Search Results (437)

Flavonoids are naturally occurring polyphenolic compounds known for their extensive range of biological activities. This review focuses on the inhibitory effects of flavonoids on acetylcholinesterase (AChE) and their potential as therapeutic agents for cognitive dysfunction. AChE, a serine hydrolase that plays a crucial role in cholinergic neurotransmission, is a key target in the treatment of cognitive impairments due to its function in acetylcholine hydrolysis. Natural polyphenolic compounds, particularly flavonoids, have demonstrated significant inhibition of AChE, positioning them as promising alternatives or adjuncts in neuropharmacology. This study specifically examines flavonoids such as quercetin, apigenin, kaempferol, and naringenin, investigating their inhibitory efficacy, binding mechanisms, and additional neuroprotective properties, including their antioxidant and anti-inflammatory effects. In vitro, in vivo, and in silico analyses reveal that these flavonoids effectively interact with both the active and peripheral anionic sites of AChE, resulting in increased acetylcholine levels and the stabilization of cholinergic signaling. Their mechanisms of action extend beyond mere enzymatic inhibition, as they also exhibit antioxidant and anti-amyloidogenic properties, thereby offering a multifaceted approach to neuroprotection. Given these findings, flavonoids hold considerable therapeutic potential as modulators of AChE, with implications for enhancing cognitive function and treating neurodegenerative diseases. Future studies should prioritize the enhancement of flavonoid bioavailability, evaluate their efficacy in clinical settings, and explore their potential synergistic effects when combined with established therapies to fully harness their potential as neurotherapeutic agents. Full article

Green chemistry focuses on reducing the environmental impacts of chemicals through sustainable practices. Traditional methods for extracting bioactive compounds from Eucalyptus marginata leaves, such as hydro-distillation and organic solvent extraction, have limitations, including long extraction times, high energy consumption, and potential toxic solvent residues. This study explored the use of supercritical fluid extraction (SFE), pressurized liquid extraction (PLE), and gas-expanded liquid (GXL) processes to improve efficiency and selectivity. These techniques were combined in a single mixture design, where CO₂ was used in the experiments carried out under SFE, while water and ethanol were used for the PLE and GXL experiments by varying the concentration of the solvents to cover all the extraction possibilities. The neuroprotective activity of the extracts was evaluated by measuring their antioxidant, anti-inflammatory, and acetylcholinesterase inhibition properties. The optimization resulted in a novel GXL extraction with an optimal ternary mixture of 27% CO₂, 55% ethanol, and 18% water, with a high degree of desirability (R² = 88.59%). Chromatographic analysis carried out by GC-MS and HPLC-ESI-MS/MS identified over 49 metabolites. The designed sustainable extraction process offers a promising approach for producing phenolic-rich plant extracts in industrial applications. Full article

Rhamnus formosana is a creeping evergreen shrub endemic to Taiwan. In traditional medicine, Rhamnaceae plants are used as herbal remedies for conditions such as itching, difficulty urinating, and constipation. This study explores the inhibitory effects of various solvent extracts and bioactive components of R. formosana on α-glucosidase, tyrosinase, acetylcholinesterase (AChE), and antioxidant activity. The 100 °C water extract exhibited strong antioxidant activity in DPPH, ABTS, superoxide, and FRAP assays. The methanol extract demonstrated the highest α-glucosidase inhibitory effect, while the ethanol extract displayed potent AChE inhibition and the acetone extract showed the most potential tyrosinase inhibitory activity among the extracts. Five main biocomponents were isolated and evaluated for their bioactivities. Among them, kaempferol (1) and quercetin (2) exhibited notable antioxidant activity in DPPH and ABTS assays. Particularly, kaempferol (1) performed the best α-glucosidase inhibitory effect, physcion (5) showed the strongest AChE inhibition, and quercetin (2) demonstrated the most potential for tyrosinase inhibitory activity. Further molecular docking studies revealed that there may be stronger binding mechanisms between bioactive components and target enzymes (including α-glucosidase, acetylcholinesterase, and tyrosinase) than the positive control. These findings suggest that bioactive extracts and compounds from the stems of R. formosana may have potential as natural antioxidant, anti-α-glucosidase, anti-AChE, and anti-tyrosinase drug candidates or dietary supplements for the management of oxidative stress-related conditions, including hyperglycemia, pigmentation disorders, and neurodegenerative diseases. Full article

