JOURNAL OF CELLULAR AND MOLECULAR MEDICINE最新文献

Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) belongs to the SPARC family of matricellular proteins. However, underlying functions of SPARCL1 in bladder cancer (BCa) remain understudied. We performed an integrated search for the expression patterns of SPARCL1 in relation to various clinicopathological features of BCa. We then carried out Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and gene set enrichment analysis (GSEA). Furthermore, we investigated the correlations between SPARCL1 and immunological features, such as tumour mutation burden (TMB), immune activation processes, immune checkpoint expression, tumour immune dysfunction and exclusion (TIDE) scores, and chemotherapeutic sensitivity in BCa. Our analysis revealed that SPARCL1 was downregulated across multiple cancers. In BCa, elevated SPARCL1 was linked with advanced histopathologic stage, higher T and N stage, and poorer prognosis in the clinical cohort. In vitro experiments demonstrated that increased SPARCL1 expression inhibited cell proliferation, migration, and invasion. Additionally, highly expressed SPARCL1 was linked to elevated immune, stromal and ESTIMATE scores, as well as an increase in naive B cells, M2 macrophages, and resting mast cells. We observed a moderate correlation between SPARCL1 expression and CD163, VSIG4 and MS4A4A, which are markers of M2 macrophages. Furthermore, SPARCL1 expression was positively related to TMB, immune activation processes, TIDE scores, immune checkpoint expression, and chemotherapeutic sensitivity in BCa. Our study highlights the potential involvement of SPARCL1 in macrophage recruitment and polarization and suggests its utility as a biomarker for prognosis in BCa.

New uses of old drugs hold great promise for clinical translation. Flubendazole, an FDA-approved antiparasitic drug, has been shown to target p53 and promote apoptosis in glioblastoma (GBM) cells. However, its damaging mechanism in GBM remains elusive. Herein, we explored the ferroptosis-inducing ability of flubendazole on GBM cells. After treating glioma cell lines U251 and LN229 with the flubendazole (DMSO <1‰), cell viability was inhibited in a concentration-dependent manner (IC₅₀ for LN229 = 0.5331 μM, IC₅₀ for U251 = 0.6809 μM), attributed to the induction of ferroptosis, as evidenced by increased MDA levels, accumulation of ROS and lipid peroxides, change in mitochondrial membrane potential and structure. Protein analysis related to ferroptosis showed upregulation of TFRC, DMT1 and p53, alongside downregulation of xCT, FHC and GPX4 (p < 0.05). All-atom docking studies demonstrated that flubendazole bound closely with xCT, and TFRC, validating its role in inducing glioma ferroptosis via modulation of these proteins. Notably, flubendazole could damage the glioblastoma stem cells (GSC) that are typically resistant to other therapies, thereby possessing advantages in stopping glioma recurrence. This study delved into the mechanisms of flubendazole-induced ferroptosis in glioma, broadening its application and providing new ideas for new uses of other old drugs.

Sepsis-induced acute lung injury (SALI) is characterized by a high incidence and mortality rate, which has caused a serious medical burden. The pharmacological effects of esculetin (ELT), such as antibacterial and anti-inflammatory actions, have been widely confirmed. However, the therapeutic effects and mechanisms of ELT on SALI still need to be further clarified. In this study, we first evaluated the therapeutic potential of ELT on a caecal ligation and puncture (CLP) induced septic rat model, particularly in the treatment of acute lung injury. Afterwards, we explored the effect of ELT on macrophage polarization in vivo and in vitro. Then, we investigated the anti-inflammatory mechanism of ELT based on modulating the metabolic reprogramming of macrophage (the effect on glycolysis in M1, and the effect on fatty acid β-oxidation in M2). In addition, macrophage metabolic inhibitors (glycolysis inhibitor: 2-DG, and fatty acid β-oxidation inhibitor: etomoxir) were used to verify the regulatory effect of ELT on macrophage metabolic reprogramming. Our results proved that ELT intervention could effectively improve the survival rate of SALI rats and ameliorate pathological injury. Next, we found that ELT intervention inhibited M1 polarization and promoted M2 polarization of macrophages in vivo and in vitro, including the downregulation of M1-related markers (CD86, iNOS), the decrease of pro-inflammatory factors (nitric oxide, IL-1β, IL-6, and TNF-α), the upregulation of M2-related markers (CD206, ARG-1), the increase of immunomodulatory factors (IL-4 and IL-10). Subsequently, seahorse analysis showed that ELT intervention inhibited the glycolytic capacity in M1, and promoted the ability of fatty acid β-oxidation in M2. Besides, ELT intervention inhibited the level of glycolysis product (lactic acid), and the expression of glycolysis-related genes (Glut1, Hk2, Pfkfb1, Pkm and Ldha) and promoted the expression of fatty acid β-oxidation related genes (Cpt1a, Cpt2, Acox1). In addition, we found that the inhibitory effect of ELT on M1 polarization was comparable to that of 2-DG, while intervention with etomoxir abolished the promoting effect of ELT on M2 polarization. ELT inhibited the inflammatory response in SALI by correcting macrophage polarization (inhibiting M1 and promoting M2). The mechanism of ELT on macrophage polarization was associated with regulating metabolic reprogramming (inhibiting glycolysis in M1 and promoting fatty acid β-oxidation in M2).

