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Graphical abstract Highlights • Management of cancers in advanced stages is a major challenge in daily practice of oncologists. • Anticancer drugs from natural sources such as trabectedin showed promising activities in randomized and controlled clinical trials. • Cancer biomarkers were recently developed for optimizing the use of these therapeutic agents and predicting their response. Abstract Intrinsic or acquired drug resistance, adverse drug reactions and tumor heterogeneity between and within cancer patients limit the efficacy of clinical management of advanced cancers. To overcome these barriers, predictive biomarkers have recently emerged to guide medical oncologists in the selection of cancer patients who will respond to various anticancer treatments and to improve the toxicity to benefit ratio. Notably, targeted therapy has significantly benefited from these advances, but the application of predictive biomarkers have been a bit slower with some drugs derived from natural sources such as trabectedin, cabazitaxel and alvocidib. In this paper, we discuss some recent advances regarding the use of cancer biomarkers to predict efficacy of some selected natural compounds with a focus on human clinical studies. [ABSTRACT FROM AUTHOR]

In recent years, there has been a great deal of attention toward the molecular machinery relevant to age-related progression controlled through the external intervention of polyphenols- an epigenetic-modulating diet. Natural products modulate cellular longevity through histone post-translational modification and can also induce the upregulation of autophagy, thus reducing the level of acetyl coenzyme A (AcCoA). In addition, the effect of caloric restriction (CR) on cancer-related chronic inflammation is of great significance in aging. In line with this, SIRT1 protein levels are expanded in response to calorie restriction mimetics (CRM), in this way acting as autophagy inducers relevant to cancer prevention. [ABSTRACT FROM AUTHOR]

Background Food choices represent a highly significant approach to combat human obesity. Dietary intake of lipids, especially polyunsaturated and monounsaturated fatty acids, is gaining popularity in the effort to reduce or eliminate the occurrence of obesity. Pecan ( Carya illinoinensis ) nuts are an abundant source of these dietary fatty acids. Moreover, they are a rich source of epigallocatechin-3-gallate (EGCG), a polyphenol with a variety of health-beneficial properties. Scope and approach In this review, we summarize the literature reports examining physiological effects associated with pecan nuts consumption and described effects of their bioactive constituents. Key findings and conclusions The growing body of evidence suggests including pecan nuts into obesity management strategies. The consumption of pecan nuts can mitigate inflammation by reducing the extent of the synthesis of inflammatory mediator molecules. Pecan nuts can also counteract the pro-inflammatory effects of a diet rich in commonly overconsumed saturated fatty acids, characteristic of the Western diet. Additionally, consumption of pecans and other nuts has been linked to reduced risk of physiological parameters associated with cardiovascular disease or metabolic disorders. Diets enriched with tree nuts and peanuts can modulate the blood level of cholesterol, adiposity, and insulin resistance. Almonds and walnuts have been so far the most studied nuts, and studies with them have led to a greater understanding of the protective effects of diverse tree nuts on human physiology. In this review, we summarize the available data indicating that pecan nuts exert similar health-promoting benefits. [ABSTRACT FROM AUTHOR]

Background: Neanotis wightiana (Wall. ex Wight & Arn) W.H. Lewis has been used in traditional medicine in India for the treatment of liver disorders. In fact, this plant is frequently used by the local people of Tripura for the treatment of liver disorder problems. In previous study on this plant we have isolated a hepatoprotective saponin, neanoside A.Purpose: Evaluation of in vivo hepatoprotective effects of isolated compounds from N. wightiana aerial parts on serum hepatic-biomarkers in CCl4- induced hepatotoxicity in rats to validate the traditional use of the plant.Study Design: This study was designed to isolate more hepatoprotective compounds from N. wightiana aerial parts and evaluate their in vivo hepatoprotective activity in animal model.Methods: The phytochemicals from the polar n-butanol fraction of methanolic extract of N. wightiana aerial parts were isolated by repeated column chromatography over Diaion HP-20 and silica gel. Among the isolated three compounds, two were known triterpenoids, ursolic acid and oleanolic acid. The new compound was named neanoside B and its structure was established as naphthalene diglucoside 1 on the basis of extensive spectroscopic (including 2D NMR) analysis. Furthermore, the hepatoprotective activity of 1 was evaluated on CCl4 -induced hepatic injured rats by oral administration at three doses (5, 10 mg and 20 mg/kg) for 7 d and the assay of serum hepatic injury marker enzymes, SGPT, SGOT, ALP and bilirubin contents and histopathological changes of injured liver tissue after 7 d The herbal hepatoprotective drug, silymarin (100 mg/kg) was as positive control.Results: The structure of the new compound, neanoside B (1) was elucidated as 1,4-dihydroxy-2-(methoxymethyl)naphthalen-3-yl-methyl-3-β-d-glucopyranosyl-(1→6)-β-d-glucopyranoside on the basis of extensive spectroscopic (including 2D-NMR) and chemical studies. The compound 1 exhibited significant in vivo hepatoprotective effect at the tested doses of 5, 10 and 20 mg/kg bw in CCl4-induced hepatotoxicity in rats. In a dose-dependent manner, 1 normalized the elevated levels of hepatic injury marker enzymes, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP) and total bilirubin and ameliorated the damage of liver tissue by reducing the necrosis and vacuoles. Possibly compound 1 ameliorated the hepatic damage in hepatotoxic rats by improving the antioxidant status. The higher dose (20 mg/kg) showed more hepatoprotective effect by reducing the elevated levels of SGPT, SGOT, ALP and bilirubin content to 388.5 ± 2.156, 160.7 ± 3.00, 198.6 ± 4.562 and 0.652 ± 0.036 IU/ml, respectively, compared to the levels in the control group (583.2 ± 6.922, 324.6 ± 4.711, 263.9 ± 4.939 and 1.533 ± 0.042 IU/ml, respectively) and the effect was comparable to that of the positive control silymarin (100 mg/kg bw) (389.4 ± 6.348, 167.9 ± 4.289, 203.3 ± 4.448 and 0.816 ± 0.030 IU/ml, respectively).Conclusions: This study indicated that isolated neanoside B (1) from Neanotis wightiana could be a potential drug in liver disorders. Further study in pharmacokinetics and long-term toxicity of compound 1 is requested for its clinical setting as effective drug in liver disorders. [ABSTRACT FROM AUTHOR]

Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product-based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a “screening hit” through a “drug lead” to a “marketed drug” is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis. While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future. [ABSTRACT FROM AUTHOR]

