Phytotherapeutic alternatives for neurodegenerative dementias: Scientific review, discussion and therapeutic proposal.

The incidence and prevalence of age-related neurodegenerative dementias have been increasing. There is no curative therapy and conventional drug treatment can cause problems for patients. Medicinal plants traditionally used for problems associated with ageing are emerging as a therapeutic resource. The main aim is to give a proposal for use and future research based on scientific knowledge and tradition. A literature search was conducted in several searchable databases. The keywords used were related to neurodegenerative dementias, ageing and medicinal plants. Boolean operators and filters were used to focus the search. As a result, there is current clinical and preclinical scientific information on 49 species used in traditional medicine for ageing-related problems, including neurodegenerative dementias. There are preclinical and clinical scientific evidences on their properties against protein aggregates in the central nervous system and their effects on neuroinflammation, apoptosis dysregulation, mitochondrial dysfunction, gabaergic, glutamatergic and dopaminergic systems alterations, monoamine oxidase alterations, serotonin depletion and oestrogenic protection. In conclusion, the potential therapeutic effect of the different medicinal plants depends on the type of neurodegenerative dementia and its stage of development, but more clinical and preclinical research is needed to find better, safer and more effective treatments.

Neuroprotective Potential of Ginkgo biloba in Retinal Diseases.

Like other tissues of the central nervous system, the retina is susceptible to damage by oxidative processes that result in several neurodegenerative disease such as age-related macular degeneration, diabetic retinopathy, glaucoma, ischaemic retinal disease, retinal disease produced by light oxidation, and detached retina, among other diseases. The use of antioxidant substances is a solution to some health problems caused by oxidative stress, because they regulate redox homeostasis and reduce oxidative stress. This is important for neurodegeneration linked to oxidation processes. In line with this, Ginkgo biloba is a medicinal plant with excellent antioxidant properties whose effects have been demonstrated in several degenerative processes, including retinal diseases associated with neurodegeneration. This review describes the current literature on the role of ginkgo in retinal diseases associated with neurodegeneration. The information leads to the conclusion that G. biloba extracts might be a good option to improve certain neurodegenerative retinal diseases, but more research is needed to determine the safety and efficacy of G. biloba in these retinal degenerative processes.

Effects of Crocus sativus L. Floral Bio-Residues Related to Skin Protection.

The cultivation of Crocus sativus L. to obtain the saffron spice generates a large amount of biowaste, constituted mainly by the flower's tepals. The aim of this work was to evaluate the antioxidant and dermo-protective effect of a complex methanolic extract of C. sativus tepals. The extract's major phenolic content was analyzed using ultra-high performance liquid chromatography with electrospray ionization, coupled with quadrupole-time-of-flight-mass spectrometry (UHPLC-ESI-QTOF-MS). Then, the antioxidant in vitro activity of the extract was studied and related to their chemical composition. Likewise, the effect on intracellular ROS levels in HepG2 and Hs27 cell culture was determined in normal culture and under hydrogen-peroxide-induced oxidative stress. Finally, tyrosinase, hyaluronidase, collagenase, elastase, and xanthine oxidase assays were carried out to determine the dermo-protective capacity of the extract. The high polyphenol content, including flavonoids and anthocyanins, explains the antioxidant effect of the extract both in vitro and in culture assays. The extract has a significant and remarkable protective capacity against oxidative stress induced in culture of the two studied cell lines. It is also remarkable in its ability to inhibit hyaluronidase, tyrosinase, and xanthine oxidase. Results pointed out this biowaste extract as a promising ingredient in the composition of cosmetics.

Phytochemical Analysis and Anti-Inflammatory Potential of Acanthus mollis L. Rhizome Hexane Extract.

The rhizomes of Acanthus mollis have traditionally been used for the treatment of several ailments involving inflammation. However, to the best of our knowledge, their chemical composition and pharmacological properties have not been studied until now. As a first approach, this study analyses the A. mollis rhizome hexane extract phytochemistry and its anti-inflammatory and antioxidant capacities in HepG2 and RAW 264.7 cell culture assays. Chemical profiling was performed with gas chromatography mass spectrometry without the modification of native molecules. Free phytosterols (such as ß-sitosterol) account for 70% of detected compounds. The anti-inflammatory capacity of the rhizome extract of A. mollis is mediated by the decrease in the NO production in RAW 264.7 that has previously been stimulated with lipopolysaccharide in a dose-dependent manner. Furthermore, HepG2 pre-treatment with the rhizome extract prevents any damage being caused by oxidative stress, both through ROS scavenge and through the antioxidant cellular enzyme system. In this respect, the extract reduced the activity of glutathione peroxidase and reductase, which were stimulated under oxidative stress conditions. Our results suggest that the extract from the rhizomes of A. mollis may constitute a potential source of natural products with anti-inflammatory activity and could validate the traditional use of A. mollis.

