JOURNAL OF CELLULAR AND MOLECULAR MEDICINE最新文献

Long noncoding RNAs (lncRNAs) are emerging as key regulators in cardiovascular diseases. This study investigated the role of lncRNA LINC01605 in aortic dissection (AD) pathogenesis through its effects on vascular smooth muscle cells (VSMCs). Bioinformatics analysis of GEO datasets (GSE107844, GSE147026) identified LINC01605 as differentially expressed in AD. Its expression was validated in human aortic tissues and VSMCs using RT-qPCR and FISH. Functional assays (CCK-8, Transwell, Western blot) assessed VSMC proliferation, migration, phenotypic switching and autophagy. SGK1 was predicted as a target via bioinformatics and confirmed by RIP assays. Ang II-induced AD mice with LINC01605 knockdown were used for in vivo validation. LINC01605 was significantly upregulated in AD aortic tissues and VSMCs. Functional studies demonstrated that LINC01605 promoted VSMC proliferation, migration, invasion, phenotypic switching and autophagy, particularly under Ang II stimulation. Mechanistically, LINC01605 targeted SGK1 to regulate VSMC function. Knockdown of LINC01605 alleviated AD pathology in mice, modulating synthetic phenotype and autophagy markers. LINC01605 plays an important role in AD. It regulates the function of VSMCs by targeting SGK1 and promotes the pathological process of AD. LINC01605 may be a potential target for AD treatment, providing new directions for the mechanism research and treatment strategies of AD.

Dyslipidaemia has been implicated in osteonecrosis through some clinical studies. However, a direct causal relationship between hyperlipidaemia and osteonecrosis remains unconfirmed, and whether lipid-lowering agents could be used to treat osteonecrosis remains unclear. This study aimed to investigate the causal role of lipid traits in osteonecrosis using Mendelian randomisation (MR) analysis, assess the potential effects and mechanisms of lipid-lowering drug targets on osteonecrosis risk and validate these findings through experimental approaches. Genome-wide association study (GWAS) data were used to analyse lipid traits, drug targets and FinnGen osteonecrosis. Statin effects were further studied in a rat model of steroid-induced osteonecrosis and in vitro cell models. MR analysis revealed a significant association between LDL-C and increased osteonecrosis risk. Genetic mimicry of HMGCR inhibitors was associated with reduced osteonecrosis risk, which was validated through colocalisation. Stem cell growth factor-β (SCGF-β) was identified as a mediator of 21.3% of HMGCR inhibitors' effect on osteonecrosis risk. Further studies confirmed simvastatin's alleviating effect on SONFH, suggesting that simvastatin promotes osteogenesis and inhibits adipogenesis of mesenchymal stem cells (MSCs), partly mediated by SCGF-β upregulation, which activates the Wnt signalling pathway. Our findings supported dyslipidaemia as a causal factor for osteonecrosis, highlighting HMGCR as a promising therapeutic target.

Amoxicillin (Amx), a β-Lactam antibiotic frequently used to treat bacterial infections, has been linked to neurological effects, including anxiety, hyperactivity, ambiguity, seizures, and behavioural changes. We examined the neurotoxic effects of Amx in zebrafish and investigated the potential of liposome-encapsulated melatonin (L-Mel) as a therapeutic intervention. Computational studies have indicated that Amx and Mel interact with GABA receptors, suggesting the potential of L-Mel in mitigating Amx-induced neurological changes. Our findings demonstrated that the nanoformulated L-Mel showed reduced toxicity in zebrafish larvae. Administration of L-Mel to Amx-affected zebrafish brain tissue significantly lowered the levels of reactive oxygen species, antioxidants (catalase, superoxide dismutase, and nitric oxide), and proinflammatory cytokines (TNF-α, IL-1β, and NF-kB), based on the fixed EC-50. Behavioural assessments revealed that L-Mel treatment notably enhanced the immobility time and swimming performance, improving the movement abilities of zebrafish with Amx-induced neuroinflammation. Moreover, the GABA/glutamate levels in the neural tissues exhibited significant recovery in the L-Mel group. Gene and protein analysis showed substantial increases in BDNF, CREBBP, ASCL, NF-κB and GABA-A R γ2 in L-Mel treated subjects. Histopathological evaluation revealed that L-Mel treatment markedly attenuated Amx-induced neurotoxicity, as evidenced by reduced neuronal degeneration and necrosis in the brain tissue, indicating a pronounced neuroprotective effect. In conclusion, our research suggests that L-Mel is a promising therapeutic agent for mitigating Amx-induced neurotoxicity.

