570 Biowissenschaften; Biologie
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Statins are a group of hypolipidemic drugs that act by competitive inhibition of the HMGR enzyme. They are generally considered effective and safe but claimed to have side effects on skeletal muscles. A molecular side effect of statins is the block of terpene biosynthesis and hence of dolichol involved in N-glycosylation and O-mannosylation of proteins. Defects in O-mannosylation lead to α-dystroglycan (α-DG) hypoglycosylation and a series of hereditary dystroglycanopathies. The current project aims to get insight into molecular pathomechanisms induced by statins in mammalian muscle cells and to unravel a potential link between these effects and statin-induced decreases of α-DG O-mannosylation. The study was based on mass spectrometric proteomics supported by western blot analysis to reveal Rosuvastatin effects on cellular pathways under high (micromolar) or low (nanomolar) conditions. Differential proteomics revealed higher statin effects on muscle cell function in micromolar than nanomolar concentration, which is reached in the patient’s plasma. We demonstrated distinct and partially overlapping patterns of fold-changed proteins under high and low statin conditions. Gene ontology term enrichment (GOTE) analyses of fold-changed proteins revealed cellular pathways related to muscle function and development are affected, even under low statin conditions, typically reached in the patient’s plasma during prophylactic medication.
The human gut microbiota harbors untapped potential for biotechnological applications. Within the phylum of Bacteroidota, Phocaeicola vulgatus stands out as a promising candidate for sustainable production of key platform chemicals like succinate. However, genetic engineering of Phocaeicola sp. remains challenging due to its intricate molecular landscape. This study lays the groundwork for manipulating the central carbon pathways in Phocaeicola vulgatus, offering insights into overcoming genetic hurdles for increased succinate yields.
In memoriam Willy Lehnert
(2023)
Dried serum spots that are well prepared can be attractive alternatives to frozen serum samples for shelving specimens in a medical or research center's biobank and mailing freshly prepared serum to specialized laboratories. During the pre-analytical phase, complications can arise which are often challenging to identify or are entirely overlooked. These complications can lead to reproducibility issues, which can be avoided in serum protein analysis by implementing optimized storage and transfer procedures. With a method that ensures accurate loading of filter paper discs with donor or patient serum, a gap in dried serum spot preparation and subsequent serum analysis shall be filled. Pre-punched filter paper discs with a 3 mm diameter are loaded within seconds in a highly reproducible fashion (approximately 10% standard deviation) when fully submerged in 10 μl of serum, named the "Submerge and Dry" protocol. Such prepared dried serum spots can store several hundred micrograms of proteins and other serum components. Serum-borne antigens and antibodies are reproducibly released in 20 μl elution buffer in high yields (approximately 90%). Dried serum spot-stored and eluted antigens kept their epitopes and antibodies their antigen binding abilities as was assessed by SDS-PAGE, 2D gel electrophoresis-based proteomics, and Western blot analysis, suggesting pre-punched filter paper discs as handy solution for serological tests.
The epithelial sodium channel (ENaC) is a key regulator of sodium homeostasis that contributes to blood pressure control. ENaC open probability is adjusted by extracellular sodium ions, a mechanism referred to as sodium self-inhibition (SSI). With a growing number of identified ENaC gene variants associated with hypertension, there is an increasing demand for medium- to high-throughput assays allowing the detection of alterations in ENaC activity and SSI. We evaluated a commercially available automated two-electrode voltage-clamp (TEVC) system that records transmembrane currents of ENaC-expressing Xenopus oocytes in 96-well microtiter plates. We employed guinea pig, human and Xenopus laevis ENaC orthologs that display specific magnitudes of SSI. While demonstrating some limitations over traditional TEVC systems with customized perfusion chambers, the automated TEVC system was able to detect the established SSI characteristics of the employed ENaC orthologs. We were able to confirm a reduced SSI in a gene variant, leading to C479R substitution in the human α-ENaC subunit that has been reported in Liddle syndrome. In conclusion, automated TEVC in Xenopus oocytes can detect SSI of ENaC orthologs and variants associated with hypertension. For precise mechanistic and kinetic analyses of SSI, optimization for faster solution exchange rates is recommended.
