Journal of Translational Internal Medicine最新文献

Background and objectives: This study aimed to explore the correlation between free fatty acid (FFA) levels and adverse outcomes in patients undergoing percutaneous coronary intervention (PCI) with or without diabetes mellitus.

Methods: In total, 10,230 patients treated with PCI were included in this study and divided into three equal groups according to FFA levels (FFA-L, FFA-M, and FFA-H groups). Subsequently, the patients were further stratified based on their diabetes status. A 5-year follow-up was conducted, with the primary endpoint defined as major adverse cardiovascular and cerebrovascular events (MACCE).

Results: During follow-up, 2108 (20.6%) patients experienced MACCE. In patients without diabetes, no significant difference was observed in the risk of MACCE among the different FFA groups. However, in patients with diabetes, the risk of MACCE was significantly higher in the FFA-L and FFA-H groups than in the FFA-M group [adjusted hazard ratio (HR), 1.238, 95% confidence interval (CI), 1.054-1.454, P = 0.009; adjusted HR: 1.220, 95% CI, 1.054-1.412, P = 0.008; respectively]. The restricted cubic spline curves showed a nonlinear U-shaped relationship between the FFA levels and the risk of MACCE in patients with diabetes, with the lowest risk observed at an FFA level of 372 μmol/L. The results of the subgroup analysis stratified by different clinical presentations and BMI were similar to those of the primary findings.

Conclusions: In patients with diabetes undergoing PCI, both elevated and decreased FFA levels were significantly associated with an increased risk of MACCE. Monitoring FFA levels is essential to help identify those at high risk.

Migrasomes are a recently identified type of membranous organelle formed during cell migration. They are produced by migratory cells and widely distributed across various cells and tissues. Migrasomes contain abundant signaling and bioactive molecules, playing crucial roles in embryonic development, angiogenesis, material transport, mitochondrial quality control, and coagulation, as well as participating significantly in numerous pathological processes. This paper provides a detailed overview of the latest advancements in migrasome biology research, including migrasome biogenesis, physiological functions, isolation, and identification, and their roles in the onset, progression, diagnosis, and treatment of clinical diseases. In addition, we propose novel hypotheses and outline future research directions addressing current challenges and potential clinical applications of migrasomes, which may inform their utilization in future clinical diagnostics and therapeutics.

Background and objectives: Non-alcoholic fatty liver disease (NAFLD) has become a growing global public health concern. Effective therapeutic strategies for NAFLD remain urgently needed. Liver-on-a-chip (LC) technology offers an innovative platform for NAFLD modeling and drug development. This study aimed to develop a biomimetic liver-chip using co-cultured human hepatocyte (HepaRG) with hepatic stellate and endothelial cells to model NAFLD, and evaluate the therapeutic potential of scalable telomerase reverse transcriptase (hTERT)-immortalized umbilical cord mesenchymal stem cell-derived exosomes (TMSC-Exo).

Methods: HepaRG cells, hepatic stellate cells, and endothelial cells were used to construct a dual-chamber biocompatible LC. The NAFLD model was induced by free fatty acid (FFA) and applied to evaluate the efficacy of resmetirom and TMSC-Exo for the treatment of NAFLD. Moreover, the high-fat (HF) diet-induced mouse model was analyzed to verify the in vitro results. Proteomic analyses were performed to explore the molecular mechanisms involved in the development of NAFLD and the effect of TMSC-Exo in treating NAFLD.

Results: Cells cultured in LC showed better viability compared to those in the Transwell system. The on-chip NAFLD model mimicked the characteristics of NAFLD in vivo, including intracellular lipid accumulation and impaired hepatocyte functions in albumin synthesis, levels of urea, CYP1A2, and CYP3A4. Both TMSC-Exo and resmetirom displayed a significant effect in reducing the lipid accumulation in the on-chip NAFLD model. The TMSC-Exo showed superior effects in elevating the levels of albumin, urea, CYP1A2, and CYP3A4. The therapeutic effects of TMSC-Exo were also confirmed in the NAFLD mouse models. Proteomic analysis found that the top 15 up- and down-regulated differentially expressed proteins in NAFLD models compared to the control group were mainly associated with lipid metabolism, endoplasmic reticulum stress, and inflammation.

Conclusions: Our on-chip NAFLD model successfully recapitulated key pathological features of hepatic steatosis and functional impairment. Using this model, we evaluated TMSC-Exo and demonstrated its significant therapeutic efficacy against NAFLD.

Background and objectives: Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder with largely elusive underlying mechanisms, although thyroid dysformation has been deemed as the most frequent cause. Methyltransferase like 3 (METTL3) serves as a pivotal writer for N⁶-methyladenosine (N6-methyladenosine, m⁶A) required for various organ development, but little is known about the significance of METTL3 and m⁶A modification in thyroid formation, in CH either. In this study, we aimed to clarify the new regulatory role of METTL3 in the occurrence and development of CH, and to provide new theoretical support and treatment ideas for the clinical treatment of CH.

Methods: Thyrocyte-specific Mettl3 knockout mouse model was constructed and subjected to morphological and functional analyses. Representative differentiation, polarization, and hormone synthesis factors were studied via immunohistochemistry, immunofluorescence staining, RT-qPCR, and thyroid hormone in serum were quantified. In vitro, function of Mettl3 and molecular mechanisms were further investigated through thyrocyte cells from different species via lentivirus mediated silencing and rescue experiments.

Results: Thyrocyte specific removal of Mettl3 caused a typical CH phenotype, with reduced thyroid hormones and body weight. Histologically, the thyroid follicle of Mettl3 deficient mice appeared as abnormally fused and enlarged structure, with significantly disturbed polarity and patterning. Mechanistically, Pax8 expression was reduced upon METTL3 loss due to damaged m⁶A modification, which resulted in compromised thyroid epithelial cell polarization, differentiation and hormone synthesis.

Conclusions: Mettl3 functions as a key player of thyroid folliculogenesis and hormone secretion by coordinating thyrocyte polarization and differentiation progression, and its deficiency may lead to congenital hypothyroidism.

The tumor microenvironment substantially influences cancer progression by mediating complex interactions between immune cells, fibroblasts, endothelial cells, and mesenchymal cells. Recent studies have identified a critical component of this ecosystem, double-positive cells (DPCs), which are characterized by simultaneously expressing two markers that are traditionally confined to completely different cell lineages or cell types. In this review, we demonstrated DPCs' formation principles, characterization, classification, functions, and clinical significance. We underscore the multifaceted contributions of DPCs in enhancing tumor invasiveness, facilitating immune evasion, and promoting drug resistance. Understanding the significance of targeting DPCs could open new avenues for therapeutic interventions in cancer treatment.