Background: The t(2;5)(p23;q35) chromosomal translocation results in the expression of the fusion protein NPM/ALK that when expressed in T-lymphocytes gives rise to anaplastic large cell lymphomas (ALCL). In search of new therapy options the dichloromethane extract of the ethnomedicinal plant Neurolaena lobata (L.) R.Br. ex Cass was shown to inhibit NPM/ALK expression.Purpose: Therefore, we analysed whether the active principles that were recently isolated and found to inhibit inflammatory responses specifically inhibit growth of NPM/ALK+ ALCL, leukaemia and breast cancer cells, but not of normal cells, and the intravasation through the lymphendothelial barrier.Methods: ALCL, leukaemia and breast cancer cells, and normal peripheral blood mononuclear cells (PBMCs) were treated with isolated sesquiterpene lactones and analysed for cell cycle progression, proliferation, mitochondrial activity, apoptosis, protein and mRNA expression, NF-κB and cytochrome P450 activity, 12(S)-HETE production and lymphendothelial intravasation.Results: In vitro treatment of ALCL by neurolenin B suppressed NPM/ALK, JunB and PDGF-Rβ expression, inhibited the growth of ALCL cells late in M phase, and induced apoptosis via caspase 3 without compromising mitochondrial activity (as a measure of general exogenic toxicity). Moreover, neurolenin B attenuated tumour spheroid intravasation probably through inhibition of NF-κB and CYP1A1.Conclusion: Neurolenin B specifically decreased pro-carcinogenic NPM/ALK expression in ALK+ ALCL cells and, via the inhibition of NF-kB signalling, attenuated tumour intra/extravasation into the lymphatics. Hence, neurolenin B may open new options to treat ALCL and to manage early metastatic processes to which no other therapies exist. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: The root bark of Lycium chinense Miller, Lycii Radicis Cortex, has been used in traditional Chinese medicine (TCM) to treat different inflammation-related symptoms, such as diabetes mellitus. The pro-inflammatory transcription factor nuclear factor kappa B (NF-?B) is a key regulator of inflammation, while the transcription factor peroxisome proliferator-activated receptor gamma (PPAR?) is a key modulator of genes involved in diabetes development. To identify putative active compound(s) from Lycii Radicis Cortex inhibiting NF-?B or activating PPAR?. Material and methods: Using activity-guided fractionation, six extracts with different polarity, isolated fractions, and purified compounds from Lycii Radicis Cortex were tested for NF-?B inhibition and PPAR? activation in vitro. The structure of the purified compounds was elucidated by NMR and MS techniques. Results: The ethyl acetate extract and the methanol extract of Lycii Radicis Cortex suppressed tumor necrosis factor alpha (TNF-?)-induced activation of NF-?B, while the dichloromethane extract activated PPAR?. Nine phenolic amide analogues, including trans-N-(p-coumaroyl)tyramine (1), trans-N-feruloyltyramine (2), trans-N-caffeoyltyramine (3), dihydro-N-caffeoyltyramine (4), three neolignanamides (5–7), and two lignanamide (8, 9), were isolated and their inhibitory potential on NF-?B was determined (1–4 were also contained in water decoction). Two of the nine isolated phenolic amides inhibited TNF-?-induced NF-?B activation. Trans-N-caffeoyltyramine was verified as the key component responsible for the NF-?B inhibition with an IC50 of 18.4?M in our cell-based test system. Activation of PPAR? was attributed to a palmitic-acid enriched fraction which displayed concentration-dependent effect ablated upon co-treatment with the PPAR? antagonist T0070907. Conclusions: Phenolic amides were confirmed as main components from Lycii Radicis Cortex responsible for NF-?B inhibition. Fatty acids were identified as the major plant constituent responsible for the PPAR? activation. Structure-activity relationship analysis suggests that the NF-?B inhibitory activity of trans-N-caffeoyltyramine may be attributed to its Michael acceptor-type structure (?,?-unsaturated carbonyl group). The data of this study contribute to a better understanding of the molecular mechanism of action of Lycii Radicis Cortex extracts in the context of inflammation. [Copyright &y& Elsevier]

Abstract: Background: Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPARγ activators. Methods: We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPARγ agonists. Results: The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPARγ ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPARγ ligand-binding domain (LBD) and acted as partial agonist in a PPARγ-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain. Conclusion: We identified honokiol as a partial non-adipogenic PPARγ agonist in vitro which prevented hyperglycemia and weight gain in vivo. General significance: This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine. [Copyright &y& Elsevier]

Abstract: Endothelial nitric oxide synthase (eNOS) mediates important vaso-protective and immunomodulatory effects. Aim of this study was to examine whether lignan derivatives isolated from the roots of the anti-inflammatory medicinal plant Krameria lappacea influence eNOS activity and endothelial nitric oxide (NO) release. The study was performed using cultured human umbilical vein endothelial cells (HUVECs) and HUVEC-derived EA.hy926 cells. Among the eleven isolated compounds only 2-(2,4-dihydroxyphenyl)-5-(E)-propenylbenzofuran (DPPB) was able to increase eNOS enzyme activity. DPPB (1–10μM) treatment for 24h induced a significant and dose-dependent increase in eNOS activity as determined by the [14C]l-arginine/[14C]l-citrulline conversion assay. Immunoblotting studies further revealed a time-dependent DPPB-induced increase in eNOS-Ser1177 and decrease in eNOS-Thr495 phosphorylation, as well as increased AMPK phosphorylation at Thr172, whereas Akt phosphorylation at Ser473 was not affected. Si-RNA-mediated knockdown of AMPK and inhibition of CaMKKβ by STO 609, as well as intracellular Ca2+ chelation by Bapta AM abolished the stimulating effect of DPPB on eNOS-Ser1177 and AMPK-Thr172 phosphorylation. Furthermore, we could show that DPPB increases intracellular Ca2+ concentrations assessed with the fluorescent dye Fluo-3-AM. DPPB enhances eNOS activity and endothelial NO release by raising intracellular Ca2+ levels and increases signaling through a CaMKKβ–AMPK dependent pathway. [Copyright &y& Elsevier]

