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The development of any commercial product should also be aimed at reducing the risk associated with it, according to the safe-by-design concept; that is, risk assessment should always be at the center of the design, and the impact on human and environmental health should be assessed and eliminated during the product development phase and not afterwards. Unfortunately, even today, most operators in any production sector implement the philosophy of "risk management" or rather of managing the problem when it occurs, using spot interventions instead of changing the approach. This argument is also valid in the production of solar filters, which have reached a satisfactory degree of efficiency in the face of a substantial underestimation of the risks associated with their possible environmental fate. In fact, solar filters have been found in bathing waters and their environmental fate may depend on various factors such as the pH of the water, the presence of organic material, metal ions and light, and, above all, the chemical agents used in the disinfection of the water itself. Thus, during disinfection processes, the generation of dozens of products with a lower molecular weight and generally of an aromatic nature has been tested, where some of them did not receive an exact structural definition and a precise evaluation of their precise toxicological profile. Therefore, it is interesting to draw a complete picture of organic sunscreens and of the byproducts obtained under different conditions and their related ecotoxicological profile.

Type 2 Diabetes is a major public health threat, and its prevalence is increasing worldwide. The abnormal accumulation of islet amyloid polypeptide (IAPP) in pancreatic β-cells is associated with the onset of the disease. Therefore, the design of small molecules able to inhibit IAPP aggregation represents a promising strategy in the development of new therapies. Here we employ in vitro, biophysical, and computational methods to inspect the ability of Silybin A and Silybin B, two natural diastereoisomers extracted from milk thistle, to interfere with the toxic self-assembly of human IAPP (hIAPP). We show that Silybin B inhibits amyloid aggregation and protects INS-1 cells from hIAPP toxicity more than Silybin A. Molecular dynamics simulations revealed that the higher efficiency of Silybin B is ascribable to its interactions with precise hIAPP regions that are notoriously involved in hIAPP self-assembly i.e., the S20-S29 amyloidogenic core, H18, the N-terminal domain, and N35. These results highlight the importance of stereospecific ligand-peptide interactions in regulating amyloid aggregation and provide a blueprint for future studies aimed at designing Silybin derivatives with enhanced drug-like properties., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The secondary metabolites of plant origin belong to different and numerous classes of organic compounds. One of these is that of dimeric phenanthrenes, symmetrical or not, characterized by a series of interesting biological activities. Of these compounds, 37 have been isolated since 1988, from only five plant families. Considering each dimer comprises two phenanthrenes and starting from the hypothesis that each dimer is obtained through a biosynthetic mechanism that involves the coupling of the corresponding radicals of the individual phenanthrene units, it is possible to identify 29 phenanthrenes, of which 6 not yet isolated. It is possible to establish that 16 known phenanthrenes can be isolated from 14 different plant species, just as 6 new phenanthrenes can be isolated from 6 different plant species. This would allow a targeted analysis of a few natural extracts from specific plant sources to identify known or new molecules, with potential and/or specific biological activities., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Silibinin is the main biologically active component of silymarin extract and consists of a mixture 1:1 of two diastereoisomeric flavonolignans, namely silybin A ( 1a ) and silybin B ( 1b ), which we call here silybins. Despite the high interest in the activity of this flavonolignan, there are still few studies that give due attention to the role of its stereochemistry and, there is still today a strong need to investigate in this area. In this regard, here we report a study concerning the radical scavenger ability and the antiproliferative activity on different cell lines, both of silybins and phosphodiester-linked silybin dimers. An efficient synthetic strategy to obtain silybin dimers in an optical pure form ( 6aa , 6ab and 6bb ) starting from a suitable building block of silybin A and silybin B, obtained by us from natural extract silibinin, was proposed. New dimers show strong antioxidant properties, determined through hydroxyl radical (HO ● ) scavenging ability, comparable to the value reported for known potent antioxidants such as quercetin. A preliminary screening was performed by treating cells with 10 and 50 μM concentrations for 48 h to identify the most sensitive cell lines. The results show that silibinin compounds were active on Jurkat, A375, WM266, and HeLa, but at the tested concentrations, they did not interfere with the growth of PANC, MCF-7, HDF or U87. In particular, both monomers ( 1a and 1b ) and dimers ( 6aa , 6ab and 6bb ) present selective anti-proliferative activity towards leukemia cells in the mid-micromolar range and are poorly active on normal cells. They exhibit different mechanisms of action in fact all the cells treated with the 1a and 1b go completely into apoptosis, whereas only part of the cells treated with 6aa and 6ab were found to be in apoptosis.

