Background: Bile salts of hepatic and microbial origin mediate interorgan cross talk in the gut-liver axis. Here, we assessed whether the newly discovered class of microbial bile salt conjugates (MBSCs) activate the main host bile salt receptors (Takeda G protein-coupled receptor 5 [TGR5] and farnesoid X receptor [FXR]) and enter the human systemic and enterohepatic circulation. Methods: N-amidates of (chenodeoxy) cholic acid and leucine, tyrosine, and phenylalanine were synthesized. Receptor activation was studied in cell-free and cell-based assays. MBSCs were quantified in mesenteric and portal blood and bile of patients undergoing pancreatic surgery. Results: MBSCs were activating ligands of TGR5 as evidenced by recruitment of Gsα protein, activation of a cAMP-driven reporter, and diminution of lipopolysaccharide-induced cytokine release from macrophages. Intestine-enriched and liver-enriched FXR isoforms were both activated by MBSCs, provided that a bile salt importer was present. The affinity of MBSCs for TGR5 and FXR was not superior to host-derived bile salt conjugates. Individual MBSCs were generally not detected (ie, < 2.5 nmol/L) in human mesenteric or portal blood, but Leu-variant and Phe-variant were readily measurable in bile, where MBSCs comprised up to 213 ppm of biliary bile salts. Conclusions: MBSCs activate the cell surface receptor TGR5 and the transcription factor FXR and are substrates for intestinal (apical sodium-dependent bile acid transporter) and hepatic (Na+ taurocholate co-transporting protein) transporters. Their entry into the human circulation is, however, nonsubstantial. Given low systemic levels and a surplus of other equipotent bile salt species, the studied MBSCs are unlikely to have an impact on enterohepatic TGR5/FXR signaling in humans. The origin and function of biliary MBSCs remain to be determined.

The authors wish to replace the ‘Author Contributions’ statement and the affiliation for Jochen Maurer of this article [...]

Background Triple-negative breast cancer (TNBC) lacks biomarkers for targeted therapy. Auger emitters display the best therapeutic effect, if delivered directly into the nucleus proximal to DNA. The nuclear protein Poly (ADP-ribose)-Polymerase 1 (PARP1) is a suitable target against which few inhibitors (PARPi) are clinically approved for treatment of breast cancer with germline BRCA mutation (BRCA mut ). In this study, a theranostic approach was investigated in a TNBC xenografted mouse model by radiolabelling a close derivative of a PARPi Olaparib (termed PARPi-01) with the Auger emitters 123/125 I. Methods TNBC cell line MDA-MB-231 was subcutaneously implanted in female NOD/SCID mice. At a tumour size of ~ 500mm 3 , [ 123 I]PARPi-01 was administered intravenously, and SPECT/CT images were obtained at 4 h or 24 h post injection (p.i). A therapy study was performed with [ 125 I]PARPi-01 in 4 doses (10 MBq/dose, 10 days apart). Tumour growth was monitored by CT scans longitudinally once per week. Upon reaching study endpoint, tissues were harvested and stained with TUNEL assay for detection of apoptosis induction. Results SPECT/CT images showed rapid hepatobiliary tracer clearance at 4 h post injection (p.i.). Retention in thyroid at 24 h p.i. suggested tracer deiodination in vivo. The tumour and liver uptake were 0.2%ID/g and 2.5%ID/g, respectively. The tumour: blood ratio was 1.3. Endogenous therapy induced a significant delay in tumour growth (doubling time increased from 8.3 to 14.2 days), but no significant survival advantage. Significantly higher apoptosis ratio was observed in [ 125 I]PARPi-01 treated tumour tissues. No radiotoxicity was detected in the liver and thyroid. Conclusion Considering the radio-cytotoxic effect in the tumour tissue and a delay on tumour doubling time, [ 125 I]PARPi-01 presents a potential radiotherapeutics for treatment of TNBC. Improvements to overcome the suboptimal pharmacokinetics are necessary for its potential clinical application.

