Marrubium vulgare Extract Improves Spatial Working Memory and Oxidative Stress Damage in Scopolamine-Treated Rats.

Background: The cholinergic neuronal loss in the basal forebrain and increasing brain oxidative stress are one of the main features of the brain suffering from Alzheimer's disease. Marrubium vulgare (M. vulgare), commonly known as 'white horehound,' possesses a variety of valuable properties, such as antioxidative, anti-inflammatory, and antidiabetic activities. Moreover, it possesses neuromodulatory properties that could potentially impact short-term memory functions. Objective: The present study was undertaken to investigate the preventive effects of water M. vulgare extract on working memory, cholinergic neurotransmission, and oxidative stress in rats with scopolamine (Sco)-induced dementia. Methods: Male Wistar rats (200-250 g) were divided into four experimental groups. The plant extract was administered orally for 21 days, and Sco (2 mg/kg) was administered intraperitoneally for 11 consecutive days. The behavioral performance of the animals was evaluated by the T-maze test. The effect of the extract on acetylcholinesterase (AChE) activity and antioxidant status in cortex and hippocampus were also monitored. Results: Our experimental data revealed that treatment with M. vulgare significantly increased the percentage of correct choices of rats with Sco-induced dementia in the T maze test (by 38%, p < 0.05). Additionally, it reduced AChE activity in the hippocampus (by 20%, p < 0.05) and alleviated oxidative stress induced by Sco, particularly in the cortex. Conclusions: M. vulgare water extract demonstrated working memory preserving effect in rats with Sco-induced dementia, AChE inhibitory activity and in vivo antioxidant potential, and deserve further attention.

Extracts of Sideritis scardica and Clinopodium vulgare Alleviate Cognitive Impairments in Scopolamine-Induced Rat Dementia.

Sideritis scardica Griseb. and Clinopodium vulgare L., belonging to the Lamiaceae family, are rich in terpenoids and phenolics and exhibit various pharmacological effects, including antioxidant, anti-inflammatory and anti-cancer activities. While the memory-enhancing impacts of S. scardica are well documented, the cognitive benefits of C. vulgare remain unexplored. This study assessed the potential effect of C. vulgare on learning and memory in healthy and scopolamine (Sco)-induced memory-impaired male Wistar rats, comparing it with the effects of S. scardica. Over a 21-day period, rats orally received extracts of cultivated S. scardica (200 mg/kg) and C. vulgare (100 mg/kg), either individually or in combination, with administration starting 10 days before and continuing 11 days simultaneously with Sco injection at a dose of 2 mg/kg intraperitoneally. The results showed that both extracts effectively mitigated Sco-induced memory impairment. Their combination significantly improved recognition memory and maintained monoaminergic function. S. scardica excelled in preserving spatial working memory, while C. vulgare exhibited comparable retention of recognition memory, robust antioxidant activity and acetylcholinesterase inhibitory activity. The extracts alleviated Sco-induced downregulation of p-CREB/BDNF signaling, suggesting neuroprotective mechanisms. The extract combination positively affected most of the Sco-induced impairments, underscoring the potential for further investigation of these extracts for therapeutic development.

Memory Recovery Effect of a New Bioactive Innovative Combination in Rats with Experimental Dementia.

Alzheimer's disease manifests as a complex pathological condition, with neuroinflammation, oxidative stress and cholinergic dysfunction being a few of the many pathological changes. Due to the complexity of the disease, current therapeutic strategies aim at a multitargeted approach, often relying on a combination of substances with versatile and complementary effects. In the present study, a unique combination of α-lipoic acid, citicoline, extracts of leaves from olive tree and green tea, vitamin D3, selenium and an immune-supporting complex was tested in scopolamine-induced dementia in rats. Using behavioral and biochemical methods, we assessed the effects of the combination on learning and memory, and elucidated the mechanisms of these effects. Our results showed that, compared to its components, the experimental combination was most efficient in improving short- and long-term memory as assessed by the step-through method as well as spatial memory as assessed by T-maze and Barnes maze underlined by decreases in AChE activity (p < 0.05) and LPO (p < 0.001), increases in SOD activity in the cortex (p < 0.05) and increases in catalase (p < 0.05) and GPx (p < 0.01) activities and BDNF (p < 0.001) and pCREB (p < 0.05) levels in the hippocampus. No significant histopathological changes or blood parameter changes were detected, making the experimental combination an effective and safe candidate in a multitargeted treatment of AD.

