Journal: International Journal of Molecular Sciences

Abbreviation

Int. j. mol. sci.

Publisher

MDPI

Journal Volumes

ISSN

1422-0067

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Publications1 - 10 of 121
  • AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the Lifespan of C. elegans
    Item type: Journal Article
    Vidovic, Tinka; Dakhovnik, Alexander; Hrabovskyi, Oleksii; et al. (2023)
    International Journal of Molecular Sciences
    The mechanistic target of rapamycin (mTOR) kinase is one of the top drug targets for promoting health and lifespan extension. Besides rapamycin, only a few other mTOR inhibitors have been developed and shown to be capable of slowing aging. We used machine learning to predict novel small molecules targeting mTOR. We selected one small molecule, TKA001, based on in silico predictions of a high on-target probability, low toxicity, favorable physicochemical properties, and preferable ADMET profile. We modeled TKA001 binding in silico by molecular docking and molecular dynamics. TKA001 potently inhibits both TOR complex 1 and 2 signaling in vitro. Furthermore, TKA001 inhibits human cancer cell proliferation in vitro and extends the lifespan of Caenorhabditis elegans, suggesting that TKA001 is able to slow aging in vivo.
  • Silicon Nitride as a Biomedical Material: An Overview
    Item type: Review Article
    Du, Xiaoyu; Lee, Seunghun S.; Blugan, Gurdial; et al. (2022)
    International Journal of Molecular Sciences
    Silicon nitride possesses a variety of excellent properties that can be specifically designed and manufactured for different medical applications. On the one hand, silicon nitride is known to have good mechanical properties, such as high strength and fracture toughness. On the other hand, the uniqueness of the osteogenic/antibacterial dualism of silicon nitride makes it a favorable bioceramic for implants. The surface of silicon nitride can simultaneously inhibit the proliferation of bacteria while supporting the physiological activities of eukaryotic cells and promoting the healing of bone tissue. There are hardly any biomaterials that possess all these properties concurrently. Although silicon nitride has been intensively studied as a biomedical material for years, there is a paucity of comprehensive data on its properties and medical applications. To provide a comprehensive understanding of this potential cornerstone material of the medical field, this review presents scientific and technical data on silicon nitride, including its mechanical properties, osteogenic behavior, and antibacterial capabilities. In addition, this paper highlights the current and potential medical use of silicon nitride and explains the bottlenecks that need to be addressed, as well as possible solutions.
  • 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.
  • Plant Dependence on Rhizobia for Nitrogen Influences Induced Plant Defenses and Herbivore Performance
    Item type: Journal Article
    Dean, Jennifer M.; Mescher, Mark C.; De Moraes, Consuelo M. (2014)
    International Journal of Molecular Sciences
    Symbiotic rhizobia induce many changes in legumes that could affect aboveground interactions with herbivores. We explored how changing the intensity of Bradyrhizobium japonicum, as modulated by soil nitrogen (N) levels, influenced the interaction between soybean (Glycine max) and herbivores of different feeding guilds. When we employed a range of fertilizer applications to manipulate soil N, plants primarily dependent on rhizobia for N exhibited increased root nodulation and higher levels of foliar ureides than plants given N fertilizer; yet all treatments maintained similar total N levels. Soybean podworm (Helicoverpa zea) larvae grew best on plants with the highest levels of rhizobia but, somewhat surprisingly, preferred to feed on high-N-fertilized plants when given a choice. Induction of the defense signaling compound jasmonic acid (JA) by H. zea feeding damage was highest in plants primarily dependent on rhizobia. Differences in rhizobial dependency on soybean did not appear to affect interactions with the phloem-feeding soybean aphid (Aphis glycines). Overall, our results suggest that rhizobia association can affect plant nutritional quality and the induction of defense signaling pathways and that these effects may influence herbivore feeding preferences and performance—though such effects may vary considerably for different classes of herbivores.
  • ACE Inhibition with Captopril Retards the Development of Signs of Neurodegeneration in an Animal Model of Alzheimer’s Disease
    Item type: Journal Article
    AbdAlla, Said; Langer, Andreas; Fu, Xuebin; et al. (2013)
    International Journal of Molecular Sciences
