JOURNAL OF CELLULAR AND MOLECULAR MEDICINE最新文献

To investigate the impact of growth hormone (GH) on branched-chain amino acids (BCAAs) catabolism in males with hypopituitarism, we measured the concentration of amino acids in 133 males with hypopituitarism and 90 age-matched healthy controls using untargeted metabolome. A rat model of hypopituitarism was established through hypophysectomy, followed by recombinant human GH (rhGH) intervention. Targeted metabolomics and label-free quantitative phosphoproteomics were utilised to assess amino acid levels in rats and explore the mechanisms of GH's effect on BCAA catabolism. Hypopituitarism exhibited elevated concentrations of BCAAs, which correlated positively with triglyceride, fasting insulin and HOMA-IR. The BCAAs were significantly elevated following hypophysectomy and were substantially reduced upon rhGH intervention. Phosphorylation proteomics analysis in liver tissues revealed that differentially expressed phosphoproteins (DEPPs) after GH treatment were predominantly involved in ‘RNA metabolic process’, ‘Diseases of signal transduction by growth factor receptors’ and ‘BCAAs degradation’. Notably, 12 proteins in the BCAA degradation pathway showed altered phosphorylation without whole protein changes. Importantly, the expression or phosphorylation modification of BCKDH, BCATs and MuRF1 were restored through rhGH intervention. Hypopituitarism exhibits elevated levels of circulating BCAAs. The increased circulating BCAAs in hypopituitarism may result from enhanced MuRF1-mediated muscle proteolysis, which greatly exceeds the BCAA degradation capacity. This study provides valuable insights into the effects of GH on BCAA catabolism at the scale of the proteomics level.

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer with a poor prognosis and high mortality. The chemotherapeutic regimen remains the predominant treatment modality for TNBC in current clinical practice. However, chemotherapy resistance significantly complicates the development of an effective treatment regimen. Furthermore, the immunosuppressive microenvironment of TNBC contributes to enhanced tumour aggressiveness. Consequently, understanding its mechanisms of progression and finding effective therapeutic interventions is crucial. Recent evidence has identified extracellular vesicles (EVs) as key mediators of cell-to-cell communication in TNBC progression and immune regulation. In view of the remarkable ability of EVs to transfer active molecules, such as proteins and nucleic acids, from parental to recipient cells, they are regarded as a promising biomarker and novel drug delivery system. In this review, we provide an overview of how EVs derived from TNBC cells and tumour microenvironment cells play a role in regulating tumour progression. We also discuss the potential of EVs for immune regulation and their application as novel therapeutic strategies and tumour markers in TNBC. The knowledge gained from studying EV-mediated communication in TNBC could lead to the development of targeted therapies and improve patient outcomes.

This study investigates the differences in ligand–receptor interactions between the communication network of vascular endothelial cells (ECs) and photoreceptor cells (PRCs)in diabetic retinopathy (DR) the mechanism was verified by animal experiments. The GSE209872 data set, including retinal specimens from five Sprague–Dawley rats induced by streptozotocin, was obtained from Gene Expression Omnibus. CM and EC data were extracted individually for reclustering, functional enrichment and trajectory analyses. Cell communication analysis was conducted to investigate the altered signals and significant ligand–receptor interactions. Moreover, novel ligand–receptor interactions were validated using immunofluorescence staining using 2, 4 and 8 weeks DR model; DR was treated with AAV-shANGPTL4, and retinal function was detected by Haematoxylin and eosin staining (HE), TUNEL and ELISA. The expression of ligand–receptor in DR Retina was detected by qPCR and immunohistochemistry. Nine cell types were determined in DR. Cellular communication results revealed four signalling pathways, including PTN, MK, ANGPTL and CXCL, that were significantly changed in DR. Furthermore, 3 ligand-receptor pairs (Ptn-Ncl, Mkd-Ncl and Angptl4-Sdc4) were obviously upregulated between ECs and PRCs, the expression of which was verified via immunofluorescence in the DR model. After treatment with AAV-shANGPTL4, the retinal thickness and average density of RGCs were decreased (p < 0.05). TUNEL staining showed that knocking down ANGPTL4 reduced the apoptosis of DR (p < 0.05), and VEGF and IGF-1 expression were downregulated (p < 0.01). The expression of ligand–receptors also decreased in the DR Model (p < 0.01). The vascular ECs and PRCs demonstrate significant heterogeneities in DR. ANGPTL4 was a decreased ligand–receptor expression and improved retinal function as a potential therapeutic target against DR.