Remdesivir-Loaded Nanoliposomes Stabilized by Chitosan/Hyaluronic Acid Film with a Potential Application in the Treatment of Coronavirus Infection.

An object of the present study was the development of liposomes loaded with the medicine Veklury® (remdesivir) stabilized by electrostatic adsorption of polysaccharide film formed from chitosans with different physicochemical characteristics and hyaluronic acid. The functionalization of the structures was achieved through the inclusion of an aptamer (oligonucleotide sequence) with specific affinity to the spike protein of the human coronavirus HCoV-OC43. The hydrodynamic size, electrokinetic potential and stability of the structures were evaluated at each step in the procedure. The encapsulation efficiency and loaded amount of remdesivir (99% and 299 µg/mL) were estimated by UV-vis spectroscopy. Our investigations showed manifestation of promising tendencies for prolonged periods of the drug release and increased effectiveness of its antiviral action. Among all studied versions of the delivery system, the most distinguished and suitable in a model coronavirus therapy are the liposomes formed from chitosan oligosaccharides. The cytotoxicity of the liposomes was determined against the HCT-8 cell line. A cytopathic effect inhibition test was used for the assessment of the antiviral activity of the compounds. The virucidal activity and the effect on the viral adsorption of the samples were reported by the end-point dilution method, and the alteration in viral titer was determined as Δlgs compared to untreated controls. The redox-modulating properties of the nanoparticles were studied in vitro in certain/several/a few chemical model systems. Our investigations showed a manifestation of promising tendencies for a prolonged effect of the drug release and increased effectiveness of its antiviral action.

Improvement of diluted semen from Muscovy (Cairina moschata) drakes by the addition of water-soluble antioxidants.

The aim of this study was to evaluate the effect of antioxidant supplementation in diluted semen from Muscovy drakes after the induction of oxidative stress (OS) on the sperm motility, kinematic parameters and biochemical markers - lipid peroxidation (LPO) levels and total glutathione (tGSH) concentration. The pooled semen was distributed equally into three parts, diluted (1:3 v/v) with IMV Canadyl, HIA-1 or AU, and stored at 4°C for 6 h. Later, the semen was equilibrated at 20-25°C for 15 min, and divided in Eppendorf tubes. The sperm samples (final concentration of 50 × 106 sperm cells/mL per sample) were incubated at 37°C for 30 min in the absence (-) or presence (+) of 0.1 mM FeSO4 + 0.5 mM H2 O2 (Fenton system) and the following combinations of antioxidants: ascorbic acid + Trolox (A + T); ascorbic acid + Desferal (A + D); Trolox + Desferal (T + D) and ascorbic acid + Trolox + Desferal (A + T + D), all of them in a final concentration of 0.1 mM. Thus, the total number of samples was 30 and in each one, the sperm motility, velocity parameters, LPO and tGSH were determined. The motility and kinematic parameters of the diluted semen with added antioxidants were restored by up to 20% after inducing OS via the Fenton reaction. Dual combinations of antioxidants (A + T, A + D, and T + D) lowered LPO levels, but not equally across different extenders. After the induction of OS, the tGSH levels in diluted semen with IMV-Canadyl were not affected by the added antioxidants. Whereas antioxidant combinations in diluted semen with HIA-1 or AU had a beneficial effect and partially restored tGSH levels. In conclusion, the results showed that the extender IMV-Canadyl is well balanced and protected the Muscovy semen under OS conditions, while the other two extenders HIA-1 and AU can be improved by adding antioxidants.