Neuroprotective Potential of Verbascoside Isolated from Acanthus mollis L. Leaves through Its Enzymatic Inhibition and Free Radical Scavenging Ability.

The phenomenon of today's ageing population has increased interest in the search for new active substances that delay the onset and development of neurodegenerative diseases. In this respect, the search for natural compounds, mainly phenolic compounds, with neuroprotective activity has become the focus of growing interest. Verbascoside is a phenylethanoid that has already presented several pharmacological activities. The purpose of this study is to isolate and identify verbascoside from Acanthus mollis leaves. Consequently, its neuroprotective ability through enzymatic inhibition and free radical scavenging ability has been analyzed both in vitro and in cell culture assays. The antioxidant capacity of verbascoside was evaluated in vitro through total antioxidant capacity, DPPH•, OH•, and O2•-scavenging activity assays. The effect of verbascoside on intracellular reactive oxygen species (ROS) levels of HepG2 and SH-SY5Y cell lines was studied in normal culture and under induced oxidative stress. The inhibitory ability of the phenylethanoid against several enzymes implied in neurodegenerative diseases (tyrosinase, MAO-A, and AChE) was analyzed in vitro. Verbascoside neuroprotective activity is at least in part related to its free radical scavenging ability. The effect of verbascoside on ROS production suggests its potential in the prevention of harmful cell redox changes and in boosting neuroprotection.

Medicinal plants and natural products as neuroprotective agents in age-related macular degeneration.

The retina may suffer neurodegenerative damages, as other tissues of the central nervous system do, and serious eye diseases may develop. One of them is age-related macular degeneration, which causes progressive loss of vision due to retina degeneration. Treatment of age-related macular degeneration focuses on antioxidant agents and anti-vascular endothelial growth factor compounds, among others, that prevent/diminish oxidative stress and reduce neovascularisation respectively. The phytochemicals, medicinal plants and/or plant-diet supplements might be a useful adjunct in prevention or treatment of age-related macular degeneration owing to their antioxidant and anti-vascular endothelial growth factor properties. This review article presents the most investigated plants and natural products in relation to age-related macular degeneration, such as saffron, ginkgo, bilberry and blueberry, curcuma or turmeric, carotenoids, polyphenols, and vitamins C and E. This study provides up-to-date information on the effects, treatments, safety and efficiency of these phytotherapy products.

Comparison of phenolic compounds profile and antioxidant properties of different sweet cherry (Prunus avium L.) varieties.

In the present work, three Spanish local varieties of Prunus avium (L.), as well as two foreign varieties were studied. The content of total phenols, flavonoids, anthocyanins, glucose and fructose of methanolic extracts from ripe fruits of each variety were analysed. A phytochemical profile of these cultivars was performed by UHPLC-qTOF-MS. The employed chromatographic method allowed a clear and rapid separation of the three main phenolic compound groups present in the extracts: hydroxycinnamic acids, anthocyanins and flavonoids. In addition, the extracts DPPH radical scavenging ability, as well as their capacity to affect xanthine/xanthine oxidase system, were determined. Finally, variations in ROS intracellular concentrations in HepG2 cell line cultures treated with cherry extracts were measured through DCFH-DA assay. All extracts showed a significant inhibitory effect on the xanthine/xanthine oxidase system. Differences between in vitro and in cell culture results evidence the interaction among the phenolic compounds of the extract.

Apoptotic and free radical scavenging properties of the methanolic extract of Gentianella alborosea.

Gentianella alborosea ("Hercampure") is a Peruvian species used in folk medicine for the treatment of a variety of health disorders. We tested the free radical scavenging (DPPH) and induction of apoptosis on a human uterus tumor cell line (HeLa) by its methanolic extract. The results showed a noticeable radical scavenging activity and a dose-dependent apoptotic effect.