PARP1 inhibitors (PARPi) are currently approved for BRCAmut metastatic breast cancer, but they have shown limited response in triple negative breast cancer (TNBC) patients. Combination of an Auger emitter with PARPis enables PARP inhibition and DNA strand break induction simultaneously. This will enhance cytotoxicity and additionally allow a theranostic approach. This study presents the radiosynthesis of the Auger emitter [125I] coupled olaparib derivative: [125I]-PARPi-01, and its therapeutic evaluation in a panel of TNBC cell lines. Specificity was tested by a blocking assay. DNA strand break induction was analysed by γH2AX immunofluorescence staining. Cell cycle analysis and apoptosis assays were studied using flow cytometry in TNBC cell lines (BRCAwt/mut). Anchorage independent growth potential was evaluated using soft agar assay. [125I]-PARPi-01 showed PARP1-specificity and higher cytotoxicity than olaparib in TNBC cell lines irrespective of BRCA their status. Cell lines harbouring DNA repair deficiency showed response to [125I]-PARPi-01 monotherapy. Combined treatment with Dox-NP further enhanced therapeutic efficiency in metastatic resistant BRCAwt cell lines. The clonogenic survival was significantly reduced after treatment with [125I]-PARPi-01 in all TNBC lines investigated. Therapeutic efficacy was further enhanced after combined treatment with chemotherapeutics. [125I]-PARPi-01 is a promising radiotherapeutic agent for low radiation dosages, and mono/combined therapies of TNBC.

Biotransformation of host bile salts by gut microbes results in generation of secondary bile salt species that have biological and physicochemical properties that are distinct from the parent compounds. There is increased awareness that a bile salt–gut microbiome axis modulates various processes in the host, including innate and adaptive immunity, by interaction of microbial bile salt metabolites with host receptors. Omics and targeted approaches have vastly expanded the number and repertoire of secondary bile salt species. A new class of microbial bile salt metabolites was reported in 2020 and comprises bile salts that are conjugated by microbial enzymes. Amino acids other than those employed by host enzymes (glycine and taurine) are used as substrates in the formation of these microbial bile salt conjugates (MBSCs). Leucocholic acid, phenylalanocholic acid and tyrosocholic acid were the first MBSCs identified in mice and humans. The number of distinct MBSCs is now approaching 50, with variation both at the level of bile salt and amino acid employed for conjugation. Evidence is emerging that MBSC generation is a common feature of human gut bacteria, and initial links with disease states have been reported. In this review, we discuss this intriguing new class of secondary bile salts, with yet enigmatic function.

The Cover Feature shows the functions of protein coding PARP10 gene in multiple processes, including DNA repair, signaling and innate immunity. Moreover, the PARP10 gene is amplified in certain solid tumors. The exogenous expression of PARP10 can induce apoptosis, an assay that has been used to screen for small molecule PARP10 inhibitors. More information can be found in the Full Paper by Patricia Korn et al.

BACKGROUND:ADP-ribosylation is a ubiquitous post-translational modification that involves both mono- and poly-ADP-ribosylation. ARTD10, also known as PARP10, mediates mono-ADP-ribosylation (MARylation) of substrate proteins. A previous screen identified protein kinase C delta (PKCδ) as a potential ARTD10 substrate, among several other kinases. The voltage-gated K+ channel Kv1.1 constitutes one of the dominant Kv channels in neurons of the central nervous system and the inactivation properties of Kv1.1 are modulated by PKC. In this study, we addressed the role of ARTD10-PKCδ as a regulator of Kv1.1.RESULTS:We found that ARTD10 inhibited PKCδ, which increased Kv1.1 current amplitude and the proportion of the inactivating current component in HeLa cells, indicating that ARTD10 regulates Kv1.1 in living cells. An inhibitor of ARTD10, OUL35, significantly decreased peak amplitude together with the proportion of the inactivating current component of Kv1.1-containing channels in primary hippocampal neurons, demonstrating that the ARTD10-PKCδ signaling cascade regulates native Kv1.1. Moreover, we show that the pharmacological blockade of ARTD10 increases excitability of hippocampal neurons.CONCLUSIONS:Our results, for the first time, suggest that MARylation by ARTD10 controls neuronal excitability.