Abstract: Various inflammatory stimuli that activate the nuclear factor kappa B (NF-κB) signaling pathway converge on a serine/threonine kinase that displays a key role in the activation of NF-κB: the I kappa B kinase β (IKK-β). Therefore, IKK-β is considered an interesting target for combating inflammation and cancer. In our study, we developed a ligand-based pharmacophore model for IKK-β inhibitors. This model was employed to virtually screen commercial databases, giving a focused hit list of candidates. Subsequently, we scored by molecular shape to rank and further prioritized virtual hits by three-dimensional shape-based alignment. One out of ten acquired and biologically tested compounds showed inhibitory activity in the low micromolar range on IKK-β enzymatic activity in vitro and on NF-κB transactivation in intact cells. Compound 8 (2-(1-adamantyl)ethyl 4-[(2,5-dihydroxyphenyl)methylamino]benzoate) represents a novel chemical class of IKK-β inhibitors and shows that the presented model is a valid approach for identification and development of new IKK-β ligands. [Copyright &y& Elsevier]

Abstract: Mineralocorticoid receptor (MR) activation in renal epithelial cells in response to the binding of aldosterone has long been implicated in the maintenance of body salt and fluid homeostasis and blood pressure control. 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is believed to confer specificity on aldosterone to activate MR by inactivating 11β-hydroxyglucocorticoids (corticosterone, cortisol) that are 100–1000 times more abundant in plasma than aldosterone and that can also bind and activate MR. Increasing evidence, however, challenges such a simple view of MR activation as well as its interaction with glucocorticoids and 11β-HSDs. In non-epithelial tissues including brain, cardiomyocytes and macrophages, 11β-hydroxyglucocorticoids seem to act as MR antagonists, and redox changes and signaling events may play pivotal roles for receptor activation in these tissues. This review addresses the emerging new view of the complex mechanisms underlying MR specificity of action, with a diversity of physiological roles and functions in different mineralocorticoid-responsive tissues. [Copyright &y& Elsevier]

Abstract: Hexose-6-phosphate dehydrogenase (H6PDH) has been shown to stimulate 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)-dependent local regeneration of active glucocorticoids. Here, we show that coexpression with H6PDH results in a dramatic shift from 11β-HSD1 oxidase to reductase activity without affecting the activity of the endoplasmic reticular enzyme 17β-HSD2. Immunoprecipitation experiments revealed coprecipitation of H6PDH with 11β-HSD1 but not with the related enzymes 11β-HSD2 and 17β-HSD2, suggesting a specific interaction between H6PDH and 11β-HSD1. The use of the 11β-HSD1/11β-HSD2 chimera indicates that the N-terminal 39 residues of 11β-HSD1 are sufficient for interaction with H6PDH. An important role of the N-terminus was indicated further by the significantly stronger interaction of 11β-HSD1 mutant Y18-21A with H6PDH compared to wild-type 11β-HSD1. The protein–protein interaction and the involvement of the N-terminus of 11β-HSD1 were confirmed by Far-Western blotting. Finally, fluorescence resonance energy transfer (FRET) measurements of HEK-293 cells expressing fluorescently labeled proteins provided evidence for an interaction between 11β-HSD1 and H6PDH in intact cells. Thus, using three different methods, we provide strong evidence that the functional coupling between 11β-HSD1 and H6PDH involves a direct physical interaction of the two proteins. [Copyright &y& Elsevier]

Abstract: The aim of this study is to establish and calculate the exact allometric relationship between the total metabolic energy per life span and the body mass in a wide range of mammals with about six orders of magnitude variation of the body mass of animals. The study shows that it exists a linear relationship between the total metabolic energy per life span PT ls (kJ) and the body mass M (kg) of 95 mammals (3 monotremes, Subclass Prototheria, 16 marsupialis (Subclass Theria, Infraclass Metatheria) and 76 placentals (Subclass Theria, Infraclass Eutheria)) from type: PT ls = A ls + M 1.0511, where P (kJ/day) is the basal rate of metabolism and T ls (days) is the mean life span of animals. The linear coefficient A ls + =7.158×105 kJ/kg is the total metabolic energy, exhausted during the life span per 1kg body mass of the animals. The mean values of the total metabolic energy per life span, per unit body mass (A ls) for orders from Subclass Prototheria and Theria (Infraclass Metatheria) and orders Xenarthra, Pholidota, Soricomorpha, Rodentia (Infraclass Eutheria) varied negligible in interval (4.656–5.80)×105 kJ/kg. The coefficient A ls grows from (7.68–8.36)×105 kJ/kg in Lagomorpha and Artiodactyla (Eutheria) to (10.58–12.64)×105 kJ/kg in orders Carnivora, Pinnipeda and Chiroptera (Eutheria). A ls grows maximum to 18.5×105 kJ/kg in Primates. Thus, the values of coefficient A ls differ maximum four-fold in all orders. Across the all species the values of A ls are changes about one order of magnitude. Consequently, our survey shows that the changes of the body mass, basal metabolic rate and the life span of animals are three mutually related parameters, so that the product A ls =(PT ls)/M remains relatively constant in comparison to 1 million fold difference in body mass and total metabolic energy per life span between mammals. [Copyright &y& Elsevier]

Abstract: 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is essential for the local activation of glucocorticoid receptors (GR). Unlike unliganded cytoplasmic GR, 11β-HSD1 is an endoplasmic reticulum (ER)-membrane protein with lumenal orientation. Cortisone might gain direct access to 11β-HSD1 by free diffusion across membranes, indirectly via intracellular binding proteins or, alternatively, by insertion into membranes. Membranous cortisol, formed by 11β-HSD1 at the ER-lumenal side, might then activate cytoplasmic GR or bind to ER-lumenal secretory proteins. Compartmentalization of 11β-HSD1 is important for its regulation by hexose-6-phosphate dehydrogenase (H6PDH), which regenerates cofactor NADPH in the ER lumen and stimulates oxoreductase activity. ER-lumenal orientation of 11β-HSD1 is also essential for the metabolism of the alternative substrate 7-ketocholesterol (7KC), a major cholesterol oxidation product found in atherosclerotic plaques and taken up from processed cholesterol-rich food. An 11β-HSD1 mutant adopting cytoplasmic orientation efficiently catalyzed the oxoreduction of cortisone but not 7KC, indicating access to cortisone from both sides of the ER-membrane but to 7KC only from the lumenal side. These aspects may be relevant for understanding the physiological role of 11β-HSD1 and for developing therapeutic interventions to control glucocorticoid reactivation. [Copyright &y& Elsevier]