To date, just over a hundred phenanthrenoid dimers have been isolated. Of these, forty-two are completely phenanthrenic in nature. They are isolated from fourteen genera of different plants belonging to only five families, of which Orchidaceae is the most abundant source. Other nine completely acetylated and five methylated dimers were also defined, which were effective in establishing the position of the free hydroxyls of the corresponding natural products, from which they were obtained by semi-synthesis. Structurally, they could be useful chemotaxonomic markers considering that some substituents are typical of a single-family, such as the vinyl group for Juncaceae. From a biogenetic point of view, it is thought that these compounds derive from the radical coupling of the corresponding phenanthrenes or by dehydrogenation of the dihydrophenanthrenoid analogs. Phenanthrenes or dihydroderivatives possess different biological activities, e.g., antiproliferative, antimicrobial, antiinflammatory, antioxidant, spasmolytic, anxiolytic, and antialgal effects. The aim of this review is to summarize the occurrence of phenanthrene dimers in the different natural sources and give a comprehensive overview of their structural characteristics and biological activities., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Therapeutic treatments with Artemisia annua have a long-established tradition in various diseases due to its antibacterial, antioxidant, antiviral, anti-malaria and anti-cancer effects. However, in relation to the latter, virtually all reports focused on toxic effects of A. annua extracts were obtained mostly through conventional maceration methods. In the present study, an innovative extraction procedure from A. annua , based on pressurised cyclic solid-liquid (PCSL) extraction, resulted in the production of a new phytocomplex with enhanced anti-cancer properties. This extraction procedure generated a pressure gradient due to compressions and following decompressions, allowing to directly perform the extraction without any maceration. The toxic effects of A. annua PCSL extract were tested on different cells, including three cancer cell lines. The results of this study clearly indicate that the exposure of human, murine and canine cancer cells to serial dilutions of PCSL extract resulted in higher toxicity and stronger propensity to induce apoptosis than that detected by subjecting the same cells to Artemisia extracts obtained through canonical extraction by maceration. Collected data suggest that PCSL extract of A. annua could be a promising and economic new therapeutic tool to treat human and animal tumours.

Prodrugs are ingenious derivatives of therapeutic agents designed to improve the pharmacokinetic profile of the drug. Here, we report an efficient and regioselective solid phase approach for obtaining new prodrugs of 9″-silybins conjugated with 3'-ribonucleotide units (uridine and adenosine) as pro-moieties. Uridine and adenosine conjugates were obtained in good yields (41-50%), beginning with silibinin and its diastereomers (silybin A and silybin B), using a NovaSyn® support functionalized with an ad hoc linker, which allowed selective detachment of only the desired products. As expected, the solubility of both uridine and adenosine conjugates was higher than that of the parental natural product (5 mg/mL and 3 mg/mL for uridine and adenosine, respectively). Our investigations revealed that uridine conjugates were quickly cleaved by RNase A, releasing silybin drugs, even at low enzyme concentrations. No toxic effects were found for any ribonucleotide conjugate on differentiated neuroblastoma SH-SY5Y cells when tested at increasing concentrations. All results strongly encourage further investigations of uridine-silybin prodrugs as potential therapeutic agents for both oral and intravenous administration. The present synthetic approach represents a valuable strategy to the future design of new prodrugs with modified nucleoside pro-moieties to modulate the pharmacokinetics of silybins or different natural products with strong pharmacological activities but poor bioavailability., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The aim of this work is to compare new and traditional extraction methods to obtain silymarin from Silybum marianum , a biennial herbaceous plant of the Asteraceae family, present throughout the Mediterranean basin and used to treat several diseases. Silymarin primarily contains flavonolignans and flavonoids and is used in some pharmaceutical preparations to improve of liver function and as a protective against some hepatotoxins. In six extracts obtained by new and traditional extraction methods, the total contents of silymarin and its main flavonolignans, total phenols and condensed tannins were evaluated in addition to their respective antioxidant capacities. By the Naviglio extractor, that is a rapid solid-liquid dynamic extraction method, it is possible to obtain a fraction quantitatively more abundant than other methods, and with a lower content of tannins and phenolic compounds but with a higher content of flavonolignans, rare and expensive, and therefore easier to separate and purify.

Curcumin is a bioactive natural compound with a wide range of pharmacological properties, including antitumor activity; however, its clinical application has been limited because of its low solubility, stability, and bioavailability. In this study, a solid phase approach was proposed for the combinatorial synthesis of a mini library of the mimics of curcumin in good purity and yield. The non-effective findings in pancreatic cancer cells switched to strong growth inhibition and cell death efficacy for PC3 prostate cancer cells, and mimic 9, in which tyrosol (TYR) and homovanillyl alcohol (HVA) units were linked by a phosphodiester bond, was quite effective not only in cell growth inhibition but also in causing strong cell death under the study conditions and treatments that were not effective in PANC1 cells. The results got more exciting when we also consider the findings in SW480 human colorectal carcinoma cell line, where the growth inhibitor effects were more in line with that of the PC3 cells, but the lack of cell death effect was more in line with the PANC1 cells., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In recent years, many studies have reported the frequent detection of antihypertensive agents such as sartans (olmesartan, valsartan, irbesartan and candesartan) in the influents and effluents of wastewater treatment plants (WWTPs) and in the superficial waters of rivers and lakes in both Europe and North America. In this paper, the degradation pathway for candesartan (CAN) was investigated by simulating the chlorination process that is normally used to reduce microbial contamination in a WWTP. Twelve isolated degradation byproducts (DPs), four of which were isolated for the first time, were separated on a C-18 column by employing a gradient HPLC method, and their structures were identified by combining nuclear magnetic resonance and mass spectrometry and comparing the results with commercial standards. On the basis of these results, a mechanism of formation starting from the parent drug is proposed. The ecotoxicity of CAN and its DPs was studied by conducting a battery of ecotoxicity tests; bioassays were performed using Aliivibrio fischeri (bacterium), Daphnia magna (planktonic crustacean) and Raphidocelis subcapitata (alga). The ecotoxicity results shed new light on the increased toxicity of DPs compared with the parent compound.

