Biology subjects

Schauer, A.

Publications and source records attributed to Schauer, A..

6 recordsLinked to original sources

bioRxiv2026

Empagliflozin preserves mitochondrial function and reduces tubular injury in obese type 2 diabetic ZSF-1 rats

Diabetic nephropathy remains the leading cause of end-stage renal disease. The ZSF-1 rat model combines features known as the metabolic syndrome, such as type 2 diabetes mellitus, hypertension and obesity, developing progressive kidney disease. In this study, we investigated the nephroprotective mechanisms of the SGLT2 inhibitor empagliflozin, focusing on mitochondrial function. Obese ZSF-1 rats were randomized at 24 weeks of age to receive either placebo or empagliflozin for eight weeks, while lean ZSF-1 rats served as healthy controls. Kidney function, assessed by glomerular filtration rate (GFR), was significantly reduced in obese rats and was not improved by empagliflozin treatment. However, obese animals exhibited increased tubular injury, tubular cast formation, and elevated total and tubular proteinuria, all of which were attenuated by empagliflozin. Mitochondrial function was evaluated in freshly isolated cortical kidney mitochondria by measuring oxygen consumption. Obese ZSF-1 rats showed impaired respiratory capacity and reduced protein expression of oxidative phosphorylation (OXPHOS) complexes II, III, IV, and V, indicating mitochondrial dysfunction. Empagliflozin treatment improved mitochondrial function by enhancing complex I- and IV-linked respiration and restoring the expression of OXPHOS complexes II, III, and IV. In addition, empagliflozin treatment was linked to improved mitochondrial dynamics and modulation of autophagic activity, suggesting enhanced mitochondrial quality control. Overall, these findings demonstrate that empagliflozin exerts nephroprotective effects primarily at the tubular level in obese ZSF-1 rats. The beneficial effects appear to be mediated through improved mitochondrial function, enhanced mitochondrial integrity, and reduced tubular injury.

physiology↗

bioRxiv2023

BMP-dependent patterning of ectoderm tissue material properties modulates lateral mesendoderm cell migration during early zebrafish gastrulation

Cell migration is a fundamental process during embryonic development. Most studies on cell migration in vivo have focussed on the migration of cells using the extracellular matrix (ECM) as their substrate for migration. In contrast, much less is known about how cells migrate on other cells, as found in early embryos when the ECM has not yet formed. Here, we show that lateral mesendoderm (LME) cells in the early zebrafish gastrula use the overlying ectoderm as their substrate for migration. We show that the lateral ectoderm is permissive for the animal pole-directed migration of LME cells, while the ectoderm at the animal pole of the gastrula halts animal pole-directed LME migration. These differences in the permissive properties of the ectoderm for LME migration are due to the lateral ectoderm being more cohesive and viscous than the animal ectoderm. Consistently, tuning cell contractility in lateral and animal ectoderm via modulation of the actomyosin cytoskeleton is sufficient to change their permissiveness for LME migration. Finally, we found that BMP signalling is critical for reducing animal ectoderm cohesion and, thus, its capacity to halt LME migration towards the animal pole. Collectively, these findings identify a critical role of ectoderm tissue cohesion and viscosity in guiding LME migration during zebrafish gastrulation.

developmental biology↗

bioRxiv2023

Robust axis elongation by Nodal-dependent restriction of BMP signaling

Embryogenesis is brought about by the coordinated activities of different signaling pathways controlling cell fate specification and morphogenesis. In vertebrate gastrulation, both Nodal and BMP signaling play key roles in germ layer specification and morphogenesis, yet their interplay to coordinate embryo patterning with morphogenesis is still insufficiently understood. Here, we took a reductionist approach using zebrafish embryonic explants to study the coordination of Nodal and BMP signaling for embryo patterning and morphogenesis. We show that Nodal signaling not only triggers explant elongation by inducing mesendodermal progenitors but also by suppressing BMP signaling activity at the site of mesendoderm induction. Ectopic BMP signaling in the mesendoderm blocks cell alignment and oriented mesendoderm intercalations, key processes to drive explant elongation. Translating these ex vivo observations to the intact zebrafish embryo showed that, similar to explants, Nodal signaling renders the dorsal domain less sensitive towards BMP signaling to allow effective cell intercalations and thus robust embryonic axis elongation. These findings suggest a dual function of Nodal signaling in embryonic axis elongation by both inducing mesendoderm and maintaining low levels of BMP signaling activity in the dorsal portion of the mesendoderm.