When optimizing the process parameters of the acidic ethanolic organosolv process, the aim is usually to maximize the delignification and/or lignin purity. However, process parameters such as temperature, time, ethanol and catalyst concentration, respectively, can also be used to vary the structural properties of the obtained organosolv lignin, including the molecular weight and the ratio of aliphatic versus phenolic hydroxyl groups, among others. This review particularly focuses on these influencing factors and establishes a trend analysis between the variation of the process parameters and the effect on lignin structure. Especially when larger data sets are available, as for process temperature and time, correlations between the distribution of depolymerization and condensation reactions are found, which allow direct conclusions on the proportion of lignin's structural features, independent of the diversity of the biomass used. The newfound insights gained from this review can be used to tailor organosolv lignins isolated for a specific application.
ESKAPEE Pathogen Biofilm Control on Surfaces with Probiotic Lactobacillaceae and Bacillus species
(2023)
Combatting the rapidly growing threat of antimicrobial resistance and reducing prevalence and transmission of ESKAPEE pathogens in healthcare settings requires innovative strategies, one of which is displacing these pathogens using beneficial microorganisms. Our review comprehensively examines the evidence of probiotic bacteria displacing ESKAPEE pathogens, with a focus on inanimate surfaces. A systematic search was conducted using the PubMed and Web of Science databases on 21 December 2021, and 143 studies were identified examining the effects of Lactobacillaceae and Bacillus spp. cells and products on the growth, colonization, and survival of ESKAPEE pathogens. While the diversity of study methods limits evidence analysis, results presented by narrative synthesis demonstrate that several species have the potential as cells or their products or supernatants to displace nosocomial infection-causing organisms in a variety of in vitro and in vivo settings. Our review aims to aid the development of new promising approaches to control pathogen biofilms in medical settings by informing researchers and policymakers about the potential of probiotics to combat nosocomial infections. More targeted studies are needed to assess safety and efficacy of different probiotic formulations, followed by large-scale studies to assess utility in infection control and medical practice.
ENaC channels
(2023)
A biodegradable blend of PBAT—poly(butylene adipate-co-terephthalate)—and PLA—poly(lactic acid)—for blown film extrusion was modified with four multi-functional chain extending cross-linkers (CECL). The anisotropic morphology introduced during film blowing affects the degradation processes. Given that two CECL increased the melt flow rate (MFR) of tris(2,4-di-tert-butylphenyl)phosphite (V1) and 1,3-phenylenebisoxazoline (V2) and the other two reduced it (aromatic polycarbodiimide (V3) and poly(4,4-dicyclohexylmethanecarbodiimide) (V4)), their compost (bio-)disintegration behavior was investigated. It was significantly altered with respect to the unmodified reference blend (REF). The disintegration behavior at 30 and 60 °C was investigated by determining changes in mass, Young’s moduli, tensile strengths, elongations at break and thermal properties. In order to quantify the disintegration behavior, the hole areas of blown films were evaluated after compost storage at 60 °C to calculate the kinetics of the time dependent degrees of disintegration. The kinetic model of disintegration provides two parameters: initiation time and disintegration time. They quantify the effects of the CECL on the disintegration behavior of the PBAT/PLA compound. Differential scanning calorimetry (DSC) revealed a pronounced annealing effect during storage in compost at 30 °C, as well as the occurrence of an additional step-like increase in the heat flow at 75 °C after storage at 60 °C. The disintegration consists of processes which affect amorphous and crystalline phase of PBAT in different manner that cannot be understood by a hydrolytic chain degradation only. Furthermore, gel permeation chromatography (GPC) revealed molecular degradation only at 60 °C for the REF and V1 after 7 days of compost storage. The observed losses of mass and cross-sectional area seem to be attributed more to mechanical decay than to molecular degradation for the given compost storage times.
Background: the potency of drugs that interfere with glucose metabolism, i.e., glucose transporters (GLUT) and nicotinamide phosphoribosyltransferase (NAMPT) was analyzed in neuroendocrine tumor (NET, BON-1, and QPG-1 cells) and small cell lung cancer (SCLC, GLC-2, and GLC-36 cells) tumor cell lines. (2) Methods: the proliferation and survival rate of tumor cells was significantly affected by the GLUT-inhibitors fasentin and WZB1127, as well as by the NAMPT inhibitors GMX1778 and STF-31. (3) Results: none of the NET cell lines that were treated with NAMPT inhibitors could be rescued with nicotinic acid (usage of the Preiss–Handler salvage pathway), although NAPRT expression could be detected in two NET cell lines. We finally analyzed the specificity of GMX1778 and STF-31 in NET cells in glucose uptake experiments. As previously shown for STF-31 in a panel NET-excluding tumor cell lines, both drugs specifically inhibited glucose uptake at higher (50 μM), but not at lower (5 μM) concentrations. (4) Conclusions: our data suggest that GLUT and especially NAMPT inhibitors are potential candidates for the treatment of NET tumors.
