Experimental Biology and Medicine最新文献

The intima, comprising the endothelium and the subendothelial matrix, plays a crucial role in atherosclerosis pathogenesis. The mechanical stress arising from disturbed blood flow (d-flow) and the stiffening of the arterial wall contributes to endothelial dysfunction. However, the specific impacts of these physical forces on the mechanical environment of the intima remain undetermined. Here, we investigated whether inhibiting collagen crosslinking could ameliorate the detrimental effects of persistent d-flow on the mechanical properties of the intima. Partial ligation of the left carotid artery (LCA) was performed in C57BL/6J mice, inducing d-flow. The right carotid artery (RCA) served as an internal control. Carotids were collected 2 days and 2 weeks after surgery to study acute and chronic effects of d-flow on the mechanical phenotype of the intima. The chronic effects of d-flow were decoupled from the ensuing arterial wall stiffening by administration of β-aminopropionitrile (BAPN), an inhibitor of collagen crosslinking by lysyl oxidase (LOX) enzymes. Atomic force microscopy (AFM) was used to determine stiffness of the endothelium and the denuded subendothelial matrix in en face carotid preparations. The stiffness of human aortic endothelial cells (HAEC) cultured on soft and stiff hydrogels was also determined. Acute exposure to d-flow caused a slight decrease in endothelial stiffness in male mice but had no effect on the stiffness of the subendothelial matrix in either sex. Regardless of sex, the intact endothelium was softer than the subendothelial matrix. In contrast, exposure to chronic d-flow led to a substantial increase in the endothelial and subendothelial stiffness in both sexes. The effects of chronic d-flow were largely prevented by concurrent BAPN administration. In addition, HAEC displayed reduced stiffness when cultured on soft vs. stiff hydrogels. We conclude that chronic d-flow results in marked stiffening of the arterial intima, which can be effectively prevented by inhibition of collagen crosslinking.

Cerebral palsy (CP) is a prevalent motor disorder originating from early brain injury or malformation, with significant variability in its clinical presentation and etiology. Early diagnosis and personalized therapeutic interventions are hindered by the lack of reliable biomarkers. This study aims to identify potential biomarkers for cerebral palsy and develop predictive models to enhance early diagnosis and prognosis. We conducted a comprehensive bioinformatics analysis of gene expression profiles in muscle samples from CP patients to identify candidate biomarkers. Six key genes (CKMT2, TNNT2, MYH4, MYH1, GOT1, and LPL) were validated in an independent cohort, and potential biological pathways and molecular networks involved in CP pathogenesis were analyzed. The importance of processes such as functional regulation, energy metabolism, and cell signaling pathways in the muscles of CP patients was emphasized. Predictive models of muscle sample biomarkers related to CP were developed and visualized. Calibration curves and receiver operating characteristic analysis demonstrated that the predictive models exhibit high sensitivity and specificity in distinguishing individuals at risk of CP. The identified biomarkers and developed prediction models offer significant potential for early diagnosis and personalized management of CP. Future research should focus on validating these biomarkers in larger cohorts and integrating them into clinical practice to improve outcomes for individuals with CP.

Cyclin-dependent kinase-like 3 (CDKL3) has been identified as an oncogene in certain types of tumors. Nonetheless, its function in hepatocellular carcinoma (HCC) is poorly understood. In this study, we conducted a comprehensive analysis of CDKL3 based on data from the HCC cohort of The Cancer Genome Atlas (TCGA). Our analysis included gene expression, diagnosis, prognosis, functional enrichment, tumor microenvironment and metabolic characteristics, tumor burden, mRNA expression-based stemness, alternative splicing, and prediction of therapy response. Additionally, we performed a cell counting kit-8 assay, TdT-mediated dUTP nick-end Labeling staining, migration assay, wound healing assay, colony formation assay, and nude mouse experiments to confirm the functional relevance of CDKL3 in HCC. Our findings showed that CDKL3 was significantly upregulated in HCC patients compared to controls. Various bioinformatic analyses suggested that CDKL3 could serve as a potential marker for HCC diagnosis and prognosis. Furthermore, CDKL3 was found to be involved in various mechanisms linked to the development of HCC, including copy number variation, tumor burden, genomic heterogeneity, cancer stemness, and alternative splicing of CDKL3. Notably, CDKL3 was also closely correlated with tumor immune cell infiltration and the expression of immune checkpoint markers. Additionally, CDKL3 was shown to independently function as a risk predictor for overall survival in HCC patients by multivariate Cox regression analysis. Furthermore, the knockdown of CDKL3 significantly inhibited cell proliferation in vitro and in vivo, indicating its role as an oncogene in HCC. Taken together, our findings suggest that CDKL3 shows promise as a biomarker for the detection and treatment outcome prediction of HCC patients.

The cornea is an avascular tissue in the eye that has multiple functions in the eye to maintain clear vision which can significantly impair one's vision when subjected to damage. Peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptor proteins comprising three different peroxisome proliferator-activated receptor (PPAR) isoforms, namely, PPAR alpha (α), PPAR gamma (γ), and PPAR delta (δ), have emerged as potential therapeutic targets for treating corneal diseases. In this review, we summarised the current literature on the therapeutic effects of PPAR agents on corneal diseases. We discussed the role of PPARs in the modulation of corneal wound healing, suppression of corneal inflammation, neovascularisation, fibrosis, stimulation of corneal nerve regeneration, and amelioration of dry eye by inhibiting oxidative stress within the cornea. We also discussed the underlying mechanisms of these therapeutic effects. Future clinical trials are warranted to further attest to the clinical therapeutic efficacy.

