Vicia faba L. Pod Valves: A By-Product with High Potential as an Adjuvant in the Treatment of Parkinson's Disease.

Vicia faba L. is a leguminous plant with seeds rich in nutritional compounds, such as polyphenols and L-dopa, a dopamine precursor and first-line treatment for Parkinson's symptoms. Recently, its by-products have been revalued as a sustainable source of bioactive compounds. In this study, aqueous extracts of Lucan broad bean pod valves (BPs) were characterized to evaluate their potential use as adjuvants in severe Parkinson's disease. L-dopa content, quantified by LC-UV, was much higher in BPs than in seeds (28.65 mg/g dw compared to 0.76 mg/g dw). In addition, vicine and convicine, the metabolites responsible for favism, were not detected in pods. LC-ESI/LTQ-Orbitrap/MS2 allowed the identification of the major polyphenolic compounds, including quercetin and catechin equivalents, that could ensure neuroprotection in Parkinson's disease. ESI(±)-FT-ICR MS was used to build 2D van Krevelen diagrams; polyphenolic compounds and carbohydrates were the most representative classes. The neuroprotective activity of the extracts after MPP+-induced neurotoxicity in SH-SY5Y cells was also investigated. BP extracts were more effective than synthetic L-dopa, even at concentrations up to 100 µg/mL, due to the occurrence of antioxidants able to prevent oxidative stress. The stability and antioxidant component of the extracts were then emphasized by using naturally acidic solutions of Punica granatum L., Ribes rubrum L., and gooseberry (Phyllanthus emblica L.) as extraction solvents.

Castanea sativa Mill. By-Products: Investigation of Potential Anti-Inflammatory Effects in Human Intestinal Epithelial Cells.

Castanea sativa Mill. (C. sativa) processing and pruning generate several by-products, including leaves, burs, and shells (inner and outer teguments), which are considered an important source of high-value phytochemicals. Ellagitannins from C. sativa leaf extracts have been described to impair H. pylori viability and inflammation in gastric cells. Furthermore, chestnut shells showed an important anti-inflammatory effect in gastric epithelial cells. Dietary polyphenols, including tannins, have been reported to interfere with targets of inflammation, including the nuclear factor κB (NF-κB). A promising role as a further therapeutical target for gut disorders has been recently proposed for the regulatory subunit of hypoxia-inducible factor (HIF-1α), as a potential stabilizer of intestinal barrier integrity. Therefore, the main objective of this work is the chemical characterization of several chestnut by-products (bud, spiny bur, wood, pericarp and episperm), together with the exploitation of their anti-inflammatory properties in intestinal cells, scavenging capacity, and stability following gastrointestinal digestion. The chemical characterization confirmed the presence of bioactive polyphenols in the extracts, including ellagitannins. In CaCo-2 cells stimulated by an IL-1ß-IFN-γ cocktail, nearly all chestnut by-products (50 µg/mL) inhibited the release of proinflammatory mediators (CXCL-10, IL-8, MCP-1, ICAM), along with the NF-κB-driven transcription, and induced the HRE-driven transcription. The stability of the most promising extracts, identified through PCA and cluster analysis, was addressed by in vitro gastrointestinal digestion. Despite the significant reduction in total polyphenol index of chestnut bud and wood after gastric and intestinal digestion, the activity of these extracts on both scavenging and anti-inflammatory parameters remained promising. These data contribute to exploit the potential of chestnut by-products as sources of dietary polyphenols with anti-inflammatory properties at the intestinal level. Moreover, this study could represent an important step to encourage the recycling and valorization of chestnut by-products, promoting the circular economy and reducing the environmental impact related to the management of agriculture waste.

In Vitro Insights into the Dietary Role of Glucoraphanin and Its Metabolite Sulforaphane in Celiac Disease.