Evaluation of Acute and Sub-Acute Toxicity, Oxidative Stress and Molecular Docking of Two Nitrofuranyl Amides as Promising Anti-Tuberculosis Agents.

Tuberculosis (TB) remains a widespread infectious disease and one of the top 10 causes of death worldwide. Nevertheless, despite significant advances in the development of new drugs against tuberculosis, many therapies and preventive measures do not lead to the expected favorable health results for various reasons. The aim of this study was to evaluate the acute and sub-acute toxicity and oxidative stress of two selected nitrofuranyl amides with high in vitro antimycobacterial activity. In addition, molecular docking studies were performed on both compounds to elucidate the possibilities for further development of new anti-tuberculosis candidates with improved efficacy, selectivity, and pharmacological parameters. Acute toxicity tests showed that no changes were observed in the skin, coat, eyes, mucous membranes, secretions, and vegetative activity in mice. The histological findings include features consistent with normal histological architecture without being associated with concomitant pathological conditions. The observed oxidative stress markers indicated that the studied compounds disturbed the oxidative balance in the mouse liver. Based on the molecular docking, compound DO-190 showed preferable binding energies compared to DO-209 in three out of four targets, while both compounds showed promising protein-ligand interactions. Thus, both studied compounds displayed promising activity with low toxicity and can be considered for further evaluation and/or lead optimization.

Effects of Sideritis scardica Extract on Scopolamine-Induced Learning and Memory Impairment in Mice.

BACKGROUND: The neurodegenerative process in Alzheimer's disease, one of the most common types of dementia worldwide, mostly affects the cholinergic neurotransmitter system and, to a lesser extent, the monoaminergic one. The antioxidant acetylcholinesterase (AChE) and triple monoamine reuptake inhibitory activity of Sideritis scardica (S. scardica) and other Sideritis species has already been reported. OBJECTIVE: To investigate the effects of S. scardica water extracts on the learning and memory processes, anxiety-like behavior, and locomotor activities in scopolamine (Sco)-induced dementia in mice. METHODS: Male Albino IRC mice were used. The plant extract was administered for 11 consecutive days in the presence or absence of Sco (1 mg/kg, i.p). The behavioural performance of the animals was evaluated by passive avoidance, T-maze, and hole-board tests. The effects of extract on AChE activity, brain noradrenalin (NA), and serotonin (Sero) content, and antioxidant status were also monitored. RESULTS: Our experimental data revealed that the S. scardica water extract caused a reduction in degree of memory impairment and anxiety-like behaviour in mice with scopolamine-induced dementia. The extract did not affect changed by the Sco AChE activity but impact reduced brain NA and Sero levels and demonstrated moderate antioxidant activity. In healthy mice we did not confirm the presence of anxiolytic-like and AChE inhibitory effects of the S. scardica water extract. The extract did not change the control Sero brain levels and reduce those of NA. CONCLUSION: S. scardica water extract demonstrated memory preserving effect in mice with scopolamine-induced dementia and deserve further attention.

Effect of Chitosan-Diosgenin Combination on Wound Healing.

The difficult-to-heal wounds continue to be a problem for modern medicine. Chitosan and diosgenin possess anti-inflammatory and antioxidant effects making them relevant substances for wound treatment. That is why this work aimed to study the effect of the combined application of chitosan and diosgenin on a mouse skin wound model. For the purpose, wounds (6 mm diameter) were made on mice's backs and were treated for 9 days with one of the following: 50% ethanol (control), polyethylene glycol (PEG) in 50% ethanol, chitosan and PEG in 50% ethanol (Chs), diosgenin and PEG in 50% ethanol (Dg) and chitosan, diosgenin and PEG in 50% ethanol (ChsDg). Before the first treatment and on the 3rd, 6th and 9th days, the wounds were photographed and their area was determined. On the 9th day, animals were euthanized and wounds' tissues were excised for histological analysis. In addition, the lipid peroxidation (LPO), protein oxidation (POx) and total glutathione (tGSH) levels were measured. The results showed that ChsDg had the most pronounced overall effect on wound area reduction, followed by Chs and PEG. Moreover, the application of ChsDg maintained high levels of tGSH in wound tissues, compared to other substances. It was shown that all tested substances, except ethanol, reduced POx comparable to intact skin levels. Therefore, the combined application of chitosan and diosgenin is a very promising and effective medication for wound healing.

