The regulation of endothelial NO synthase (eNOS) employs multiple different cellular control mechanisms impinging on level and activity of the enzyme. This review aims at summarizing the current ...knowledge on the posttranslational modifications of eNOS, including acylation, nitrosylation, phosphorylation, acetylation, glycosylation and glutathionylation. Sites, mediators and impact on enzyme localization and activity of the single modifications will be discussed. Moreover, interdependence, cooperativity and competition between the different posttranslational modifications will be elaborated with special emphasis on the susceptibility of eNOS to metabolic cues.
Nuclear receptors (NRs) represent attractive targets for the treatment of metabolic syndrome-related diseases. In addition, natural products are an interesting pool of potential ligands since they ...have been refined under evolutionary pressure to interact with proteins or other biological targets.
This review aims to briefly summarize current basic knowledge regarding the liver X (LXR) and farnesoid X receptors (FXR) that form permissive heterodimers with retinoid X receptors (RXR). Natural product-based ligands for these receptors are summarized and the potential of LXR, FXR and RXR as targets in precision medicine is discussed.
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.
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In light of the emerging interplay between redox and metabolic signaling pathways we investigated the potential cross talk between nuclear factor E2-related factor 2 (Nrf2) and AMP-activated kinase ...(AMPK), central regulators of the cellular redox and energy balance, respectively. Making use of xanthohumol (XN) as an activator of both the AMPK and the Nrf2 signaling pathway we show that AMPK exerts a positive influence on Nrf2/heme oxygenase (HO)-1 signaling in mouse embryonic fibroblasts. Genetic ablation and pharmacological inhibition of AMPK blunts Nrf2-dependent HO-1 expression by XN already at the mRNA level. XN leads to AMPK activation via interference with mitochondrial function and activation of liver kinase B1 as upstream AMPK kinase. The subsequent AMPK-mediated enhancement of the Nrf2/HO-1 response does not depend on inhibition of the mammalian target of rapamycin, inhibition of glycogen synthase kinase 3β, or altered abundance of Nrf2 (total and nuclear). However, reduced endoplasmic reticulum stress was identified and elaborated as a step in the AMPK-augmented Nrf2/HO-1 response. Overall, we shed more light on the hitherto incompletely understood cross talk between the LKB1/AMPK and the Nrf2/HO-1 axis revealing for the first time involvement of the unfolded protein response as an additional player and suggesting tight cooperation between signaling pathways controlling cellular redox, energy, or protein homeostasis.
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•Activated AMPK boosts the Nrf2/HO‐1 signaling axis in xanthohumol‐treated cells.•Xanthohumol leads to AMPK activation in an LKB1‐dependent manner.•The AMPK boost hits on a step prior to or at transcription of HO‐1 mRNA.•Inhibition of GSK3β or mTOR is not involved in the observed AMPK boost.•Higher ER stress accounts for the lower Nrf2/HO1 response in AMPK‐deficient cells.
Agonists of the nuclear receptor PPARγ are therapeutically used to combat hyperglycaemia associated with the metabolic syndrome and type 2 diabetes. In spite of being effective in normalization of ...blood glucose levels, the currently used PPARγ agonists from the thiazolidinedione type have serious side effects, making the discovery of novel ligands highly relevant.
Natural products have proven historically to be a promising pool of structures for drug discovery, and a significant research effort has recently been undertaken to explore the PPARγ-activating potential of a wide range of natural products originating from traditionally used medicinal plants or dietary sources. The majority of identified compounds are selective PPARγ modulators (SPPARMs), transactivating the expression of PPARγ-dependent reporter genes as partial agonists. Those natural PPARγ ligands have different binding modes to the receptor in comparison to the full thiazolidinedione agonists, and on some occasions activate in addition PPARα (e.g. genistein, biochanin A, sargaquinoic acid, sargahydroquinoic acid, resveratrol, amorphastilbol) or the PPARγ-dimer partner retinoid X receptor (RXR; e.g. the neolignans magnolol and honokiol). A number of in vivo studies suggest that some of the natural product activators of PPARγ (e.g. honokiol, amorfrutin 1, amorfrutin B, amorphastilbol) improve metabolic parameters in diabetic animal models, partly with reduced side effects in comparison to full thiazolidinedione agonists. The bioactivity pattern as well as the dietary use of several of the identified active compounds and plant extracts warrants future research regarding their therapeutic potential and the possibility to modulate PPARγ activation by dietary interventions or food supplements.
Covering: 1994 to 2020
Retinoic acid receptor-related orphan receptors (RORs) belong to a subfamily of the nuclear receptor superfamily and possess prominent roles in circadian rhythm, metabolism, ...inflammation, and cancer. They have been subject of research for over two decades and represent attractive but challenging drug targets. Natural products were among the first identified ligands of RORs and continue to be of interest to this day. This review focuses on ligands and indirect modulators of RORs from natural sources and explores their roles in a therapeutic context.
This review provides a comprehensive overview of natural product ligands of RAR-related orphan receptors (RORs).