developmental biology↗

bioRxiv2022

Analysis of SMAD1/5 target genes in a sea anemone reveals ZSWIM4-6 as a novel BMP signaling modulator

BMP signaling has a conserved function in patterning the dorsal-ventral body axis in Bilateria and the directive axis in anthozoan cnidarians. So far, cnidarian studies have focused on the role of different BMP signaling network components in regulating pSMAD1/5 gradient formation. Much less is known about the target genes downstream of BMP signaling. To address this, we generated a genome-wide list of direct pSMAD1/5 target genes in the anthozoan Nematostella vectensis, several of which were conserved in Drosophila and Xenopus. Our ChIP-Seq analysis revealed that many of the regulatory molecules with documented bilaterally symmetric expression in Nematostella are directly controlled by BMP signaling. Among the so far uncharacterized BMP-dependent transcription factors and signaling molecules we identified several, whose bilaterally symmetric expression may be indicative of their involvement in secondary axis patterning. One of these molecules, zswim4-6, encodes a novel nuclear modulator of the pSMAD1/5 gradient potentially promoting BMP-dependent gene repression. Strikingly, overexpression of the zebrafish homologue zswim5 suggests that its effect on the pSMAD1/5 gradient is conserved between anthozoan Cnidaria and Bilateria.

developmental biology↗

bioRxiv2020

Validation of an LC-MS/MS Assay for the Simultaneous Determination of Bictegravir, Doravirine, and Raltegravir in Human Plasma

Bictegravir (BIC), an integrase inhibitor, and doravirine (DOR), a non-nucleoside reverse transcriptase inhibitor, were recently approved by the US FDA for HIV treatment and are recommended first line treatment options. Because certain clinical scenarios warrant using them in combination, we developed a fully validated LC-MS/MS method for simultaneous measurement of BIC and DOR, along with a legacy integrase inhibitor, raltegravir (RAL), in human plasma over a clinically relevant 1000-fold range for each analyte. These analytes were extracted from the plasma by protein precipitation with their stable, isotopically labeled internal standards (BIC-d5, 13C6-DOR, and RAL-d6). Following extraction, samples were analyzed by reverse phase chromatography on a Waters Atlantis T3 C18 (50×2.1mm, 3um particle size) column with subsequent detection by electrospray ionization in positive ion mode on an AB Sciex API-5000 triple quadrupole mass spectrometer. The assay was linear (R2>0.994) over the selected calibration ranges (20.0-20,000ng/mL (BIC), 3.00-3,000ng/mL (DOR), and 10.0-10,000 (RAL)). The assay was accurate (inter-assay %Bias ≤±8.5) and precise (inter-assay %CV ≤11.4). This method was validated according to FDA guidance for industry and can be used to assess the pharmacokinetics of two newly approved antiretrovirals, or to support therapeutic drug monitoring for modern antiretroviral therapy.Competing Interest StatementThe authors have declared no competing interest.View Full Text

pharmacology and toxicology↗

bioRxiv2017

Understanding the dynamics of scaffold-mediated signaling

Many signaling networks involve scaffold proteins that bind multiple kinases in kinase cascades. While scaffolds play a fundamental role in regulating signaling, few hypotheses regarding their function have been rigorously examined. Here, we used dynamical models of scaffold signaling to investigate the impact scaffolds have on network behavior. We considered two paradigms of scaffold assembly: as either the nucleation point for assembly of discrete multi-subunit proteins (the machine paradigm) or a platform upon which kinases independently associate (the ensemble paradigm). We found that several well-accepted hypotheses regarding the role of scaffolds in regulating signal response either do not hold or depend critically on the assembly paradigm employed. In addition to providing novel insights into the function of scaffold proteins, our work suggests experiments that could distinguish between assembly paradigms. Our findings should also inform attempts to target scaffold proteins for therapeutic intervention and the design of scaffolds for synthetic biology.

systems biology↗