Sulforaphane is considered the bioactive metabolite of glucoraphanin after dietary consumption of broccoli sprouts. Although both molecules pass through the gut lumen to the large intestine in stable form, their biological impact on the first intestinal tract is poorly described. In celiac patients, the function of the small intestine is affected by celiac disease (CD), whose severe outcomes are controlled by gluten-free dietary protocols. Nevertheless, pathological signs of inflammation and oxidative stress may persist. The aim of this study was to compare the biological activity of sulforaphane with its precursor glucoraphanin in a cellular model of gliadin-induced inflammation. Human intestinal epithelial cells (CaCo-2) were stimulated with a pro-inflammatory combination of cytokines (IFN-γ, IL-1ß) and in-vitro-digested gliadin, while oxidative stress was induced by H2O2. LC-MS/MS analysis confirmed that sulforaphane from broccoli sprouts was stable after simulated gastrointestinal digestion. It inhibited the release of all chemokines selected as inflammatory read-outs, with a more potent effect against MCP-1 (IC50 = 7.81 µM). On the contrary, glucoraphanin (50 µM) was inactive. The molecules were unable to counteract the oxidative damage to DNA (γ-H2AX) and catalase levels; however, the activity of NF-κB and Nrf-2 was modulated by both molecules. The impact on epithelial permeability (TEER) was also evaluated in a Transwell® model. In the context of a pro-inflammatory combination including gliadin, TEER values were recovered by neither sulforaphane nor glucoraphanin. Conversely, in the context of co-culture with activated macrophages (THP-1), sulforaphane inhibited the release of MCP-1 (IC50 = 20.60 µM) and IL-1ß (IC50 = 1.50 µM) only, but both molecules restored epithelial integrity at 50 µM. Our work suggests that glucoraphanin should not merely be considered as just an inert precursor at the small intestine level, thus suggesting a potential interest in the framework of CD. Its biological activity might imply, at least in part, molecular mechanisms different from sulforaphane.

Pigmented corn as a gluten-free source of polyphenols with anti-inflammatory and antioxidant properties in CaCo-2 cells.

A high number of varieties from corn (Zea mays L.) have been consumed for long time all over the world, however pigmented varieties are recently gaining renewed attention due to their beneficial effects and polyphenolic content. The natural lack of gluten makes corn suitable for consumption by celiac population, who need to control their inflammatory state through an appropriate gluten-free diet. The biological effects of polyphenols from pigmented corn are poorly investigated in the context of celiac disease. In this work, we analyzed through HPLC-DAD the phenolic composition of two Italian purple and red varieties ("Scagliolo Rosso" and "Rostrato di Rovetta", respectively) comparing their effects in human intestinal epithelial cells (CaCo-2 cells). The possible impact of gastro-intestinal digestion following oral consumption was assessed as well. The phenolic profile showed the presence of phenolic acids in both varieties, while anthocyanins were identified in Scagliolo Rosso only. After simulated digestion, the level of polyphenols did not significantly change and paralleled with an increased scavenging activity. In CaCo-2 cells, stimulated by a proinflammatory cocktail containing gliadin-derived peptides (IL-1ß, IFN-γ, digested gliadin), pigmented corn extracts inhibited the release of CXCL-10 and sICAM-1, with mechanisms partially ascribed to NF-κB impairment. At the same concentration (200 µg/mL), ROS production and catalase depletion were reverted through Nrf-2-independent mechanisms. Our data suggest that polyphenols from pigmented corns might help in controlling the inflammatory and oxidative state of people with celiac disease at intestinal level, at concentrations potentially achievable through a gluten-free diet.

Minor Cannabinoids as Inhibitors of Skin Inflammation: Chemical Synthesis and Biological Evaluation.

Despite millennia of therapeutic plant use, deliberate exploitation of Cannabis's diverse biomedical potential has only recently gained attention. Bioactivity studies focus mainly on cannabidiol (CBD) and tetrahydrocannabinol (THC) with limited information about the broader cannabinome's "minor phytocannabinoids". In this context, our research targeted the synthesis of minor cannabinoids containing a lateral chain with 3 or 4 carbon atoms, focusing on cannabigerol (CBG) and cannabichromene (CBC) analogues. Using known and innovative strategies, we achieved the synthesis of 11 C3 and C4 analogues, five of which were inhibitors of skin inflammation, with the CBG-C4 ester derivative emerging as the most potent compound.

Catha edulis Leaves: Morphological Characterization and Anti-Inflammatory Properties in an In Vitro Model of Gastritis.

