First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT6 Agents with a Beneficial Neuroprotective Profile against Alzheimer's Disease.

Alzheimer's disease (AD) has a complex and not-fully-understood etiology. Recently, the serotonin receptor 5-HT6 emerged as a promising target for AD treatment; thus, here a new series of 5-HT6R ligands with a 1,3,5-triazine core and selenoether linkers was explored. Among them, the 2-naphthyl derivatives exhibited strong 5-HT6R affinity and selectivity over 5-HT1AR (13-15), 5-HT7R (14 and 15), and 5-HT2AR (13). Compound 15 displayed high selectivity for 5-HT6R over other central nervous system receptors and exhibited low risk of cardio-, hepato-, and nephrotoxicity and no mutagenicity, indicating its "drug-like" potential. Compound 15 also demonstrated neuroprotection against rotenone-induced neurotoxicity as well as antioxidant and glutathione peroxidase (GPx)-like activity and regulated antioxidant and pro-inflammatory genes and NRF2 nuclear translocation. In rats, 15 showed satisfying pharmacokinetics, penetrated the blood-brain barrier, reversed MK-801-induced memory impairment, and exhibited anxiolytic-like properties. 15's neuroprotective and procognitive-like effects, stronger than those of the approved drug donepezil, may pave the way for the use of selenotriazines to inhibit both causes and symptoms in AD therapy.

The redox riddle of selenium sulfide.

Selenium sulfide, in analogy with selenium dioxide, is often considered as SeS2. At closer inspection, however, selenium sulfide represents a large family of rather complicated molecules which differ depending on the mode of preparation. Together, these compounds share extraordinarily low solubility in virtually any solvent with a biological activity rather impressive for such simple molecules. The surface reactivity of such microscopic and nanoscopic materials, prepared chemically or by fermentation, may provide an answer to this riddle and explain activities by a combination of physical, redox, metal binding, covalent, and non-covalent interactions with biomolecules and cells.

Ribes nigrum L. Extract-Mediated Green Synthesis and Antibacterial Action Mechanisms of Silver Nanoparticles.

Silver nanoparticles (Ag NPs) represent one of the most widely employed metal-based engineered nanomaterials with a broad range of applications in different areas of science. Plant extracts (PEs) serve as green reducing and coating agents and can be exploited for the generation of Ag NPs. In this study, the phytochemical composition of ethanolic extract of black currant (Ribes nigrum) leaves was determined. The main components of extract include quercetin rutinoside, quercetin hexoside, quercetin glucuronide, quercetin malonylglucoside and quercitrin. The extract was subsequently employed for the green synthesis of Ag NPs. Consequently, R. nigrum leaf extract and Ag NPs were evaluated for potential antibacterial activities against Gram-negative bacteria (Escherichia coli ATCC 25922 and kanamycin-resistant E. coli pARG-25 strains). Intriguingly, the plant extract did not show any antibacterial effect, whilst Ag NPs demonstrated significant activity against tested bacteria. Biogenic Ag NPs affect the ATPase activity and energy-dependent H+-fluxes in both strains of E. coli, even in the presence of N,N'-dicyclohexylcarbodiimide (DCCD). Thus, the antibacterial activity of the investigated Ag NPs can be explained by their impact on the membrane-associated properties of bacteria.

Selenium and tellurium in the development of novel small molecules and nanoparticles as cancer multidrug resistance reversal agents.

Selenium is an essential trace element that is crucial for cellular antioxidant defense against reactive oxygen species (ROS). Recently, many selenium-containing compounds have exhibited a wide spectrum of biological activities that make them promising scaffolds in Medicinal Chemistry, and, in particular, in the search for novel compounds with anticancer activity. Similarly, certain tellurium-containing compounds have also exhibited substantial biological activities. Here we provide an overview of the biological activities of seleno- and tellurocompounds including chemopreventive activity, antioxidant or pro-oxidant activity, modulation of the inflammatory processes, induction of apoptosis, modulation of autophagy, inhibition of multidrug efflux pumps such as P-gp, inhibition of cancer metastasis, selective targeting of tumors and enhancement of the cytotoxic activity of chemotherapeutic drugs, as well as overcoming tumor drug resistance. A review of the chemistry of the most relevant seleno- or tellurocompounds with activity against resistant cancers is also presented, paying attention to the synthesis of these compounds and to the preparation of bioactive selenium or tellurium nanoparticles. Based on these data, the use of these seleno- and tellurocompounds is a promising approach in the development of strategies that can drive forward the search for novel therapies or adjuvants of current therapies against drug-resistant cancers.