We showed previously that capsaicin, an active compound of chili peppers, can inhibit platelet-derived growth factor-induced proliferation in primary rat vascular smooth muscle cells (VSMCs). The ...inhibition of BrdU incorporation by capsaicin in these cells was revoked by BCTC, which might be explained by a role of TRPV1 in VSMCs proliferation. To further pursue the hypothesis of a TRPV1-dependent effect of capsaicin, we investigated TRPV1 expression and function. Commercially available antibodies against two different TRPV1 epitopes (N-terminus and C-terminus) were rendered invalid in detecting TRPV1, as shown: i) in western blot experiments using control lysates of TRPV1-expressing (PC-12 and hTRPV1 transfected HEK293T) and TRPV1-downregulated (CRISPR/Cas gene edited A10) cells, and ii) by substantial differences in staining patterns between the applied antibodies using fluorescence confocal microscopy. The TRPV1 agonists capsaicin, resiniferatoxin, piperine and evodiamine did not increase intracellular calcium levels in primary VSMCs and in A10 cells. Using RT qPCR, we could detect a rather low TRPV1 expression in VSMCs at the mRNA level (Cp value around 30), after validating the primer pair in NGF-stimulated PC-12 cells. We conclude that rat vascular smooth muscle cells do not possess canonical TRPV1 channel activity, which could explain the observed antiproliferative effect of capsaicin.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In different countries and areas of the world, traditional medicine has been and is still used for the treatment of various disorders, including chest pain or liver complaints, of which we now know ...that they can be linked with altered lipid and cholesterol homeostasis. As ATP-binding cassette transporter A1 (ABCA1) plays an essential role in cholesterol metabolism, its modulation may be one of the molecular mechanisms responsible for the experienced benefit of traditional recipes. Intense research activity has been dedicated to the identification of natural products from traditional medicine that regulate ABCA1 expression.
This review surveys natural products, originating from ethnopharmacologically used plants, fungi or marine sources, which influence ABCA1 expression, providing a reference for future study.
Information on regulation of ABCA1 expression by natural compounds from traditional medicine was extracted from ancient and modern books, materia medica, and electronic databases (PubMed, Google Scholar, Science Direct, and ResearchGate).
More than 60 natural compounds from traditional medicine, especially traditional Chinese medicine (TCM), are reported to regulate ABCA1 expression in different in vitro and in vivo models (such as cholesterol efflux and atherosclerotic animal models). These active compounds belong to the classes of polyketides, terpenoids, phenylpropanoids, tannins, alkaloids, steroids, amino acids and others. Several compounds appear very promising in vivo, which need to be further investigated in animal models of diseases related to ABCA1 or in clinical studies.
Natural products from traditional medicine constitute a large promising pool for compounds that regulate ABCA1 expression, and thus may prevent/treat diseases related to cholesterol metabolism, like atherosclerosis or Alzheimer's disease. In many cases, the molecular mechanisms of these natural products remain to be investigated.
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Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of glucose and lipid metabolism and therefore an important pharmacological target to combat metabolic diseases. Since the ...currently used full PPARγ agonists display serious side effects, identification of novel ligands, particularly partial agonists, is highly relevant. Searching for new active compounds, we investigated extracts of the underground parts of Notopterygium incisum, a medicinal plant used in traditional Chinese medicine, and observed significant PPARγ activation using a PPARγ-driven luciferase reporter model. Activity-guided fractionation of the dichloromethane extract led to the isolation of six polyacetylenes, which displayed properties of selective partial PPARγ agonists in the luciferase reporter model. Since PPARγ activation by this class of compounds has so far not been reported, we have chosen the prototypical polyacetylene falcarindiol for further investigation. The effect of falcarindiol (10 µM) in the luciferase reporter model was blocked upon co-treatment with the PPARγ antagonist T0070907 (1 µM). Falcarindiol bound to the purified human PPARγ receptor with a Ki of 3.07 µM. In silico docking studies suggested a binding mode within the ligand binding site, where hydrogen bonds to Cys285 and Glu295 are predicted to be formed in addition to extensive hydrophobic interactions. Furthermore, falcarindiol further induced 3T3-L1 preadipocyte differentiation and enhanced the insulin-induced glucose uptake in differentiated 3T3-L1 adipocytes confirming effectiveness in cell models with endogenous PPARγ expression. In conclusion, we identified falcarindiol-type polyacetylenes as a novel class of natural partial PPARγ agonists, having potential to be further explored as pharmaceutical leads or dietary supplements.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•In depth investigation of purslane showed the occurrence of bioactive polar lipids.•LC-MSn analysis putatively identified oxylipins, glyco-, phospho- and sphingolipids.•Unusual phytofuranes, ...phytoprostanes and glucuronosylglicerols were found.•Purslane lipid enriched fractions inhibited the NF-kB transcription factor.•Purslane lipid enriched fractions induced activation of PPAR-ɣ and Nrf2 pathways.
Considering the ongoing interest in foods rich in nutrients like polyunsaturated fatty acids and bioactive polar lipids, the chemical and biological investigation of Portulaca oleracea (purslane), a herbaceous plant typically appreciated in Mediterranean and Asiatic diet, was carried out. The LC-ESI/HRMS/MSn analysis of extracts and lipid enriched fractions of purslane edible parts provided a comprehensive polar lipid profile, ranging from linear and cyclic oxylipins to high molecular weight lipids including glycolipids, phospholipids and sphingolipids. The evaluation of the anti-inflammatory potential by in vitro reporter gene assays highlighted the ability of purslane lipid enriched fractions, at a concentration of 20 µg/ml, to inhibit the TNF-α-stimulated NF-kB pathway by 30–40% and to activate PPAR-ɣ and Nrf2 transcription factors to the same extent or more than the positive control, respectively. Altogether, these results encourage to revalue purslane in human nutrition as a source of bioactive polar lipids.
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