Current molecular medicine最新文献

Background: Colon cancer is a highly prevalent tumor with a high mortality rate worldwide. SLC41A2 is a member of the solute carrier family, but its role in colon cancer is still unclear.

Methods: The relationship between the expression level of SLC41A2 and clinicopathological features in colon cancer was investigated using data from the TCGA database. The differential expression genes of SLC41A2 were identified the potential role of SLC41A2 in colon cancer was analysed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. By transfecting plasmids or siRNA to overexpress or knock down SLC41A2 in colon cancer cells, the effects of SLC41A2 on colon cancer cell proliferation, migration, and apoptosis were detected through EdU, MTT, wound-healing, Transwell, and JC-1 experiments. Western blot and ubiquitination experiments validated the regulation of GSK3β stability by SLC41A2. Rescue experiments and CCK8 assays confirmed the regulatory effect of SLC41A2 on GSK3β.

Results: Compared to normal tissues, SLC41A2 exhibited a lower expression level in colon cancer, and the expression levels of SLC41A2 were correlated with the stage and Tumor Node Metastasis (TNM) classification. GO and KEGG analyses displayed that SLC41A2 primarily affected the growth factor activity and Wnt signaling pathway. Furthermore, elevated expression of SLC41A2 notably decreased the proliferation, migration and invasion of colon cancer cells, along with increased apoptosis. The overexpression of SLC41A2 and rescue experiments confirmed that SLC41A2 enhances the protein stability of GSK3β by inhibiting its ubiquitin-proteasome degradation and causes the upregulation of GSK3β, thereby suppressing the progression of colon cancer.

Conclusion: SLC41A2 was lowly expressed in colon cancer tissues or cells. By inhibiting the ubiquitin-proteasome degradation of GSK3β, SLC41A2 can significantly upregulate the expression of GSK3β, which ultimately suppresses the proliferation and migration of colon cancer cells.

Gut microbes influence the progression of human malignancies through their recognition by the immune system and their effects on numerous metabolic pathways. Long non-coding RNA is a key target of intestinal microbiota involved in the progression of human malignant tumors. Current research shows that there is a close cross-talk between long non-coding RNA Snhg9 and intestinal microorganisms, and it is widely involved in the progression of human malignant tumors. An in-depth study of the interaction between long non-coding RNA and intestinal flora and the intrinsic regulatory mechanism of snhg9 will provide new and powerful therapeutic targets for future research on human malignant tumors.

Introduction: This study aimed to investigate the role of JAK2 (Janus kinase 2)/STAT3 (signal transducer and activator of transcription 3) signaling in liver injury during severe acute pancreatitis (SAP), focusing on pancreatic elastase- and lipopolysaccharide (LPS)-induced Kupffer cell (KC) activation.

Methods: A rat SAP model was established via retrograde taurocholic acid infusion into the biliopancreatic duct. Inflammatory cytokine levels and JAK2/STAT3 pathway activity were quantified in liver tissues. KCs were treated with elastase/LPS ± AG490 (JAK2 inhibitor). Proinflammatory cytokines, RNA, and protein expression were analyzed.

Results and discussion: SAP rats exhibited elevated TNF-α, IL-6, and IL-18 levels in both serum and liver tissues, with JAK2/STAT3 pathway activation. AG490 administration suppressed JAK2/STAT3 activation, reduced inflammation, and alleviated liver injury. Similarly, KCs treated with elastase and LPS showed increased proinflammatory cytokine levels and JAK2/STAT3 upregulation, which were mitigated by AG490 treatment.

Conclusion: The findings highlighted the pivotal role of the JAK2/STAT3 signaling pathway in SAP-induced liver injury. Selective inhibition of this pathway by AG490 could reduce inflammation and protect against liver damage, suggesting its potential as a therapeutic target for inflammatory liver diseases.

Background: Studies have shown that abnormal stress is a significant inducer of Intervertebral Disc Degeneration (IVDD). Although traction force is commonly used to delay IVDD, its effects on Nucleus Pulposus Cells (NPCs) and their secreted exosomes remain unclear. In addition, this study systematically revealed the relationship between miR-8485 and IVDD for the first time.

Methods: Cellular experiments were performed using a Flexcell cell stretching platform to apply traction force to NPCs. After optimizing loading parameters, NPCderived exosomes (NPCs-exo) were isolated and subjected to miRNA high-throughput sequencing. Differentially expressed miRNAs were identified, and their regulatory effects on the Wnt/β-catenin pathway were investigated. Ex vivo rabbit spinal samples were used to validate the cellular experimental results under traction force loading.