Origanum vulgare L. extract-mediated synthesis of silver nanoparticles, their characterization and antibacterial activities.

Plant extracts serve as reducing and coating agents and are, therefore, commonly employed for the generation of silver (Ag) nanoparticles (NPs). Plant extract mediated synthesis of Ag NPs is a green, environmentally friendly and cost-effective technique which offers a new and potential alternative to chemically synthesized NPs, decreasing the utilization of hazardous and toxic chemicals and protecting the environment. Origanum vulgare L. extracts were evaluated for total flavonoid and phenol content. The free radical scavenging activity was determined employing 2,2-diphenyl-1-picrylhydrazyl assay. Ag NPs were produced exploiting ethanolic extracts of O. vulgare L. leaves. The generation of Ag NPs was carried out both in light and dark conditions. The biosynthesized Ag NPs were characterized employing microscopic and spectroscopic techniques. Antibacterial activities of Ag NPs were determined following appropriate methods. The results revealed that energy of photons was required to reduce Ag+ to Ag0. According to scanning electron microscopy reports, biologically formed Ag NPs ranged in size from 1 to 50 nmand were presented instability causing aggregation. They indicated that O. vulgare L. extracts were rich in flavonoids and phenols and exhibited strong antioxidant activity. Ag NPs exhibited good antibacterial activity immediately after production. Gram-positive strains showed higher sensitivity to Ag NPs compared to Gram-negative stains. Ag NPs can serve as an effective antibacterial agent against antibiotic-resistant strains. The kanamycin-resistant strain was more sensitive to Ag NPs than the ampicillin-resistant strain. Thus, Origanum extract-mediated synthesized Ag NPs can be recommended as alternative effective antibacterial agents, but their activity depended on bacterial species and strains.

The Caucasian flora: a still-to-be-discovered rich source of antioxidants.

Cellular redox homeostasis is a state of balance between the formation of Usually Reactive Oxygen and / or Nitrogen Species (ROS/RNS), endogenous antioxidant defence systems, and exogenous dietary antioxidants. The disturbance of redox homeostasis, by the overproduction of endogenous ROS/RNS, may increase the risk of development of so-called civilisation diseases. The solution seems to be either the increased production of endogenous or consumption of exogenous antioxidants. Plant-borne antioxidants act via different chemical and molecular mechanisms, such as decreasing the level of oxidative damage in cells directly by reacting with ROS/RNS or indirectly - by inhibition of the activity and expression of free radical generating enzymes or by enhancing the activity or expression of intracellular antioxidant defence enzymes. Despite the fact that the Caucasian flora is rich of health promoting edible/medicinal plants, recent studies concerning the biological activity of these plants are very scarce. This review is summarising the state-of-art on the health-promoting potential of plants representing the Caucasian flora, whose antioxidant capacity have been investigated in various in vitro models.

Inorganic Polysulfides and Related Reactive Sulfur­Selenium Species from the Perspective of Chemistry.

Polysulfides (H2Sx) represent a class of reactive sulfur species (RSS) which includes molecules such as H2S2, H2S3, H2S4, and H2S5, and whose presence and impact in biological systems, when compared to other sulfur compounds, has only recently attracted the wider attention of researchers. Studies in this field have revealed a facet-rich chemistry and biological activity associated with such chemically simple, still unusual inorganic molecules. Despite their chemical simplicity, these inorganic species, as reductants and oxidants, metal binders, surfactant-like "cork screws" for membranes, components of perthiol signalling and reservoirs for inorganic hydrogen sulfide (H2S), are at the centre of complicated formation and transformation pathways which affect numerous cellular processes. Starting from their chemistry, the hidden presence and various roles of polysulfides in biology may become more apparent, despite their lack of clear analytical fingerprints and often murky biochemical footprints. Indeed, the biological chemistry of H2Sx follows many unexplored paths and today, the relationship between H2S and its oxidized H2Sx species needs to be clarified as a matter of "unmistaken identity". Simultaneously, emerging species, such as HSSeSH and SenS8-n, also need to be considered in earnest.

No time to waste organic waste: Nanosizing converts remains of food processing into refined materials.

