JOURNAL OF CELLULAR AND MOLECULAR MEDICINE最新文献

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The above article, published online on 11 August 2016, in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor-in-Chief, Stefan N. Constantinescu, the Foundation for Cellular and Molecular Medicine, and John Wiley and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.

Abnormal Wnt5a expression, mitochondrial abnormalities and calcium overload have been detected in many metabolic diseases. However, the association of Wnt5a–Ca²⁺ and mitochondrial dysfunction in diabetic nephropathy (DN) progression remains unknown. We used streptozotocin-induced DBA2/J male mice as a DN model. The mice were treated with losartan (10 mg/kg/d*12 w) or losartan (10 mg/kg/d*12 w) + levamlodipine (5 mg/kg/d*12 w). High glucose (HG) (40 mmol/L)-induced HK-2 cells were used for in vitro experiments. Wnt5a and mitochondrial calcium uniporter (MCU) expression, mitochondrial dynamics, morphological changes and Ca²⁺ concentration were detected in different groups. Levamlodipine, a kind of calcium channel blocker, in combination with losartan ameliorated tubular injury and reversed mitochondrial fragmentation and dynamic dysfunction more efficiently than losartan alone in diabetic mice. Wnt5a induced Ca²⁺ uptake and aggravated mitochondrial fusion–fission disorder in HG-stimulated HK-2 cells. In addition, increased MCU formation was found in the mitochondria of tubular cells under HG stimulation and was upregulated by the activation of the Wnt5a–Ca²⁺ pathway. Our study showed that the Wnt5a–Ca²⁺ signalling pathway was involved in Ca²⁺ overload-induced mitochondrial dysfunction possibly through MCU in tubular injury and DN progression. A calcium channel blocker in combination with a renin–angiotensin system inhibitor (RASi) could be a promising therapeutic strategy in DN patients.

Chronic atrophic gastritis (CAG) is a precancerous lesion characterised by gastric mucosal atrophy and inflammation. Identifying key molecular mechanisms and potential therapeutic targets is essential to improve patient outcomes. Key modules and differentially expressed genes (DEGs) were recognised in the GSE153224 dataset using weighted gene co-expression network analysis (WGCNA) and examination of differential expression. IGFBP7 was identified as a hub gene by protein–protein interaction (PPI) network and expression validation. CAG patients’ blood parameters and gastric mucosal health status were evaluated before and after the treatment of vitamin C (VC). In addition, we investigated the effects of VC and N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) on GES-1 cells, including cell viability, apoptosis and the expression of inflammatory and angiogenic markers. WGCNA identified that the blue module was significantly associated with CAG with a correlation coefficient 0.924. Among 93 overlapping genes, IGFBP7 was notably underexpressed and selected as a hub gene. ROC analysis confirmed the high diagnostic performance of IGFBP7. CAG patients treated with VC showed significant improvement in blood parameters and improved gastric mucosal health. In vitro, VC increased cell viability, reduced cytotoxicity and apoptosis and lowered COX-2 and apoptosis-related protein expression in MNNG-treated GES-1 cells. Knockdown of IGFBP7 further influenced these effects. MNNG upregulated HIF-1α/VEGF signalling proteins, which VC attenuated. Combined VC and IGFBP7 knockdown showed potential protective effects. This study highlights the regulatory role of VC and IGFBP7 in CAG and demonstrates their potential as therapeutic targets for improving gastric mucosal health and mitigating inflammation.

It has become increasingly recognised that MATN1-AS1 is involved in multiple tumour development. The role of MATN1-AS1 in clear cell renal cell carcinoma (ccRCC), however, is still largely unrecognised. This study investigated the molecular functions of MATN1-AS1 in promoting ccRCC metastasis and sunitinib resistance. MATN1-AS1 was found to be mainly located in the cytoplasm and was upregulated in ccRCC, and a positive association was seen between greater levels of MATN1-AS1 expression and worse clinical outcomes. Downregulating MATN1-AS1 significantly hindered cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT). MATN1-AS1 promoted tumour growth and metastasis in vivo. Mechanismly, MATN1-AS1 targeted microRNA miR-214-5p, thereby upregulating E2F2 and promoting E2F2-mediated EMT. We discovered that MATN1-AS1 also promoted sunitinib resistance via E2F2 in vitro. Collectively, our research uncovered the protumor characteristics of MATN1-AS1 and suggested it as a therapeutic target for reverse sunitinib resistance in ccRCC.