Abstract: A linear relationship exists between total metabolic energy per life span PT ls (kJ) and body mass M (kg) of 54 poikilothermic species (Protozoa, Nematoda, Mollusca, Asteroidae, Insecta, Arachnoidae, Crustacea, Pisces, Amphibia, Reptilia and Snakes): PT ls = M 1.0838, where P (kJ/day) is the rate of metabolism and T ls (days) is the life span of animals. The linear coefficient =3.7×105 kJ/kg is the total metabolic energy, exhausted during the life span per 1kg body mass of animals. This linear coefficient can be regarded as relatively constant metabolic parameter for poikilothermic organisms, ranging from 0.1×105 to 5.5×105 kJ/kg, in spite of 17-degree differences between metabolic rate and body mass of animals. A linear relationship between total metabolic energy per life span and body mass of only 48 poikilothermic multicellular animals (without Protozoa) is: PT ls = M 0.9692 with linear coefficient =2.34×105 kJ/kg. Since a power relationship exists between the rate of metabolism and body mass of animals of the type: P = aM k (a and k are the alometric constants), an empiric rule could be formulated, that life span is a time interval for which the total metabolic energy per life span becomes proportional to body mass of animals and power coefficient k becomes ≈1.0. [Copyright &y& Elsevier]

By interconverting glucocorticoids, llβ-hydroxysteroid dehydrogenase type 1 (llβ-HSD1) exerts an important pre-receptor function and is currently considered a promising therapeutic target. In addition, l1&betaHSD1 plays a potential role in 7-ketocholesterol metabolism. Here we investigated the role of the Nterminal region on enzymatic activity and addressed the relevance of llβ-HSD1 orientation into the endoplasmic reticulum (ER) lumen. Previous studies revealed that the luminal orientation of llβ-HSD1 and 50-kDa esterase/arylacetamide deacetylase (E3) is determined by their highly similar N-terminal transmembrane domains. Substitution of Lys5 by Set in llβ-HSD1, but not of the analogous Lys4 by Ile in E3, led to an inverted topology in the ER membrane, indicating the existence of a second topological determinant. Here we identified Glu25/Glu26 in llβ.HSD1 and Asp25 in E3 as the second determinant for luminal orientation. Our results suggest that the exact location of specific residues rather than net charge distribution on either side of the helix is critical for membrane topology. Analysis of charged residues in the N-terminal domain revealed an essential role of Lys35/Lys36 and Glu25/Glu26 on enzymatic activity, suggesting that these residues are responsible for the observed stabilizing effect of the N-terminal membrane anchor on the catalytic domain of llβ-HSD1. Moreover, activity measurements in intact cells expressing wildtype llβ-HSD1, facing the ER lumen, or mutant K5S/ K6S, facing the cytoplasm, revealed that the luminal orientation is essential for efficient oxidation of cortisol. Furthermore, we demonstrate that llβ-HSD1, but not mutant K5S/K6S with cytoplasmic orientation, catalyzes the oxoreduction of 7-ketocholesterol. llβ-HSD1 and E3 constructs with cytosolic orientation of their catalytic moiety should prove useful in future studies addressing the physiological function of these proteins. [ABSTRACT FROM AUTHOR]

A rapid screening assay for chemicals inhibiting 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 or type 2 using lysates from stably transfected cells was developed. Here, we tested a series of environmental chemicals for anti-11β-HSD activities. Inhibition of 11β-HSD2, which may cause cortisol-dependent activation of the mineralocorticoid receptor with sodium retention and hypertension, was observed for several compounds, with diethylcarbamate being the most potent inhibitor (IC50 6.3 μM). Abietic acid inhibited both 11β-HSD1 (IC50 27 μM for reduction and 2.8 μM for oxidation) and 11β-HSD2 (IC50 12 μM). Our results demonstrate for the first time that flavanone selectively inhibits 11β-HSD1 reductase activity: this enzyme being considered as essential for the local activation of glucocorticoids and representing a potential target for the therapeutic treatment of diabetes type 2. Flavanone and 2′-hydroxyflavanone efficiently inhibited reductive (IC50 18 and 10 μM) but not oxidative activity. We observed a reduced inhibitory effect of hydroxylated flavanone derivatives and of flavones containing a double-bond between atom C2 and C3. Flavanone was specific for 11β-HSD1 and did not inhibit 11β-HSD2. Our results reveal that a variety of environmental compounds exert distinct inhibitory effects on 11β-HSD1 and 11β-HSD2, opening the possibility for selectively modulating local cortisone/cortisol availability in vivo. [Copyright &y& Elsevier]

The power coefficient k decreases along evolution in an allometric relationship between the oxygen consumption rate and the body mass of animals. This theoretical study investigated the role of the power coefficient k and its behavior along evolution. The animals were organized in three groups according to the values of the power coefficient k as follows: (I) from unicellular Prokaryotes to Eukaryotes; (II) from Mytilus and Annelida to Pisces; (III) from Reptilia to Mammals and Aves. At the beginning of each animal group (stage), the value of k was close to 0.9–1.0 and at the end of the stage it was close to 0.67–0.70. Exponential sharp increase of the power coefficient k was observed during the biological transition from Protozoa to simply organized Metazoa and in the transition from Poikylothermic to Homothermic organisms (e.g. from Pisces to Reptilia). Also, when using the periodogram regression analysis, a cyclic (periodic) pattern in this increase was observed (i.e. period T&ap;8–11 units, P<0.05). It was postulated that the power coefficient k, as with the coefficient a, might represent the increase of complexity of animal organization within each group. [Copyright &y& Elsevier]

Background: Tylophorine (TYL) is an alkaloid with antiproliferative action in cancer cells. Vascular smooth muscle cell (VSMC) proliferation and neointima formation contribute to restenosis after percutaneous coronary interventions.Hypothesis/purpose: Our goal was to examine the potential of TYL to inhibit VSMC proliferation and migration, and to dissect underlying signaling pathways.Study Design and Methods: TYL was administered to platelet-derived growth factor (PDGF-BB)-stimulated, serum-stimulated, quiescent and unsynchronized VSMC of rat and human origin. BrdU incorporation and resazurin conversion were used to assess cell proliferation. Cell cycle progression was analyzed by flow cytometry of propidium iodide-stained nuclei. Expression profiles of proteins and mRNAs were determined using western blot analysis and RT-qPCR. The Click-iT OPP Alexa Fluor 488 assay was used to monitor protein biosynthesis.Results: TYL inhibited PDGF-BB-induced proliferation of rat aortic VSMCs by arresting cells in G1 phase of the cell cycle with an IC50 of 0.13 µmol/l. The lack of retinoblastoma protein phosphorylation and cyclin D1 downregulation corroborated a G1 arrest. Inhibition of proliferation and cyclin D1 downregulation were species- and stimulus-independent. TYL also decreased levels of p21 and p27 proteins, although at later time points than observed for cyclin D1. Co-treatment of VSMC with TYL and MG132 or cycloheximide (CHX) excluded proteasome activation by TYL as the mechanism of action. Comparable time-dependent downregulation of cyclin D1, p21 and p27 in TYL- or CHX-treated cells, together with decreased protein synthesis observed in the Click-iT assay, suggests that TYL is a protein synthesis inhibitor. Besides proliferation, TYL also suppressed migration of PDGF-activated VSMC. In a human saphenous vein organ culture model for graft disease, TYL potently inhibited intimal hyperplasia.Conclusion: This unique activity profile renders TYL an interesting lead for the treatment of vasculo-proliferative disorders, such as restenosis. [ABSTRACT FROM AUTHOR]

