Journal: International Journal of Molecular Sciences

Abbreviation

Int. j. mol. sci.

Publisher

MDPI

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ISSN

1422-0067

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Publications 1 - 10 of 119
  • Effects of Early Life Stress on Bone Homeostasis in Mice and Humans
    Item type: Journal Article
    Würtz-Kozak, Karin; Roszkowski, Martin; Cambria, Elena; et al. (2020)
    International Journal of Molecular Sciences
    Bone pathology is frequent in stressed individuals. A comprehensive examination of mechanisms linking life stress, depression and disturbed bone homeostasis is missing. In this translational study, mice exposed to early life stress (MSUS) were examined for bone microarchitecture (μCT), metabolism (qPCR/ELISA), and neuronal stress mediator expression (qPCR) and compared with a sample of depressive patients with or without early life stress by analyzing bone mineral density (BMD) (DXA) and metabolic changes in serum (osteocalcin, PINP, CTX-I). MSUS mice showed a significant decrease in NGF, NPYR1, VIPR1 and TACR1 expression, higher innervation density in bone, and increased serum levels of CTX-I, suggesting a milieu in favor of catabolic bone turnover. MSUS mice had a significantly lower body weight compared to control mice, and this caused minor effects on bone microarchitecture. Depressive patients with experiences of childhood neglect also showed a catabolic pattern. A significant reduction in BMD was observed in depressive patients with childhood abuse and stressful life events during childhood. Therefore, future studies on prevention and treatment strategies for both mental and bone disease should consider early life stress as a risk factor for bone pathologies.
  • Electrospun DegraPol Tube Delivering Stem Cell/Tenocyte Co-Culture-Derived Secretome to Transected Rabbit Achilles Tendon-In Vitro and In Vivo Evaluation
    Item type: Journal Article
    Rieber, Julia Sarah; Miescher, Iris; Wolint, Petra; et al. (2025)
    International Journal of Molecular Sciences
    Tendon ruptures have recently reached incidences of 18-35 cases/100,000 and often lead to adhesion formation during healing. Furthermore, scar formation may result in inferior biomechanics and often leads to re-ruptures. To address these problems, we cultivated rabbit adipose-derived stem cells in a co-culture with rabbit Achilles tenocytes and harvested their secretome. Following a cell-free approach, we incorporated such secretome into an electrospun tube via emulsion electrospinning. These novel implants were characterized by SEM, the WCA, and FTIR. Then, they were implanted in the rabbit Achilles tendon full transection model with an additional injection of secretome, and the adhesion extent as well as the biomechanics of extracted tendons were assessed three weeks postoperatively. The fiber thickness was around 3-5 mu m, the pore size 11-13 mu m, and the tube wall thickness approximately 265 mu m. The WCA indicated slightly hydrophilic surfaces in the secretome-containing layer, with values of 80-90 degrees. In vivo experiments revealed a significant reduction in adhesion formation (-22%) when secretome-treated tendons were compared to DegraPol (R) (DP) tube-treated tendons (no secretome). Furthermore, the cross-sectional area was significantly smaller in secretome-treated tendons compared to DP tube-treated ones (-32%). The peak load and stiffness of secretome-treated tendons were not significantly different from native tendons, while tendons treated with pure DP tubes exhibited significantly lower values. We concluded that secretome treatment supports tendon healing, with anti-adhesion effects and improved biomechanics at 3 weeks, making this approach interesting for clinical application.
  • Undetected Neuromuscular Disease in Patients after Heart Transplantation
    Item type: Journal Article
    Bekele, Biniam Melese; Gazzerro, Elisabetta; Schoenrath, Felix; et al. (2024)
    International Journal of Molecular Sciences