Modern food processing results in considerable amounts of side-products, such as grape seeds, walnut shells, spent coffee grounds, and harvested tomato plants. These materials are still rich in valuable and biologically active substances and therefore of interest from the perspective of waste management and "up-cycling". In contrast to traditional, often time consuming and low-value uses, such as vermicomposting and anaerobic digestion, the complete conversion into nanosuspensions unlocks considerable potentials of and new applications for such already spent organic materials without the need of extraction and without producing any additional waste. In this study, nanosuspensions were produced using a sequence of milling and homogenization methods, including High Speed Stirring (HSS) and High Pressure Homogenization (HPH) which reduced the size of the particles to 200-400 nm. The resulting nanosuspensions demonstrated nematicidal and antimicrobial activity and their antioxidant activities exceeded the ones of the bulk materials. In the future, this simple nanosizing approach may fulfil several important objectives, such as reducing and turning readily available waste into new value and eventually closing a crucial cycle of agricultural products returning to their fields - with a resounding ecological impact in the fields of medicine, agriculture, cosmetics and fermentation. Moreover, up-cycling via nanosizing adds an economical promise of increased value to residue-free waste management.

Nematicidal and antimicrobial activities of methanol extracts of 17 plants, of importance in ethnopharmacology, obtained from the Arabian Peninsula.

AIM/BACKGROUND: The development of resistance to synthetic drugs by target organisms is a major challenge facing medicine, yet locked within plants are phytochemicals used in herbal medicine (especially in the Arabian Peninsula) that may find application in this regard. In pursuit of unlocking these "hidden treasures," the methanol extracts of leaves, aerial parts, fruits, and resins of 17 plants used in the Arabian Peninsula were screened for antimicrobial activities. MATERIALS AND METHODS: The nematicidal, antibacterial, and antifungal activities were determined using appropriate assays. Steinernema feltiae, Staphylococcus carnosus, Escherichia coli, and Saccharomyces cerevisiae were used as test organisms. Concentrations of the extracts ranging from 0.5 to 20 mg/ml were tested and appropriate statistical tests performed on the data generated. RESULTS: The results show that extracts from Solanum incanum, Chenopodium murale, Commiphora myrrha, Anthemis nobilis, and Achillea biebersteinii were the most active and had very high activities against two or more of the test organisms at low concentrations. Extracts of the leaves of S. incanum and resins of Ferula asafoetida were the most active nematicides, with significant activity at 0.5 mg/ml. Extracts of C. myrrha and C. murale had the most active antibacterial activity with inhibition zones of 12-15 mm and minimum inhibitory concentrations (MICs) of 2.5 mg/ml for both bacteria. Extracts of the leaves of A. biebersteinii were the most active fungicide, giving an MIC of 1.5 mg/ml. CONCLUSION: The results validate the use of these plants in ethnopharmacology, and open new vistas of opportunities for the development of cheap but effective agents that may be useful against infectious diseases.

Inspired by Nature: The Use of Plant-derived Substrate/Enzyme Combinations to Generate Antimicrobial Activity in situ.

The last decade has witnessed a renewed interest in antimicrobial agents. Plants have received particular attention and frequently rely on the spontaneous enzymatic conversion of an inactive precursor to an active agent. Such two-component substrate/enzyme defence systems can be reconstituted ex vivo. Here, the alliin/alliinase system from garlic seems to be rather effective against Saccharomyces cerevisiae, whilst the glucosinolate/myrosinase system from mustard appears to be more active against certain bacteria. Studies with myrosinase also confirm that enzyme and substrate can be added sequentially. Ultimately, such binary systems hold considerable promise and may be employed in a medical or agricultural context.

Aspects of a Distinct Cytotoxicity of Selenium Salts and Organic Selenides in Living Cells with Possible Implications for Drug Design.

Selenium is traditionally considered as an antioxidant element and selenium compounds are often discussed in the context of chemoprevention and therapy. Recent studies, however, have revealed a rather more colorful and diverse biological action of selenium-based compounds, including the modulation of the intracellular redox homeostasis and an often selective interference with regulatory cellular pathways. Our basic activity and mode of action studies with simple selenium and tellurium salts in different strains of Staphylococcus aureus (MRSA) and Saccharomyces cerevisiae indicate that such compounds are sometimes not particularly toxic on their own, yet enhance the antibacterial potential of known antibiotics, possibly via the bioreductive formation of insoluble elemental deposits. Whilst the selenium and tellurium compounds tested do not necessarily act via the generation of Reactive Oxygen Species (ROS), they seem to interfere with various cellular pathways, including a possible inhibition of the proteasome and hindrance of DNA repair. Here, organic selenides are considerably more active compared to simple salts. The interference of selenium (and tellurium) compounds with multiple targets could provide new avenues for the development of effective antibiotic and anticancer agents which may go well beyond the traditional notion of selenium as a simple antioxidant.