Khat leaves, indigenous to eastern Africa, have been chewed for centuries for their stimulant effects, attributed to alkaloids such as cathinone and cathine. Although associated with gastric disorders like gastritis and gastro-oesophageal reflux disease, the underlying molecular mechanisms remain unclear. This study aimed to examine the morpho-anatomy of khat leaves using light microscopy and histochemistry and to assess the effects of leaf extracts and alkaloids on human gastric epithelial cells (GES-1). The study identified specific cells in the palisade-spongy transition zone as storage sites for psychoactive alkaloids. Leaf extracts were prepared by mimicking the chewing process, including a prolonged salivary phase followed by a gastric phase. Cytotoxicity and cell viability were evaluated using LDH and MTT assays, respectively. Additionally, the impact on IL-8 secretion, a key chemokine in gastric inflammation, was analysed under normal and TNF-α-stimulated conditions. The results showed no increase in cytotoxicity up to 250 µg/mL. However, there was a significant decrease in cell metabolism and a reduction in both basal and TNF-α-induced IL-8 secretion, but cathinone and cathine were inactive. These findings suggest that khat may not directly cause the gastric issues reported in the literature, which would rather be attributed to other confounding factors, highlighting the need for further research to clarify its biological impacts.

Investigation into the Anti-Acne Effects of Castanea sativa Mill Leaf and Its Pure Ellagitannin Castalagin in HaCaT Cells Infected with Cutibacterium acnes.

Acne vulgaris is a prevalent skin disorder affecting many young individuals, marked by keratinization, inflammation, seborrhea, and colonization by Cutibacterium acnes (C. acnes). Ellagitannins, known for their antibacterial and anti-inflammatory properties, have not been widely studied for their anti-acne effects. Chestnut (Castanea sativa Mill., C. sativa), a rich ellagitannin source, including castalagin whose acne-related bioactivity was previously unexplored, was investigated in this study. The research assessed the effect of C. sativa leaf extract and castalagin on human keratinocytes (HaCaT) infected with C. acnes, finding that both inhibited IL-8 and IL-6 release at concentrations below 25 µg/mL. The action mechanism was linked to NF-κB inhibition, without AP-1 involvement. Furthermore, the extract displayed anti-biofilm properties and reduced CK-10 expression, indicating a potential role in mitigating inflammation, bacterial colonization, and keratosis. Castalagin's bioactivity mirrored the extract's effects, notably in IL-8 inhibition, NF-κB inhibition, and biofilm formation at low µM levels. Other polyphenols, such as flavonol glycosides identified via LC-MS, might also contribute to the extract's biological activities. This study is the first to explore ellagitannins' potential in treating acne, offering insights for developing chestnut-based anti-acne treatments pending future in vivo studies.

From Primary Data to Ethnopharmacological Investigations on Achillea erba-rotta subsp. moschata (Wulfen) I.Richardson as a Remedy against Gastric Ailments in Valmalenco (Italy).

(1) Background: Within the framework of the European Interreg Italy-Switzerland B-ICE & Heritage project (2018-2022), this study originated from a three-year ethnobotanical survey in Valmalenco (Sondrio, Italy). Following a preliminary work published by our group, this research further explored the folk therapeutic use of Achillea erba-rotta subsp. moschata (Wulfen) I.Richardson (Asteraceae) for dyspepsia disorders, specifically its anti-inflammatory potential at a gastrointestinal level. (2) Methods: Semi-structured interviews were performed. The bitter taste was investigated through molecular docking software (PLANTS, GOLD), while the anti-inflammatory activity of the hydroethanolic extract, infusion, and decoction was evaluated based on the release of IL-8 and IL-6 after treatment with TNFα or Helicobacter pylori. The minimum inhibitory concentration and bacterial adhesion on the gastric epithelium were evaluated. (3) Results: In total, 401 respondents were interviewed. Molecular docking highlighted di-caffeoylquinic acids as the main compounds responsible for the interaction with bitter taste receptors. The moderate inhibition of IL-6 and IL-8 release was recorded, while, in the co-culture with H. pylori, stronger anti-inflammatory potential was expressed (29-45 µg/mL). The concentration-dependent inhibition of H. pylori growth was recorded (MIC = 100 µg/mL), with a significant anti-adhesive effect. (4) Conclusions: Confirming the folk tradition, the study emphasizes the species' potentiality for dyspepsia disorders. Future studies are needed to identify the components mostly responsible for the biological effects.