Quinovic acid is a key constituent of cat's claw (Uncaria tomentosa) extract and exhibits antioxidant and anti-inflammatory activities. In this study, we investigated the potential of quinovic acid to enhance natural killer (NK) cell activity by using the KHYG-1 cell line. Our data indicated that quinovic acid increased the expression levels of cytolytic molecules, including perforin, granzymes A and B, Fas ligand, and granulysin, and induced the phosphorylation of the transcription factors CREB and STAT4, thereby enhancing cytotoxic activity against K562 cells. Furthermore, when KHYG-1 cells were cocultured with K562 cells in the presence of quinovic acid, we observed an increase in the expression of t-Bid, cleaved caspases 3, 8, and 9, and PARP, promoting apoptosis in K562 cells. Quinovic acid also reduced the expression of SET, Ape1, and HMGB2, effectively inhibiting the DNA repair mechanism in target cells. Similar results were observed in other cancer cell lines. In addition, quinovic acid induced interferon-gamma secretion by upregulating the Ras/MAPK and PI3K/AKT/mTOR signalling pathways through the activation of NKG2D and other NK receptors. These effects were observed not only in KHYG-1 cells but also in NK cells derived from adult patients with head and neck squamous cell carcinoma. Our findings suggest that quinovic acid enhances NK cell cytotoxicity, showing promise as a potential therapeutic against various cancer cell types.

Sjögren's Syndrome (SS) and Type 1 Diabetes (T1D) are autoimmune disorders that can co-occur in patients, leading to complex clinical presentations. Despite observational evidence of their co-occurrence, the underlying genetic mechanisms remain poorly understood. To investigate the shared genetic factors and pathways between SS and T1D, we conducted a comprehensive analysis using multiomic approaches. Conditional and conjunctional false discovery rate analyses were performed to identify genetic polygenicity and overlap between the two diseases. Functional annotation and pathway analysis identified SNPs with regulatory potential. Furthermore, Mendelian Randomization (MR) analyses were employed to investigate causal associations between gene expression and disease risk. Single-cell differential gene expression analysis was also employed to validate the associations of risk genes with T1D and SS. Our analysis identified 36 shared loci, revealing common genetic enrichment between SS and T1D. Functional annotation and pathway analysis revealed 52 credible genes involved in cysteine-related processes, apoptotic signalling and immune responses. MR analyses revealed that AC007283.5 was positively linked with both SS and T1D, while PLEKHM1 and CRHR1-T1 were negatively associated. Additionally, CERS2 was positively associated with SS, DEF6 was positively associated with T1D, and KANSL1-AS1 was negatively associated with T1D, indicating the presence of complex regulatory mechanisms. Moreover, Single-cell differential gene expression analysis confirmed the dysregulation of risk genes in SS and T1D. This study identified shared genetic factors and pathways underlying SS and T1D, highlighting cysteine-related processes and apoptotic signalling. The findings underscore the complex interplay of autoimmunity and the need for targeted treatments addressing their common mechanisms.

