Biology subjects

Minder, L.

Publications and source records attributed to Minder, L..

4 recordsLinked to original sources

bioRxiv2026

Lanifibranor (IVA-337) - a pan-PPAR agonist suppresses TGF-β1-induced cardiac fibrosis and rescues cardiomyocyte function

Background: Cardiac fibrosis is a hallmark of many cardiovascular diseases, driven by sustained fibroblast activation and excessive extracellular matrix deposition, leading to myocardial stiffening and impaired contractility. Current therapies inadequately address this process. This study evaluated the antifibrotic potential of lanifibranor, a balanced pan-peroxisome proliferator-activated receptors (PPARs) agonist, in TGF-beta1-induced cardiac fibrosis. Methods: Human cardiac microtissues, along with 2D and 3D cardiac fibroblast and cardiomyocyte cultures, were used to assess cell viability, structure, metabolism, contractility, and gene expression. Results: Lanifibranor reduced TGF-beta1-induced fibrosis by limiting fibroblast activation and matrix deposition without affecting viability. In fibroblasts, these effects were associated with partial restoration of mitochondrial respiration and reduced focal adhesion maturation. In cardiac microtissues, lanifibranor improved contraction kinetics, decreased profibrotic transcriptional activity, and preserved bioenergetic homeostasis despite altered nucleotide balance. In cardiomyocytes, treatment normalized contractility and calcium handling while maintaining metabolic stability. Conclusions: Lanifibranor attenuates TGF-beta1-driven cardiac fibrosis by combining antifibrotic effects with metabolic and functional improvements in human models.

pharmacology and toxicology↗

bioRxiv2026

The dual PPAR-α/δ agonist elafibranor attenuates TGF-β1-induced cardiac fibrosis through redox-metabolic and bioenergetic reprogramming in human cardiac models

BackgroundCardiac fibrosis drives adverse myocardial remodelling through persistent fibroblast activation, ECM deposition, and impaired cardiac function. Current therapies offer limited protection against cardiac fibrosis progression. Elafibranor is a dual PPAR-/{delta} agonist approved for the treatment of liver disease. However, its effects in human models of cardiac fibrosis remain insufficiently explored. MethodsElafibranor was evaluated in complementary human in vitro TGF-{beta}1-induced cardiac fibrosis models: 2D primary fibroblasts, 3D fibroblast spheroids, spontaneously contracting 3D cardiac microtissues, and hiPSC-derived cardiomyocytes. Viability, apoptosis, fibroblast activation, ECM remodelling, mitochondrial respiration, nucleotide and NAD pools, calcium handling, contractility, and transcriptomic profiles were assessed. ResultsAt non-cytotoxic concentrations, elafibranor attenuated TGF-{beta}1-driven cardiac fibrosis responses. In 2D cardiac fibroblasts, it reduced myofibroblast differentiation, procollagen 11 secretion, and partially restored mitochondrial respiratory capacity. In 3D spheroids, it preserved viability, attenuated caspase-3/7 activation, and suppressed procollagen 11 release. In cardiac microtissues, elafibranor reduced ECM accumulation, shifted transcriptomic profiles toward redox-metabolic/cytoprotective pathways, altered adenine nucleotide and NAD pools, and partially recovered contraction parameters. In hiPSC-derived cardiomyocytes, elafibranor modulated calcium handling, contractility, and mitochondrial respiration. ConclusionsElafibranor mitigates TGF-{beta}1-driven cardiac fibrosis by suppressing fibroblast activation and ECM remodelling while promoting adaptive metabolic, redox, and bioenergetic responses, supporting balanced PPAR-/{delta} activation as a potential therapeutic strategy for cardiac fibrosis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/745425v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@2de670org.highwire.dtl.DTLVardef@173fea6org.highwire.dtl.DTLVardef@537e7aorg.highwire.dtl.DTLVardef@194b846_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2026

Dysferlin is a novel regulator of COMP-positive matrifibrocytes in heart failure

Background and AimsCardiac fibrosis is a major contributor to heart failure (HF), yet mechanisms limiting pathological fibroblast activation remain incompletely understood. We identified dysferlin (DYSF), a membrane repair protein, as highly induced in HF fibroblasts and investigated its role in regulating profibrotic responses. MethodsCardiac fibroblasts from patients with end-stage HF and unaffected donor hearts were analysed by liquid chromatography-tandem mass spectrometry and bulk RNA sequencing. Dysferlin expression was validated in independent cohorts. Selected gene/protein expression was validated using single-cell/single-nucleus RNA sequencing and multiplex immunofluorescence of human myocardium from dilated cardiomyopathy (DCM), ischaemic cardiomyopathy (ICM), acute myocardial infarction (AMI), and unaffected hearts. Functional studies were performed in human and mouse cardiac fibroblasts using siRNA-mediated silencing and TGF-{beta} stimulation, and in engineered human 3D cardiac microtissues. Fibrotic remodelling, autophagy, apoptosis, and contractile function were assessed by molecular, histological, biochemical and functional analyses. ResultsDysferlin abundance was markedly increased in HF fibroblasts. Across HF myocardium, DYSF was enriched in activated fibroblasts but largely excluded from COMP-enriched fibrotic regions, consistent with a role in restraining fibroblast state transitions. Although induced by TGF-{beta}, DYSF silencing enhanced extracellular matrix production, increased FOSL2 expression, and promoted differentiation into COMP-positive matrifibrocytes. In engineered human cardiac microtissues, DYSF silencing exacerbated fibrosis, increased apoptosis, and impaired contractility. Mechanistically, dysferlin restrained the TGF-{beta}-FOSL2-autophagy signalling axis, whereas FOSL2 suppressed DYSF expression, defining a reciprocal regulatory circuit. Silencing FOSL2 or MXRA5 increased dysferlin levels, while mRNA-protein discordance implicated S-acylation as a potential regulator of dysferlin protein abundance. ConclusionsDysferlin is a stress-inducible antifibrotic regulator that limits maladaptive fibroblast differentiation and myocardial fibrosis, thereby representing a potential therapeutic target to attenuate adverse cardiac remodelling in HF. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/745492v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@46ae02org.highwire.dtl.DTLVardef@4a0b99org.highwire.dtl.DTLVardef@13fa574org.highwire.dtl.DTLVardef@18777d4_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2021

Intrabody induced cell death by targeting the T. brucei cytoskeletal protein TbBILBO1

Trypanosoma brucei belongs to a genus of protists that cause life-threatening and economically important diseases of human and animal populations in Sub-Saharan Africa. T. brucei cells are covered in surface glycoproteins some of which are used to escape the host immune system. Exo-/endocytotic trafficking of these and other molecules occurs via a single copy organelle called the flagellar pocket (FP). The FP is maintained and enclosed around the flagellum by the flagellar pocket collar (FPC). To date, the most important cytoskeletal component of the FPC is an essential, calcium-binding, polymer-forming protein called TbBILBO1. In searching for novel immune-tools to study this protein, we raised nanobodies against TbBILBO1. Nanobodies (Nb) that were selected according to their binding properties to TbBILBO1, were tested as immunofluorescence tools, and expressed as intrabodies (INb). One of them, Nb48, proved to be the most robust nanobody and intrabody. We further demonstrate that inducible, cytoplasmic expression of INb48 was lethal to these parasites, producing abnormal phenotypes resembling those of TbBILBO1 RNAi knockdown. Our results validate the feasibility of generating functional single-domain antibody derived intrabodies to target trypanosome cytoskeleton proteins.

cell biology↗