Intracellular diagnostics: hunting for the mode of action of redox-modulating selenium compounds in selected model systems.

Redox-modulating compounds derived from natural sources, such as redox active secondary metabolites, are currently of considerable interest in the field of chemoprevention, drug and phytoprotectant development. Unfortunately, the exact and occasionally even selective activity of such products, and the underlying (bio-)chemical causes thereof, are often only poorly understood. A combination of the nematode- and yeast-based assays provides a powerful platform to investigate a possible biological activity of a new compound and also to explore the "redox link" which may exist between its activity on the one side and its chemistry on the other. Here, we will demonstrate the usefulness of this platform for screening several selenium and tellurium compounds for their activity and action. We will also show how the nematode-based assay can be used to obtain information on compound uptake and distribution inside a multicellular organism, whilst the yeast-based system can be employed to explore possible intracellular mechanisms via chemogenetic screening and intracellular diagnostics. Whilst none of these simple and easy-to-use assays can ultimately substitute for in-depth studies in human cells and animals, these methods nonetheless provide a first glimpse on the possible biological activities of new compounds and offer direction for more complicated future investigations. They may also uncover some rather unpleasant biochemical actions of certain compounds, such as the ability of the trace element supplement selenite to induce DNA strand breaks.

Gist of medicinal plants of Pakistan having ethnobotanical evidences to crush renal calculi (kidney stones).

Human civilization is facing the problem of kidney stones since ancient ages. Although mortality rate is not so high, yet it affects the victim's quality of life. The patient suffers from intense pain and many other symptoms modifying his life style and affecting his socioeconomic status. Many drugs and invasive methods have also been developed for the treatment, but these are highly costly and unaffordable for poor people and the rate of reoccurrence is also high. The use of medicinal plants is both affordable and effective in this respect. In this article, 35 medicinal plants of Pakistan origin and their crucial information have been enumerated in alphabetical order of plant's scientific name, family, place (distribution), part used, local name, habit, major constituents and references. It can also be seen that all parts are used for the treatment of kidney stones. Leaves represent 28% contribution, whole plants and seeds 12%, fruits and roots 11% contribution in this respect. Flowers contribute 8% in the treatment of kidney stone while branches, bark, bushes, buds, milk and shoots contribute only 3% in the removal of kidney stones. Habits of plants were also taken under consideration. It was noticed that herbs are the most useful life form in this regard which contributed 63% for the removal of kidney stone. Shrubs contributed 20%, trees 11% while bushes and weeds contributed 3% for the removal of kidney stones.

Combating of scorpion bite with Pakistani medicinal plants having ethno-botanical evidences as antidote.

Although the majority of serious cases in the world are concerned with snake bite envenomation, but those which are caused by scorpion stings are also famous for causing extreme pain. The present view is an attempt to enlist scientifically ignored medicinal plants of Pakistan exhibiting anti-scorpion venom activity. In this review data of 35 medicinal plants is collected with their families, parts used, distribution in Pakistan, and major constituents present in plant. Amaranthaceae, Astraceae and Euphorbiaceae represent 3 species. Anacardiaceae, Asclepidaceae and Liliaceae represent 2 species. Araceae, Capparidaceae, Ceasalpinaceae, Cyperaceae, Labiatae, Lamiaceae, Meliaceae, Menispermaceae, Oleaceae, Oxalidaceae, Pinaceae, Polygonaceae, Rhamnaceae, Rubiaceae, Solanaceae, Valerianaceae and Zingiberaceae represented single medicinal plant with anti scorpion potential. According to literature, all parts are used in anti scorpion envenomination. Leaves exhibit 30%, whole plant 9%, fruit, bark and seeds 8% anti scorpion activity. Bulb and stems show 5% contribution in this respect and twigs, resins, inflorescence, latex and flowers express 3% potential. This article may assist the researchers to bring innovation in natural product field for scorpion bite envenomation. However, these medicinal plants are still requiring pharmacological and phytochemical investigation in order to be claimed as effective in scorpion bite envenomation.