International Journal of Molecular Sciences最新文献

Fibrosis represents a terminal pathological manifestation encountered in numerous chronic diseases. The process involves the persistent infiltration of inflammatory cells, the transdifferentiation of fibroblasts into myofibroblasts, and the excessive deposition of extracellular matrix (ECM) within damaged tissues, all of which are characteristic features of organ fibrosis. Extensive documentation exists on fibrosis occurrence in vital organs such as the liver, heart, lungs, kidneys, and skeletal muscles, elucidating its underlying pathological mechanisms. Regular exercise is known to confer health benefits through its anti-inflammatory, antioxidant, and anti-aging effects. Notably, exercise exerts anti-fibrotic effects by modulating multiple pathways, including transforming growth factor-β1/small mother decapentaplegic protein (TGF-β1/Samd), Wnt/β-catenin, nuclear factor kappa-B (NF-kB), reactive oxygen species (ROS), microRNAs (miR-126, miR-29a, miR-101a), and exerkine (FGF21, irisin, FSTL1, and CHI3L1). Therefore, this paper aims to review the specific role and molecular mechanisms of exercise as a potential intervention to ameliorate organ fibrosis.

RAD52 plays crucial roles in several aspects of mammalian cells, including DNA double-strand breaks repair, viral infection, cancer development, and antibody class switching. To comprehensively elucidate the role of RAD52 in maintaining genome stability and uncover additional functions of RAD52 in mammals, we performed the transcriptomics and proteomics analysis of the liver of RAD52 knockout mice. Transcriptomics analysis reveals overexpression of mitochondrial genes in the liver of RAD52 knockout (RAD52KO) mice. Proteomics analysis of RAD52KO mice shows that damage recognition proteins Cul4b and Rad23a in the process of nucleotide excision repair pathway are overexpressed. Furthermore, gene ontology and KEGG enrichment analysis (accessed on 20 November 2024) from integrated omics shows that differentially expressed genes are significantly enriched in pathways related to mitochondrial oxidative phosphorylation and nucleotide metabolism in the liver of RAD52KO mice. In addition, mRNA and protein levels of Bhmt1b are elevated in the liver of RAD52KO mice. Taken together, this study provides valuable insights into the function and mechanism of RAD52.

Apurinic/apyrimidinic (AP) sites are endogenous DNA lesions widespread in human cells. Having no nucleobases, they are noncoding and promutagenic. AP site repair is generally initiated through strand incision by AP endonuclease 1 (APE1). Although AP sites' repair in regular B-DNA has been studied extensively, their processing in G-quadruplexes (G4s) has received much less attention. Here, we used the hTERT promoter region that is capable of forming three stacked parallel G4s to understand how AP sites can influence higher-order quadruplex folding and stability and how a G4 affects the efficiency of human APE1-mediated AP site processing. We designed a series of synthetic single- and double-stranded DNA constructs of varying lengths containing a stable AP site analog in both G- and C-rich strands at positions corresponding to somatic driver mutations. Using circular dichroism, we studied the effect of the AP site on hTERT G4 structure and stability. Bio-layer interferometry and gel-based approaches were employed to characterize APE1 binding to the designed DNA substrates and AP site processing. It was shown that (i) an AP site leads to G4 destabilization, which depends on the lesion location in the G4 scaffold; (ii) APE1 binds tightly to hTERT G4 structure but exhibits greatly reduced cleavage activity at AP sites embedded in the quadruplex; and (iii) a clear correlation was revealed between AP site-induced hTERT G4 destabilization and APE1 activity. We can hypothesize that reduced repair of AP sites in the hTERT G4 is one of the reasons for the high mutation rate in this promoter region.

O-Methyldehydroserine, ΔSer(Me), is a non-standard α,β-dehydroamino acid, which occurs naturally in Cyrmenins with potential pharmaceutical application. The C-terminal part and the side chain of the ΔSer(Me) residue constitute the β-methoxyacrylate unit, responsible for antifungal activity of Cyrmenins. The short model, Ac-ΔSer(Me)-OMe, was analyzed considering the geometrical isomer Z (1) and E (2). The Ramachandran diagrams were created for both isomers, using quantum chemical calculations, to show possible conformations for isolated molecules (in vacuo), in weakly polar (chloroform) and polar (water) environments. The Ac-(Z)-ΔSer(Me)-OMe (1) was synthesized and the single-crystal X-ray diffraction analysis together with FT-IR spectra were performed. The detailed analysis of the conformations of the (Z)-ΔSer(Me) residue is presented considering the intra- and intermolecular interactions as well as their influence on the β-methoxyacrylate part. It is concluded that the β-methoxyacrylate structural motif is able to maintain a planar geometry, crucial for biological activity, regardless of the conformation adopted by O-methyldehydroserine.

Salt tolerance is a critical trait for plant survival and productivity in saline environments. Development of salt tolerant crops is a practical strategy for addressing soil salinity issues. In this study, RNA-Seq analysis was performed using two wheat cultivars with contrasting salt tolerance (Neixiang188, tolerant and Barra, sensitive) at 6 h and 24 h after salinity treatment to determine the genetic variations reflected in the RNA expression patterns and identify key genes associated with salt tolerance. Our results revealed that there were 2983 upregulated and 1091 downregulated differentially expressed genes (DEGs), which were found in common in the two accessions. Meanwhile, 529 salt tolerant associated DEGs were subjected to GO function annotation, KEGG enrichment, and protein-protein interaction (PPI) network prediction. Finally, a theoretical framework outlining the salt tolerance mechanisms of Neixiang188 was proposed. It can be inferred that Neixiang188 possesses superior ion homeostasis, ROS detoxification, and osmotic adjustment abilities compared to Barra when subjected to saline stress. The present research sheds light on the genetic foundation of salt tolerance in wheat and offers candidate genes for genetic manipulation. Our research insights enhance the comprehension of the molecular mechanisms underlying salt stress responses and could guide future breeding efforts for improving salt tolerance in crops.

