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- 2020 (14) (entfernen)
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- Englisch (14)
Schlagworte
- Alzheimer's disease (1)
- Alzheimer′s disease (1)
- Cecropia telenitida (1)
- Eriodictyon californicum (1)
- Flavonoids (1)
- G-protein coupled receptor (1)
- HPLC–MS (1)
- In vivo studies (1)
- Microglia (1)
- Natural product hybrids (1)
- Phenolic acids (1)
- Red Sea (1)
- Robuvit\(^®\) (1)
- acids (1)
- bioactivity (1)
- biodiversity (1)
- biophysics (1)
- blood brain barrier (1)
- cerebEND cells (1)
- chiral resolution (1)
- circular dichroism (1)
- complementary medicine (1)
- drugs (1)
- estrogens (1)
- extraction (1)
- flavonoids (1)
- fluorescent ligands (1)
- fluorescent probes (1)
- forms (1)
- homodimerization (1)
- human (1)
- human breast (1)
- hydrogels (1)
- hypoxia (1)
- hysterectomy (1)
- imaging (1)
- isosteviol sodium (1)
- liquid chromatography electrospray ionization tandem mass spectrometry (1)
- maceration (1)
- marine metagenomics (1)
- marine natural products (1)
- marine organisms (1)
- matrix metalloproteinases (1)
- microscopy (1)
- multiple linear regression (1)
- muscarinic M1 receptor (1)
- neuroprotection (1)
- oak wood (1)
- oak wood extract (1)
- opioid ligands (1)
- opioid receptors (1)
- oxidative stress (1)
- polyphenols (1)
- post-operative recovery (1)
- post-surgery recovery (1)
- pressurized microwave‐assisted extraction (1)
- serjanic acid (1)
- single-molecule microscopy (1)
- solubility (1)
- sterubin (1)
- strategy (1)
- transport (1)
- type 2 diabetes (1)
- urolithins (1)
Institut
- Institut für Pharmazie und Lebensmittelchemie (14) (entfernen)
EU-Projektnummer / Contract (GA) number
- 26230120009 (1)
Plant extracts from Cecropia genus have been used by Latin-American traditional medicine to treat metabolic disorders and diabetes. Previous reports have shown that roots of Cecropia telenitida that contains serjanic acid as one of the most prominent and representative pentacyclic triterpenes. The study aimed to isolate serjanic acid and evaluate its effect in a prediabetic murine model by oral administration. A semi-pilot scale extraction was established and serjanic acid purification was followed using direct MALDI-TOF analysis. A diet induced obesity mouse model was used to determine the impact of serjanic acid over selected immunometabolic markers. Mice treated with serjanic acid showed decreased levels of cholesterol and triacylglycerols, increased blood insulin levels, decreased fasting blood glucose and improved glucose tolerance, and insulin sensitivity. At transcriptional level, the reduction of inflammation markers related to adipocyte differentiation is reported.
Hysterectomy has a variety of medical indications and improves pre-operative symptoms but might compromise the quality of life during recovery due to symptoms such as fatigue, headache, nausea, depression, or pain. The aim of the present study was to determine the effect of a standardized extract from French oak wood (Quercus robur) containing at least 40% polyphenols of the ellagitannins class, Robuvit\(^®\), on convalescence and oxidative stress of women after hysterectomy. Recovery status was monitored with the SF-36 questionnaire. The supplementation with Robuvit\(^®\) (300 mg/day) during 4 weeks significantly improved general and mental health, while under placebo some items significantly deteriorated. Oxidative stress and enhancement of MMP–9 activity was significantly reduced by Robuvit\(^®\) versus placebo. After 8 weeks of intervention, the patients’ condition improved independently of the intervention. Our results suggest that the use of Robuvit\(^®\) as a natural supplement relieves post-operative symptoms of patients after hysterectomy and reduces oxidative stress. The study was registered with ID ISRCTN 11457040 (13/09/2019).