    (1) Heart transplantation (HTX) improves the overall survival and functional status of end-stage heart failure patients with cardiomyopathies (CMPs). The majority of CMPs have genetic causes, and the overlap between CMPs and inherited myopathies is well documented. However, the long-term outcome in skeletal muscle function and possibility of an undiagnosed underlying genetic cause of both a cardiac and skeletal pathology remain unknown. (2) Thirty-nine patients were assessed using open and standardized interviews on muscle function, a quality-of-life (EuroQol EQ-5D-3L) questionnaire, and a physical examination (Medical Research Council Muscle scale). Whole-exome sequencing was completed in three stages for those with skeletal muscle weakness. (3) Seven patients (17.9%) reported new-onset muscle weakness and motor limitations. Objective muscle weakness in the upper and lower extremities was seen in four patients. In three of them, exome sequencing revealed pathogenic/likely pathogenic variants in the genes encoding nexilin, myosin heavy chain, titin, and SPG7. (4) Our findings support a positive long-term outcome of skeletal muscle function in HTX patients. However, 10% of patients showed clinical signs of myopathy due to a possible genetic cause. The integration of genetic testing and standardized neurological assessment of motor function during the peri-HTX period should be considered.
  • Initiation of Conceptus Elongation Coincides with an Endometrium Basic Fibroblast Growth Factor (FGF2) Protein Increase in Heifers
    Item type: Journal Article
    Chiumia, Daniel; Schulke, Katy; Groebner, Anna E.; et al. (2020)
    International Journal of Molecular Sciences
    Fibroblast growth factors (FGF) play an important role during embryo development. To date, the role of FGF and the respective receptors (FGFR) during the preimplantation phase in cattle are not fully characterized. We examined FGF1, FGF2, FGFR1, FGFR2, and FGFR3 in cyclic and early pregnant heifers at Days 12, 15, and 18 after insemination (Day 0). Endometrial FGF1 mRNA transcript abundance in heifers varied significantly with respect to the day after insemination, the pregnancy status, and their interaction. The expression was higher in nonpregnant than in pregnant heifers at Day 18. The conceptus transcripts abundance of FGFR2 and FGFR3 were significantly lower at Day 15 than 18. In the endometrium, FGF1 protein abundance significantly decreased from Day 12 onwards and FGF2 protein abundance showed a minor, but a significant increase at Day 15 in comparison to Days 12 and 18. We concluded that the decrease in FGF1 mRNA expression in pregnant heifers at Day 18 points towards a potential contribution of FGF1 in the preimplantation process. Additionally, successful embryo elongation might require a spatiotemporal FGF2 protein increase in the endometrium.
  • Natural Dibenzo-α-Pyrones: Friends or Foes?
    Item type: Review Article
    Aichinger, Georg (2021)
    International Journal of Molecular Sciences
    Natural dibenzo-α-pyrones (DAPs) can be viewed from two opposite angles. From one angle, the gastrointestinal metabolites urolithins are regarded as beneficial, while from the other, the emerging mycotoxin alternariol and related fungal metabolites are evaluated critically with re-gards to potential hazardous effects. Thus, the important question is: can the structural characteris-tics of DAP subgroups be held responsible for distinct bioactivity patterns? If not, certain toxicolog-ical and/or pharmacological aspects of natural DAPs might yet await elucidation. Thus, this review focuses on comparing published data on the two groups of natural DAPs regarding both adverse and beneficial effects on human health. Literature on genotoxic, estrogenic, endocrine-disruptive effects, as well as on the induction of the cellular anti-oxidative defense system, anti-inflammatory properties, the inhibition of kinases, the activation of mitophagy and the induction of autophagy, is gathered and critically reviewed. Indeed, comparing published data suggests similar bioactivity profiles of alternariol and urolithin A. Thus, the current stratification into hazardous Alternaria toxins and healthy urolithins seems debatable. An extrapolation of bioactivities to the other DAP sub-class could serve as a promising base for further research. Conclusively, urolithins should be further evaluated toward high-dose toxicity, while alternariol derivatives could be promising chemicals for the development of therapeutics.