Background: Elettaria cardamomum (Cardamom) and Foeniculum vulgare (Fennel) are well-known spices and are also used as natural mouth fresheners. This study was performed to evaluate their neuroprotective ability based on certain acellular and cellular assays. Methods: Hexane and ethyl acetate extracts were prepared using cardamom and fennel seeds. GC/MS was performed for the identification of important bioactive compounds. Cell-based assays were performed using SH-SY5Y cells. Hydrogen peroxide was used for the induction of oxidative stress, and evaluation was done based on neuroprotection, reduced reactive oxygen species, and restoration of mitochondrial membrane potential (MMP). Additionally, anti-Aβ fibrillization/oligomerization activities were also analyzed along with anti-acetylcholinesterase activity. Results: α-Terpinyl acetate and anethol were identified as major phytocompounds in cardamom and fennel, respectively. Cardamom extracts and α-terpinyl acetate were more potent acetylcholinesterase (AChE) inhibitors than fennel extracts and anethol [IC₅₀ cardamom extracts, 130–150 μg/mL; α-terpinyl acetate, 61.87 μg/mL; anethol, 374.2 μg/mL; fennel extracts, >1 mg/mL] and showed mixed-type inhibition. Only the extracts displayed potent anti-Aβ fibrilization activity (>50%). Anethol showed potent anti-Aβ oligomerization activity (>50%), followed by α-terpinyl acetate and fennel-H (~36%). The neuroprotective potential of the spice extracts/phytochemicals was evaluated in SH-SY5Y cells by using H₂O₂-induced oxidative stress. Cardamom-EA displayed the best neuroprotection (0.01 to 30 μg/mL). No neuroprotection was observed by α-terpinyl acetate and anethol. Cardamom extracts and fennel-H restored the normal reactive oxygen species (ROS) levels at 30 µg/mL and 1 µg/mL, respectively. Conclusion: Overall, the extracts provided better neuroprotection than the pure compounds in cellular assays and displayed strong anti-Aβ fibrilization activity. Full article

Hops (Humulus lupulus L.) are widely recognized for their use in brewing, but they also possess significant pharmacological properties due to their rich bioactive compounds, with many varieties exhibiting diverse characteristics. This study investigates the chemical composition and biological activities of extracts from six hop varieties, focusing on quantifying xanthohumol and lupulone using High-Performance Liquid Chromatography (HPLC) and Total Phenolic Content (TPC) analysis. The hop varieties demonstrated significant variability in bioactive compound concentrations, with Aurora showing the highest xanthohumol (0.665 mg/g) and Zwiegniowski the highest lupulone (9.228 mg/g). TPC analysis revealed Aurora also had the highest phenolic content (22.47 mg GAE/g). Antioxidant activities were evaluated using DPPH, ABTS, CUPRAC, and FRAP assays, with Aurora and Oregon Fuggle displaying the most potent capacities. Aurora, in particular, showed the highest activity across multiple assays, including significant acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and tyrosinase inhibition, with IC₅₀ values of 24.39 mg/mL, 20.38 mg/mL, and 9.37 mg/mL, respectively. The chelating activity was also assessed, with Apolon demonstrating the strongest metal ion binding capacity (IC₅₀ = 1.04 mg/mL). Additionally, Aurora exhibited the most effective hyaluronidase inhibition (IC₅₀ = 10.27 mg/mL), highlighting its potential for anti-inflammatory applications. The results underscore the influence of genetic and environmental factors on the bioactive compound profiles of hop varieties and their biological activity offering promising avenues for pharmaceutical and nutraceutical applications. However, further studies are needed to fully understand the potential interactions between hop cones components. Full article

Waltheria, a genus within the Malvaceae family, is abundantly distributed in tropical and subtropical areas worldwide. Many species of this genus are widely utilized in various ways, including chewing, in folk medicine, acting as an anti-inflammatory agent, and treating gastrointestinal disorders, rheumatism, and asthma, among other conditions. These applications are largely due to their secondary metabolites, primarily quinolone alkaloids and cyclopeptides. Several biological activities have been reported for Waltheria species, including antifungal, anticancer, trypanocidal, acetylcholinesterase inhibitory, potential anti-HIV, antinociceptive, analgesic, anti-inflammatory, antibacterial, antioxidant, and leishmanicidal activities. This review not only presents information on isolated alkaloids and their biological activities but also delves into biosynthetic, chemosystematic, medicinal chemistry, and total synthesis aspects. Additionally, the manuscript highlights other applications of alkaloids of the genus, such as a study on their herbicidal activity, which shows significant potential for agricultural use. Full article