Extraction is a key step in studying compounds from plants and other natural sources. The common use of high temperatures in pressurized microwave‐assisted extraction (PMAE) makes it unsuitable for the extraction of compounds with low or unknown thermal stability. This study aimed at determining the suitability of low‐temperature, short‐time PMAE in attaining yields comparable to those of prolonged maceration at room temperature. Additionally, we explored the phytochemical differences of the extracts from both techniques. Maceration at room temperature for 24 hr and PMAE at 40–45°C and 10 bar for 30 min were carried out on 18 samples from 14 plant species at a solvent‐to‐feeds ratio of 10. The PMAE yields of 16 out of 18 samples were within the proportions of 91–139.2% as compared with the respective extracts from maceration. Varying numbers of nonmatching peaks were noted in MS chromatograms of five extract pairs, indicating selective extraction of some compounds. Low‐temperature PMAE can attain reasonable extraction efficiency with the added value of sparing compounds of low thermal stability. The method can also enable the recovery of compounds distinct from those obtained by maceration.
Alzheimer′s disease (AD) is a neurological disorder with still no preventive or curative treatment. Flavonoids are phytochemicals with potential therapeutic value. Previous studies described the flavanone sterubin isolated from the Californian plant Eriodictyon californicum as a potent neuroprotectant in several in vitro assays. Herein, the resolution of synthetic racemic sterubin (1) into its two enantiomers, (R)‐1 and (S)‐1, is described, which has been performed on a chiral chromatographic phase, and their stereochemical assignment online by HPLC‐ECD coupling. (R)‐1 and (S)‐1 showed comparable neuroprotection in vitro with no significant differences. While the pure stereoisomers were configurationally stable in methanol, fast racemization was observed in the presence of culture medium. We also established the occurrence of extracted sterubin as its pure (S)‐enantiomer. Moreover, the activity of sterubin (1) was investigated for the first time in vivo, in an AD mouse model. Sterubin (1) showed a significant positive impact on short‐ and long‐term memory at low dosages.
Opioid receptors (ORs) are classified among the oldest and best investigated drug targets due to their fundamental role in the treatment of pain and related disorders. ORs are divided in three conventional subtypes (μ, κ, δ) and the non‐classical nocicepetin receptor. All ORs are family A G protein‐coupled receptors (GPCRs), and are located on the cell surface. Modern biophysical methods use light to investigate physiological processes at organismal, cellular and subcellular level. Many of these methods rely on fluorescent ligands, thus highlighting their importance. This review addresses the advancements in the development of opioid fluorescent ligands and their use in biological, pharmacological and imaging applications.
Understanding intramammary estrogen homeostasis constitutes the basis of understanding the role of lifestyle factors in breast cancer etiology. Thus, the aim of the present study was to identify variables influencing levels of the estrogens present in normal breast glandular and adipose tissues (GLT and ADT, i.e., 17β-estradiol, estrone, estrone-3-sulfate, and 2-methoxy-estrone) by multiple linear regression models. Explanatory variables (exVARs) considered were (a) levels of metabolic precursors as well as levels of transcripts encoding proteins involved in estrogen (biotrans)formation, (b) data on breast cancer risk factors (i.e., body mass index, BMI, intake of estrogen-active drugs, and smoking) collected by questionnaire, and (c) tissue characteristics (i.e., mass percentage of oil, oil%, and lobule type of the GLT). Levels of estrogens in GLT and ADT were influenced by both extramammary production (menopausal status, intake of estrogen-active drugs, and BMI) thus showing that variables known to affect levels of circulating estrogens influence estrogen levels in breast tissues as well for the first time. Moreover, intratissue (biotrans)formation (by aromatase, hydroxysteroid-17beta-dehydrogenase 2, and beta-glucuronidase) influenced intratissue estrogen levels, as well. Distinct differences were observed between the exVARs exhibiting significant influence on (a) levels of specific estrogens and (b) the same dependent variables in GLT and ADT. Since oil% and lobule type of GLT influenced levels of some estrogens, these variables may be included in tissue characterization to prevent sample bias. In conclusion, evidence for the intracrine activity of the human breast supports biotransformation-based strategies for breast cancer prevention. The susceptibility of estrogen homeostasis to systemic and tissue-specific modulation renders both beneficial and adverse effects of further variables associated with lifestyle and the environment possible.