Pyrazolo[3,4-c]pyridazines as novel and selective inhibitors of cyclin-dependent kinases.

Pyrazolopyridazine 1a was identified in a high-throughput screening carried out by BASF Bioresearch Corp. (Worcester, MA) as a potent inhibitor of CDK1/cyclin B and shown to have selectivity for the CDK family. Analogues of the lead compound have been synthesized and their antitumor activities have been tested. A molecular model of the complex between the lead compound and the CDK2 ATP binding site has been built using a combination of conformational search and automated docking techniques. The stability of the resulting complex has been assessed by molecular dynamics simulations and the experimental results obtained for the synthesized analogues have been rationalized on the basis of the proposed binding mode for compound 1a. As a result of the SAR study, monofuryl 1o has been synthesized and is one of the most active compounds against CDK1 of this series.

Chalcones as Promising Lead Compounds on Cancer Therapy.

Chalcones constitute a group of phenolic compounds that command an increasing interest on cancer research. Natural chalcones are widespread through the plant kingdom. The most abundant and investigated chalcones are isoliquiritigenin, flavokawain and xanthohumol, which are present in the Fabaceae, Piperaceae, Cannabaceae, and Moraceae families. These chalcones have been shown to be promising lead antitumor-chemopreventive drugs by three different activities: antioxidants, cytotoxic and apoptosis inducers. In the recent years, SAR (structure-activity relationship) has contributed towards the improvement of anticancer properties of chalcones by substituting aryl rings and introducing heterocyclic moieties. This review summarizes the anticancer activities shown by natural chalcones and the SAR and describes how different chemical moiety modifications could lead them to be therapeutically useful in the treatment of cancer.

Synthesis, biological activity, and quantitative structure-activity relationship study of azanaphthalimide and arylnaphthalimide derivatives.

A series of quinoline derivatives as aza analogues of the naphthalene chromophore and a series of "nonfused" tricyclic aromatic systems, in particular 5-arylquinolines and 5- or 6-aryl and heteroaryl naphthalene systems, were synthesized and evaluated for growth-inhibitory properties in several human cell lines. The analysis of quantitative structure-antitumor activity relationships for the growth-inhibitory properties is also reported. Findings suggest that these compounds may not express their cytotoxicity via interaction on DNA.

Synthesis, antitumor activity, molecular modeling, and DNA binding properties of a new series of imidazonaphthalimides.

A series of mono and bisintercalators based on the 5,8-dihydrobenz[de]imidazo[4,5-g]isoquinoline-4,6-dione system were synthesized and evaluated for growth inhibitory properties in several human cell lines. All target compounds showed activity in the micromolar range. Representative compounds were evaluated using UV--vis spectroscopy and viscosimetric determinations, showing that they behave as DNA intercalators. Molecular modeling techniques were used in order to rationalize the moderate activity observed for bisnaphthalimides.

Effect on tumor necrosis factor-α production and antioxidant ability of black alder, as factors related to its anti-inflammatory properties.

Alders exhibit several uses in different areas and also offer some nutritional and medicinal values. The bark and leaves from black alder [Alnus glutinosa (L.) Gaertn] are used in folk medicine for the treatment of inflammatory processes and other health disorders. This study assessed if an extract of A. glutinosa stem bark exhibits some biological properties linked to improving the inflammatory state, which could partly justify its ethnopharmacological use. Therefore, various aspects of antioxidant activity as well as the effect on tumor necrosis factor-α (TNF-α) production were evaluated. The phytochemical study revealed the presence of terpenes, saponins, tannins, flavonoids, and anthraquinones (by high-performance thin-layer chromatography). The betulinic acid content in the extract, determined by reversed-phase high-performance liquid chromatography (validated method), was 0.72±0.027%. In addition, high amounts for total phenols as well as flavonoids were determined. The extract exhibited a 2,2'-diphenylpicrylhydrazyl radical scavenging capacity similar to that of ascorbic acid and had a significant effect on superoxide anion scavenging, superior to that of ascorbic acid. It was also able to protect HeLa cells from induced oxidative stress. In the TNF-α assay, levels of this citokine were depressed by the extract in HL-60 cells. To test the effect of the extract on cell proliferation, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed. According to the results, the antioxidant properties displayed by the extract of A. glutinosa stem bark, together with the effect on TNF-α levels, suggest that these activities, linked to a successful reduction in inflammatory processes, may support, in part, its ethnopharmacological use.