    Increased generation of reactive oxygen species (ROS) is a significant pathological feature in the brains of patients with Alzheimer’s disease (AD). Experimental evidence indicates that inhibition of brain ROS could be beneficial in slowing the neurodegenerative process triggered by amyloid-beta (Abeta) aggregates. The angiotensin II AT1 receptor is a significant source of brain ROS, and AD patients have an increased brain angiotensin-converting enzyme (ACE) level, which could account for an excessive angiotensin-dependent AT1-induced ROS generation. Therefore, we analyzed the impact of ACE inhibition on signs of neurodegeneration of aged Tg2576 mice as a transgenic animal model of AD. Whole genome microarray gene expression profiling and biochemical analyses demonstrated that the centrally active ACE inhibitor captopril normalized the excessive hippocampal ACE activity of AD mice. Concomitantly, the development of signs of neurodegeneration was retarded by six months of captopril treatment. The neuroprotective profile triggered by captopril was accompanied by reduced amyloidogenic processing of the amyloid precursor protein (APP), and decreased hippocampal ROS, which is known to enhance Abeta generation by increased activation of beta- and gamma-secretases. Taken together, our data present strong evidence that ACE inhibition with a widely used cardiovascular drug could interfere with Abeta-dependent neurodegeneration.
  • 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.
  • High Flexibility of RNaseH2 Catalytic Activity with Respect to Non-Canonical DNA Structures
    Item type: Journal Article
    Dede, Maria; Napolitano, Silvia; Melati, Anna; et al. (2021)
    International Journal of Molecular Sciences
    Ribonucleotides misincorporated in the human genome are the most abundant DNA lesions. The 2′-hydroxyl group makes them prone to spontaneous hydrolysis, potentially resulting in strand breaks. Moreover, their presence may decrease the rate of DNA replication causing replicative fork stalling and collapse. Ribonucleotide removal is initiated by Ribonuclease H2 (RNase H2), the key player in Ribonucleotide Excision Repair (RER). Its absence leads to embryonic lethality in mice, while mutations decreasing its activity cause Aicardi–Goutières syndrome. DNA geometry can be altered by DNA lesions or by peculiar sequences forming secondary structures, like G-quadruplex (G4) and trinucleotide repeats (TNR) hairpins, which significantly differ from canonical B-form. Ribonucleotides pairing to lesioned nucleotides, or incorporated within non-B DNA structures could avoid RNase H2 recognition, potentially contributing to genome instability. In this work, we investigate the ability of RNase H2 to process misincorporated ribonucleotides in a panel of DNA substrates showing different geometrical features. RNase H2 proved to be a flexible enzyme, recognizing as a substrate the majority of the constructs we generated. However, some geometrical features and non-canonical DNA structures severely impaired its activity, suggesting a relevant role of misincorporated ribonucleotides in the physiological instability of specific DNA sequences.
  • Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases
    Item type: Journal Article
    Maggi, Jordi; Koller, Samuel; Bähr, Luzy; et al. (2021)
    International Journal of Molecular Sciences
    The purpose of this study was to develop a flexible, cost-efficient, next-generation sequencing (NGS) protocol for genetic testing. Long-range polymerase chain reaction (PCR) amplicons of up to 20 kb in size were designed to amplify entire genomic regions for a panel (n = 35) of inherited retinal disease (IRD)-associated loci. Amplicons were pooled and sequenced by NGS. The analysis was applied to 227 probands diagnosed with IRD: (A) 108 previously molecularly diagnosed, (B) 94 without previous genetic testing, and (C) 25 undiagnosed after whole-exome sequencing (WES). The method was validated with 100% sensitivity on cohort A. Long-range PCR-based sequencing revealed likely causative variant(s) in 51% and 24% of proband from cohorts B and C, respectively. Breakpoints of 3 copy number variants (CNVs) could be characterized. Long-range PCR libraries spike-in extended coverage of WES. Read phasing confirmed compound heterozygosity in 5 probands. The proposed sequencing protocol provided deep coverage of the entire gene, including intronic and promoter regions. Our method can be used (i) as a first-tier assay to reduce genetic testing costs, (ii) to elucidate missing heritability cases, (iii) to characterize breakpoints of CNVs at nucleotide resolution, (iv) to extend WES data to non-coding regions by spiking-in long-range PCR libraries, and (v) to help with phasing of candidate variants.
  • The Pattern of RNA Editing Changes in Pleural Mesothelioma upon Epithelial-Mesenchymal Transition
    Item type: Journal Article
    Felley-Bosco, Emanuela; Qi, Weihong; Jean, Didier; et al. (2023)
    International Journal of Molecular Sciences
    Pleural mesothelioma (PM) is a cancer where epithelioid, biphasic and sarcomatoid histotypes are observed. Sarcomatoid PM is characterized by mesenchymal features. Multi-omics have been used to characterize the epithelial-to-mesenchymal (EMT) phenotype at the molecular level. We contribute to this effort by including the analysis of RNA editing. We extracted samples with the highest vs. lowest Epithelial score from two PM cohorts and observed increased RNA editing in introns and decreased RNA editing in 3′UTR upon EMT. The same was observed in primary PM primary cultures stratified by transcriptomics analysis into two groups, one of them enriched with mesenchymal features. Our data demonstrate that, as has been observed in other cancer types, RNA editing associates to EMT phenotype in PM.
  • 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.
Publications1 - 10 of 121