Microbial, mammalian, and plant cells produce and contain secondary metabolites, which typically are soluble in water to prevent cell damage by crystallization. The formation of ion pairs, for example, with carboxylic acids or mineral acids, is a natural blueprint to maintain basic metabolites in solution. Here, we aim at showing whether the mostly large carboxylates form soluble protic ionic liquids (PILs) with the basic natural product papaverine resulting in enhanced aqueous solubility. The obtained PILs were characterized by H-1-N-15 HMBC nuclear magnetic resonance (NMR) and in the solid state using X-ray powder diffraction, differential scanning calorimetry, and dissolution measurements. Furthermore, their supramolecular pattern in aqueous solution was studied by means of potentiometric and photometrical solubility, NMR aggregation assay, dynamic light scattering, zeta potential, and viscosity measurements. Thereby, we identified the naturally occurring carboxylic acids, citric acid, malic acid, and tartaric acid, as being appropriate counterions for papaverine and which will facilitate the formation of PILs with their beneficial characteristics, like the improved dissolution rate and enhanced apparent solubility.
Bioprinting has emerged as a valuable threedimensional (3D) biomanufacturing method to fabricate complex hierarchical cell-containing constructs. Spanning from basic research to clinical translation, sterile starting materials are crucial. In this study, we present pharmacopeia compendial sterilization methods for the commonly used bioink component alginate. Autoclaving (sterilization in saturated steam) and sterile filtration followed by lyophilization as well as the pharmacopeia non-compendial method, ultraviolet (UV)-irradiation for disinfection, were assessed. The impact of the sterilization methods and their effects on physicochemical and rheological properties, bioprinting outcome, and sterilization efficiency of alginate were detailed. Only sterile filtration followed by lyophilization as the sterilization method retained alginate's physicochemical properties and bioprinting behavior while resulting in a sterile outcome. This set of methods provides a blueprint for the analysis of sterilization effects on the rheological and physicochemical pattern of bioink components and is easily adjustable for other polymers used in the field of biofabrication in the future.
The muscarinic M\(_1\) acetylcholine receptor is an important drug target for the treatment of various neurological disorders. Designing M\(_1\) receptor-selective drugs has proven challenging, mainly due to the high conservation of the acetylcholine binding site among muscarinic receptor subtypes. Therefore, less conserved and topographically distinct allosteric binding sites have been explored to increase M\(_1\) receptor selectivity. In this line, bitopic ligands, which target orthosteric and allosteric binding sites simultaneously, may provide a promising strategy. Here, we explore the allosteric, M1-selective BQCAd scaffold derived from BQCA as a starting point for the design, synthesis, and pharmacological evaluation of a series of novel bitopic ligands in which the orthosteric moieties and linker lengths are systematically varied. Since β-arrestin recruitment seems to be favorable to therapeutic implication, all the compounds were investigated by G protein and β-arrestin assays. Some bitopic ligands are partial to full agonists for G protein activation, some activate β-arrestin recruitment, and the degree of β-arrestin recruitment varies according to the respective modification. The allosteric BQCAd scaffold controls the positioning of the orthosteric ammonium group of all ligands, suggesting that this interaction is essential for stimulating G protein activation. However, β-arrestin recruitment is not affected. The novel set of bitopic ligands may constitute a toolbox to study the requirements of β-arrestin recruitment during ligand design for therapeutic usage.
Ischemic stroke is one of the leading causes of death worldwide. It damages neurons and other supporting cellular elements in the brain. However, the impairment is not only confined to the region of assault but the surrounding area as well. Besides, it also brings about damage to the blood-brain barrier (BBB) which in turn leads to microvascular failure and edema. Hence, this necessitates an on-going, continuous search for intervention strategies and effective treatment. Of late, the natural sweetener stevioside proved to exhibit neuroprotective effects and therapeutic benefits against cerebral ischemia-induced injury. Its injectable formulation, isosteviol sodium (STVNA) also demonstrated favorable results. Nonetheless, its effects on the BBB have not yet been investigated to date. As such, this present study was designed to assess the effects of STVNA in our in vitro stroke model of the BBB.The integrity and permeability of the BBB are governed and maintained by tight junction proteins (TJPs) such as claudin-5 and occludin. Our data show increased claudin-5 and occludin expression in oxygen and glucose (OGD)-deprived murine brain capillary cerebellar endothelial cells (cerebEND) after STVNa treatment. Likewise, the upregulation of the transmembrane protein integrin-αv was also observed. Finally, cell volume was reduced with the simultaneous administration of STVNA and OGD in cerebEND cells. In neuropathologies such as stroke, the failure of cell volume control is a major feature leading to loss of cells in the penumbra as well as adverse outcomes. Our initial findings, therefore, point to the neuroprotective effects of STVNA at the BBB in vitro, which warrant further investigation for a possible future clinical intervention.