Changes in the Oxidative Status of Dual-Purpose Hens Rearing in the Free-Range System during Cold, Thermoneutral and Hot Period.

This study aimed to assess the changes in the oxidative status of six genotypes of free-range laying hens during cold, thermoneutral, and hot periods by measuring the levels of lipid peroxidation (LPO), total glutathione (tGSH), and the activity of antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in erythrocyte suspension, in relation with their egg production. Two identical experiments were conducted in two consecutive years. Thermal stress adversely affected the oxidative status of hens. The induced OS is expressed by an increase in LPO and the activities of antioxidant enzymes SOD and GPx during cold and hot periods and a decrease in CAT and tGSH during the cold period in both years. The factor "temperature period", compared to "year" and "genotype", had the most significant influence on all biochemical parameters (p < 0.001). Significant phenotypic correlations (p < 0.05) were detected among studied biochemical parameters, except between SOD and tGSH. The chicken genotypes showed differences in their susceptibility to OS and this had an effect on egg production­from 37.87% to 74.93%. The OS is genotypically specific and can play a significant role in determining welfare and egg production in free-range systems.

New Myrtenal-Adamantane Conjugates Alleviate Alzheimer's-Type Dementia in Rat Model.

Alzheimer's disease (AD) is a neurodegenerative disease associated with memory impairment and other central nervous system (CNS) symptoms. Two myrtenal-adamantane conjugates (MACs) showed excellent CNS potential against Alzheimer's models. Adamantane is a common pharmacophore for drug design, and myrtenal (M) demonstrated neuroprotective effects in our previous studies. The aim of this study is to evaluate the MACs' neuroprotective properties in dementia. METHODS: Scopolamine (Scop) was applied intraperitoneally in Wistar rats for 11 days, simultaneously with MACs or M as a referent, respectively. Brain acetylcholine esterase (AChE) activity, noradrenaline and serotonin levels, and oxidative brain status determination followed behavioral tests on memory abilities. Molecular descriptors and docking analyses for AChE activity center affinity were performed. RESULTS: M derivatives have favorable physicochemical parameters to enter the CNS. Both MACs restored memory damaged by Scop, showing significant AChE-inhibitory activity in the cortex, in contrast to M, supported by the modeling analysis. Moderate antioxidant properties were manifested by glutathione elevation and catalase activity modulation. MACs also altered noradrenaline and serotonin content in the hippocampus. CONCLUSION: For the first time, neuroprotective properties of two MACs in a rat dementia model were observed. They were stronger than the natural M effects, which makes the substances promising candidates for AD treatment.

Snail Mucus Protective Effect on Ethanol-Induced Gastric Ulcers in Mice.