  • Neurosteroids Mediate Neuroprotection in an In Vitro Model of Hypoxic/Hypoglycaemic Excitotoxicity via δ-GABA A Receptors without Affecting Synaptic Plasticity
    Item type: Journal Article
    Puig-Bosch, Xènia; Ballmann, Markus; Bieletzki, Stefan; et al. (2023)
    International Journal of Molecular Sciences
    Neurosteroids and benzodiazepines are modulators of the GABAA receptors, thereby causing anxiolysis. Furthermore, benzodiazepines such as midazolam are known to cause adverse side-effects on cognition upon administration. We previously found that midazolam at nanomolar concentrations (10 nM) blocked long-term potentiation (LTP). Here, we aim to study the effect of neurosteroids and their synthesis using XBD173, which is a synthetic compound that promotes neurosteroidogenesis by binding to the translocator protein 18 kDa (TSPO), since they might provide anxiolytic activity with a favourable side-effect profile. By means of electrophysiological measurements and the use of mice with targeted genetic mutations, we revealed that XBD173, a selective ligand of the translocator protein 18 kDa (TSPO), induced neurosteroidogenesis. In addition, the exogenous application of potentially synthesised neurosteroids (THDOC and allopregnanolone) did not depress hippocampal CA1-LTP, the cellular correlate of learning and memory. This phenomenon was observed at the same concentrations that neurosteroids conferred neuroprotection in a model of ischaemia-induced hippocampal excitotoxicity. In conclusion, our results indicate that TSPO ligands are promising candidates for post-ischaemic recovery exerting neuroprotection, in contrast to midazolam, without detrimental effects on synaptic plasticity.
  • A MicroRNA Next-Generation-Sequencing Discovery Assay (miND) for Genome-Scale Analysis and Absolute Quantitation of Circulating MicroRNA Biomarkers
    Item type: Journal Article
    Khamina, Kseniya; Diendorfer, Andreas B.; Skalicky, Susanna; et al. (2022)
    International Journal of Molecular Sciences
    The plasma levels of tissue-specific microRNAs can be used as diagnostic, disease severity and prognostic biomarkers for chronic and acute diseases and drug-induced injury. Thereby, the combination of diverse microRNAs into biomarker signatures using multivariate statistics seems especially powerful from the perspective of tissue and condition specific microRNA shedding into the plasma. Although next-generation sequencing (NGS) technology enables one to analyse circulating microRNAs on a genome-scale level, it suffers from potential biases (e.g., adapter ligation bias) and lacks absolute transcript quantitation as well as tailor-made quality controls. In order to develop a robust NGS discovery assay for genome-scale quantitation of circulating microRNAs, we first evaluated the sensitivity, repeatability and ligation bias of four commercially available small RNA library preparation protocols. The protocol from RealSeq Biosciences was selected based on its performance and usability and coupled with a novel panel of exogenous small RNA spike-in controls to enable quality control and absolute quantitation, thus ensuring comparability of data across independent NGS experiments. The established microRNA Next-Generation-Sequencing Discovery Assay (miND) was validated for its relative accuracy, precision, analytical measurement range and sequencing bias and was considered fit-for-purpose for microRNA biomarker discovery. Summarized, all these criteria were met, and thus, our analytical platform is considered fit-for-pur-pose for microRNA biomarker discovery from biofluids in the setting of any diagnostic, prognostic or patient stratification need. The established miND assay was tested on serum, cerebrospinal fluid (CSF), synovial fluid (SF) and extracellular vesicles (EV) extracted from cell culture medium of primary cells and proved its potential to be used across different sample types.
  • Histopathological Gap in Aortic Diseases: A Prospective Analysis
    Item type: Journal Article
    Banceu, Cosmin Marian; Gurzu, Simona; Satala, Catalin-Bogdan; et al. (2023)
    International Journal of Molecular Sciences