Synthesis and biological evaluation of novel indolocarbazoles with anti-angiogenic activity.

A novel series of indolocarbazoles were synthesized and their antiproliferative activity against HUVEC, LoVo, DLD-1 and ST-486 cell lines, was investigated. Those staurosporine analogs in which a substituted dimethylaminoalkoxy chain was attached to the indolic nitrogen showed interesting activity and selectivity with respect to HUVEC proliferation. The effect on capillary tube formation in 3-dimensional matrigel matrix was studied using the most active compounds. Evaluation of their in vivo anti-angiogenic activity in a murine Lewis lung cancer model was also analyzed.

Peroxisome proliferator-activated receptorα agonists differentially regulate inhibitor of DNA binding expression in rodents and human cells.

Inhibitor of DNA binding (Id2) is a helix-loop-helix (HLH) transcription factor that participates in cell differentiation and proliferation. Id2 has been linked to the development of cardiovascular diseases since thiazolidinediones, antidiabetic agents and peroxisome proliferator-activated receptor (PPAR) gamma agonists, have been reported to diminish Id2 expression in human cells. We hypothesized that PPARα activators may also alter Id2 expression. Fenofibrate diminished hepatic Id2 expression in both late pregnant and unmated rats. In 24 hour fasted rats, Id2 expression was decreased under conditions known to activate PPARα. In order to determine whether the fibrate effects were mediated by PPARα, wild-type mice and PPARα-null mice were treated with Wy-14,643 (WY). WY reduced Id2 expression in wild-type mice without an effect in PPARα-null mice. In contrast, fenofibrate induced Id2 expression after 24 hours of treatment in human hepatocarcinoma cells (HepG2). MK-886, a PPARα antagonist, did not block fenofibrate-induced activation of Id2 expression, suggesting a PPARα-independent effect was involved. These findings confirm that Id2 is a gene responsive to PPARα agonists. Like other genes (apolipoprotein A-I, apolipoprotein A-V), the opposite directional transcriptional effect in rodents and a human cell line further emphasizes that PPARα agonists have different effects in rodents and humans.

Bioactive properties of Tynanthus panurensis (Bureau) Sanwith bark extract, the Amazonian "clavo huasca".

Tynanthus panurensis (Bureau) Sanwith (Bignoniaceae) is a liana vine used in traditional Amazonian medicine as a tonic and energizer as well as a treatment for rheumatism. These traditional indications prompted this study of the antioxidant and anti-inflammatory activities of T. panurensis bark extract (ETP). Phytochemical analysis of ETP showed the presence of saponins and a high concentration of phenols and flavonoids. A battery of in vitro tests revealed that the extract has free radical-scavenging antioxidant properties and reduces microsomal lipid peroxidation, uric acid synthesis, and tumor necrosis factor-α production. The anti-inflammatory properties of ETP were further confirmed in vivo in a rat carrageenan edema model, in which the extract exhibited a potent activity. These results support the idea that T. panurensis bark extract could be beneficial for treating inflammation and are in agreement with one of the main traditional uses of this plant.

Discovering a new analogue of thalidomide which may be used as a potent modulator of TNF-alpha production.

A new series of imide derivatives related to thalidomide were synthesized and evaluated as modulators of TNF-alpha production. These derivatives enhance TNF-alpha production using human leukemia HL-60 cells induced with 12-O-tetradecanoylphorbol 13-acetate (TPA), while inhibiting TNF-alpha production induced with okadaic acid (OA) in the same cell line. The diphenylmaleimide derivative 2f, was found to be the most active product, producing a strong modulation of the cytokine level.

Synthesis and biological activity of N,N-dialkylaminoalkyl-substituted bisindolyl and diphenyl pyrazolone derivatives.

New compounds, structurally related to the potent protein kinase C inhibitor staurosporine, with a bisindolylpyrazolone framework and substituted on the pyrazolone nitrogens with N,N-dialkylaminoalkyl side chain, were synthesized and evaluated for growth-inhibitory properties in several human cell lines. Many showed inhibition of TNF-alpha production in response to the tumor promotor TPA on HL-60 cells. The apoptotic activity on HeLa cells has been examined for several of these compounds.