Investigating the Molecular Mechanisms Underlying Early Response to Inflammation and Helicobacter pylori Infection in Human Gastric Epithelial Cells.

Helicobacter pylori is a leading cause of chronic gastric inflammation, generally associated with gastritis and adenocarcinoma. Activation of the NF-κB pathway mainly contributes to the inflammatory phenotype observed in H. pylori infection in humans and experimental models. Since the gastric epithelium undergoes rapid turnover, inflammation and pathogenicity of H. pylori result from early phase and chronically activated pathways. In the present study we investigated the early host response to H. pylori in non-tumoral human gastric epithelial cells (GES-1). To dissect the pathogen-specific mechanisms we also examined the response to tumor necrosis factor (TNF), a prototypical cytokine. By analyzing the activation state of NF-κB signaling, cytokine expression and secretion, and the transcriptome, we found that the inflammatory response of GES-1 cells to H. pylori and TNF results from activation of multiple pathways and transcription factors, e.g., NF-κB and CCAAT/enhancer-binding proteins (CEBPs). By comparing the transcriptomic profiles, we found that H. pylori infection induces a less potent inflammatory response than TNF but affects gene transcription to a greater extent by specifically inducing transcription factors such as CEBPß and numerous zinc finger proteins. Our study provides insights on the cellular pathways modulated by H. pylori in non-tumoral human gastric cells unveiling new potential targets.

A validated LC-MS/MS method for quantitative determination of L-dopa in Fagioli di Sarconi beans (Phaseolus vulgaris L.).

An analytical method based on ultrasound assisted extraction (UAE) and liquid chromatography coupled to electrospray tandem mass spectrometry (LC-ESI/MS/MS) was validated and applied for determining L-dopa in four ecotypes of Fagioli di Sarconi beans (Phaseolus vulgaris L.), marked with the European label PGI (Protected Geographical Indication). The selectivity of the proposed method was ensured by the specific fragmentation of the analyte. Simple isocratic chromatographic conditions and mass spectrometric detection in multiple reaction monitoring (MRM) acquisition mode were used for sensitive quantification. The LC-ESI/MS/MS method was validated within a linear range of 0.001-5.000 µg/mL. Values of 0.4 and 1.1 ng/mL were obtained for the limits of detection and quantification, respectively. The repeatability, inter-day precision, and recovery values ranges were 0.6%-4.5%, 5.4%-9.9%, and 83%-93%, respectively. Fresh and dried beans, as well as pods, cultivated exclusively with organic methods avoiding any synthetic fertilizers and pesticides were analyzed showing an L-dopa content ranging from 0.020 ± 0.005 to 2.34 ± 0.05 µg/g dry weight.

Anti-Inflammatory, Antioxidant Activities, and Phytochemical Characterization of Edible Plants Exerting Synergistic Effects in Human Gastric Epithelial Cells.

Dietary bioactive compounds from natural sources (e.g., herbal medicines, foods) are known to potentially suppress acute or chronic inflammation and promote the effectiveness of treatment to reduce the harmful effects of gastritis alone or in combination. In this regard, we have characterized four Cameroonian spice extracts, namely Aframomum citratum, Dichrostachys glomerata, Tetrapleura tetraptera, and Xylopia parviflora through reverse phase-high-performance liquid chromatography (RP-HPLC), ultra-performance liquid chromatography-electrospray ionization high-resolution mass spectrometry (UPLC-ESI-HRMS/MS), and Fourier transform infrared spectroscopic (FTIR) analyses and investigated their antioxidant and synergistic anti-inflammatory activities in human gastric adenocarcinoma (AGS) and gastric epithelial (GES-1) cells. The extracts showed a high amount of total phenolic (TPC: 150-290 mg gallic acid equivalents (GAE)/g of extract) and flavonoid content (TFC: 35-115 mg catechin equivalents (CE)/g of extract) with antioxidant properties in a cell-free system (1,1-Diphenyl-2-picryl-hydrazyl (DPPH) half maximal inhibitory concentration (IC50s) ≤ 45 µg/mL; 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) half maximal inhibitory concentration (IC50s) ≤ 29 µg/mL. The extracts in combination (MIX) exert a synergistic beneficial effect (combination index (CIs) < 1 and dose reduction index (DRIs) > 1) on inflammatory markers (interleukin (IL)-8 and -6 release, and nuclear factor kappa B (NF-κB) driven transcription) in human gastric epithelial cells, which may result from the presence of phenolic compounds (phenolic acids, flavonoids) or other compounds (protein, lipid, aromatic, and polysaccharide compounds) tentatively identified in the extracts. The general findings of the present study provide supporting evidence on the chemical composition of four Cameroonian dietary plants and their significant synergistic inhibitory activities on inflammatory markers of gastric epithelial cells.