Marine natural products have achieved great success as an important source of new lead compounds for drug discovery. The Red Sea provides enormous diversity on the biological scale in all domains of life including micro- and macro-organisms. In this review, which covers the literature to the end of 2019, we summarize the diversity of bioactive secondary metabolites derived from Red Sea micro- and macro-organisms, and discuss their biological potential whenever applicable. Moreover, the diversity of the Red Sea organisms is highlighted as well as their genomic potential. This review is a comprehensive study that compares the natural products recovered from the Red Sea in terms of ecological role and pharmacological activities.
μ‐Opioid receptors (μ‐ORs) play a critical role in the modulation of pain and mediate the effects of the most powerful analgesic drugs. Despite extensive efforts, it remains insufficiently understood how μ‐ORs produce specific effects in living cells. We developed new fluorescent ligands based on the μ‐OR antagonist E‐p‐nitrocinnamoylamino‐dihydrocodeinone (CACO), that display high affinity, long residence time and pronounced selectivity. Using these ligands, we achieved single‐molecule imaging of μ‐ORs on the surface of living cells at physiological expression levels. Our results reveal a high heterogeneity in the diffusion of μ‐ORs, with a relevant immobile fraction. Using a pair of fluorescent ligands of different color, we provide evidence that μ‐ORs interact with each other to form short‐lived homodimers on the plasma membrane. This approach provides a new strategy to investigate μ‐OR pharmacology at single‐molecule level.
Ellagitannins are signature constituents of oak wood and their consumption has been associated with various health benefits. In vivo, they undergo metabolic degradation including gut microbial metabolism yielding urolithins. Only limited data is available about compounds being present in blood after intake of an extract from French oak wood, Robuvit®. In the course of a randomized, double-blind, controlled clinical investigation, 66 patients undergoing hysterectomy received placebo or 300 mg Robuvit® per day before and over 8 weeks after surgery. Serum and blood cell samples were analyzed by liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). The number of urolithin producers and the urolithin levels increased after intake of Robuvit®. In serum samples, the median concentration of urolithin A was 14.0 ng/ml [interquartile range (IQR) 57.4] after 8 weeks. Urolithin B was determined at 22.3 ng/ml (IQR 12.6), urolithin C at 2.66 ng/ml (IQR 2.08). In blood cells, lower concentrations and only urolithins A and B were detected. A statistically significant association of lower post-surgical pain scores with metabotype A was detected (p < 0.05). To conclude, supplementation with French oak wood extract raised urolithin generation in patients and suggested health advantages for urolithin-producers.
Alzheimer's disease (AD) is a multifactorial disease and the most common form of dementia. There are no treatments to cure, prevent or slow down the progression of the disease. Natural products hold considerable interest for the development of preventive neuroprotectants to treat neurodegenerative disorders like AD, due to their low toxicity and general beneficial effects on human health with their anti-inflammatory and antioxidant features. In this work we describe regioselective synthesis of 7-O-ester hybrids of the flavonoid taxifolin with the phenolic acids cinnamic and ferulic acid, namely 7-O-cinnamoyltaxifolin and 7-O-feruloyltaxifolin. The compounds show pronounced overadditive neuroprotective effects against oxytosis, ferroptosis and ATP depletion in the murine hippocampal neuron HT22 cell model. Furthermore, 7-O-cinnamoyltaxifolin and 7-O-feruloyltaxifolin reduced LPS-induced neuroinflammation in BV-2 microglia cells as assessed by effects on the levels of NO, IL6 and TNFα. In all in vitro assays the 7-O-esters of taxifolin and ferulic or cinnamic acid showed strong overadditive activity, significantly exceeding the effects of the individual components and the equimolar mixtures thereof, which were almost inactive in all of the assays at the tested concentrations. In vivo studies confirmed this overadditive effect. Treatment of an AD mouse model based on the injection of oligomerized Aβ\(_{25-35}\) peptide into the brain to cause neurotoxicity and subsequently memory deficits with 7-O-cinnamoyltaxifolin or 7-O-feruloyltaxifolin resulted in improved performance in an assay for short-term memory as compared to vehicle and mice treated with the respective equimolar mixtures. These results highlight the benefits of natural product hybrids as a novel compound class with potential use for drug discovery in neurodegenerative diseases due to their pharmacological profile that is distinct from the individual natural components.