There is a paucity of research examining the molecular mechanisms underlying sex differences of clinical phenotypes and the prognosis in hypertrophic cardiomyopathy (HCM). The dataset GSE36961 was retrieved from Gene Expression Omnibus (GEO) database and comprehensive bioinformatics was employed to identify the core genes linked to sex differences in HCM patients. Additionally, gene set enrichment analysis (GSEA) was conducted to detect downstream signalling pathways. Furthermore, experimental validation was carried out using hearts from spontaneously hypertensive rats (SHRs). A comprehensive analysis revealed the identification of 208 differentially expressed genes (DEGs) in female patients with HCM with a notable downregulation of seven core genes. Notably, there were sex differences in the expression of ras dexamethasone-induced protein 1 (RASD1) and myosin 6 (MYH6) in HCM. Gene ontology (GO) analysis and GSEA demonstrated an enrichment of autophagy-related processes in disease progression in HCM females. Specifically, spearman's correlation analysis revealed a positive correlation between nicotinamide phosphoribosyl transferase (NAMPT) and RASD1 levels, particularly among female patients (R = 0.569, p < 0.001). Additionally, animal models confirmed that cardiac hypertrophy was more pronounced in SHR females compared to males. SHR females exhibited lower mRNA and protein expressions of RASD1 and NAMPT, which were associated with impaired autophagy. In this study, bioinformatics and validation using external data sets and animal models of left ventricular hypertrophy suggested that the RASD1/NAMPT axis is potentially a crucial mechanism underlying the elevated risk of cardiovascular disorders in HCM females, also pointing potentially prognostic biomarkers.

The mortality rate of oesophageal squamous cell carcinoma (ESCC) remains high, and conventional TNM systems cannot accurately predict its prognosis, thus necessitating a predictive model. In this study, a 17-gene prognosis-related gene signature (PRS) predictive model was constructed using the random survival forest algorithm as the optimal algorithm among 99 machine-learning algorithm combinations based on data from 260 patients obtained from TCGA and GEO. The PRS model consistently outperformed other clinicopathological features and previously published signatures with superior prognostic accuracy, as evidenced by the receiver operating characteristic curve, C-index and decision curve analysis in both training and validation cohorts. In the Cox regression analysis, PRS score was an independent adverse prognostic factor. The 17 genes of PRS were predominantly expressed in malignant cells by single-cell RNA-seq analysis via the TISCH2 database. They were involved in immunological and metabolic pathways according to GSEA and GSVA. The high-risk group exhibited increased immune cell infiltration based on seven immunological algorithms, accompanied by a complex immune function status and elevated immune factor expression. Overall, the PRS model can serve as an excellent tool for overall survival prediction in ESCC and may facilitate individualized treatment strategies and predction of immunotherapy for patients with ESCC.

RETRACTION: Y. Diao, B. Jin, L. Huang, and W. Zhou, “MiR-129-5p Inhibits Glioma Cell Progression In Vitro and In Vivo by Targeting TGIF2,” Journal of Cellular and Molecular Medicine 22, no. 4 (2018): 2357–2367. doi: 10.1111/jcmm.13529.

The above article, published online on 12 February 2018 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Stefan Constantinescu; The Foundation for Cellular and Molecular Medicine; and John Wiley and Sons Ltd. The retraction has been agreed following an investigation into concerns raised by a third party, which revealed inappropriate duplications of image panels (Figure 4A and 6G) between this and other articles that were either previously published or published later in the same year by different group of authors. Thus, the editors consider the conclusions of this manuscript substantially compromised. The authors and their institute were informed of the concerns and the decision to retract but they remained unresponsive.