The current study aimed to identify and analyze the 100 most cited papers on the topic of nutraceuticals and functional foods. Scopus database was searched to extract bibliometric data. Two-thirds of the 100 most cited papers were reviews. Papers were mostly published in food science and nutrition journals, and one-third were published in seven journals, namely: British Journal of Nutrition (6), Critical Reviews in Food Science and Nutrition (6), Journal of Food Science (5), Trends in Food Science and Technology (5) , American Journal of Clinical Nutrition (4) , Food Chemistry (4) and Journal of Nutrition (4). Topics with high citation counts dealt with prebiotics, probiotics, antioxidants and phenolic content. Hot topics with over 1000 citations per paper include bifidobacterium (1147), colon (1032) and lipid metabolism (1013). The United States and Europe were major places of origin. These results can serve as a quick benchmarking reference for researchers or general public members. [ABSTRACT FROM AUTHOR]

Plants used in traditional medicine represent an important source of new lead compounds. However, cell-based in vitro screening assays with plant material are hampered by the complex nature of plant extracts as mixtures of active and inactive components. Bulk constituents, such as chlorophyll and polyphenols were previously shown to interfere with several biological in vitro assays. Their influence on anti-inflammatory cell-based testing systems has not been thoroughly investigated. Hence, the present study was aimed at comparing different procedures for the removal of bulk constituents from plant extracts and examining the influence of their elimination on selected cell-based anti-inflammatory assays. Malva sp. and Glechoma hederacea L., two plants used in traditional European medicine for the treatment of inflammatory disorders, were subjected to three different methods for the removal of chlorophyll and polyphenols, respectively. Removal of bulk constituents was confirmed by HPLC and mass spectrometry. Extracts were tested before and after the purification procedure, to determine their potential to inhibit the activation of the transcription factor NF-κB in reporter gene assay and to interfere with the secretion of the chemokine IL-8 after stimulation of endothelial cells with tumor necrosis factor (TNF-α) or lipopolysaccharide (LPS). Removal of chlorophyll from tested extracts led to a strong decrease in the anti-inflammatory activities, due to loss of bioactive constituents. In contrast, the effect of the polyphenol-free extracts was either not changed or significantly increased, depending on the purification method used. The study concluded that clearance of bulk compounds represents a valuable strategy for cell-based in vitro anti-inflammatory evaluation of plant extracts. Liquid–liquid partitioning was identified as the optimal method for the elimination of both chlorophyll and polyphenols. It is recommended that removal of chlorophyll from extracts always be accompanied by HPLC profiling to detect a possible loss of active constituents. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Walnut, Juglans regia L. (Juglandaceae), is one of the medicinal plants used to treat diabetic symptoms in Austrian folk medicine. The air-dried green leaves are either used as aqueous decoctions or liquor preparations and are consumed on a daily basis. We investigated the hypoglycemic effect of a methanolic Juglans regia leaf extract on glucose uptake, protein tyrosine phosphatase 1B (PTP1B) inhibition and peroxisome proliferator-activated receptor gamma (PPARγ) activation. Material and methods: Hypoglycemic activity was assessed by glucose-uptake in C2C12 myocytes, inhibition of PTP1B and activation of PPARγ. Phytochemical characterization of the extract was carried out by LC–MS and GC–MS. Results: Methanolic Juglans regia leaf extract enhanced the glucose uptake rate in C2C12 myocytes at concentrations of 25µg/mL compared to untreated cells. This activity may partly be explained by the inhibition of PTP1B but not PPARγ agonism. LC–MS analyses revealed chlorogenic acid (1), 3-p-coumaroylquinic acid (2), a trihydroxynaphthalene-hexoside (3), as well as eight flavonoids (4–11) as main phenolic constituents in the active extract. Conclusions: The finding that Juglans regia leaf extract enhances glucose uptake and inhibits PTP1B provides an in vitro-based rationale for the traditional use of walnut leaf preparations against elevated blood-glucose levels. [Copyright &y& Elsevier]

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Black pepper, the fruits of Piper nigrum L., is well known as "the king of spices" and used as seasoning and condiments globally. In addition to being an important food additive, black pepper is also used as a traditional medicine to treat vomiting, abdominal pain, and diarrhea, among others. Piperine is a major pungent alkaloid identified in the fruits of P. nigrum (black pepper), whose content is at a range of ~5–13%. Black pepper and piperine have shown protective effect on CVDs. Literature search was conducted to systematically review the cardiovascular protective effect of both black pepper and its major bioactive constituent piperine. Black pepper was reported to regulate lipid metabolism, inflammation, and oxidation status in CVDs. Piperine exhibited beneficial effect by targeting many processes associated with atherosclerosis. Piperine is able to prevent lipid peroxidation, oxidized low-density lipoprotein uptake in macrophages, lipid droplet formation, and adhesion of inflammatory cells to endothelial monolayer, promote cholesterol efflux from macrophages, as well as improve lipid profile. Besides, piperine may ameliorate myocardial ischemia, cardiac injury, and cardiac fibrosis, exhibit antihypertensive and antithrombosis effect, as well as prevent arterial stenosis by inhibiting vascular smooth muscle cell proliferation. The summarized information could provide the basis to develop black pepper or piperine as a food additive to prevent or treat CVDs. [Display omitted] • Black pepper regulates lipid metabolism, inflammation, and oxidation status. • Piperine has beneficial effects in many processes of atherosclerosis development. • Piperine attenuated hypertension, cardiac injury and cardiac fibrosis. • Black pepper and piperine exhibited cardiovascular protective effects. [ABSTRACT FROM AUTHOR]