Alzheimer's disease (AD) is a multifactorial pathology that requires multifaceted agents able to address its peculiar nature. Increasing evidence has shown that aggregation of amyloid β (Aβ) and oxidative stress are strictly interconnected, and their modulation might have a positive and synergic effect in contrasting AD-related impairments. Herein, a new and efficient fragment-based approach towards tyrosol phosphodiester derivatives (TPDs) has been developed starting from suitable tyrosol building blocks and exploiting the well-established phosphoramidite chemistry. The antioxidant activity of new TPDs has been tested as well as their ability to inhibit Aβ protein aggregation. In addition, their metal chelating ability has been evaluated as a possible strategy to develop new natural-based entities for the prevention or therapy of AD. Interestingly, TPDs containing a catechol moiety have demonstrated highly promising activity in inhibiting the aggregation of Aβ 40 and a strong ability to chelate biometals such as Cu II and Zn II ., (© 2020 Wiley-VCH GmbH.)

The discovery of various sartans, which are among the most used antihypertensive drugs in the world, is increasingly frequent not only in wastewater but also in surface water and, in some cases, even in drinking or groundwater. In this paper, the degradation pathway of olmesartan acid, one of the most used sartans, was investigated by simulating the chlorination process normally used in a wastewater treatment plant to reduce similar emerging pollutants. The structures of nine isolated degradation byproducts (DPs), eight of which were isolated for the first time, were separated via chromatography column and HPLC methods, identified by combining nuclear magnetic resonance and mass spectrometry, and justified by a proposed mechanism of formation beginning from the parent drug. Ecotoxicity tests on olmesartan acid and its nine DPs showed that 50% of the investigated byproducts inhibited the target species Aliivibrio fischeri and Raphidocelis subcapitata , causing functional decreases of 18% and 53%, respectively.

Diclofenac (DCF) is the most widely prescribed non-steroidal anti-inflammatory drug in the world and it has been detected in drinking and surface waters. In this paper, the effect of chlorination process on DCF in aqueous solutions was investigated and the structures of 14 isolated degradation by-products (DPs), of which nine are new, have been determined from combining mass spectrometry and nuclear magnetic resonance data and justified by a proposed mechanism of formation beginning from the parent drug. Some degradation by-products show only one phenyl, others are dimers or trimers of the parental compound, which has undergone oxidative decarboxylation of the side chain and/or chlorination of this or one or both aromatic rings. Ecotoxicological bioassays evidenced the following sensitivities D. magna < R. subcapitata < A. fischeri. The isolated DPs (DP1-8, except for DP9) exhibited effects ≥ 50 % in the exposed microalgae and crustaceans showing toxicities mainly ranked from slight to acute., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In the panorama of modified G-quadruplexes (G4s) with interesting proprieties, here, it has been reported the synthesis of new modified d(TGGGAG) sequences forming G-quadruplexes, with the insertion of a riboflavin unit (Rf, vitamin B 2 ). Exploiting the flavin similarity with the hydrogen bond pattern of guanine and aiming at mimic a typical nucleoside scaffold, the synthesis of the riboflavin building block 3 it has been efficiently carried out. The effect of insertion of riboflavin mimic nucleoside on the G-quadruplex properties has been here, for the first time investigated. A biophysical characterization of Rf-modified sequences (A-D) has been carried out by circular dichroism (CD), fluorescence spectroscopy, differential scanning calorimetry (DSC) and native gel electrophoresis. CD and electrophoresis data have suggested that Rf-modified sequences are able to form parallel tetramolecular G4 structures similar to that of the unmodified sequence. Analysis of the DSC thermograms has revealed that all modified G-quadruplexes have a higher thermal stability compared with the natural sequence, particularly the stabilisation is higher when the Rf residue is introduced at the 3'-end. Further, DSC analysis has revealed that the Rf residues introduced at the 3'-end are able to form additional stabilising interactions, energetically almost comparable to the enthalpic contribution of a G-tetrad. Fluorescence measurement are consistent with this result showing that the Rf residues introduced at 3'-end are able to form stacking interactions with the adjacent bases within the G-quadruplex structure. The whole of data suggested that the introduction of Rf unit can stabilize G-quadruplex structures and can be a promising candidate for future theranostic applications., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Beer is one of the most consumed alcoholic beverages in the world, rich in chemical compounds of natural origin with high nutritional and biological value. It is made up of water, barley malt, hops, and yeast. The main nutrients are carbohydrates, amino acids, minerals, vitamins, and other compounds such as polyphenols which are responsible for the many health benefits associated with this consumption of drinks. Hops and malt are one of the raw materials for beer and are a source of phenolic compounds. In fact, about 30% of the polyphenols in beer comes from hops and 70%-80% from malt. Natural compounds of foods or plants exert an important antioxidant activity, counteracting the formation of harmful free radicals. In the presence of an intense stressing event, cells activate specific responses to counteract cell death or senescence which is known to act as a key-task in the onset of age-related pathologies and in the loss of tissue homeostasis. Many studies have shown positive effects of natural compounds as beer polyphenols on biological systems. The main aims of our research were to determine the polyphenolic profile of three fractions, coming from stages of beer production, the mashing process (must), the filtration process (prehopping solution), and the boiling process with the addition of hops (posthopping solution), and to evaluate the effects of these fractions on Dental-derived Stem Cells (D-dSCs) and human intestinal epithelial lines (Caco-2 cells). Furthermore, we underline the bioavailability of beer fraction polyphenols by carrying out the in vitro intestinal absorption using the Caco-2 cell model. We found an antioxidant, proliferating, and antisenescent effects of the fractions deriving from the brewing process on D-dSCs and Caco-2 cells. Finally, our results demonstrated that the bioavailability of polyphenols is greater in beer than in the control standards used, supporting the future clinical application of these compounds as potential therapeutic tools in precision and translational medicine., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2020 Marina Di Domenico et al.)