Nowadays, an increased interest in natural compounds with preventive or therapeutic potential for various diseases has been observed. Given the involvement of oxidative stress in the pathogenesis of gastric ulcer (GU) and the wide range of bioactive compounds isolated from snails, this study aimed to investigate the protective effect of Cornu aspersum (Müller, 1774) mucus on ethanol-induced GUs. Male albino mice were divided into Control, Ethanol, Mucus + Ethanol and Mucus + Omeprazole treated groups. The GUs were induced by administration of 96% ethanol (10 mL/kg, per os). One hour before ulcer induction, the mice of Mucus + Ethanol group were pretreated with mucus (20 mg/kg, per os), and the mice of Mucus + Omeprazole group were pretreated with omeprazole (20 mg/kg, per os). Ethanol administration caused grave lesions of gastric mucosa and a significant decrease of glutathione (GSH) and superoxide dismutase (SOD), catalase, and glutathione reductase (GR) activities. In the animals with mucus or omeprazole pre-administration compared to the Ethanol group, the following were observed: only a small number of hemorrhagic fields, significantly reduced GU index with calculated 73% protection by mucus and 78% protection by omeprazole, and significant recovery of mucosal GSH and SOD and GR activities. In addition, the mucus inhibited Helicobacter pylori growth. Thus, the protective effect of C. aspersum mucus on both gastric mucosa and gastric antioxidant potential in ethanol-induced GU model suggests that it may serve as a good tool for prevention of this disease.

Anti-Coronavirus Efficiency and Redox-Modulating Capacity of Polyphenol-Rich Extracts from Traditional Bulgarian Medicinal Plants.

Background: The use of various herbal therapists as part of traditional medicine in different parts of the world, including Bulgaria, is due to the knowledge accumulated over the centuries by people about their valuable biological activities. In this study, we investigate extracts from widely used Bulgarian medicinal plants for their ability to prevent the coronavirus infection of cells by testing different mechanisms of antiviral protection, their polyphenol content, and redox-modulating capacity. Methods: The influence on the stage of viral adsorption, the inhibition of extracellular virions, and the protective effect on uninfected cells of the plant's extracts were reported by the end-point dilution method, and virus titer (in Δ lgs) was determined as compared to the untreated controls. The total content of polyphenols and flavonoids was also determined. We tested the antioxidant power of the extracts by their ability to inhibit the generation of superoxide anionic radicals and to scavenge DPPH radicals. We determined their iron-reducing, copper-reducing, and metal-chelating antioxidant powers. Results: Most of the extracts tested suppress the extracellular virions of HCov. They also inhibit the stage of viral adsorption to the host cell to varying degrees and have a protective effect on healthy cells before being subjected to viral invasion. The examined extracts contained significant levels of polyphenols and quercetin-like flavonoids and showed remarkable antioxidant, radical, and redox-modulating effects. Conclusions: All of these 13 extracts from Bulgarian medicinal plants tested can act as antioxidants and antiviral and symptomatic drugs for the management of coronavirus infection.

Chromatographic Profile and Redox-Modulating Capacity of Methanol Extract from Seeds of Ginkgo biloba L. Originating from Plovdiv Region in Bulgaria.

Oxidative stress underlies the pathogenesis of many diseases, which determines the interest in natural substances with antioxidant properties. Ginkgo biloba L. leaves are well known and widely used in the pharmaceutical industry, but the therapeutic properties of the seeds are less studied. This study aimed to identify the chromatographic profile and to evaluate the antioxidant properties of methanol extract from seeds of G. biloba (GBSE). In the GBSE, flavonoids and terpenes were found as terpenes predominated. The GBSE antioxidant capacity determined by 2,2 azino-bis (3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS) and 1-diphenyl-2-picrylhydrazyl (DPPH) methods were equal to 1.34% and 0.58% of the activity of reference substance Trolox, respectively. The results of the ferric reducing antioxidant power method showed that the effect of concentration 1 mg/mL (w/v) GBSE was equal to 7.418 mM FeSO4 used as a standard. The cupric reducing antioxidant capacity activity of the GBSE was found to be 215.39 µmol Trolox/g GBSE and is presented as Trolox equivalent. The metal chelation effect of 1 mg/mL (w/v) GBSE was equal to that obtained for 0.018 mM EDTA. In conclusion, GBSE showed a good ability to neutralize ABTS and DPPH radicals and could have a beneficial effect in pathological conditions with oxidative stress etiology.