The underlying mechanisms of sepsis-induced myocardial dysfunction (SIMD) remain elusive, and no targeted therapies currently exist. This study aimed to explore the expression features and functional effects of cholesterol 25-hydroxylase (CH25H) in SIMD in vitro. CH25H was identified as an upregulated gene related to SIMD through bioinformatics analysis. Its upregulation was validated in the myocardial tissue of SIMD mice as well as in lipopolysaccharide (LPS)-induced primary cardiomyocytes and AC16 cells. CH25H overexpression elevated 25-hydroxycholesterol levels and aggravated oxidative stress, mitochondrial dysfunction, apoptosis, and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and NF-κB pathway activation in AC16 cells. The effect of CH25H overexpression was similar to that induced by LPS treatment. Conversely, silencing CH25H attenuated these LPS-induced injuries. Furthermore, CH25H overexpression exacerbated oxidative stress, mitochondrial dysfunction, and apoptosis in LPS-stimulated AC16 cells, and these effects of CH25H overexpression can be counteracted by the NLRP3 inhibitor. In conclusion, CH25H may promote LPS-induced cardiomyocyte injury through NLRP3/NF-κB pathway activation.

Ovarian cancer (OC) is a high-mortality gynaecological malignancy, and the role of PANoptosis, a comprehensive cell death mechanism, in its prognosis remains unexplored. This study aims to clarify it, potentially guiding OC diagnosis and treatment. We analysed the ovarian data from TCGA and GTEx, and the GSE184880 scRNA-seq dataset from GEO. Spatial data and pathological images were sourced from the 10X Genomics website and GDC Portal. Features were extracted using CellProfiler and ResNet-50, and a PANoptosis-related pathomics prognostic model (PANPM) powered by deep learning was developed. The PANoptosis-related hub gene STAT4 potentially served as a protective factor for patients with OC. A better prognosis in OC was found linked to higher PANoptosis. The PANPM, manifesting distinct advantages for clinical application by accurately extracting pathological features, performed excellently in validation and the high-risk group indicated a poor prognosis. Additionally, STAT4⁺ T cells may inhibit OC, by activating the PANoptosis of epithelial cells through TNFSF12-TNFRSF12A and TNF-TNFRSF1A, which sheds light on potential therapeutic interventions involving STAT4⁺ T cells.

Kidney renal clear cell carcinoma (KIRC) is associated with abnormal ribosome production (RiboSis), but how this affects tumour growth and response to immunotherapy is still unclear. In this study, we analysed large-scale multi-omics data using machine learning. Using single-cell RNA sequencing and gene network analysis (hdWGCNA), we found a key RiboSis-related gene group. We then classified KIRC tumours into two subtypes based on RiboSis activity. Patients with subtype 1 lived significantly longer, and this group showed activation of tumour-promoting pathways. Using machine learning, we identified PTGER4 as a potential tumour suppressor. Higher PTGER4 levels were linked to better survival in multiple patient groups. Tumours with high PTGER4 also had stronger immune cell activity and higher levels of immunotherapy-related markers, suggesting they may respond better to immune-based treatments. PTGER4 also predicted better outcomes with certain chemotherapy drugs. Further analysis confirmed that PTGER4 is involved in immune-related pathways and is often reduced in tumours, supporting its role in slowing cancer progression. Lab experiments confirmed that PTGER4 helps block tumour growth. These findings suggest PTGER4 plays a central role in KIRC progression and treatment response. Targeting RiboSis-related mechanisms and PTGER4-related pathways could lead to better therapies for KIRC patients.

Pyroptosis is a gasdermins-dependent programmed cell death (PCD) characterised by progressive cellular swelling and plasma membrane rupture (PMR). This process releases intracellular contents that amplify inflammatory cascades and immune activation, involving the pathogenesis of various disorders such as tumours, heart and vascular diseases, diabetic complications and inflammatory/infectious disorders. With the advancement of research, the regulatory role of noncoding RNA (ncRNA) in the pyroptosis pathway was delineated. Among, studies have demonstrated that circular RNAs (circRNAs) regulate the pyroptosis cascade mainly through three principal mechanisms: functioning as miRNA sponges, modulating protein activity and encoding functional polypeptides. Numerous circRNAs regulating pyroptosis have been characterised, indicating their significant role in this process and associated disease progression. This review systematically summarised current knowledge on the regulatory mechanisms of circRNAs in canonical, noncanonical and caspase-3/8-mediated pyroptosis pathways. We further discussed their pathophysiological roles in disease development and potential clinical applications, aiming to advance mechanistic understanding, facilitate clinical translation and inform diagnostic and therapeutic strategies.