Biology subjects

Martins, I.

Publications and source records attributed to Martins, I..

4 recordsLinked to original sources

bioRxiv2026

Mesenchymal Stromal Cell Therapeutic Potential to RestoreNeurovascular Integrity in Machado-Joseph Disease

BackgroundMachado-Joseph disease (MJD), or Spinocerebellar Ataxia type 3 (SCA3), is a neurodegenerative disorder caused by an expansion of the CAG repeat in the MJD1/ATXN3 gene, which encodes for a polyglutamine-expansion in Ataxin-3. Similar to what occurs in other neurodegenerative disorders, the cerebrovascular system, particularly the blood-brain barrier (BBB), is impaired in MJD. BBB is an important cellular barrier that controls homeostasis of the central nervous system, and its disruption compromises neuronal function. To date, there is no disease-modifying therapy for MJD. Our group previously demonstrated that MSC administration can ameliorate the phenotype of MJD transgenic mice. However, the effect of MSC on the neurovascular unit and BBB integrity remains unexplored in the context of MJD. In the present work, we aimed to evaluate the therapeutic potential of MSC in mitigating vascular abnormalities and BBB disruption in MJD. MethodsEight-month-old MJD transgenic mice were treated with two consecutive bone marrow-MSC intravenous injections (1 week apart). Behavioral tests to assess motor coordination were conducted before and after treatment. Vascular structure, function, and BBB disruption were evaluated by immunohistochemistry and western blot. ResultsMSC administration partially restored vascular impairment in MJD transgenic mice. Treated mice exhibited improved gait and motor performance footprint and beam walking tests) and concurrently attenuated vascular dysfunction. Specifically, MSC-treated mice exhibited a decrease in collagen IV surface area and stabilized cerebellar blood supply. Additionally, MSC treatment diminished BBB permeability to the Evans blue (EB) dye in MJD mice and restored the levels of important adherent and tight junction-associated proteins in the cellular membrane, including vascular endothelial cadherin (VE-cadherin), claudin-5, and occludin, in a sex-specific manner. Conclusionsour results highlight significant cerebrovascular dysregulations in MJD, which are sex-dependent and progress with the disease stage. Moreover, our findings suggest that MSC administration partially reverted vascular impairments, providing valuable insights into the mechanisms underlying the therapeutic potential of MSC in MJD. Graphical AbstractMSC treatment partially reverts neurovascular dysregulation in MJD. MJD mice exhibit increased vessel coverage, increased BBB permeability, and altered TJ and AJ expression and subcellular localization. MSC administration modulates vessel coverage, reduces BBB leakage, and partially normalizes TJ/AJ subcellular localization. List of abbreviations: AJ - Adherent junction; BBB - Blood-Brain barrier; MJD- Machado-Joseph disease; MSC - mesenchymal stromal cell; TJ - thigh junction. Created with BioRender.com O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/703043v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@8fa0a2org.highwire.dtl.DTLVardef@17b13f9org.highwire.dtl.DTLVardef@15c5ce3org.highwire.dtl.DTLVardef@d67539_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Lysosomal membrane permeabilization enhances the anticancer effects of RNA Polymerase I transcription inhibitors

Lysosomes are known to contribute to the development of drug resistance through a variety of mechanisms that include the sequestration of drugs within their compartments and the activation of adaptive stress pathways. Although targeting POL I (RNA polymerase I) exhibits anticancer effects, little attention has been paid to the contribution of lysosomes to the efficacy and resistance of RNA POL I inhibitors. In this study, we investigated this aspect in the context of two potent POL I inhibitors, CX-3543 (Quarfloxin) and CX-5461 (Pidnarulex). Unexpectedly, CX-3543 was discovered to be sequestered in the lysosomal compartment. This resulted in the permeabilization of lysosomal membranes (LMP) and the subsequent activation of cellular stress adaptation pathways, including the transcription factor (TFEB) and autophagy. Disruption of TFEB or autophagy increased cell sensitivity to CX-3543, highlighting the cytoprotective role of these processes against cell death induced by this compound. Moreover, targeting lysosomal membranes using chloroquine derivatives or blue light excitation induced substantial LMP, resulting in the liberation of CX-3543 from lysosomes. This effect amplified both the inhibition of DNA-to-RNA transcription and cell death induced by CX-3543. Similar effects were observed when chloroquine derivatives were combined with CX-5461. Furthermore, combining CX-3543 with the chloroquine derivative DC661 reduced the growth of fibrosarcoma established in immunocompetent mice more efficiently than either agent alone. Altogether, our results uncover an unanticipated lysosome-related mechanism that contributes to the resistance of cancer cells to POL I transcription inhibitors, as well as a strategy to combat this resistance.

cancer biology↗

bioRxiv2023

Cutin-Derived Oligomers Act as Damage-Associated Molecular Patterns in Arabidopsis thaliana

The cuticle constitutes the outermost defensive barrier of most land plants. It comprises a polymeric matrix - cutin, surrounded by soluble waxes. Moreover, the cuticle constitutes the first line of defense against pathogen invasion, while also protecting the plant from many abiotic stresses. Aliphatic monomers in cutin have been suggested to act as immune elicitors in plants. This study analyses the potential of tomato cutin oligomers to act as damage-associated molecular patterns (DAMPs) able to induce a rapid immune response in the model plant Arabidopsis. Cutin oligomeric mixtures led to Ca2+ influx and MAPK activation in Arabidopsis. Comparable responses were measured for cutin, which was also able to induce a reactive oxygen species (ROS) burst. Furthermore, treatment of Arabidopsis with cutin oligomers resulted in a unique transcriptional reprogramming profile, having many archetypal features of pattern-triggered immunity (PTI). Targeted spectroscopic and spectrometric analyses of the cutin oligomers suggest that the elicitors compounds consist mostly of two up to three 10,16-dihydroxyhexadecanoic acid monomers linked together through ester bonds. This study demonstrates that cutin breakdown products can act as DAMPs; a novel class of elicitors deserving further characterization.

plant biology↗

bioRxiv2020

Depletion of senescent cells improves functional recovery after spinal cord injury

Persistent senescent cells (SCs) are known to underlie ageing-related chronic disorders, but it is now recognized that SCs may be at the center of tissue remodeling events, namely during development or organ repair. Here we show that two distinct senescence profiles are induced in the context of a spinal cord injury between the regenerating zebrafish and the non-regenerating mouse. While induced-SCs in the zebrafish are progressively cleared out, they accumulate over time in mice. Depletion of SCs in spinal cord injured mice, with different senolytic drugs, improved locomotor, sensory and bladder functions. This functional recovery is associated with improved myelin sparing, reduced fibrotic scar, attenuated inflammation and increased axonal growth. Targeting SCs is a promising therapeutic strategy not only for spinal cord injuries but potentially for other organs that lack regenerative competence.

neuroscience↗