    Aortic dissection (AD) is a critical cardiovascular condition with the potential for devastating consequences. This study evaluated the histological changes in the aorta wall in patients with AD and aortic aneurysm (AA) who received surgical aortic replacement. Histopathological data showed that modifications of the media layer (p = 0.0197), myxomatous aspect (p = 0.0001), and subendothelial layer degeneration (p = 0.0107) were more frequently seen in AA versus AD samples. Patients with AA were approximately twice as likely to develop histological changes than those with AD (p = 0.0037). Patients with moderate or severe medial degeneration had a higher chance of developing AD (p = 0.0001). Because the histopathological score proved to be a predictor of both in-hospital and overall mortality, its evaluation should become the standard of care in any patients who undergo aortic replacement. Individualized postoperative management might be influenced by the histopathological aspect of the aortic layer.
  • Bioactive and Elastic Emulsion Electrospun DegraPol Tubes Delivering IGF-1 for Tendon Rupture Repair
    Item type: Journal Article
    Rieber, Julia; Meier-Bürgisser, Gabriella; Miescher, Iris; et al. (2023)
    International Journal of Molecular Sciences
    Tendon injuries can result in two major drawbacks. Adhesions to the surrounding tissue may limit the range of motion, while fibrovascular scar formation can lead to poor biomechanical outcomes. Prosthetic devices may help to mitigate those problems. Emulsion electrospinning was used to develop a novel three-layer tube based on the polymer DegraPol (DP), with incorporated insulin-like growth factor-1 (IGF-1) in the middle layer. Scanning electron microscopy was utilized to assess the fiber diameter in IGF-1 containing pure DP meshes. Further characterization was performed with Fourier Transformed Infrared Spectroscopy, Differential Scanning Calorimetry, and water contact angle, as well as through the assessment of mechanical properties and release kinetics from ELISA, and the bioactivity of IGF-1 by qPCR of collagen I, ki67, and tenomodulin in rabbit Achilles tenocytes. The IGF-1-containing tubes exhibited a sustained release of the growth factor up to 4 days and showed bioactivity by significantly upregulated ki67 and tenomodulin gene expression. Moreover, they proved to be mechanically superior to pure DP tubes (significantly higher fracture strain, failure stress, and elastic modulus). The novel three-layer tubes intended to be applied over conventionally sutured tendons after a rupture may help accelerate the healing process. The release of IGF-1 stimulates proliferation and matrix synthesis of cells at the repair site. In addition, adhesion formation to surrounding tissue can be reduced due to the physical barrier.
  • Synergistic Effects of Insulin-like Growth Factor-1 and Platelet-Derived Growth Factor-BB in Tendon Healing
    Item type: Journal Article
    Rieber, Julia Sarah; Wolint, Petra; Meier-Bürgisser, Gabriella; et al. (2025)
    International Journal of Molecular Sciences
    Tendon ruptures are common musculoskeletal injuries associated with prolonged healing and complications such as adhesion formation and rerupture. Despite advancements in treatment strategies, full functional recovery remains a challenge. Growth factors (GFs) like insulin-like growth factor-1 (IGF-1) and platelet-derived growth factor-BB (PDGF-BB) play key roles in tendon repair and may have synergistic effects when applied together. To support tendon healing, a bioactive electrospun polymer scaffold made of Degrapol (R) (DP) was developed, incorporating IGF-1, PDGF-BB, or both. A range of in vitro and in vivo analyses were performed to assess scaffold structure, cell behavior, gene expression, metabolism, and biomechanical and adhesion outcomes three weeks post-surgery. Interestingly, the combined application of IGF-1 and PDGF-BB did not simply amplify individual effects but showed a complex interaction. Depending on the parameter and time point, the combination led to either enhanced or reduced responses compared to single-factor treatments, indicating a synergistic modulation rather than a purely additive effect. These findings suggest that the combination of IGF-1 and PDGF-BB can modulate key cellular and molecular processes in tendon regeneration, making this approach a promising strategy to improve tendon healing.
Publications 1 - 10 of 119