Melatonin is a hormone released by the pineal gland that regulates the sleep-wake cycle. It has been widely studied for its therapeutic effects on Alzheimer's disease (AD), particularly through the amyloidosis, oxidative stress, and neuroinflammation pathways. Nevertheless, the mechanisms through which it exerts its neuroprotective effects in AD are still largely unknown. Data mining was used to identify potential gene targets that link melatonin's effects to AD pathways, yielding a comprehensive view of the underlying molecular mechanisms. We identified 3397 genes related to AD from DisGeNet and 329 melatonin gene targets from ChEMBL, which revealed 223 overlapping genes and the potential shared pathways. These genes were used to construct a protein-protein interaction (PPI) network comprising 143 nodes and 823 edges, which demonstrated significant PPI enrichment. A cluster analysis highlighted two key clusters centered on MMP2 and NR3C1, with both genes playing crucial roles in steroid hormone signaling, apoptosis, and monoamine neurotransmission. Gene Ontology (GO) enrichment and KEGG pathway analyses further elucidated their involvement in critical pathways, for instance, steroid hormone signaling and apoptosis regulation, significantly influencing AD pathology through mechanisms such as extracellular matrix remodeling, epigenetic modifications, and neuroinflammation. Our findings emphasize MMP2 and NR3C1 as important gene targets for future research on melatonin treatment in AD, paving the way for further investigations into their roles in AD pathophysiology.

MicroRNA (miR)-126 is frequently downregulated in malignancies, including breast cancer (BC). Despite its tumor-suppressive role, the mechanisms underlying miR-126 deregulation in BC remain elusive. Through silencing experiments, we identified Early B Cell Factor 1 (EBF1), ETS Proto-Oncogene 2 (ETS2), and Krüppel-Like Factor 2 (KLF2) as pivotal regulators of miR-126 expression. These transcription factors were found to be downregulated in BC due to epigenetic silencing or a "poised but not transcribed" promoter state, impairing miR-126 expression. Gene Ontology analysis of differentially expressed miR-126 target genes in the Cancer Genome Atlas: Breast Invasive Carcinoma (TCGA-BRCA) cohort revealed their involvement in cancer-related pathways, primarily signal transduction, chromatin remodeling/transcription, and differentiation/development. Furthermore, we defined interconnections among transcription factors, miR-126, and target genes, identifying a potential feed-forward loop (FFL) crucial in maintaining cellular identity and preventing the acquisition of stemness properties associated with cancer progression. Our findings propose that the dysregulation of the EBF1/ETS2/KLF2/miR-126 axis disrupts this FFL, promoting oncogenic transformation and progression in BC. This study provides new insights into the molecular mechanisms of miR-126 downregulation in BC and highlights potential targets for therapeutic intervention. Further research is warranted to clarify the role of this FFL in BC, and to identify novel therapeutic strategies aimed at modulating this network as a whole, rather than targeting individual signals, for cancer management.

The red blood cell (RBC) membrane is unique and crucial for maintaining structural-functional relationships. Maternal smoking induces significant changes in the morphological, rheological, and functional parameters of both maternal and foetal RBCs, mainly due to the continuous generation of the free radicals. The major aim of this study was to follow the consequences of a secondary stressor, like fungal infection, on the already compromised RBC populations. The impact of Candida infection, a growing health concern, was investigated on four blood sample groups: mothers and their neonates originating from non-smoking versus smoking populations. Here, we searched for phenotypical and molecular markers that precisely reflected the effect of Candida infection on the RBC membrane; this included the level of hemolysis, appearance of morphological variants, formation of the lipid peroxidation marker 4-hydroxyl-nonenal, arrangement of the Band 3 molecules and activation of the Caspase 3. In most of the examined cases, the fungal infection increased the adverse symptoms induced by smoking, indicating a general stress response, likely due to an altered redox state of the cells. However, we were able to identify an atypical phenotype (clustered populations with shrinkage and membrane blebbing) in both the non-smoking and smoking populations, which might be a unique marker for Candida spp. infection.

Liver diseases, particularly metabolic dysfunction-associated steatotic liver disease (MASLD), have emerged as a major global health concern, affecting millions of individuals and leading to increased morbidity and mortality [...].

In this study, the drought-responsive gene HvFBX158 from barley was transferred to Arabidopsis thaliana, and overexpression lines were obtained. The phenotypic characteristics of the transgenic plants, along with physiological indicators and transcription level changes of stress-related genes, were determined under drought treatment. Under drought stress, transgenic plants overexpressing HvFBX158 exhibited enhanced drought tolerance and longer root lengths compared to wild-type plants. Additionally, malondialdehyde and hydrogen peroxide contents were significantly lower in transgenic lines, while superoxide dismutase activity was elevated. Quantitative RT-PCR showed that the expression levels of drought and stress response genes, including AtP5CS, AtDREB2A, AtGSH1, AtHSP17.8, and AtSOD, were significantly upregulated. Transcriptome analysis further confirmed that HvFBX158 regulated multiple stress tolerance pathways. In summary, the overexpression of the HvFBX158 gene enhanced drought tolerance in Arabidopsis thaliana by regulating multiple stress response pathways. This study provides a practical basis for improving drought-resistant barley varieties and lays a foundation for subsequent research on F-box family genes for stress resistance in barley.