The abnormal deposition of Aβ amyloid deposits in the brain is a hallmark of Alzheimer's disease (AD). Based on this evidence, many current therapeutic approaches focus on the development of small molecules halting Aβ aggregation. However, due to the temporary and elusive structures of amyloid assemblies, the rational design of aggregation inhibitors remains a challenging task. Here we combine ThT assays and MD simulations to study Aβ aggregation in the presence of the natural compounds tyrosol (TY), 3-hydroxytyrosol (HDT), and 3-methoxytyrosol (homovanillyl alcohol - HVA). We show that albeit HDT is a potent inhibitor of amyloid growth, TY and HVA catalyze fibril formation. An inspection of MD simulations trajectories revealed that the different effects of these three molecules on Aβ 1 - 40 aggregation are ascribable to their capacity to arrange H-bonds network between the ligand (position C-3) and the peptide (Glu22). We believe that our results may contribute to the design of more effective and safe small molecules able to contrast pathogenic amyloid aggregation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is linked to the abnormal accumulation of amyloid β peptide (Aβ) aggregates in the brain. Silybin B, a natural compound extracted from milk thistle ( Silybum marianum ), has been shown to significantly inhibit Aβ aggregation in vitro and to exert neuroprotective properties in vivo . However, further explorations of silybin B's clinical potential are currently limited by three main factors: (a) poor solubility, (b) instability in blood serum, and (c) only partial knowledge of silybin's mechanism of action. Here, we address these three limitations. We demonstrate that conjugation of a trehalose moiety to silybin significantly increases both water solubility and stability in blood serum without significantly compromising its antiaggregation properties. Furthermore, using a combination of biophysical techniques with different spatial resolution, that is, TEM, ThT fluorescence, CD, and NMR spectroscopy, we profile the interactions of the trehalose conjugate with both Aβ monomers and oligomers and evidence that silybin may shield the "toxic" surfaces formed by the N-terminal and central hydrophobic regions of Aβ. Finally, comparative analysis with silybin A, a less active diastereoisomer of silybin B, revealed how even subtle differences in chemical structure may entail different effects on amyloid inhibition. The resulting insight on the mechanism of action of silybins as aggregation inhibitors is anticipated to facilitate the future investigation of silybin's therapeutic potential.

Recently, many studies highlighted the consistent finding of irbesartan in effluents from wastewater treatment plants (WWTPs) and in some rivers and lakes in both Europe and North America, suggesting that no >80% can be removed by specific treatments. The present investigation attempts to study the chemical fate of irbesartan in a simulated chlorination step, mimicking the conditions of a WWTP. A total of six disinfection by-products were identified, five were completely new, and separated on a C-18 column by employing a gradient HPLC method. Initially, a complete mass fragmentation pathway of the drug was established with the help of MS/TOF, and subsequently, the disinfection by-products were subjected to MS/TOF mass studies to obtain their mass and fragment pattern. The MS results helped to assign tentative structures to the disinfection products, which were verified through 1D and 2D NMR experiments. The chemical structures of the new compounds have been justified by a proposed mechanism of formation. A preliminary ecotoxicity assessment with the crustacean Daphnia magna showed that some of the identified by-products were up to 12-times more toxic than irbesartan., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The pharmacological relevance of ODNs forming G-quadruplexes as anti-HIV agents has been extensively reported in the literature over the last few years. Recent detailed studies have elucidated the peculiar arrangement adopted by many G-quadruplex-based aptamers and provided insight into their mechanism of action. In this review, we have reported the history of a strong anti-HIV agent: the 6-mer d(TGGGAG) sequence, commonly called "Hotoda's sequence". In particular, all findings reported on this sequence and its modified sequences have been discussed considering the following research phases: (i) discovery of the first 5'-modified active d(TGGGAG) sequences; (ii) synthesis of a variety of end-modified d(TGGGAG) sequences; (iii) biophysical and NMR investigations of natural and modified Hotoda's sequences; (iv); kinetic studies on the most active 5'-modified d(TGGGAG) sequences; and (v) extensive anti-HIV screening of G-quadruplexes formed by d(TGGGAG) sequences. This review aims to clarify all results obtained over the years on Hotoda's sequence, revealing its potentiality as a strong anti-HIV agent (EC 50 = 14 nM).

In recent years, many studies have highlighted the consistent finding of tramadol (TRA) in the effluents from wastewater treatment plants (WTPs) and also in some rivers and lakes in both Europe and North America, suggesting that TRA is removed by no more than 36% by specific disinfection treatments. The extensive use of this drug has led to environmental pollution of both water and soil, up to its detection in growing plants. In order to expand the knowledge about TRA toxicity as well as the nature of its disinfection by-products (DBPs), a simulation of the waste treatment chlorination step has been reported herein. In particular, we found seven new by-products, that together with TRA, have been assayed on different living organisms ( Aliivibrio fischeri, Raphidocelis subcapitata and Daphnia magna ), to test their acute and chronic toxicity. The results reported that TRA may be classified as a harmful compound to some aquatic organisms whereas its chlorinated product mixture showed no effects on any of the organisms tested. All data suggest however that TRA chlorination treatment produces a variety of DBPs which can be more harmful than TRA and a risk for the aquatic environment and human health.