Neurological pain (NP) is always accompanied by symptoms of depression, which seriously affects physical and mental health. In this study, we identified the common hub genes (Co-hub genes) and related immune cells of NP and major depressive disorder (MDD) to determine whether they have common pathological and molecular mechanisms. NP and MDD expression data was downloaded from the Gene Expression Omnibus (GEO) database. Common differentially expressed genes (Co-DEGs) for NP and MDD were extracted and the hub genes and hub nodes were mined. Co-DEGs, hub genes, and hub nodes were analyzed for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Finally, the hub nodes, and genes were analyzed to obtain Co-hub genes. We plotted Receiver operating characteristic (ROC) curves to evaluate the diagnostic impact of the Co-hub genes on MDD and NP. We also identified the immune-infiltrating cell component by ssGSEA and analyzed the relationship. For the GO and KEGG enrichment analyses, 93 Co-DEGs were associated with biological processes (BP), such as fibrinolysis, cell composition (CC), such as tertiary granules, and pathways, such as complement, and coagulation cascades. A differential gene expression analysis revealed significant differences between the Co-hub genes ANGPT2, MMP9, PLAU, and TIMP2. There was some accuracy in the diagnosis of NP based on the expression of ANGPT2 and MMP9. Analysis of differences in the immune cell components indicated an abundance of activated dendritic cells, effector memory CD8⁺ T cells, memory B cells, and regulatory T cells in both groups, which were statistically significant. In summary, we identified 6 Co-hub genes and 4 immune cell types related to NP and MDD. Further studies are needed to determine the role of these genes and immune cells as potential diagnostic markers or therapeutic targets in NP and MDD.

[This retracts the article DOI: 10.1177/1535370217703975.].

Atherosclerosis has traditionally been considered as a disorder characterized by the accumulation of cholesterol and thrombotic materials within the arterial wall. However, it is now understood to be a complex inflammatory disease involving multiple factors. Central to the pathogenesis of atherosclerosis are the interactions among monocytes, macrophages, and neutrophils, which play pivotal roles in the initiation, progression, and destabilization of atherosclerotic lesions. Recent advances in our understanding of atherosclerosis pathogenesis, coupled with results obtained from experimental interventions, lead us to propose the hypothesis that atherosclerosis may be reversible. This paper outlines the evolution of this hypothesis and presents corroborating evidence that supports the potential for atherosclerosis regression through the restoration of vascular copper homeostasis. We posit that these insights may pave the way for innovative therapeutic approaches aimed at the reversal of atherosclerosis.

The lack of effective treatment options for an increasing number of cancer cases highlights the need for new anticancer therapeutic strategies. Immunotherapy mediated by Salmonella enterica Typhimurium is a promising anticancer treatment. Candidate strains for anticancer therapy must be attenuated while retaining their antitumor activity. Here, we investigated the attenuation and antitumor efficacy of two S. enterica Typhimurium mutants, ΔtolRA and ΔihfABpmi, in a murine melanoma model. Results showed high attenuation of ΔtolRA in the Galleria mellonella model, and invasion and survival in tumor cells. However, it showed weak antitumor effects in vitro and in vivo. Contrastingly, lower attenuation of the attenuated ΔihfABpmi strain resulted in regression of tumor mass in all mice, approximately 6 days after the first treatment. The therapeutic response induced by ΔihfABpmi was accompanied with macrophage accumulation of antitumor phenotype (M1) and significant increase in the mRNAs of proinflammatory mediators (TNF-α, IL-6, and iNOS) and an apoptosis inducer (Bax). Our findings indicate that the attenuated ΔihfABpmi exerts its antitumor activity by inducing macrophage infiltration or reprogramming the immunosuppressed tumor microenvironment to an activated state, suggesting that attenuated S. enterica Typhimurium strains based on nucleoid-associated protein genes deletion could be immunotherapeutic against cancer.

Osteosarcoma is a form of bone cancer that predominantly impacts osteoblasts, the cells responsible for creating fresh bone tissue. Typical indications include bone pain, inflammation, sensitivity, mobility constraints, and fractures. Utilising imaging techniques such as X-rays, MRI scans, and CT scans can provide insights into the size and location of the tumour. Additionally, a biopsy is employed to confirm the diagnosis. Analysing genes with distinct expression patterns unique to osteosarcoma can be valuable for early detection and the development of effective treatment approaches. In this research, we comprehensively examined the entire transcriptome and pinpointed genes with altered expression profiles specific to osteosarcoma. The study mainly aimed to identify the molecular fingerprint of osteosarcoma. In this study, we processed 90 FFPE samples from PathWest with an almost equal number of osteosarcoma and healthy tissues. RNA was extracted from Paraffin-embedded tissue; RNA was sequenced, the sequencing data was analysed, and gene expression was compared to the healthy samples of the same patients. Differentially expressed genes in osteosarcoma-derived samples were identified, and the functions of those genes were explored. This result was combined with our previous studies based on FFPE and fresh samples to perform a meta-analysis. We identified 1,500 identical differentially expressed genes in PathWest osteosarcoma samples compared to normal tissue samples of the same patients. Meta-analysis with combined fresh tissue samples identified 530 differentially expressed genes. IFITM5, MMP13, PANX3, and MAGEA6 were some of the most overexpressed genes in osteosarcoma samples, while SLC4A1, HBA1, HBB, AQP7 genes were some of the top downregulated genes. Through the meta-analysis, 530 differentially expressed genes were identified to be identical among FFPE (105 FFPE samples) and 36 fresh bone samples. Deconvolution analysis with single-cell RNAseq data confirmed the presence of specific cell clusters in FFPE samples. We propose these 530 DEGs as a molecular fingerprint of osteosarcoma.

[This retracts the article DOI: 10.1177/15353702231199070.].