Oesophageal cancer (EC) is a common gastrointestinal malignancy and includes oesophageal squamous cell carcinoma (ESCC) and oesophageal adenocarcinoma (EAC) sub-types. Gene signatures predicting patient outcomes are not routinely used in clinical practice, particularly owing to batch effects and data standardisation. Here, we sought to establish and validate a reliable signature of senescence-related genes (SRGs) that would aid in predicting prognosis in patients with EC. We downloaded transcriptomics data, and a novel pairwise comparison algorithm selected valid SRG pairs (SRGPs) to construct a prognostic SRGP signature. The SRGPs were verified using Kaplan–Meier survival and receiver operating characteristic curve analyses. Additionally, the relationships between the SRGP signatures and prognosis, immune cell infiltration and chemotherapeutic drug responsiveness were evaluated. The random forest algorithm identified the most clinically significant genes, followed by experimental validation. 19 and 26 SRGP signatures were created for ESCC (n = 81) and EAC (n = 79), respectively. Patients with EC were divided into two groups based on the median risk score. The Kaplan–Meier analysis demonstrated significant differences in overall survival between the ESCC and EAC groups (p < 0.001). The sub-types exhibited different immune signatures. IRF5 was the most clinically significant gene for ESCC. It was highly expressed in ESCC cells, and IRF5 knockdown inhibited cell migration and proliferation, while promoting apoptosis and senescence. The SRGP signature may predict prognosis and immunotherapeutic responses, and IRF5 is a potential target gene for ESCC.

Disulfidptosis, a new form of programmed cell death, plays a role in multiple types of cancer. However, research on disulfidptosis in glioma is lacking. A disulfidptosis-associated risk score was constructed using Cox regression modelling, while LASSO regression was applied for feature selection. To explore the relationship between the risk score and the immune microenvironment, we employed CIBERSORT, ssGSEA and ESTIMATE algorithms. Additionally, wet lab experiments were conducted to validate the functional role of the key disulfidptosis gene RPN1, demonstrating its ability to promote glioma cell proliferation and migration. Disulfidptosis genes were significantly upregulated in gliomas, influencing clinical features and survival. The risk score effectively predicted OS and varied among clinical subgroups. High-risk scores correlated with tumour growth, invasion and immunosuppression. Patients with different risk scores showed distinct immune cell infiltration patterns. Most immune checkpoints and chemokines were positively associated with risk scores. Laboratory findings confirmed that RPN1 significantly promoted glioma cell proliferation and migration. Disulfidptosis-based risk assessment stratifies glioma prognosis and reveals immune microenvironment characteristics, offering insights for personalised treatment strategies.

Cerebral ischaemia–reperfusion injury (CIRI), resulting from thrombolytic therapy for ischaemic stroke, presents a considerable challenge during postoperative recovery. Formononetin (FMN) has shown promise in the prevention and treatment of neurological diseases. However, its specific mechanism in ameliorating CIRI remains uncertain. Initially, we established a CIRI rat model to evaluate FMN's therapeutic potential by assessing neurological function, infarct area and pathological changes. Subsequently, we employed metabolomics technology to investigate FMN's impact on metabolite levels in the ischaemic brain tissue of CIRI rats. Based on the metabolomics findings, we validated FMN's effects on nicotinate and nicotinamide metabolism, as well as alanine, aspartate and glutamate metabolism, along with its influence on neuronal injury and repair. Our investigation unveiled that FMN intervention significantly diminished the Longa score and asymmetry score in CIRI rats, constricted the infarct area and ameliorated pathological alterations in the ischaemic brain tissue, including reduced DCI index and augmented Nissl body count. Metabolomics analysis indicated that FMN exerted regulatory effects on nicotinate and nicotinamide metabolism, as well as alanine, aspartate and glutamate metabolism. Following FMN intervention, there was a notable increase in the levels of related metabolites such as nicotinamide (NAM), L-aspartic acid (L-Asp), fumaric acid (FA), gamma-aminobutyric acid (GABA) and L-glutamic acid (L-Glu). RT-qPCR and Western blot outcomes demonstrated that FMN upregulated the gene and protein expression of key enzymes adenylosuccinate lyase (ADSL) and glutamic acid decarboxylase (GAD) involved in alanine, aspartate and glutamate metabolism. Moreover, FMN intervention bolstered SOD activity, diminished MDA and ROS levels and reduced TUNEL-positive expression. Furthermore, FMN intervention elevated ATP levels and markedly increased Ki67-positive expression. FMN exhibits the potential to alleviate oxidative stress injury in CIRI rats by enhancing nicotinate and nicotinamide metabolism along with alanine, aspartate and glutamate metabolism, consequently reinstating energy metabolism and conferring neuroprotective effects to ameliorate CIRI.