Ellagitannins from Castanea sativa Mill. Leaf Extracts Impair H. pylori Viability and Infection-Induced Inflammation in Human Gastric Epithelial Cells.

Helicobacter pylori (H. pylori) is an etiologic factor of peptic ulcer disease and gastric cancer. Virulent strains of H. pylori are correlated with the severity of gastritis, due to NF-κB activation and IL-8 expression at the epithelial level. Ellagitannins have been documented for antibacterial and anti-inflammatory activities, thus suggesting their potential use in gastritis. Recently, several authors, including our group, demonstrated that tannin-rich extracts from chestnut byproducts, at present considered agricultural waste, display promising biological activities. In this work, we detected high levels of polyphenols in hydroalcoholic extracts from chestnut leaves (Castanea sativa L.). Among polyphenols, the ellagitannin isomers castalagin and vescalagin (about 1% w/w of dry extract) were identified as potential bioactive compounds. In GES-1 cells infected by H. pylori, leaf extract and pure ellagitannins inhibited IL-8 release (IC50 ≈ 28 µg/mL and 11 µM, respectively). Mechanistically, the anti-inflammatory activity was partly due to attenuation of NF-κB signaling. Moreover, the extract and pure ellagitannins reduced bacterial growth and cell adhesion. A simulation of the gastric digestion suggested that the bioactivity might be maintained after oral administration. At the transcriptional level, castalagin downregulated genes involved in inflammatory pathways (NF-κB and AP-1) and cell migration (Rho GTPase). To the best of our knowledge, this is the first investigation in which ellagitannins from plant extracts have demonstrated a potential role in the interaction among H. pylori and human gastric epithelium.

Exploring In Vitro the Combination of Cistus × incanus L. and Castanea sativa Mill. Extracts as Food Supplement Ingredients against H. pylori Infection.

Cistus spp. have been traditionally used for inflammatory and infectious disorders, including gastrointestinal ailments, in the Mediterranean area. Among them, Cistus × incanus L. is one of the most frequently cited species in the literature for a variety of biological activities which include inflammatory diseases. Cistus spp. aerial parts are rich in polyphenols such as condensed and hydrolysable tannins, procyanidins, and flavonoids, which show gastroprotective activities. The purpose of the present study is to investigate the biological activities of a hydroalcoholic extract from Cistus × incanus L. aerial parts in gastric epithelial cells (GES-1) infected with H. pylori. The extracts inhibited IL-8 and NF-κB induced by H. pylori and showed antibacterial activity after simulated digestion. Since our previous paper reported interesting results on the ability of Castanea sativa Mill. leaf extract to decrease inflammatory conditions in H. pylori-infected gastric cells, the combination of Castanea sativa and Cistus × incanus extracts was also investigated, showing strong anti-inflammatory activity and inhibition of bacterial adhesion. This association of botanicals is proposed herein as a novel food supplement capable of counteracting gastric inflammatory conditions.

Development and Validation of a Reversed-Phase HPLC Method with UV Detection for the Determination of L-Dopa in Vicia faba L. Broad Beans.