In recent years, there has been increasing interest in dimeric molecules due to reports of their promising therapeutic value in the treatment of numerous diseases (such as cancer, HIV, Alzheimer's and, malaria). Many reports in the literature have highlighted the ability of these molecules to interact not only with specific biologic receptors but also to induce a biological response that more than doubles the results of the corresponding monomeric counterpart. In this regard, flavonolignan dimers or simply bi- flavonolignans are an emerging class of dimeric compounds that unlike bi -flavonoids, which are very widespread in nature, consist of synthetic dimers of some flavonolignans isolated from the milk thistle Silybum marianum [L. Gaertn. (Asteraceae)]. This mini-review will discuss recent developments in the synthesis, characterization and antioxidant activity of new families of flavonolignan dimers, in light of emerging medicinal chemistry strategies.

New silibinin phosphodiester glyco-conjugates were synthesized by efficient phosphoramidite chemistry and were fully characterized by 2D-NMR. A wide-ranging study focused on the determination of their pKa and E° values as well as on their radical scavenging activities by different assays (DPPH, ABTS + and HRSA) was conducted. The new glyco-conjugates are more water-soluble than silibinin, and their radical scavenging activities are higher than those of silibinin. The conjugation therefore improves both the water solubilities and antioxidant activities of the flavonolignan moieties. The serum stability was evaluated under physiological conditions, and the glyco-conjugates degraded with half-lives of 40-70 h, making them useful in pro-drug approaches. We started by treating androgen-dependent prostate cancer (PCa) LNCaP cells and then expanded our studies to androgen-independent PCa PC3 and DU145 cells. In most cases, the new derivatives significantly reduced both total and live cell numbers, albeit at different levels. Anti-HIV activities were evaluated and the glucosamine-phosphate silibinin derivative showed higher activity (IC 50  = 73 μM) than silibinin., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The biological relevance of tetramolecular G-quadruplexes especially as anti-HIV agents has been extensively reported in the literature over the last years. In the light of our recent results regarding the slow G-quadruplex folding kinetics of ODNs based on d(TGGGAG) sequence, here we report a systematic anti-HIV screening to investigate the impact of the G-quadruplex folding on their anti-HIV activity. In particular, varying the single stranded concentrations of ODNs, it has been tested a pool of ODN sample solutions with different G-quadruplex concentrations. The anti-HIV assays have been designed favouring the limited kinetics involved in the tetramolecular G4-association based on the d(TGGGAG) sequence. Aiming to determine the stoichiometry of G-quadruplex structures in the same experimental conditions of the anti-HIV assays, a native gel electrophoresis was performed. The gel confirmed the G-quadruplex formation for almost all sample solutions while showing the formation of high order G4 structures for the more concentrated ODNs solutions. The most significant result is the discovery of a potent anti-HIV activity of the G-quadruplex formed by the natural d(TGGGAG) sequence (IC 50  = 14 nM) that, until now, has been reported to be completely inactive against HIV infection., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The self-assembling of the amyloid β (Aβ) peptide into neurotoxic aggregates is considered a central event in the pathogenesis of Alzheimer's disease (AD). Based on the "amyloid hypothesis", many efforts have been devoted to designing molecules able to halt disease progression by inhibiting Aβ self-assembly. Here, we combine biophysical (ThT assays, TEM and AFM imaging), biochemical (WB and ESI-MS), and computational (all-atom molecular dynamics) techniques to investigate the capacity of four optically pure components of the natural product silymarin (silybin A, silybin B, 2,3-dehydrosilybin A, 2,3-dehydrosilybin B) to inhibit Aβ aggregation. Despite TEM analysis demonstrated that all the four investigated flavonoids prevent the formation of mature fibrils, ThT assays, WB and AFM investigations showed that only silybin B was able to halt the growth of small-sized protofibrils thus promoting the formation of large, amorphous aggregates. Molecular dynamics (MD) simulations indicated that silybin B interacts mainly with the C-terminal hydrophobic segment 35 MVGGVV 40 of Aβ40. Consequently to silybin B binding, the peptide conformation remains predominantly unstructured along all the simulations. By contrast, silybin A interacts preferentially with the segments 17 LVFF 20 and 27 NKGAII 32 of Aβ40 which shows a high tendency to form bend, turn, and β-sheet conformation in and around these two domains. Both 2,3-dehydrosilybin enantiomers bind preferentially the segment 17 LVFF 20 but lead to the formation of different small-sized, ThT-positive Aβ aggregates. Finally, in vivo studies in a transgenic Caenorhabditis elegans strain expressing human Aβ indicated that silybin B is the most effective of the four compounds in counteracting Aβ proteotoxicity. This study underscores the pivotal role of stereochemistry in determining the neuroprotective potential of silybins and points to silybin B as a promising lead compound for further development in anti-AD therapeutics.

Sideritis species have been used in folk medicine for their antimicrobial, antiulcerogenic, digestive and anti-inflammatory properties. Over the years, the phytochemistry of the genus Sideritis has been studied, and various terpenoids, sterols, coumarins and especially flavonoid aglycones and glycosides have been identified. In particular, species from the Balkan Peninsula have been studied and were found to be rich in flavonoids, with valuable antioxidant activity. In the folk medicine of the Balkan countries, Sideritis raeseri is used as a herbal tea in the treatment of inflammation, gastrointestinal disorders and coughs, and also as a tonic, whereas extracts are used as a component of dietary supplements for anaemia. Its dried inflorescences are used to prepare a beverage called 'mountain tea'. In light of the considerable interest generated in the chemistry, pharmacological properties and commercial value of S. raeseri Boiss. & Heldr., we review and summarise the available literature on these plants. The review details the chemical composition of the essential oil, its mineral and polyphenol contents, the naming of these plants and their physicochemical characterisation, and the nuclear magnetic resonance spectral data and biological properties associated with the plant extracts, with a focus on their potential chemotherapeutic applications. © 2016 Society of Chemical Industry., (© 2016 Society of Chemical Industry.)