Inflammatory bowel disease (IBD) and Sepsis are both characterised by immune dysregulation. Notably, IBD is a factor in the increase in septic infections. However, these two conditions' shared molecular and pathophysiological mechanisms remain unclear. We used ‘limma’ and ‘WGCNA’ analyses to identify common DEGs between these two conditions. Single-cell RNA sequencing further assessed immune cell heterogeneity. We used machine learning algorithms to construct and identify diagnostic markers for Sepsis, which we then validated using receiver operating characteristic curve (ROC) analysis. A mouse model of IBD combined with Sepsis was constructed, and real-time PCR and western blot validated the expression of BCL2A1 and CEBPB. It was found that 58 shared DEGs identified in both IBD and Sepsis were highly enriched in immune and inflammation-related pathways. Single-cell analysis revealed that CD14⁺ monocytes (or IL1B⁺ macrophages) primarily express these hub genes. Both conditions significantly increased the proportion of this cell type compared to healthy controls. Finally, BCL2A1 and CEBPB were identified as potential biomarkers that have strong diagnostic potential. Furthermore, we confirmed that levels of BCL2A1 and CEBPB were elevated in mice with IBD complicated by Sepsis through real-time PCR and observed that IBD exacerbates the progression of Sepsis. We conclude that IL1B⁺ macrophages expressing high levels of these hub genes play a key role in the immune dysregulation associated with both IBD and Sepsis. The overlapping gene expression and pathway alterations in these cells indicate shared common molecular mechanisms, suggesting new strategies for targeted therapeutic interventions.

One main cause of persistent back discomfort is intervertebral disc degeneration (IDD), with inflammation and extracellular matrix (ECM) degradation playing critical roles. This study investigates the role of ZIP8, a zinc transporter, in IDD pathogenesis, focusing on its effects on inflammatory responses, ECM degradation and Wnt/β-catenin signalling pathway. ZIP8 was identified as a hub gene from the GSE27494 dataset through bioinformatics analysis. The role of ZIP8 was investigated in nucleus pulposus (NP) cells and RAW 264.7 macrophages. An in vivo IDD rat model was used to assess the consequences of ZIP8 overexpression. The involvement of the Wnt/β-catenin pathway was examined, and the effect on macrophage polarisation was analysed. ZIP8 overexpression in NP cells led to increased inflammatory cytokine production and enhanced NF-κB pathway activation, while ZIP8 knockdown alleviated these effects. In vitro, ZIP8 knockdown reduced IL-1β–induced apoptosis and ECM degradation, promoting cell viability. In vivo, ZIP8 overexpression exacerbated disc degeneration, as evidenced by magnetic resonance imaging (MRI) and histological assessments. Additionally, modulation of ZIP8, in conjunction with the Wnt/β-catenin signalling pathway, revealed its involvement in regulating apoptosis and proliferation in NP cells. In RAW 264.7 macrophages, ZIP8 knockdown inhibited M1 macrophage polarisation and reduced proinflammatory cytokine expression, while promoting anti-inflammatory responses. ZIP8 is a key regulator in IDD, affecting inflammation, ECM integrity and Wnt/β-catenin signalling pathways. Targeting ZIP8 by knockdown may offer therapeutic potential in IDD by modulating inflammatory responses and protecting ECM structure, offering a novel approach to IDD treatment.