Li Y, Zhang D, Meng Y, et al. Distribution characteristics of Purkinje fibres in the canine left ventricle. J Cell Mol Med. 2024;28(18):e70117. doi: https://doi.org/10.1111/jcmm.70117.

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The pathological activation of cardiac fibroblasts (CFs) plays a crucial role in the development of pressure overload-induced cardiac remodelling and subsequent heart failure (HF). Growing evidence demonstrates that multiple microRNAs (miRNAs) are abnormally expressed in the pathophysiologic process of cardiovascular diseases, with miR-425 recently reported to be potentially involved in HF. In this study, we aimed to investigate the effects of fibroblast-derived miR-425-5p in pressure overload-induced HF and explore the underlying mechanisms. C57BL/6 mice were injected with a recombinant adeno-associated virus specifically designed to overexpress miR-425-5p in CFs, followed by transverse aortic constriction (TAC) surgery. Neonatal mouse CFs (NMCFs) were transfected with miR-425-5p mimics and subsequently stimulated with angiotensin II (Ang II). We found that miR-425-5p levels were significantly downregulated in HF mice and Ang II-treated NMCFs. Notably, fibroblast-specific overexpression of miR-425-5p markedly inhibited the proliferation and differentiation of CFs, thereby alleviating myocardial fibrosis, cardiac hypertrophy and systolic dysfunction. Mechanistically, the cardioprotective actions of miR-425-5p may be achieved by targeting the TGF-β1/Smad signalling. Interestingly, miR-425-5p mimics-treated CFs could also indirectly affect cardiomyocyte hypertrophy in this course. Together, our findings suggest that fibroblast-derived miR-425-5p mitigates TAC-induced HF, highlighting miR-425-5p as a potential diagnostic and therapeutic target for treating HF patients.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality, with tumour heterogeneity, fueled by cancer stem cells (CSCs), intricately linked to treatment resistance. Therefore, it is imperative to advance therapeutic strategies targeting CSCs in NSCLC. In this study, we utilized RNA sequencing to investigate metabolic pathway alterations in NSCLC CSCs and identified a crucial role of nitric oxide (NO) metabolism in governing CSC stemness, primarily through modulation of the Notch1 protein. Mechanistically, NO-induced S-nitrosylation of Notch1 facilitated its interaction with the deubiquitylase UCHL1, leading to increased Notch1 protein stability and enhanced CSC stemness. By inhibiting NO synthesis and downregulating UCHL1 expression, we validated the impact of NO on the Notch signalling pathway and CSC stemness. Importantly, targeting NO effectively reduced CSC populations within patient-derived organoids (PDOs) during radiotherapy. This mechanism presents a promising therapeutic target to surmount radiotherapy resistance in NSCLC treatment.

We investigated the potential role of hydrogen sulfide (H₂S) as a novel therapy for diabetic peripheral neuropathy in diabetic rats. A single dose of streptozotocin (60 mg/kg) was applied to the rats for the diabetic rat models. Sodium bisulfide (50 μmol/kg/d) was injected intraperitoneally daily for 2 weeks as H₂S treatment. Electromyogram, haematoxylin eosin staining, transmission electron microscopy, western blotting and enzyme-linked immunosorbent assay were then performed. H₂S treatment did not affect body weights, blood glucose levels or liver function of diabetic rats, while the creatine levels of the H₂S-treated diabetic rats decreased compared with the diabetic control rats. H₂S treatment for 2 weeks did not affect the sciatic nerve conduction velocity of the diabetic rats. However, H₂S treatment relieved neurons loss and cell atrophy of dorsal root ganglion, and axon degeneration of sciatic nerve in diabetic rats. Serum super oxide dismutase (SOD) levels and SOD2 levels in the sciatic nerve of diabetic rats were lower than the non-diabetic rats but were restored after H₂S treatment. Serum and sciatic nerve homogenate malondialdehyde and aldose reductase expression were higher in diabetic rats but decreased significantly after H₂S treatment. Our study revealed that H₂S alleviates neural degeneration in diabetic rats probably by reducing oxidative stress and downregulating aldose reductase expression.