Capsella bursa-pastoris (L.) Medik. (shepherd’s purse) is a medicinal plant recently introduced to European Pharmacopoeia. The main active compounds responsible for the activity profile of the raw material are flavonoids, phenolic acids, amino acids, phytosterols, vitamins and bioelements. This species is known for its properties supporting the functioning of the digestive system and antihemorrhagic properties in the ethnomedicine of Far Eastern countries. Modern research confirms these directions of activity. Additionally, the latest studies prove the anti-inflammatory, antioxidant, antibacterial, antifungal, acetylcholinesterase and anticancer properties and supportive action in the treatment of gynecological diseases. Shepherd’s purse herb also has a strong position as an edible plant due to the growing interest in this plant as “healthy food”. The protective, softening, antibacterial and antioxidant properties of sprout and herb extracts are useful in the production of modern cosmetics. Moreover, C. bursa-pastoris is valuable thanks to phytoremediation properties and the numerous practical uses in biotechnology for the creation of new resistant varieties of crop plants from the Brassicaceae family. Full article

Cholinesterases are enzymes that break down the neurotransmitter acetylcholine in the nervous system. The two main types are acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). AChE inhibitors are used to treat Alzheimer’s disease by increasing acetylcholine levels. BChE activity increases in later stages of Alzheimer’s, suggesting it might contribute to the disease. In previous experiments, it was found that a newly designed hybrid of galantamine (GAL) and curcumin (CCN) (compound 4b) decreases the activity of BChE in murine brain homogenates. Here, we explore this observation using molecular dynamics simulations. GAL and CCN were also studied for comparison. The structures of the complexes between the BChE and the ligands were predicted by molecular docking. Then, molecular dynamics simulations were performed to evaluate the stability of the complexes and the interactions between the ligands and the enzyme over a simulated time of 1 μs. All three ligands formed stable complexes with BChE. Compound 4b formed more hydrogen bonds and other interactions with BChE compared to GAL and CCN, suggesting a stronger binding affinity. The stronger binding of 4b to BChE might explain its superior anti-BChE activity observed in previous experiments. Full article

Numerous experimental studies suggest the potential for resveratrol (RVT) to be useful in the Alzheimer’s disease treatment, but its low bioavailability limits its application. This study aimed to assess the potential of resveratrol-loaded micelles as a neuronal delivery platform to protect rats from scopolamine-induced memory impairment. Resveratrol was incorporated into Pluronic micelles, and the effects of micellar (mRVT) and pure resveratrol (RVT) were compared in the model of scopolamine-induced dementia in male Wistar rats. Memory performance was assessed by a T maze test. The effect of the treatment on specific neurotransmitter levels and protein expression in the cortex and the hippocampus were evaluated biochemically. Our results revealed that the polymeric micelles were in nanoscale (approximately 33 nm) and reached 79% encapsulation efficiency. The treatment with mRVT demonstrated better spatial memory protective effect. The biochemical assays showed that mRVT in a dose of 10 mg/kg enhanced the effects of the pure drug in regard to noradrenalin neurotransmission and acetylcholinesterase inhibitory activity in the hippocampus. Furthermore, micellar resveratrol increased the cAMP-response element-binding protein expression in the cortex and hippocampus of rats as well as the Bcl2/BAX ratio, which indicated an anti-apoptotic effect in the experimental dementia model. In conclusion, our results indicated the potential of a micellar system loaded with resveratrol for neurodegenerative diseases treatment. Full article

Background: Curcuminoids, the bioactive compounds found in turmeric, exhibit potent antioxidant, anti-inflammatory, and neuroprotective properties. This study aims to enhance the extraction of curcuminoids from turmeric using environmentally friendly solvents supercritical CO₂ (scCO₂) combined with natural deep eutectic solvents (NADESs) in one process, and to evaluate the resulting biological activity. Methods: A Box–Behnken statistical design was applied to optimize scCO₂ extraction conditions—pressure, CO₂ volume, and temperature—to maximize curcuminoid yield. Next, the menthol and lactic acid NADESs were selected, and these two solvents were combined into a single turmeric extraction process. The biological activity of the resulting extract was evaluated using antioxidant assays (ferric reducing antioxidant power and 2,2-diphenyl-1-picrylhydrazyl) and enzyme inhibition assays (acetylcholinesterase, butyrylcholinesterase, and tyrosinase). Toxicity assessments were conducted on the aquatic invertebrates Daphnia pulex, Artemia sp., and Chironomus aprilinus. Results: The most effective extraction was achieved using a menthol–lactic acid NADES as a cosolvent, integrated at a 1:20 ratio of plant material to NADESs while in combination with scCO₂. The optimized scCO₂–NADES extraction resulted in a high curcuminoid yield (33.35 mg/g), outperforming scCO₂ extraction (234.3 μg/g), NADESs ultrasound-assisted extraction (30.50 mg/g), and alcohol-based solvents (22.95–26.42 mg/g). In biological assays, the extract demonstrated significant antioxidant activity and effective inhibition of enzymes (acetylcholinesterase, butyrylcholinesterase, and tyrosinase). Toxicity studies showed a concentration-dependent response, with EC₅₀ for Chironomus aprilinus at the level of 0.098 μL/mL and Daphnia pulex exhibiting high sensitivity to the extract. Conclusions: This study highlights the potential of combining NADESs and scCO₂ extraction in one process, demonstrating the effectiveness of scCO₂–NADES extraction in maximizing curcuminoid yield and enhancing bioactivity. Full article