L-Dopa (LD), a substance used medically in the treatment of Parkinson's disease, is found in several natural products, such as Vicia faba L., also known as broad beans. Due to its low chemical stability, LD analysis in plant matrices requires an appropriate optimization of the chosen analytical method to obtain reliable results. This work proposes an HPLC-UV method, validated according to EURACHEM guidelines as regards linearity, limits of detection and quantification, precision, accuracy, and matrix effect. The LD extraction was studied by evaluating its aqueous stability over 3 months. The best chromatographic conditions were found by systematically testing several C18 stationary phases and acidic mobile phases. In addition, the assessment of the best storage treatment of Vicia faba L. broad beans able to preserve a high LD content was performed. The best LD determination conditions include sun-drying storage, extraction in HCl 0.1 M, chromatographic separation with a Discovery C18 column, 250 × 4.6 mm, 5 µm particle size, and 99% formic acid 0.2% v/v and 1% methanol as the mobile phase. The optimized method proposed here overcomes the problems linked to LD stability and separation, thus contributing to the improvement of its analytical determination.

Hydrolyzable Tannins in the Management of Th1, Th2 and Th17 Inflammatory-Related Diseases.

Plants rich in hydrolyzable tannins were traditionally used all over the world for a variety of chronic inflammatory disorders, including arthritis, colitis, and dermatitis. However, the knowledge of their immunological targets is still limited though fundamental for their rational use in phytotherapy. The recent advances regarding the pathogenesis of inflammatory-based diseases represent an opportunity to elucidate the pharmacological mechanism of plant-derived metabolites with immunomodulatory activity. This review collects recent articles regarding the role of hydrolyzable tannins and their gut metabolites in Th1, Th2, and Th17 inflammatory responses. In line with the traditional use, rheumatoid arthritis (RA), inflammatory bowel diseases (IBDs), psoriasis, atopic dermatitis (AD), and asthma were the most investigated diseases. A substantial body of in vivo studies suggests that, beside innate response, hydrolyzable tannins may reduce the levels of Th-derived cytokines, including IFN-γ, IL-17, and IL-4, following oral administration. The mode of action is multitarget and may involve the impairment of inflammatory transcription factors (NF-κB, NFAT, STAT), enzymes (MAPKs, COX-2, iNOS), and ion channels. However, their potential impact on pathways with renewed interest for inflammation, such as JAK/STAT, or the modulation of the gut microbiota demands dedicate studies.

Effect of an herbal formulation containing Peganum harmala L. and Fraxinus excelsior L. on oxidative stress, memory impairment and withdrawal syndrome induced by morphine.

Background: Traditional Persian medicine has introduced effective remedies in opioid dependence care. One of the most widely used remedies is an herbal formulation containing Peganum harmala L. and Fraxinus excelsior L. (HF). This study investigated the effects of HF to attenuate the withdrawal signs and rewarding effects in morphine-dependent rats.Methods: Forty-nine male Wistar rats were randomly divided into seven groups. The control and vehicle groups received normal saline and sodium carboxymethyl cellulose, respectively. The morphine group received morphine for one week. The single and daily dose of HF groups received morphine similar to the morphine group, and HF (1.4 and 2.8 g/kg) once a day in the daily dose group and only on the last day of the experiment in the single dose of HF group. Finally, the withdrawal signs as well biochemical tests were evaluated. The behavioral parameters were assessed by conditioned place preference (CPP), elevated plus-maze and Y-maze tests. The antioxidant activity of HF was evaluated by measurement of serum contents of malondialdehyde, stable nitric oxide metabolites and total antioxidant capacity (TAC). Moreover, the protein expression of c-fos was assessed by western blotting.Results: Daily treatment with HF significantly reduced the score of CPP behavioral test, all of the withdrawal signs, TAC and the c-fos protein level.Conclusions: The results indicated that HF might be a promising complementary treatment in reducing morphine-induced physical and psychological dependence probably through modulation of c-fos protein expression.

Single and Repeated Exposure to Cannabidiol Differently Modulate BDNF Expression and Signaling in the Cortico-Striatal Brain Network.