Results: NPCs-exo were found to be internalized by NPCs, and traction force promoted NPCs-exo secretion. High-throughput sequencing and differential expression analysis identified miR-8485 as a differentially expressed miRNA in NPCsexo secreted under Cyclic Mechanical Tension (CMT) conditions. Dual-luciferase reporter assays confirmed the targeted regulatory relationship between miR-8485 and GSK-3β, as well as its involvement in the Wnt/β-catenin pathway-mediated regulation of NPCs degeneration. Ex vivo experiments, including morphological and immunofluorescence analyses, revealed that the traction group exhibited better morphology than the pressure group, with a more organized AF, NP, and higher NPCs content, though some loss persisted. Both groups showed significant differences in ECM markers (Collagen II, Aggrecan, MMP3) compared to the control (p < 0.05). Additionally, the traction group had significantly higher Collagen II and Aggrecan levels than the pressure group (p < 0.05).

Conclusion: CMT can promote the secretion of NPCs-exo, which are internalized by the NPCs. Through the delivery of miR-8485, NPCs-exo target and regulate GSK-3β, thereby enhancing Wnt/β-catenin pathway activity. This mechanism increases NPCs viability and extracellular matrix synthesis while suppressing apoptosis, ultimately delaying IVDD progression. Immunofluorescence staining in animal experiments confirmed that traction force effectively improves extracellular matrix expression in the IVD and mitigates stress-induced morphological alterations of the IVD.

Lung cancer is one of the most prevalent malignancies and a leading cause of cancer-related deaths worldwide. E3 ubiquitin ligase activity is a common feature of most TRIM proteins, highlighting the family's critical role in regulating the biological behaviors of tumor cells and influencing various cellular physiological activities, including apoptosis, innate immunity, development, and intracellular signaling. In lung cancer, certain TRIM proteins function either as oncoproteins or cancer suppressors. This review explores the unique function of TRIM in lung cancer development, focusing on the molecular processes of TRIM proteins. Finally, we provide an overview of recent advancements in the prognosis and therapeutic strategies for lung cancer involving TRIM proteins.

Acute Kidney Injury (AKI) is a critical condition characterized by a rapid decline in kidney function, often resulting from ischemia-reperfusion, nephrotoxicity, or inflammation. Current treatments primarily rely on renal replacement therapies, which remain limited and controversial. The pregnane X receptor (PXR), a nuclear receptor involved in drug metabolism, immune regulation, and cellular homeostasis, has emerged as a promising target for AKI therapy. Preclinical studies suggest that PXR activation demonstrates protective effects in AKI through multiple mechanisms, including reducing inflammation, oxidative stress, and mitochondrial dysfunction. Specifically, PXR modulates nuclear factor-κB (NF-κB) signaling, supports mitochondrial function, regulates apoptosis, and enhances renal hemodynamics, thus mitigating AKI progression. Furthermore, PXR's role in the gut-liver-kidney axis strengthens intestinal barrier integrity and bile acid homeostasis, contributing to renal protection. Recent advances in research on the PXR agonists rifampicin and tanshinone IIA (TanIIA) highlight the potential of PXR-targeted therapies to mitigate nephrotoxicity and promote kidney recovery. This review provides a comprehensive analysis of PXR's protective mechanisms in AKI, underscoring its therapeutic potential and paving the way for new treatment strategies.

Hemochromatosis is an autosomal recessive iron overload disorder. It occurs due to a failure in the hepcidin response, leading to systemic iron overload. The high iron levels in the plasma stored in various organs cause injury and permanent damage. There are two types of hemochromatosis: primary and secondary. In non- HFE hemochromatosis, mutations in the HJV, HAMP, TRF2, and SLC40A1 genes are implicated, with the associated condition classified as type I hemochromatosis. In contrast, juvenile hemochromatosis (type II hemochromatosis/ HFE II) is linked to mutations in the hemojuvelin gene or the antimicrobial peptide hepcidin. In this study, relevant literature in databases, including PubMed, MEDLINE records, Cochrane Central Register of Controlled Trials (CENTRAL), Google Scholar, and Embase, was searched. Our study inclusion criteria encompassed both experimental and observational studies or a combination of both, with data derived from the human population. The exclusion criteria included animal models, observational studies, and unpublished data. Hepcidin is usually up-regulated in response to high serum iron, but it is unexpectedly low in patients with hemochromatosis because of mutations in HFE, hemojuvelin (JH), and transferrin receptor 2 (TfR2). TfR2, expressed by hepatocytes, is mutated in hemochromatosis type III. Future research directions include exploring the molecular mechanisms underlying the effects of the TFR2 gene variant on iron homeostasis and liver damage and investigating potential therapeutic targets for treating hemochromatosis-related liver disease. Additionally, further epidemiological and modern genetic engineering studies are needed to better understand the prevalence and impact of hemochromatosis on liver health in different populations.