In Vitro Study of the Biological Potential of Wastewater Obtained after the Distillation of Four Bulgarian Oil-Bearing Roses.

The wastewater after rose oil distillation is usually discharged into the drainage systems and it represents a serious environmental problem. While being rich in polyphenols, which have beneficial biological activity and application in the pharmaceutical industry, limited research has been carried out about the biological activity of the specific wastewaters per se. Wastewaters after distillation of the four Bulgarian oil-bearing roses Rosa damascena Mill., R. alba L., R. centifolia L., and R. gallica L. exerted significant antioxidant activity and good antiherpes simplex virus type-1 (HSV-1) activity while maintaining a good toxicological safety profile (low cytotoxic effect) towards normal cell lines. More precisely, the non-tumorigenic cells were a human (HEK-293 embryonic kidney cells) and a mouse cell line (CCL-1 fibroblasts, which are recommended as a standard for cytotoxicity evaluation in Annex C of ISO 10993-5). The concentrations that achieved antioxidant and radical scavenging effects (0.04-0.92% v/v) were much lower than most of the maximum tolerated concentrations for the tissue culture cells (0.2-3.4% v/v). The wastewaters had a weak antiproliferative effect against Staphylococcus aureus. None of the wastewaters had activity against Gram-negative bacteria or a bactericidal or antifungal effect. We can conclude that these four species, which are the most preferred species worldwide for producing high-quality rose oil, have the potential to be developed as promising antioxidant and antiherpesvirus nutraceuticals.

Effect of prooxidants and chelator Desferal on the oxidative status and sperm motility of Muscovy semen.

This study aimed to establish the sensitivity of Muscovy duck semen to oxidative stress (OS) and the effect of Desferal, applied as an antioxidant. The effect of three prooxidant systems in presence and absence of Desferal were tested on the motility and kinetic parameters (determined using CASA system), as well as the level of lipid peroxidation (LPO) and glutathione (tGSH) of Muscovy semen. The semen was diluted (1:3 v/v) with four extenders (saline solution, IMV Canadyl, HIA-1, and AU) and stored at 4 °C for 6 h. The cooled semen was divided into aliquots (50 × 106 sperm cells/mL), which were incubated at 37 °C for 30 min with one of the following prooxidative agents: ferrous sulfate (FeSO4, 0.1 mM), hydrogen peroxide (H2O2, 1 mM), and Fenton system (FeSO4(Fe2+), 0.1 mM + H2O2, 1 mM), in the presence or absence of Desferal (0.1 mM). The addition of FeSO4 + H2O2 or FeSO4 regardless of the used extender, as well as the addition of H2O2 to the diluted semen with saline solution significantly increased the levels of LPO (P < 0.05). With the lowest prooxidant effect was H2O2. The application of Desferal reduced significantly (P < 0.05) the LPO levels induced by FeSO4 + H2O2 or FeSO4 and in a weaker degree by H2O2. Among all prooxidants, FeSO4 + H2O2 decreased in the greatest extent the tGSH concentration in semen diluted with each used extenders in comparison to the relevant control. The addition of Desferal in semen diluted with HIA-1 extender and incubated with FeSO4, and H2O2, showed the best restoration of tGSH level, close to that of respectively controls. The studied prooxidants significantly reduced total, progressive, and kinetic sperm motility (P < 0.05). Although the inclusion of Desferal reduced the sperm OS, it did not improve the impaired by OS sperm motility.

Antimicrobial and Antioxidant Potential of Scenedesmus obliquus Microalgae in the Context of Integral Biorefinery Concept.