Cannabidiol (CBD) is a phytocannabinoid contained in the Cannabis sativa plant, devoid of psychotomimetic effects but with a broad-spectrum pharmacological activity. Because of its pharmacological profile and its ability to counteract the psychoactive Δ9-tetrahydrocannabinol (Δ9THC), CBD may be a potential treatment for several psychiatric and neurodegenerative disorders. In this study, we performed a dose-response evaluation of CBD modulatory effects on BDNF, a neurotrophin subserving pleiotropic effects on the brain, focusing on the cortico-striatal pathway for its unique role in the brain trafficking of BDNF. Male adult rats were exposed to single and repeated CBD treatments at different dosing regimen (5, 15, and 30 mg/kg), to investigate the rapid modulation of the neurotrophin (1 h after the single treatment) as well as a potential drug-free time point (24 h after the repeated treatment). We show here, for the first time, that CBD can be found in the rat brain and, specifically, in the medial prefrontal cortex (mPFC) following single or repeated exposure. In fact, we found that CBD is present in the mPFC of rats treated either acutely or repeatedly with the phytocannabinoid, with a clear dose-response profile. From a molecular standpoint, we found that single, but not repeated, CBD exposure upregulates BDNF in the mPFC, while the repeated exposure increased BDNF only in the striatum, with a slight decrease in the mPFC. Together, these data reveal a CBD dose-dependent and anatomically specific modulation of BDNF, which may be functionally relevant and may represent an added value for CBD as a supplement.

Unveiling the Ability of Witch Hazel (Hamamelis virginiana L.) Bark Extract to Impair Keratinocyte Inflammatory Cascade Typical of Atopic Eczema.

Hamamelis virginiana L. bark extract is a traditional remedy for skin affections, including atopic dermatitis/eczema (AD). Hamamelis preparations contain tannins, including hamamelitannin (HT), although their pharmacological role in AD is still unknown. This study aimed to study the rational for its topical use by considering the impact of crucial biomarkers on AD pathogenesis. A standardized extract (HVE) (0.5−125 µg/mL) was compared to hamamelitannin (HT), its main compound (0.5−5 µg/mL), in a model of human keratinocytes (HaCaTs), challenged with an AD-like cytokine milieu (TNF-α, IFN-γ, and IL-4). HVE inhibited the release of mediators involved in skin autoimmunity (IL-6 and IL-17C) and allergy (TSLP, IL-6, CCL26, and MMP-9) with a concentration-dependent fashion (IC50s < 25 µg/mL). The biological mechanism was ascribed, at least in part, to the impairment of the NF-κB-driven transcription. Moreover, HVE counteracted the proliferative effects of IL-4 and recovered K10, a marker of skin differentiation. Notably, HT showed activity on well-known targets of IL-4 pathway (CCL26, K10, cell proliferation). To the best of our knowledge, this work represents the first demonstration of the potential role of Hamamelis virginiana in the control of AD symptoms, such as itch and skin barrier impairment, supporting the relevance of the whole phytocomplex.

Anti-Inflammatory and Anti-Acne Effects of Hamamelis virginiana Bark in Human Keratinocytes.

Cutibacterium acnes (C. acnes) is recognized as one of the main triggers of the cutaneous inflammatory response in acne vulgaris, a chronic skin disorder with a multifactorial origin. Witch hazel (Hamamelis virginiana L.) is a plant widely used for skin inflammatory conditions, with some preliminary anti-inflammatory evidence on the skin, but lacking data on acne conditions. This study aimed to evaluate the effect of a glycolic extract from Hamamelis virginiana bark (HVE) versus C. acnes-induced inflammation in human keratinocytes (HaCaT). Phytochemical investigations of HVE identified hamamelitannin (HT) and proanthocyanidins as the most abundant compounds (respectively, 0.29% and 0.30% w/wextract). HVE inhibited C. acnes-induced IL-6 release (IC50: 136.90 µg/mL), by partially impairing NF-κB activation; however, no antibacterial or antibiofilm activities were found. In addition, HVE showed greater anti-inflammatory activity when TNF-α was used as a proinflammatory stimulus (IC50 of 38.93 µg/mL for IL-8 release), partially acting by antioxidant mechanisms, as shown for VEGF inhibition. The effects of HVE are primarily based on the proanthocyanidin content, as HT was found inactive on all the parameters tested. These results suggest further investigations of HVE in other inflammatory-based skin diseases.