Dielectric surface modifications (DSMs) can improve the performance of organic thin-film transistors (OTFTs) significantly. In order to gain a deeper understanding of this performance enhancement and to facilitate high-mobility transistors, perylene based devices utilizing novel dielectric surface modifications have been produced. Novel DSMs, based on derivates of tridecyltrichlorosilane (TTS) with different functional end-groups as well as polymeric dielectrics have been applied to tailor the adhesion energy of perylene. The resulting samples were characterized by electronic transport measurements, scanning probe microscopy, and X-ray diffraction (XRD). Measurements of the surface free energy of the modified dielectric enabled the calculation of the adhesion energy of perylene upon these novel DSMs by the equation-of-state approach. These calculations demonstrate the successful tailoring of the adhesion energy. With these novel DSMs, perylene thin-films with a superior film quality were produced, which enabled high-performance perylene-based OTFTs with high charge-carrier mobility.

Natural gas guzzlers There has been an increasing interest in organisms thriving at marine gas seeps, in particular microbes that utilize methane. Surprisingly, there seems to have been comparatively little work done on the fate of the other abundant hydrocarbons in natural gases — ethane, propane and butane. Now sediments collected from hydrocarbon seep areas in the Gulf of Mexico and the Gulf of California have yielded microbial cultures that utilize propane and butane under anoxic conditions similar to those prevailing in gas reservoirs. These biochemically unusual bacteria may be responsible for the observed alteration of gases in seeps and other gas reservoirs.

Two routes to optically active α-silyl-substituted α-hydroxyacetic acids are described. As a key step, the first utilizes O-H insertion reactions of (R)-and (S)-phenylethanol into benzyl 2-silyl-2-diazoacetates in the presence of [Rh 2 (OAc) 4 ]. Alternatively, asymmetric reductions of benzyl 2-silyl-2-oxoacetates using (R)-Alpine-Borane® afford the corresponding α-hydroxy esters with up to 91% ee.

The formation of metabolites during anaerobic biodegradation of saturated hydrocarbons directly from crude oil in the absence of oxygen was investigated using a denitrifying bacterium, the Azoarcus-like strain HxN1, which can utilise C6–C8 n-alkanes anaerobically as growth substrates. Various alkylsuccinates (apparently diastereomers) with alkyl chains (probably linked at C-2) ranging from C4 to C8 were detected by gas chromatography–mass spectrometry. These metabolites apparently result from the activation reaction of C4–C8 alkanes with cellular fumarate, analogous to the recently established reaction of pure n-hexane with fumarate in strain HxN1 to yield (1-methylpentyl)succinate. Other succinates carried substituents derived from cyclopentane and methylcyclopentane and hence indicated an activation of such cycloalkanes. Since n-butane, n-pentane or cycloalkanes as single compounds did not support growth of strain HxN1, their apparent products point to co-metabolic reactions during utilisation of the C6–C8 n-alkanes. Furthermore, methyl-branched and cyclopentyl-substituted fatty acids were detected. This finding is explained by a further metabolism of the substituted succinates via carbon skeleton rearrangement and decarboxylation. All metabolites detected in the oil-grown cultures were also identified in cultures grown with defined mixtures of saturated hydrocarbons. Results are of potential value for an understanding of metabolite formation in hydrocarbon-rich anoxic environments from the viewpoint of bacterial physiology.

A new chiral MeO-PEG-supported ferrocenyl oxazoline was synthesized and successfully employed in the enantioselective phenyl transfer to aldehydes. The products were obtained in high yields and with excellent enantioselectivities (up to 97% ee). Furthermore, the recovery of the ferrocene was facile, and catalyst efficiency was maintained in subsequent reactions.