levels, the extract obtained from the leaves notably decreased NO and L-citrulline levels at concentrations ranging from 250 to 500 µg/mL. Herein, F. curtipes is valorized due to its modulatory effects on inflammatory mediators and also as a source of bioactive phenols, which may fuel further studies on the development of nutraceuticals.

Flavonoid Composition of Salacia senegalensis (Lam.) DC. Leaves, Evaluation of Antidermatophytic Effects, and Potential Amelioration of the Associated Inflammatory Response.

Predominantly spread in West Tropical Africa, the shrub Salacia senegalensis (Lam.) DC. is known because of its medicinal properties, the leaves being used in the treatment of skin diseases. Prompted by the ethnomedicinal use, a hydroethanolic extract obtained from the leaves of the plant was screened against a panel of microbial strains, the majority of which involved in superficial infections. The extract was found to be active against the dermatophytes Trichophyton rubrum and Epidermophyton floccosum. Notable results were also recorded regarding the attenuation of the inflammatory response, namely the inhibitory effects observed against soybean 5-lipoxygenase (IC50 = 71.14 µg mL-1), no interference being recorded in the cellular viability of RAW 264.7 macrophages and NO levels. Relevantly, the extract did not lead to detrimental effects against the keratinocyte cell line HaCaT, at concentrations displaying antidermatophytic and anti-inflammatory effects. Flavonoid profiling of S. senegalensis leaves was achieved for the first time, allowing the identification and quantitation of myricitrin, three 3-O-substituted quercetin derivatives, and three other flavonoid derivatives, which may contribute, at least partially, to the observed antidermatophytic and anti-inflammatory effects. In the current study, the plant S. senegalensis is assessed concerning its antidermatophytic and anti-inflammatory properties.