To investigate what properties make tetramolecular G-quadruplex ODNs good anti-HIV aptamers, we studied the stoichiometry and the self-assembly kinetics of the highly active 5'-end modified G-quadruplexes based on the d(TGGGAG) sequence. Our results demonstrate that the 5'-end conjugation does not necessarily increase the folding rate of the G-quadruplex; indeed, it ascribes anti-HIV activity. Unexpectedly, the G4-folding kinetics of the inactive G4 is similar to that of the 5'-end modified sequences. ESI-MS studies also revealed the formation of higher order G4 structures identified as octameric complexes along with tetramolecular G-quadruplexes.

Aristotelia chilensis ([Molina], Stuntz) a member of the family Eleocarpaceae, is a plant native to Chile that is distributed in tropical and temperate Asia, Australia, the Pacific Area, and South America. The juice of its berries has important medicinal properties, as an astringent, tonic, and antidiarrhoeal. Its many qualities make the maqui berry the undisputed sovereign of the family of so-called &quot;superfruits&quot;, as well as a valuable tool to combat cellular inflammation of bones and joints. Recently, it is discovered that the leaves of the maqui berry have important antibacterial and antitumour activities. This review provides a comprehensive overview of the traditional use, phytochemistry, and biological activity of A. chilensis using information collected from scientific journals, books, and electronic searches. Anthocyanins, other flavonoids, alkaloids, cinnamic acid derivatives, benzoic acid derivatives, other bioactive molecules, and mineral elements are summarized. A broad range of activities of plant extracts and fractions are presented, including antioxidant activity, inhibition of visible light-induced damage of photoreceptor cells, inhibition of α-glucosidase, inhibition of pancreatic lipase, anti-diabetic effects, anti-inflammatory effects, analgesic effects, anti-diabetes, effective prevention of atherosclerosis, promotion of hair growth, anti-photo ageing of the skin, and inhibition of lipid peroxidation. Although some ethnobotanical uses have been supported in in vitro experiments, further studies of the individual compounds or chemical classes of compounds responsible for the pharmacological effects and the mechanisms of action are necessary. In addition, the toxicity and the side effects from the use of A. chilensis, as well as clinical trials, require attention.

Stevia rebaudiana Bertoni is a small perennial shrub of the Asteraceae (Compositae) family that is native to South America, particularly Brazil and Paraguay, where it is known as "stevia" or "honey leaf" for its powerful sweetness. Several studies have suggested that in addition to their sweetness, steviosides and their related compounds, including rebaudioside A and isosteviol, may offer additional therapeutic benefits. These benefits include anti-hyperglycaemic, anti-hypertensive, anti-inflammatory, anti-tumor, anti-diarrheal, diuretic, and immunomodulatory actions. Additionally, critical analysis of the literature supports the anti-bacterial role of steviosides on oral bacteria flora. The aim of this review is to show the emerging results regarding the anti-cariogenic properties of S. rebaudiana Bertoni. Data shown in the present paper provide evidence that stevioside extracts from S. rebaudiana are not cariogenic. Future research should be focused on in vivo studies to evaluate the effects on dental caries of regular consumption of S. rebaudiana extract-based products.

High fat and/or carbohydrate intake are associated with an elevated risk for obesity and chronic diseases such as diabetes and cardiovascular diseases. The harmful effects of a high fat diet could be different, depending on dietary fat quality. In fact, high fat diets rich in unsaturated fatty acids are considered less deleterious for human health than those rich in saturated fat. In our previous studies, we have shown that rats fed a high fat diet developed obesity and exhibited a decrease in oxidative capacity and an increase in oxidative stress in liver mitochondria. To investigate whether polyunsaturated fats could attenuate the above deleterious effects of high fat diets, energy balance and body composition were assessed after two weeks in rats fed isocaloric amounts of a high-fat diet (58.2% by energy) rich either in lard or safflower/linseed oil. Hepatic functionality, plasma parameters, and oxidative status were also measured. The results show that feeding on safflower/linseed oil diet attenuates the obesogenic effect of high fat diets and ameliorates the blood lipid profile. Conversely, hepatic steatosis and mitochondrial oxidative stress appear to be negatively affected by a diet rich in unsaturated fatty acids.

The synthesis and a preliminary evaluation of the pairing properties of ribo-cyclohexanyl nucleic acids (r-CNA) is herein reported. Incorporation of a single r-CNA nucleotide into natural duplexes did not enhance their stability, while a very high pairing selectivity for RNA was found. As deduced by comparative analysis of Tm and NMR data, a relationship between pairing selectivity and conformational preferences of the "sugar" moiety of r-CNA (and more generally of six-membered nucleic acids) was suggested.