Abstract: Glucocorticoids play an essential role in the regulation of key physiological processes, including immunomodulation, brain function, energy metabolism, electrolyte balance and blood pressure. Exposure to naturally occurring compounds or industrial chemicals that impair glucocorticoid action may contribute to the increasing incidence of cognitive deficits, immune disorders and metabolic diseases. Potentially, “glucocorticoid disruptors” can interfere with various steps of hormone action, e.g. hormone synthesis, binding to plasma proteins, delivery to target cells, pre-receptor regulation of the ratio of active versus inactive hormones, glucocorticoid receptor (GR) function, or export and degradation of glucocorticoids. Several recent studies indicate that such chemicals exist and that some of them can cause multiple toxic effects by interfering with different steps of hormone action. For example, increasing evidence suggests that organotins disturb glucocorticoid action by altering the function of factors that regulate the expression of 11β-hydroxysteroid dehydrogenase (11β-HSD) pre-receptor enzymes, by direct inhibition of 11β-HSD2-dependent inactivation of glucocorticoids, and by blocking GR activation. These observations emphasize on the complexity of the toxic effects caused by such compounds and on the need of suitable test systems to assess their effects on each relevant step. [Copyright &y& Elsevier]

A comprehensive study was performed for the first time to compare two structurally related substance classes, namely indazole-5-carboxamides (11 – 16) and (indazole-5-yl)methanimines (17 – 22). Both chemical entities are potent, selective and reversible MAO-B inhibitors and, therefore, may serve as promising lead structures for the development of drug candidates against Parkinson's disease (PD) and other neurological disorders. Compounds 15 (K i = 170 pM, SI = 25907) and 17 (K i = 270 pM, SI = 16340) were the most potent and selective MAO-B inhibitors in both series. To investigate the multi-target inhibitory activity, all compounds were further screened for their potency against human AChE and BuChE enzymes. Compound 15 was found to be the most potent and selective AChE inhibitor in all series (h AChE IC 50 = 78.3 ± 1.7 μM). Moreover, compounds 11 and 17 showed no risk of drug-induced hepatotoxicity and a wider safety window, as determined in preliminary cytotoxicity screening. Molecular modeling studies into the human MAO-B enzyme-binding site supported by a HYDE analysis suggested that the imine linker similarly contributes to the total binding energy in methanimines 17 – 22 as the amide spacer in their carboxamide analogs 11 – 16. Amplified photophysical evaluation of compounds 17 and 20 , including single X-ray analysis, photochemical experiments, and quantum-chemical calculations, provided insights into their more favourable isomeric forms and structural features, which contribute to their biologically active form and promising drug-like properties. Image 1 • A comparative study of carboxamides vs. methaimines as selective and reversible MAO-B inhibitors has been performed. • Methanimines 17 – 22 exhibit similar or even higher potency against h MAO-B than their carboxamide analogs 11 – 16. • Compounds 11 and 17 showed no risk of drug-induced hepatotoxicity. [ABSTRACT FROM AUTHOR]

Natural compounds are often characterized by high biological activity and sometimes toxicity. This also applies to compounds contained in the herb mistletoe. The objective of this study was to investigate short-term effects (up to 48 h) of mistletoe toxins on mouse hepatocytes. Standardized mistletoe extract Iscador P was given to female mice as a single injection (0.1 mg/kg b.w., 1 mg/kg b.w., or 2 mg/kg b.w). Activities of lysosomal hydrolases: acid phosphatase, cathepsins D and L, N-acetyl-β-D-hexosaminidase, β-D-glucuronidase, β-D-glucosidase and cytosolic proteases: arginine and leucine aminopeptidases were analyzed in the liver fractions 24 and 48 h after the injection. The morphology of hepatocytes was examined by light and transmission electron microscopy. Iscador P caused a decrease in the activity of all lysosomal hydrolases (except cathepsins) in the lysosomal pellet, and an increase in the activity of both aminopeptidases and β-D-glucuronidase in the cytosol. However, despite membranotropic properties of the viscotoxins, we did not find a significant labilising effect on the lysosomal membranes. Only β-D-glucuronidase activity was relocated to the supernatant of lysosomal fraction. Microscopic examinations revealed that hepatocyte mitochondria were enlarged and increased in number, whereas the surface of the rough endoplasmic reticulum was decreased significantly. • Short-term effects of mistletoe toxins on the mouse hepatocytes were investigated. • Decrease in the activity of almost all hydrolases in lysosomal fraction was noted. • Reduction in the number of primary lysosomes was observed. • Mistletoe extract induces changes in intracellular degradation processes. [ABSTRACT FROM AUTHOR]