Alzheimer’s disease (AD) is a complex/multifactorial brain disorder involving hundreds of defective genes, epigenetic aberrations, cerebrovascular alterations, and environmental risk factors. The onset of the neurodegenerative process is triggered decades before the first symptoms appear, probably due to a combination of genomic and epigenetic phenomena. Therefore, the primary objective of any effective treatment is to intercept the disease process in its presymptomatic phases. Since the approval of acetylcholinesterase inhibitors (Tacrine, Donepezil, Rivastigmine, Galantamine) and Memantine, between 1993 and 2003, no new drug was approved by the FDA until the advent of immunotherapy with Aducanumab in 2021 and Lecanemab in 2023. Over the past decade, more than 10,000 new compounds with potential action on some pathogenic components of AD have been tested. The limitations of these anti-AD treatments have stimulated the search for multi-target (MT) drugs. In recent years, more than 1000 drugs with potential MT function have been studied in AD models. MT drugs aim to address the complex and multifactorial nature of the disease. This approach has the potential to offer more comprehensive benefits than single-target therapies, which may be limited in their effectiveness due to the intricate pathology of AD. A strategy still unexplored is the combination of epigenetic drugs with MT agents. Another option could be biotechnological products with pleiotropic action, among which nosustrophine-like compounds could represent an attractive, although not definitive, example. Full article

Background/Objectives: Diabetes mellitus (DM), a widespread endocrine disorder characterized by chronic hyperglycemia, can cause nerve damage and increase the risk of neurodegenerative diseases such as Alzheimer’s disease (AD). Effective blood glucose management is essential, and sitagliptin (SITG), a dipeptidyl peptidase-4 (DPP-4) inhibitor, may offer neuroprotective benefits in type 2 diabetes mellitus (T2DM). Methods: T2DM was induced in rats using nicotinamide (NICO) and streptozotocin (STZ), and biomarkers of AD and DM-linked enzymes, inflammation, oxidative stress, and apoptosis were evaluated in the brain. Computational studies supported the in vivo findings. Results: SITG significantly reduced the brain enzyme levels of acetylcholinesterase (AChE), beta-secretase-1 (BACE-1), DPP-4, and glycogen synthase kinase-3β (GSK-3β) in T2DM-induced rats. It also reduced inflammation by lowering cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB). Additionally, SITG improved oxidative stress markers by reducing malondialdehyde (MDA) and enhancing glutathione (GSH). It increased anti-apoptotic B-cell lymphoma protein-2 (Bcl-2) while reducing pro-apoptotic markers such as Bcl-2-associated X (BAX) and Caspace-3. SITG also lowered blood glucose levels and improved plasma insulin levels. To explore potential molecular level mechanisms, docking was performed on AChE, COX-2, GSK-3β, BACE-1, and Caspace-3. The potential binding affinity of SITG for the above-mentioned target enzymes were 10.8, 8.0, 9.7, 7.7, and 7.9 kcal/mol, respectively, comparable to co-crystallized ligands. Further binding mode analysis of the lowest energy conformation revealed interactions with the critical residues. Conclusions: These findings highlight SITG’s neuroprotective molecular targets in T2DM-associated neurodegeneration and its potential as a therapeutic approach for AD, warranting further clinical investigations. Full article