Background/aim: Silybin is the main component of silymarin with antioxidant, anti-inflammatory and cytoprotective actions. Our aim was to compare the effect of silybin used as single substance, silybin-phosphatidylcholine complex (SilPho), and derivatives of silybin (MannpSil, GalpSil, GlcpSil, LactpSil) on MKN28 and HepG2 cell viability and cell death, in vitro, after induction of oxidative stress., Materials and Methods: Oxidative stress was induced by incubating HepG2 and MKN28 cells with xanthine oxidase in the presence of its substrate xanthine. Cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazoliumbromide assay. Determination of Malondialdehyde (MDA) in MKN28 cells was performed by high-performance liquid chromatography. Quantitative analysis of apoptotic cells was carried-out using annexin., Results: SilPho and new silybin glycoconjugates did not affect cell viability, while silybin induced about 50% cell death in both MKN28 and in HepG2 cells. Pre-treatment of cells with silybin and new silybin glycoconjugates (before oxidative stress induction) did not affect cell viability, while SilPho had a protective effect. Exposure of MKN28 cells to oxidative stress caused a two-fold increase in cellular MDA concentration compared to untreated cells. Moreover, pre-treatment with SilPho, but not with silybin, significantly prevented oxidative stress-induced increase in cellular Malondialdehyde. Moreover, silybin induced apoptosis potentiated by oxidative stress, while SilPho did not induce any effect. Oxidative stress caused cell death primarily by necrosis, antagonized by SilPho., Conclusion: The protective effect of SilPho is partially due to inhibition of radical oxidative species., (Copyright © 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

We describe the facile syntheses of new modified oligonucleotides based on d(TG3AG) that form bimolecular G-quadruplexes and possess a HEG loop as an inversion of polarity site 3'-3' or 5'-5' and aromatic residues conjugated to the 5'-end through phosphodiester bonds. The conjugated hairpin G-quadruplexes exhibited parallel orientation, high thermal stability, elevated resistance in human serum and high or moderate anti-HIV-1 activity with low cytotoxicity. Further, these molecules showed significant binding to HIV envelope glycoproteins gp120, gp41 and HSA, as revealed by SPR assays. As a result, these conjugated hairpins represent the first active anti-HIV-1 bimolecular G-quadruplexes based on the d(TG3AG) sequence., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Gymnema sylvestre R. Br. is one of the most important medicinal plants that grows in tropical forests in India and South East Asia. Its active ingredients and extracts of leaves and roots are used in traditional medicine to treat various ailments and they are present in the market for pharmaceutical and parapharmaceutical products. Commercial products based on substances of plant origin that are generally connoted as natural have to be subjected to monitoring and evaluation by health authorities for their potential impacts on public health. The monitoring and evaluation of these products are critical because the boundary between a therapeutic action and a functional or healthy activity has not yet been defined in a clear and unambiguous way. Therefore, these products are considered borderline products, and they require careful and rigorous studies, in order to use them as complement and/or even replacement of synthetic drugs that are characterized by side effects and high economic costs. This review explores the traditional uses, chemical composition and biological activity of G. sylvestre extracts, providing a general framework on the most interesting extracts and what are the necessary studies for a complete definition of the range of activities.

New silibinin glyco-conjugates have been synthesized by efficient method and in short time. Exploiting our solution phase strategy, several structurally diverse silibinin glyco-conjugates (gluco, manno, galacto, and lacto-) were successfully realized in very good yields and in short time. In preliminary study to evaluate their antioxidant and neuroprotective activities new derivatives were subjected to DPPH free radical scavenging assay and the Xanthine oxidase (XO) inhibition models assay. Irrespective of the sugar moiety examined, new glyco-conjugates are more than 50 times water-soluble of silibinin. In the other hand they exhibit a radical scavenging activities slightly higher than to silibinin and XO inhibition at least as silibinin., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Novel conjugated G-quadruplex-forming d(TG3AG) oligonucleotides, linked to hydrophobic groups through phosphodiester bonds at 5'-end, have been synthesized as potential anti-HIV aptamers, via a fully automated, online phosphoramidite-based solid-phase strategy. Conjugated quadruplexes showed pronounced anti-HIV activity with some preference for HIV-1, with inhibitory activity invariably in the low micromolar range. The CD and DSC monitored thermal denaturation studies on the resulting quadruplexes, indicated the insertion of lipophilic residue at the 5'-end, conferring always improved stability to the quadruplex complex (20<ΔTm<40°C). The data suggest no direct functional relationship between the thermal stability and anti-HIV activity of the folded conjugated G-quartets. It would appear that the nature of the residue at 5' end of the d(TG3AG) quadruplexes plays an important role in the thermodynamic stabilization but a minor influence on the anti-HIV activity. Moreover, a detailed CD and DSC analyses indicate a monophasic behaviour for sequences I and V, while for ODNs (II-IV) clearly show that these quadruplex structures deviate from simple two-state melting, supporting the hypothesis that intermediate states along the dissociation pathway may exist., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A first solid phase approach to obtain monosubstituted CD conjugates to different labels has been developed. A new solid support has been designed to get a variety of C-6 monofunctionalized CDs (α, β, MeβCD and HPβCD) covalently linked through a phosphodiester bridge to different labels, in highly pure form and under very mild detachment conditions., (This journal is © The Royal Society of Chemistry 2012)