Highlights • MIF acts cytokine, enzyme, endocrine hormone and chaperon-like molecule. • D-DT, a member of the MIF family, exerts non-redundant effects from MIF. • MIF and D-DT are up-regulated in immune-inflammatory, and chronic disorders. • Inhibition of MIF and/or D-DT may represent a novel therapeutic avenue. Macrophage migration inhibitory factor (MIF) is a protein that acts as a cytokine-, enzyme-, endocrine- and chaperon-like molecule. It binds to the cell-surface receptor CD74 in association with CD44, which activates the downstream signal transduction pathway. In addition, MIF acts also as a noncognate ligand for C-X-C chemokine receptor type 2 (CXCR2), type 4 (CXCR4), and type 7 (CXCR7). Recently, D-dopachrome tautomerase (D-DT), a second member of the MIF superfamily, was identified. From a pharmacological and clinical point of view, the nonredundant biological properties of MIF and D-DT anticipate potential synergisms from their simultaneous inhibition. Here, we focus on the role of MIF and D-DT in human immune-inflammatory, autoimmune, and chronic respiratory diseases, providing an update on the progress made in the identification of specific small-molecule inhibitors of these proteins. Teaser MIF and D-DT exert a broad range of functions, and their expression is often dysregulated in immune-inflammatory and chronic disorders. Pharmacological strategies targeting MIF and/or D-DT could represent a novel therapeutic avenue for human diseases. [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance The genus Vanda (Family: Orchidaceae) comprises about 73 species mainly distributed in Southeast Asia. Plants belonging to this genus are being used in the traditional medicine systems in Asian countries specially in India, Nepal, China and Bangladesh. Aim of the review The aim of this work was to review the scientific work about medicinal orchids of the genus Vanda regarding their traditional uses, reported bioactive components, and pharmacological activities. Materials and methods The information related to traditional uses, pharmacological activities, and bioactive compounds was systematically collected from the scientific literature databases including SciFinder, Scopus, PubMed and Google Scholar, published books and conference proceedings. Results The literature survey revealed diverse traditional uses of different species of Vanda , mainly against indigestion, wounds, hepatitis, dyspepsia, bronchitis, piles, rheumatism, and bone fracture. However, only few of them are investigated scientifically for their chemical constituents and pharmacological activities. Bioactive compounds including eucomic acid derivatives, phenanthrene derivatives and other phenolic compounds are reported from Vanda species. Different extracts were so far evaluated for number of pharmacological activities including neuroprotective, anti-aging, antimicrobial, anti-inflammatory, antioxidant, membrane stabilizing, wound healing and hepato-protective activities. Conclusion Vanda spp. are of much significance as ornamental flowers, but also used widely in traditional medicines and have potential for their diverse pharmacological activities. However, many members of the genus Vanda need further detailed studies regarding chemical constituents and mechanism-based pharmacological activities. Similarly, further studies should also focus on the conservation, cultivation and sustainable utilization of these species. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Abstract An extensive study was performed to develop a series of (pyrrolo-pyridin-5-yl)benzamides as reversible MAO-B inhibitors. Compounds 14 (NTZ-2020, h MAO-B IC 50 = 1.11 nM, K i = 0.56 nM, >9000-fold selective versus MAO-A) and 15 (NTZ-2027, h MAO-B IC 50 = 3.27 nM, K i = 1.45 nM, SI > 3058) are identified as the most promising BBB permeable derivatives within the series of (1 H -pyrrolo[3,2- b ]pyridine-5-yl)benzamides, combining both high potency and selectivity with optimal physicochemical and drug-like properties required for CNS active drugs. Extended photophysical analysis, including single X-ray analysis, quantum-chemical calculations and spectroscopic experiments provided insights into their tautomerism and structural behavioral, which relates to their biologically active form. The reversible MAO-B inhibitor 14 (NTZ-2020) exhibits a neuroprotective effect on cortical neuron survival and induces neurite network outgrowth. These effects are associated with a good BBB penetration of 14 that was confirmed in a triple cell neurovascular unit (NVU) model. Graphical abstract Image 1 Highlights • Selective and reversible MAO-B inhibitors have been developed. • (Pyrrolo-pyridin-5-yl)benzamides 10 , 14 – 16 show high BBB in vitro permeability. • Compound 15 exhibits also excellent water solubility. • Compound 14 showed a large neuroprotective effect on cortical neurons. • The neuroprotective effect of 14 observed also in a cell-based neurovascular unit model (+BBB). [ABSTRACT FROM AUTHOR]

Many natural products have been so far tested regarding their potency to inhibit vascular smooth muscle cell proliferation, a process involved in atherosclerosis, pulmonary hypertension and restenosis. Compounds studied in vitro and in vivo as VSMC proliferation inhibitors include, for example indirubin-3′-monoxime, resveratrol, hyperoside, plumericin, pelargonidin, zerumbone and apamin. Moreover, taxol and rapamycin, the most prominent compounds applied in drug-eluting stents to counteract restenosis, are natural products. Numerous studies show that natural products have proven to yield effective inhibitors of vascular smooth muscle cell proliferation and ongoing research effort might result in the discovery of further clinically relevant compounds. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are a major cause of human death worldwide. Excessive proliferation of vascular smooth muscle cells contributes to the etiology of such diseases, including atherosclerosis, restenosis, and pulmonary hypertension. The control of vascular cell proliferation is complex and encompasses interactions of many regulatory molecules and signaling pathways. Herein, we recapitulated the importance of signaling cascades relevant for the regulation of vascular cell proliferation. Detailed understanding of the mechanism underlying this process is essential for the identification of new lead compounds (e.g., natural products) for vascular therapies. [ABSTRACT FROM AUTHOR]

The current trend of combining state of the art technologies with quondam treatments in order to overcome existing gaps in the clinical area determined an increased interest into polyphenols, common dietary phytochemicals, for the prevention and treatment of chronic diseases, especially cancer. The reemergence of polyphenols in the cancer field is sustained by advanced-omics technologies able to identify coding and non-coding genes and their related signaling pathways modulated by natural compounds. Identification of the structural correspondence between interacting molecules will allow the development of more targeted and informed therapeutic strategies for cancer management. [ABSTRACT FROM AUTHOR]

The ubiquitin-proteasome pathway (UPP) is the main non-lysosomal proteolytic system responsible for degradation of most intracellular proteins, specifically damaged and regulatory proteins. The UPP is implicated in all aspects of the cellular metabolic networks including physiological or pathological conditions. Alterations in the components of the UPP can lead to stabilization of oncoproteins or augmented degradation of tumour suppressor favouring cancer appearance and progression. Polyphenols are natural compounds that can modulate proteasome activity or the expression of proteasome subunits. All together and due to the pleiotropic functions of UPP, there is a great interest in this proteasome system as a promising therapeutic target for the development of novel anti-cancer drugs. In the present review, the main features of the UPP and its implication in cancer development and progression are described, highlighting the importance of bioactive polyphenols that target the UPP as potential anti-cancer agents. [ABSTRACT FROM AUTHOR]

Natural products are gaining much momentum worldwide because they have a broad spectrum of biological effects and present excellent opportunities for bioproducts development. With this fact, this study has been designed to investigate for the first time the effects of the ethyl acetate (EA), methanolic (MeOH), and water (W) extracts of Lotus aegaeus (La) and Iberis sempervirens (Is) on key enzymes as well as to quantify antioxidant capacities. The total phenolic and flavonoid content were determined using colorimetric methods and the individual phenolic compounds were assessed by LC–MS/MS analysis. Quercetin hexoside was the dominant compound in L. aegaeus , particularly in methanol extract, while the ethyl acetate and methanol extracts of I. sempervirens were characterized by the presence scopoletin and hinic acid. The antioxidant abilities of the investigated extracts were tested using different assays including free radical scavenging, reducing power, phosphomolybdenum, and metal chelating. All the extracts showed strong antioxidant abilities. For both species, the ethyl acetate extracts were more potent against cholinesterases and α-amylase, while the methanol extracts were most active against α-glucosidase. Only the water extract, followed by methanol of I. sempervirens exhibited notable inhibitory activity against tyrosinase. In addition, the dominant compounds were docked against tyrosinase and α-glucosidase to investigate their predicted binding affinity and interactions with the active site. In conclusion, L. aegaeus and I. sempervirens showed potent biological attributes, which advocates for further studies to explore their potential use as phytopharmaceuticals. [ABSTRACT FROM AUTHOR]