Isovaleric acidemia (IVA), due to isovaleryl-CoA dehydrogenase (IVD) deficiency, results in the accumulation of isovaleryl-CoA, isovaleric acid and secondary metabolites. The increase in these metabolites decreases mitochondrial energy production and increases oxidative stress. This contributes to the neuropathological features of IVA. A general assumption in the literature exists that glycine N-acyltransferase (GLYAT) plays a role in alleviating the symptoms experienced by IVA patients through the formation of N-isovalerylglycine. GLYAT forms part of the phase II glycine conjugation pathway in the liver and detoxifies excess acyl-CoA’s namely benzoyl-CoA. However, very few studies support GLYAT as the enzyme that conjugates isovaleryl-CoA to glycine. Furthermore, GLYATL1, a paralogue of GLYAT, conjugates phenylacetyl-CoA to glutamine. Therefore, GLYATL1 might also be a candidate for the formation of N-isovalerylglycine. Based on the findings from the literature review, we proposed that GLYAT or GLYATL1 can form N-isovalerylglycine in IVA patients. To test this hypothesis, we performed an in-silico analysis to determine which enzyme is more likely to conjugate isovaleryl-CoA with glycine using AutoDock Vina. Thereafter, we performed in vitro validation using purified enzyme preparations. The in-silico and in vitro findings suggested that both enzymes could form N-isovaleryglycine albeit at lower affinities than their preferred substrates. Furthermore, an increase in glycine concentration does not result in an increase in N-isovalerylglycine formation. The results from the critical literature appraisal, in-silico, and in vitro validation, suggest the importance of further investigating the reaction kinetics and binding behaviors between these substrates and enzymes in understanding the pathophysiology of IVA.
This research studies in detail four different assays, namely DPPH (2,2-diphenyl-1-picrylhydrazyl), ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)), FRAP (ferric ion reducing antioxidant potential) and FC (Folin-Ciocalteu), to determine the antioxidant capacity of standard substances as well as 50 organosolv lignins, and two kraft lignins. The coefficient of variation was determined for each method and was lowest for ABTS and highest for DPPH. The best correlation was found for FRAP and FC, which both rely on a single electron transfer mechanism. A good correlation between ABTS, FRAP and FC, respectively, could be observed, even though ABTS relies on a more complex reaction mechanism. The DPPH assay merely correlates with the others, implying that it reflects different antioxidative attributes due to a different reaction mechanism. Lignins obtained from paulownia and silphium have been investigated for the first time regarding their antioxidant capacity. Paulownia lignin is in the same range as beech wood lignin, while silphium lignin resembles wheat straw lignin. Miscanthus lignin is an exception from the grass lignins and possesses a significantly higher antioxidant capacity. All lignins possess a good antioxidant capacity and thus are promising candidates for various applications, e. g. as additives in food packaging or for biomedical purposes.
The Concordia Research Station provides a unique location for preparatory activities for future human journey to Mars, to explore microbial diversity at subzero temperatures, and monitor the dissemination of human-associated microorganisms within the pristine surrounding environment. Amplicon sequencing was leveraged to investigate the microbial diversity of surface snow samples collected monthly over a two-year period, at three distances from the Station (10, 500, and 1000 m). Even when the extracted total DNA was below the detection limit, 16S rRNA gene sequencing was successfully performed on all samples, while 18S rRNA was amplified on 19 samples out of 51. No significant relationships were observed between microbial diversity and seasonality (summer or winter) or distance from the Concordia base. This suggested that if present, the anthropogenic impact should have been below the detectable limit. While harboring low microbial diversity, the surface snow samples were characterized by heterogeneous microbiomes. Ultimately, our study corroborated the use of DNA sequencing-based techniques for revealing microbial presence in remote and hostile environments, with implications for Planetary Protection during space missions and for life-detection in astrobiology relevant targets.