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Over the past decade, studies have demonstrated that circulating long non-coding RNAs (lncRNAs)—recognised for their stability and ease of detection—serve as crucial regulators and potential biomarkers in multiple diseases. LncRNAs regulate key processes, including endothelial function, vascular remodelling, and myocardial hypertrophy, all of which influence CVD progression. Additionally, lncRNAs display cell-, tissue-, and disease-specific expression patterns, making them ideal therapeutic targets or tools. This review presents a comprehensive overview of the current understanding of lncRNAs in CVDs, examining their mechanisms of action and recent research advances. It also addresses the use of lncRNAs as diagnostic and prognostic markers, as well as potential applications of RNA therapeutics in novel treatment strategies.

Ferroptosis plays a crucial role in the pathogenesis of osteoarthritis (OA), and inhibition of chondrocyte ferroptosis effectively alleviates OA progression. Krüppel-like factor 9 (KLF9) is demonstrated to be upregulated in OA, but its molecular mechanism remains unclear. The study aimed to investigate the role of KLF9 in OA progression. Primary chondrocytes were treated with IL-1β to establish an OA cell model, and showed that KLF9 was highly expressed in IL-1β-incubated chondrocytes. Knockdown of KLF9 alleviated IL-1β-induced chondrocyte degeneration. In addition, chondrocytes treated with IL-1β showed a decreased methylation proportion in the KLF9 gene promoter. DNA methyltransferase 1 (DNMT1) directly bound to the KLF9 promoter, and overexpression of DNMT1 inhibited KLF9 expression by promoting its promoter methylation in chondrocytes. Subsequently, KLF9 shRNA and pcDNA-CYP1B1 were individually or altogether transfected into chondrocytes. KLF9 shRNA inhibited Cytochrome P450 1B1 (CYP1B1) expression in chondrocytes, and pcDNA-CYP1B1 abrogated the inhibitory effect of KLF9 shRNA on IL-1β-induced chondrocyte ferroptosis. Moreover, Ferrostatin-1 (Fer-1, an inhibitor of ferroptosis) reversed the promotion of pcDNA-CYP1B1 on IL-1β-induced chondrocyte ferroptosis. Finally, in vivo experiments showed that KLF9 shRNA significantly suppressed the cartilage tissue damage, ferroptosis, and the IHC scores of KLF9 and CYP1B1 in rats. In conclusion, our results suggested that KLF9, epigenetic silenced by DNMT1, promoted extracellular signal-regulated kinase (ERK)-mediated ferroptosis of OA chondrocytes through transcriptionally regulating CYP1B1. Thus, KLF9 is expected to be a new target for the treatment of OA.

This study constructed a prognostic model combining machine learning-based immune infiltration-related genes in each CRC subtype. We used publicly accessible gene expression data and clinical information on colorectal cancer patients. Integrated bioinformatics analysis was used for the identification of immune-wise genes. Machine learning algorithms, like LASSO regression and random forest, were utilised to identify the most important genes that may serve as predictors for patient prognosis. Univariate Cox regression, consensus clustering as well as machine learning algorithms were conducted to construct a prognostic risk scoring model. Analysis of functional enrichment, immune infiltration analyses and copy number variations as well as mutational burdens was performed and validated at the single-cell level. A machine learning-based model is designed with good predictive power—an area under the receiver operating characteristic curve (AUC-ROC) of C-index in cross-validation. The model also achieved good calibration and discrimination ability to stratify patients into high- and low-risk groups with a statistically significant difference in OS (p < 0.05). We have integrated multiple types of gene network features into machine learning systems based on the characteristics of integrating networks with Multi-Expense Learning algorithms, and we propose a robust approach for predicting CRC molecular subtype patient survival. This model could potentially steer personalised treatment strategies and ameliorate outcomes in patients. Although validation in other cohorts and clinical situations is necessary, it may be useful.

In this research, we conducted an in-depth analysis of differentially expressed genes associated with mitochondrial depolarisation in non-small cell lung cancer (NSCLC) using single-cell sequencing. By combining our findings with cuproptosis-related genes, we identified 10 significant risk genes: DCN, PTHLH, CRYAB, HMGCS1, DSG3, ZFP36L2, SCAND1, NUDT4, NDUFA4L2 and RPL36A, using univariate Cox regression analysis and machine learning methods. These genes form the core of our prognosis risk prediction model, which demonstrated high specificity and accuracy in predicting patient outcomes, as evidenced by ROC curve analysis. Kaplan–Meier curves further confirmed that patients in the low-risk group had significantly better survival rates compared to those in the high-risk group. Our models also provided valuable insights into the tumour microenvironment, immunotherapy sensitivity and chemotherapy response. To facilitate the quantification of the probability of patient survival, we incorporated clinical data into a nomogram. We comprehensively analysed the mutation status and expression patterns of the 10 risk genes using bulk transcriptomic, single-cell and spatial transcriptomic datasets. Drug target predictions highlighted DSG3, PTHLH, ZFP36L2, DCN and NDUFA4L2 as promising therapeutic targets. Notably, RPL36A emerged as a potential tumour marker for NSCLC, with its expression validated in lung cancer cell lines through qPCR. This study has established a predictive models based on mitochondrial depolarisation genes associated with cuproptosis, aiding clinicians in forecasting overall survival and guiding personalised treatment strategies. The identification of novel tumour markers has paved the way for targeted therapies, and therapeutic targets are critical for advancing the treatment of NSCLC.