Small-scale photobioreactors (PBRs) in the inoculum stage were designed with internal (red or green) and external white LED light as an initial step of a larger-scale installation aimed at fulfilling the integral biorefinery concept for maximum utilization of microalgal biomass in a multifunctional laboratory. The specific growth rate of Scenedesmus obliquus (Turpin) Kützing biomass for given cultural conditions was analyzed by using MAPLE software. For the determination of total polyphenols, flavonoids, chlorophyll "a" and "b", carotenoids and lipids, UHPLC-HRMS, ISO-20776/1, ISO-10993-5 and CUPRAC tests were carried out. Under red light growing, a higher content of polyphenols was found, while the green light favoured the flavonoid accumulation in the biomass. Chlorophylls, carotenoids and lipids were in the same order of magnitude in both samples. The dichloromethane extracts obtained from the biomass of each PBR synergistically potentiated at low concentrations (0.01-0.05 mg/mL) the antibacterial activity of penicillin, fluoroquinolones or oregano essential oil against the selected food-borne pathogens (Staphylococcus aureus, Escherichia coli and Salmonella typhimurium) without showing any in vitro cytotoxicity. Both extracts exhibited good cupric ion-reducing antioxidant capacity at concentrations above 0.042-0.08 mg/mL. The UHPLC-HRMS analysis revealed that both extracts contained long chain fatty acids and carotenoids thus explaining their antibacterial and antioxidant potential. The applied engineering approach showed a great potential to modify microalgae metabolism for the synthesis of target compounds by S. obliquus with capacity for the development of health-promoting nutraceuticals for poultry farming.

In Vivo Toxicity, Redox-Modulating Capacity and Intestinal Permeability of Novel Aroylhydrazone Derivatives as Anti-Tuberculosis Agents.

The emergence and spread of Mycobacterium tuberculosis strains resistant to many or all anti-tuberculosis (TB) drugs require the development of new compounds both efficient and with minimal side effects. Structure-activity-toxicity relationships of such novel, structurally diverse compounds must be thoroughly elucidated before further development. Here, we present the aroylhydrazone compounds (3a and 3b) regarding their: (i) acute and subacute toxicity in mice; (ii) redox-modulating in vivo and in vitro capacity; (iii) pathomorphology in the liver, kidney, and small intestine tissue specimens; and (iv) intestinal permeability. The acute toxicity test showed that the two investigated compounds exhibited low toxicity by oral and intraperitoneal administration. Changes in behavior, food amount, and water intake were not observed during 14 days of the oral administration at two doses of 1/10 and 1/20 of the LD50. The histological examination of the different tissue specimens did not show toxic changes. The in vitro antioxidant assays confirmed the ex vivo results. High gastrointestinal tract permeability at all tested pH values were demonstrated for both compounds. To conclude, both compounds 3a and 3b are highly permeable with low toxicity and can be considered for further evaluation and/or lead optimization.

Redox-Modulating Capacity and Antineoplastic Activity of Wastewater Obtained from the Distillation of the Essential Oils of Four Bulgarian Oil-Bearing Roses.

The wastewater from the distillation of rose oils is discharged directly into the soil because it has a limited potential for future applications. The aim of the present study was to determine in vitro the chromatographic profile, redox-modulating capacity, and antineoplastic activity of wastewater obtained by distillation of essential oils from the Bulgarian Rosa alba L., Rosa damascena Mill., Rosa gallica L., and Rosa centifolia L. We applied UHPLC-HRMS for chromatographic analysis of rose wastewaters, studied their metal-chelating and Fe(III)-reducing ability, and performed MTT assay for the evaluation of cytotoxic potential against three tumorigenic (HEPG2-hepatocellular adenocarcinoma, A-375-malignant melanoma, A-431-non-melanoma epidermoid squamous skin carcinoma) and one non-tumorigenic human cell lines (HaCaT-immortalized keratinocytes). The median inhibitory concentrations (IC50) were calculated with nonlinear modeling using the MAPLE® platform. The potential of the wastewaters to induce apoptosis was also examined. Mono-, di-, and acylated glycosides of quercetin and kaempferol, ellagic acid and its derivatives as main chemical components, and gallic acid and its derivatives-such as catechin and epicatechin-were identified. The redox-modulating capacity of the samples (TPTZ test) showed that all four wastewaters exhibited the properties of excellent heavy metal cleaners, but did not exert very strong cytotoxic effects. The lowest IC50 rate was provided in wastewater from R. centifolia (34-35 µg/mL of gallic acid equivalents after a 72 h period for all cell lines). At 24 and 48 hours, the most resistant cell line was HEPG2, followed by HaCaT. After 72 h of exposure, the IC50 values were similar for tumor and normal cells. Still, R. damascena had a selectivity index over 2.0 regarding A-431 non-melanoma skin cancer cells, showing a good toxicological safety profile in addition to moderate activity-IC50 of 35 µg/mL polyphenols. The obtained results related to wastewaters acquired after the distillation of essential oils from the Bulgarian R. alba, R. damascena, R. gallica, and R. centifolia direct our attention to further studies for in-depth elucidation of their application as detoxifying agents under oxidative damage conditions in other experimental datasets.