V-type nerve agents are exceedingly toxic chemical warfare agents that irreversibly inhibit acetylcholinesterase (AChE), leading to acetylcholine accumulation in synapses and the disruption of neurotransmission. VG or O.O-diethyl S-(diethylamino)ethyl phosphorothiolate was the first compound of this class that was synthesized. The selenocholines (-Se-), cholines (-O-), and methylene-cholines (-CH₂-) analogs of V-agents have been synthesized and their anti-AChE activities reported. Nevertheless, the aminocholine derivatives have not been pursued. Here, we have designed and synthesized a series of phosphorylated aminocholines analogs of VG that were characterized by NMR spectroscopy (H1, C13, P31, and TOCSY). Their pharmacological properties were analyzed in silico, while their toxicological properties were in vitro investigated using the SH-SY5Y cellular model. Despite the drug likeness of the new compounds, these fail to inhibit AChE in vitro and in cellulo. This may be partially explained by the fact that aminocholine is not a good leaving group compared to thiocholine. Remarkably, one of the compounds (P4) was found to even increase the activity of AChE. These compounds may serve as new nerve agent mimics that are safer alternatives for testing countermeasures. Importantly, P4 may act as a lead compound for developing a new class of alternative nerve agent pretreatments that are safer from pyridostigmine. Full article

The Azorean Cryptomeria japonica forest operations and wood industry generate considerable foliage biomass residues that are used for local essential oil (EO) production. However, research on seasonal variation of C. japonica EO remains scarce. In this study, the EOs from fresh Azorean C. japonica foliage (Az–CJF) collected in autumn (Aut) and spring (Spr) were obtained via hydrodistillation and investigated for their physical properties, yield, chemical composition, and bioactivities. Both EOs presented a strong odor, a yellowish color, a density around 0.9 g·mL⁻¹, and similar yields (approximately 1% v/w, dry matter). Nevertheless, the GC–MS analyses showed a decrease in monoterpene hydrocarbons (MH) and an increase in oxygenated sesquiterpenes (OS) contents in Spr–EO compared with Aut–EO (16% vs. 35% for MH and 45% vs. 31% for OS, respectively). In addition, the predominant components were kaur-16-ene (23%) for Spr–EO and phyllocladene (19%) for Aut–EO, revealing that both EOs were rich in diterpene hydrocarbons (29% vs. 26%). Concerning its toxicity against brine shrimp, a low mortality (0–38%) was observed at a concentration range of 100–180 μg·mL⁻¹. Regarding the anti-cholinesterase properties, both EOs were inactive against acetylcholinesterase but showed anti-butyrylcholinesterase activity superior to (–)-α-pinene, a major compound of Az–CJF EO (IC₅₀ values: 84, 148, and 648 μg·mL⁻¹ for Spr–EO, Aut–EO, and α-pinene, respectively). Overall, the results indicate the potential benefit of both seasonal EOs in Alzheimer’s disease treatment. In conclusion, this study demonstrated that season strongly influences the Az–CJF EO quantitative composition and thus its bioactivity, aiding in the selection of the most high-quality raw materials for use in Azorean C. japonica EO aromatherapy industry. Full article

The therapeutic potential of plant extracts has attracted significant interest, especially regarding indigenous species with health-promoting properties. Gymnema inodorum, native to Northern Thailand, is recognized for its rich phytochemical profile; however, the impact of various extraction techniques on its phenolic composition and bioactivity remains underexplored. Optimizing extraction methods is essential to enhance the pharmacological efficacy of this plant’s bioactive compounds. This study investigated the influence of four extraction methods—ethanol maceration, ethanol reflux, aqueous decoction, and microwave-assisted extraction—on the bioactive profile of G. inodorum leaves, with a focus on the phenolic content and biological activities. Antioxidant activities were evaluated using DPPH, ABTS, and FRAP assays, while the total phenolic and flavonoid contents were quantified by colorimetric methods. High-Performance Liquid Chromatography (HPLC) quantified gymnemic acid and key phenolic compounds. Among the methods, ethanol reflux yielded the highest antioxidant activities (DPPH and ABTS scavenging), with a total phenolic content of 82.54 mg GAE/g and flavonoid content of 31.90 mg QE/g. HPLC analysis identified sinapic acid, myricetin, and p-hydroxybenzoic acid as major phenolics. Furthermore, the ethanol reflux extract displayed potent anti-diabetic activity, with IC₅₀ values of 13.36 mg/mL for α-amylase and 7.39 mg/mL for α-glucosidase, as well as strong anti-inflammatory activity (IC₅₀ of 1.6 mg/mL) and acetylcholinesterase inhibition (IC₅₀ of 1.2 mg/mL). These findings suggest that ethanol reflux extraction is a highly effective method for producing bioactive-rich G. inodorum extracts, with substantial pharmacological potential for developing herbal remedies and nutraceuticals, particularly in enhancing therapeutic approaches for diabetes and other health-related conditions. Full article