Background: Leukemia is marked by clonal hematopoietic stem cell expansion and metabolic reprogramming. The BNT162b2 mRNA COVID-19 vaccine has been proven effective, though questions remain about its broader physiological effects. This study investigates metabolomic alterations in leukemic bone marrow potentially associated with BNT162b2 vaccination.

Objective: To compare the bone marrow metabolomic profiles of leukemia patients with and without BNT162b2 vaccination, and healthy unvaccinated controls, to explore potential metabolic differences.

Methods: Bone marrow samples were obtained from three groups: vaccinated leukemia patients (n=7), unvaccinated leukemia patients without COVID-19 history (n=2), and unvaccinated healthy controls (n=7). Untargeted metabolomics was performed using LC-QTOF-MS. Data were analyzed using XCMS and MetaboAnalyst 5.0 to identify statistically significant metabolite differences and affected pathways. Fold change >1.5 and p<0.05 were considered significant.

Results: Distinct metabolic profiles were observed between the leukemia and control groups. Increased glycolysis, pentose phosphate pathway activity, and altered tryptophan, lipid, and heme metabolism were noted in leukemia samples. Metabolic changes in vaccinated patients (ASL) were more similar to unvaccinated leukemia patients (LO) than to healthy controls, with minor vaccine-associated variations. Notable metabolites included 5-methoxyindoleacetate, phosphorylcholine, and tetrahydrofolic acid.

Conclusion: This preliminary study identified altered metabolic pathways in leukemia bone marrow and suggests metabolomic differences associated with BNT162b2 vaccination. While the findings do not support a causal link between mRNA vaccination and leukemia development, they highlight the need for further studies to understand vaccine-induced metabolic modulation in hematological contexts.

Background: The relationship between heavy metals, particularly lead (Pb), and diabetic kidney disease (DKD) remains unclear, especially regarding exposure thresholds. This study investigates the association between blood Pb levels and DKD risk using data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018.

Methods: A total of 1,343 participants were included, with 508 diagnosed with DKD. Baseline characteristics were compared between DKD and non-DKD groups. Multivariate generalized linear models (GLMs) and weighted logistic regression were used to assess correlations between blood Pb levels and DKD risk. A nomogram was developed to evaluate the predictive power of significant clinical characteristics.

Results: Key clinical characteristics, including age, marital status, and serum Pb levels, differed significantly between DKD and non-DKD groups. Serum Pb was identified as a significant risk factor (ORs: 1.18-1.39, p < 0.01). The nomogram demonstrated good predictive accuracy (AUC = 0.717).

Conclusion: Elevated blood Pb levels are significantly associated with DKD, with a non-linear relationship and a defined threshold. These findings highlight the potential role of Pb exposure in DKD pathogenesis and suggest the utility of blood Pb monitoring in diabetic patients.

Aim: The pathogenesis of diabetic kidney disease (DKD) is complex, and the specific biomarkers for detecting early diagnosis and monitoring kidney function deterioration are insufficient, which affects the prognosis of patients. The complement activation in glomeruli and renal interstitium contributes to the aggravation of DKD. Several key complement proteins, such as complement factor 3 (C3), CD59, and complement factor H-related protein 2 (CFHR2) were reported to be potential biomarkers for early diagnosis and prognosis for DKD.

Methods: In the current study, we focus on CFHR2, to investigate its capability and sensitivity as a DKD biomarker. As a non-invasive detection sample, urine has the characteristic of convenient sampling. In the current study, the urine samples were collected from three groups: diabetic patients without albuminuria, with microalbuminuria, and macroalbuminuria, to analyze whether CFHR2 was associated with albuminuria concentration and declined renal function. Meanwhile, the urinary neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and C3 were also examined by enzyme-linked immunosorbent assay (ELISA) to compare with CFHR2 to determine whether CFHR2 had an advantage in predicting the early detection and progression of DKD. The Spearman correlation analysis was performed for the correlation analysis. The receiver operating characteristic curve was used to analyze the diagnostic efficacy.

Results: CFHR2 had superior diagnostic power to predict the early occurrence of DKD and disease progression, compared with NGAL, microalbumin, and C3 in urine.

Conclusion: CFHR2 has satisfactory potential to be a biomarker for early diagnosis and risk of progression of DKD.