Effects of New Galantamine Derivatives in a Scopolamine Model of Dementia in Mice.

Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive functions decline, is a leading cause for dementia and currently ranked as the sixth foremost cause of death. As of present, treatment of AD is symptomatic without convincing therapeutic benefits and new, effective, therapeutic agents are pursued. Due to massive loss of cholinergic neurons and decreased acetylcholine levels, cholinesterase inhibitors like galantamine, remain the backbone of pharmacological treatment of the disease. In the present study, using behavioral and biochemical methods, four newly synthesized galantamine derivatives, Gal 34, Gal 43, Gal 44, and Gal 46, were evaluated for a beneficial effect in a scopolamine model of dementia in mice. They were designed to have all the advantages of galantamine and additionally to inhibit ß-secretase and exert favorable effects on plasma lipids. Behavioral tests included step-through inhibitory avoidance, T-maze, and the hole-board test, whereas biochemical evaluations involved assessment of acetylcholinesterase activity, brain monoamines levels, lipid peroxidation, catalase, glutathione peroxidase, and superoxide dismutase activities along with measurement of total glutathione. Results show that Gal 43, Gal 44, and, in particular, Gal 46 are especially effective in improving both short- and long-term memory and in the case of Gal 46 having a significant effect on exploratory activity as well. Although Gal 34 did not show behavioral effects as convincing as those of the other three galantamine derivatives, it demonstrated persuasive antioxidant and restorative capacities, making all four galantamine derivatives promising AD treatment agents and prompting further research, especially that in many of our studies they performed better than galantamine.

New Galantamine Derivatives with Inhibitory Effect on Acetylcholinesterase Activity.

BACKGROUND: Inhibitors of acetylcholinesterase (AChE) are used to treat many disorders, among which are neurodegenerative upsets, like Alzheimer's disease (AD). One of the limited licensed AChE inhibitors (AChEIs) used as drugs is the natural compound galantamine (Gal). OBJECTIVE: As Gal is a toxic compound, here we expose data about its four derivatives in hybrid peptide-norgalantamine molecules, which have shown 100 times lower toxicity. METHODS: Four newly synthesized galantamine derivatives have been involved in docking analysis made by Molegro Virtual Docker. Biological assessments were performed on ICR male mice. The change in short and long-term memory performance was evaluated by passive avoidance test. AChE activity and levels of main oxidative stress parameters: lipid peroxidation, total glutathione (GSH), enzyme activities of catalase (CAT), superoxide dismutase, and glutathione peroxidase were measured in brain homogenates. RESULTS: Our experimental data revealed that the new hybrid molecules did not impair memory performance in healthy mice. Two of the compounds demonstrated better than Gal AChE inhibitory activity in the brain. None of them changed the level of lipid peroxidation products, one of the compounds increased GSH levels, and all of them increased CAT enzyme activity. CONCLUSION: The new galantamine-peptide hybrids demonstrated a potential for inhibition of AChE and antioxidant activity and deserve further attention.