Silybin is the major flavonolignan of silymarin and it displays a plethora of biological effects, generally ascribed to its antioxidant properties. Herein we shall describe an efficient synthetic strategy to obtain a variety of new and more water-soluble silybin and 2,3-dehydrosilybin (DHS) derivatives in which the 23-hydroxyl group was converted to a sulfate, phosphodiester, or amine group, using a solution-phase approach. Furthermore a new and efficient method for the preparation of DHS from silybin was developed and optimised. The antioxidant properties of the new compounds were evaluated in a cellular model in vivo and they displayed an antioxidant activity comparable to or higher than silybin and DHS, being able to prevent H(2)O(2)-induced generation of intracellular reactive oxygen species (ROS). Most of the derivatives also displayed a better hydrophilicity while retaining the biological activities of silybin and they might broaden the in vivo applications of this class of natural compounds., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Novel hybrid oligonucleotides carrying the G-quadruplex-forming d(5'TGGGAG3') sequence, conjugated with mono- or disaccharides at the 3' or 5'-end through phosphodiester bonds, have been synthesized as potential anti-HIV agents, via a fully automated, online phosphoramidite-based solid-phase strategy. CD-monitored thermal denaturation studies on the resulting quadruplexes indicated the insertion of a single monosaccharide at the 3'-end as the optimal modification, conferring improved stability to the quadruplex complex. In addition, the 3'-conjugation with glucose or mannose converted the anti-HIV inactive unmodified oligomer into active compounds. On the contrary, the 5'-tethering with these monosaccharides, as well as the conjugation, either at the 5' or 3'-end, with sucrose, were in all cases detrimental to quadruplex stability and did not improve the biological activity. On the basis of the assumption that the kinetically and thermodynamically favored formation of the quadruplex complex is a prerequisite for efficient antiviral activity, a novel bis-conjugated oligonucleotide was designed. This combined a mannose residue at the 3'-phosphate end with bulky aromatic tert-butyldiphenylsilyl (TBDPS) group at the 5'-end, previously shown to markedly favor the formation of quadruplex complexes. The 5',3'-bis-conjugated 6-mer, for which a detailed biophysical characterization has been carried out, resulted in 3-fold greater antiviral activity against HIV-1 than the sole 3'-glyco-conjugated oligonucleotide.

We here describe the synthesis of a series of novel bicyclic ribonucleoside derivatives, with 18-crown-6 ether moieties attached via their ribose 2- and 3- positions, as first examples of crown ether ring-fused nucleosides, to be evaluated as antiviral and/or antitumoral agents.

Novel amphiphilic cyclic disaccharide analogues, in which the saccharide units are connected through stable phosphodiester linkages (CyPLOS, Cyclic Phosphate-Linked OligoSaccharides) and decorated with long lipophilic tentacles at the 2- and 3-OH moieties, have been synthesized. Their propensity to self-aggregation has been investigated by means of 1H and 31P NMR experiments, making it possible to determine for these macrocycles critical aggregation concentration values in the millimolar range.

Patulin is a toxic secondary metabolite of a number of fungal species belonging to the genera Penicillum and Aspergillus. It has been mainly isolated from apples and apple products contaminated with the common storage-rot fungus of apples, Penicillum expansum, but it has also been extracted from rotten fruits, moldy feeds, and stored cheese. Human exposure to patulin can lead to serious health problems, and according to a long-term investigation in rats, the World Health Organization has set a tolerable weekly intake of 7 ppb body weight. The content of patulin in foods has been restricted to 50 ppb in many countries. Conventional analytical detection methods involve chromatographic analyses, such as HPLC, GC, and, more recently, techniques such as LC/MS and GC/MS. However, extensive protocols of sample cleanup are required prior to the analysis, and to accomplish it, expensive analytical instrumentation is necessary. An immunochemical analytical method, based on highly specific antigen-antibody interactions, would be desirable, offering several advantages compared to conventional techniques, i.e., low cost per sample, high selectivity, high sensitivity, and high throughput. In this paper, the synthesis of two new derivatives of patulin is described, along with their conjugation to the bovine serum albumin for the production of polyclonal antibodies. Finally, a fluorescence competitive immunoassay was developed for the on-line detection of patulin.

[structure: see text] A new and versatile on-line automated solid-phase approach to obtain cyclic PNA (I and III) and cyclic PNA-DNA chimeras (II) in highly pure form has been developed. Starting from a Tentagel matrix functionalized with a 3-chloro-4-hydroxyphenylacetic linker, the synthesis of representative, new cyclic molecules by standard peptide and phosphoramidite-based chemistry has been achieved.

CyPLOS (cyclic phosphate-linked oligosaccharides), that is, novel cyclic oligosaccharide surrogates, consisting of two, three, and four phenyl-beta-D-glucopyranoside units, 4,6-linked through stable phosphodiester bonds, were prepared by a straightforward and efficient solid-phase protocol. The assembly of the linear precursors was achieved by standard phosphoramidite chemistry on an automated DNA synthesizer, using a suitably protected 4-phosphoramidite derivative of D-glucose as the building block. For the crucial cyclization step a phosphotriester methodology was exploited, followed by a mild basic treatment releasing the desired cyclic molecules in solution in a highly pure form. The cyclic dimer and trimer were also independently prepared by classical solution synthesis, basically following the same approach. The solution structural preferences of the cyclic dimer and trimer, obtained by detailed NMR analysis, are also reported.

The online solid-phase synthesis of oligonucleotides conjugated at the 3' end with [1-6]-linked oligosaccharide mimics having the O-glycosidic linkages replaced by amide bonds is here described. The assembly of the carbohydrate domain has been carried out by exploiting classical solid phase peptide synthetic protocols, starting from solid supports functionalized with 1-azido sugars, in association with suitably protected 1-azido uronic acids of glucose and lactose, chosen as model addition monomers. After the insertion of a flexible linker, elongation of the oligodeoxyribonucleotide (ODN) chain was performed by standard automated phosphoramidite protocols. 3'-Glycoconjugated 18-mers exhibited an increased enzymatic stability with respect to the same unmodified ODN sequence. UV thermal denaturation experiments showed that the presence of the oligosaccharide tail at the 3' end of the oligonucleotides did not negatively interfere with their duplex formation abilities.

An easy and efficient strategy to obtain new nucleoside based solid supports in which the nucleoside moieties have been anchored to the solid support through the nucleobase is here proposed. A simple and efficient solid-phase synthesis of 5' and 3'-derivatized uridine analogues has so been developed, following methodologies well established in organic chemistry.