Postoperative cognitive dysfunction (POCD) is common in older adult patients and affects their prognosis. Studies suggested that autophagy and oxidative stress are key factors in the pathogenesis of POCD. This study aimed to determine whether electroacupuncture (EA) pre-treatment improves POCD in aged rats and the underlying mechanisms. We established a model of POCD by using propofol anaesthesia and caesarean section in aged mice and assessed whether electroacupuncture at the Baihui and Neiguan points modulates autophagy and oxidative stress involved in the pathological process of POCD. The Morris water maze test assessed postoperative cognitive function. Oxidative stress was assessed using flow cytometry and enzyme-linked immunosorbent assay (ELISA) to determine the levels of superoxide dismutase (SOD), reactive oxygen species (ROS) and malondialdehyde (MDA). Transmission electron microscopy was used to observe the ultrastructure of the hippocampal cord neurons. In addition, protein blotting and quantitative real-time polymerase chain reaction (PCR) assays were performed to assess SIRT1, FOXO1, and autophagy markers at both the protein and mRNA levels. The results showed that anaesthesia/surgery significantly impaired cognitive performance, increased oxidative stress, decreased autophagy in the hippocampus, damaged hippocampal neurones and disrupted the mitochondrial structure in aged rats. EA pre-treatment improved cognitive function, restored neuronal and mitochondrial function, increased Beclin-1 and SIRT1 levels and attenuated oxidative damage and autophagy dysfunction in POCD rats. In conclusion, EA pre-treatment improved POCD in aged rats, and this mechanism may be related to the enhancement of autophagy and the inhibition of oxidative stress through SIRT1/FOXO1 signalling.

RETRACTION: H. Tian, Q. Liu, S. Qin, C. Zong, Y. Zhang, S. Yao, N. Yang, T. Guan, and S. Guo, “Synthesis and Cardiovascular Protective Effects of Quercetin 7-O-Sialic Acid,” Journal of Cellular and Molecular Medicine 21, no. 1 (2017): 107–120, https://doi.org/10.1111/jcmm.12943.

The above article, published online on 11 August 2016, in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor-in-Chief, Stefan N. Constantinescu, the Foundation for Cellular and Molecular Medicine, and John Wiley and Sons Ltd. Following publication, concerns were raised by third parties that Figures 3 and 5 contained duplicated images. The authors acknowledged the duplications but were unable to provide the uncropped western blot raw data. The retraction has been agreed upon because of the duplication concerns, affecting the interpretation of the data and results presented.

Osteoarthritis presents a significant clinical challenge due to its high prevalence and the resultant impairment of patients' motor function. Osteoarthritic chondrocytes are characterised by inflammation and metabolic disturbances. Pioglitazone, an agonist of peroxisome proliferator-activated receptor γ (PPAR-γ), has been demonstrated to exert anti-inflammatory effects across various diseases. This study aims to investigate the potential protective effects of Pioglitazone on osteoarthritic chondrocytes. An in vitro chondrocyte inflammation model was established utilising IL-1β. The impact of Pioglitazone on chondrocyte inflammation and extracellular matrix synthesis was evaluated through enzyme-linked immunosorbent assay, immunofluorescence staining and Alcian blue staining. The affinity of Pioglitazone for PPAR-γ was investigated using molecular docking techniques. Alterations in chondrocyte glycolysis and oxidative phosphorylation were examined using the Seahorse XF Analyser, and the influence of Pioglitazone on glucose uptake and the mitochondrial electron transport chain was further analysed. Pioglitazone was gavaged in a mouse OA model established by anterior cruciate ligament transection to evaluate the therapeutic efficacy of Pioglitazone. Our findings indicate that Pioglitazone mitigates chondrocyte inflammation and osteoarthritis in murine models by inhibiting the expression of inflammatory mediators such as TNF-α, IL-6 and PGE2, and by preventing the degradation of aggrecan and collagen II. Furthermore, Pioglitazone significantly upregulated the expression of glucose transporter 1 and stabilised the mitochondrial proton delivery chain in a PPAR-γ-dependent manner, thereby enhancing chondrocyte glucose uptake, glycolysis, and oxidative phosphorylation. These effects were partially reversed by the PPAR-γ antagonist GW9662. Pioglitazone can confer chondroprotective benefits in osteoarthritis by activating PPAR-γ.