The modulatory interactions between neurotensin (NT) and the dopaminergic neurotransmitter system in the brain suggest that NT may be associated with the progression of Parkinson's disease (PD). NT exerts its neurophysiological effects by interactions with the human NT receptors type 1 (hNTS1) and 2 (hNTS2). Therefore, both receptor subtypes are promising targets for the development of novel NT-based analogs for the treatment of PD. In this study, we used a virtually guided molecular modeling approach to predict the activity of NT(8–13) analogs by investigating the docking models of ligands designed for binding to the human NTS1 and NTS2 receptors. The importance of the residues at positions 8 and/or 9 for hNTS1 and hNTS2 receptor binding affinity was experimentally confirmed by radioligand binding assays. Further in vitro ADME profiling and in vivo studies revealed that, compared to the parent peptide NT(8–13), compound 10 exhibited improved stability and BBB permeability combined with a significant enhancement of the motor function and memory in a mouse model of PD. The herein reported NTS1/NTS2 dual-specific NT(8–13) analogs represent an attractive tool for the development of therapeutic strategies against PD and potentially other CNS disorders. [Display omitted] • NT(8–13) analogs as dual hNTS1 and hNTS2 receptor ligands have been developed. • Replacement of Arg8 and/or Arg9 by Lys and/or Cav residues led to compounds 10 – 14. • All peptide mimetics showed sub-nanomolar activity at both hNTS1/2 receptors. • The hNTS1R full agonist 10 exhibits improved stability and BBB permeability. • Compound 10 demonstrated in vivo efficacy in a mouse model of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Statins are the most common drugs administered for patients with cardiovascular disease. However, due to statin-associated muscle symptoms, adherence to statin therapy is challenging in clinical practice. Certain nutraceuticals, such as red yeast rice, bergamot, berberine, artichoke, soluble fiber, and plant sterols and stanols alone or in combination with each other, as well as with ezetimibe, might be considered as an alternative or add-on therapy to statins, although there is still insufficient evidence available with respect to long-term safety and effectiveness on cardiovascular disease prevention and treatment. These nutraceuticals could exert significant lipid-lowering activity and might present multiple non-lipid-lowering actions, including improvement of endothelial dysfunction and arterial stiffness, as well as anti-inflammatory and antioxidative properties. The aim of this expert opinion paper is to provide the first attempt at recommendation on the management of statin intolerance through the use of nutraceuticals with particular attention on those with effective low-density lipoprotein cholesterol reduction. [ABSTRACT FROM AUTHOR]

The dysregulation of autophagy is involved in the pathogenesis of a broad range of diseases, and accordingly universal research efforts have focused on exploring novel compounds with autophagy-modulating properties. While a number of synthetic autophagy modulators have been identified as promising cancer therapy candidates, autophagy-modulating phytochemicals have also attracted attention as potential treatments with minimal side effects. In this review, we firstly highlight the importance of autophagy and its relevance in the pathogenesis and treatment of cancer. Subsequently, we present the data on common phytochemicals and their mechanism of action as autophagy modulators. Finally, we discuss the challenges associated with harnessing the autophagic potential of phytochemicals for cancer therapy. [ABSTRACT FROM AUTHOR]

Alkaloids are well-studied secondary metabolites, with recent preclinical studies evidencing that many of them exhibit anti-cancer, anti-depressant, anti-nociceptive, anti-inflammatory, anti-pyretic, anti-platelet, anti-oxidant, and anti-bacterial properties. Aconitum is a genus rich of diverse alkaloids. More than 450 alkaloids have been identified in a variety of species. Songorine is a C 20 diterpenoid alkaloid and 12-keto analog of napelline, isolated from Aconitum soongaricum and was associated with a heterogeneous panel of biological functions. However, the bioactivity profile of this natural product has not been reviewed up to now. The present manuscript aims to summarize the most important biological activities associated with songorine administration in preclinical models. The most significant data found in the scientific literature were evaluated in order to summarize the potential clinical utility of songorine in a diverse spectrum of pathologies and conditions. Songorine and its derivatives have many pharmacological effects including anti-arrhythmic, anti-cardiac-fibrillation, excitation of synaptic transmission, anxiolytic effects, anti-nociceptive, anti-inflammatory, anti-arthritis effects, and a regenerative effect in a skin excision wound animal model. Despite its outstanding pharmacotherapeutic potential, songorine has never been tested in clinical trials. Therefore, further evaluation is required to better evaluate its clinical utility. [ABSTRACT FROM AUTHOR]

Inflammation comprises the reaction of the body to injury, in which a series of changes of the terminal vascular bed, blood, and connective tissue tends to eliminate the injurious agent and to repair the damaged tissue. It is a complex process, which involves the release of diverse regulatory mediators. The current anti-inflammatory agents are challenged by multiple side effects and thus, new effective therapies are highly needed. The aim of this review is to summarize the described microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors or transcriptional suppressors from medicinal plants, which could be an ideal approach in the management of inflammatory disorders, but need further clinical trials in order to be ultimately validated. [ABSTRACT FROM AUTHOR]

Background The fruits of Malpighia glabra and M. emarginata (Family: Malpighiaceae) are commonly known as ‘Acerola cherry’ or ‘Barbados cherry’. Acerola fruits are well known for their high content of vitamin C, phenolic compounds, including benzoic acid derivatives, phenylpropanoids, flavonoids, anthocyanins, and carotenoids. In recent years, there is a growing interest in the role of Acerola as a nutraceutical or functional food with increasing market value. Extracts and bioactive compounds isolated from Acerola are studied for their various health promoting activities and biological activities such as antioxidant, antitumor, antihyperglycemic and skin protecting/skin whitening. Scope and approach This article reviewed the scientific studies regarding the bioactive chemical constituents and the health beneficial effects of Acerola extracts and isolated compounds. These findings may help in future research concerning Acerola and Acerola based nutritional products. Key findings and conclusions Acerola fruits can be considered as good candidates for the development of novel functional foods. However, detailed in vitro , in vivo and clinical studies, particularly mechanism-based studies are needed for the development of evidence-based functional food products in future. [ABSTRACT FROM AUTHOR]