Journal of Translational Internal Medicine最新文献

Mitochondrial dysfunction is increasingly recognized as a critical driver in the pathogenesis of cardiovascular diseases. Mitochondrial quality control (MQC) is an ensemble of adaptive mechanisms aimed at maintaining mitochondrial integrity and functionality and is essential for cardiomyocyte viability and optimal cardiac performance under the stress of cardiovascular pathology. The key MQC components include mitochondrial fission, fusion, mitophagy, and mitochondria-dependent cell death, each contributing uniquely to cellular homeostasis. The dynamic interplay among these processes is intricately linked to pathological phenomena, such as redox imbalance, calcium overload, dysregulated energy metabolism, impaired signal transduction, mitochondrial unfolded protein response, and endoplasmic reticulum stress. Aberrant mitochondrial fission is an early marker of mitochondrial injury and cardiomyocyte apoptosis, whereas reduced mitochondrial fusion is frequently observed in stressed cardiomyocytes and is associated with mitochondrial dysfunction and cardiac impairment. Mitophagy is a protective, selective autophagic degradation process that eliminates structurally compromised mitochondria, preserving mitochondrial network integrity. However, dysregulated mitophagy can exacerbate cellular injury, promoting cell death. Beyond their role as the primary energy source of the cell, mitochondria are also central regulators of cardiomyocyte survival, mediating apoptosis and necroptosis in reperfused myocardium. Consequently, MQC impairment may be a determining factor in cardiomyocyte fate. This review consolidates current insights into the regulatory mechanisms and pathological significance of MQC across diverse cardiovascular conditions, highlighting potential therapeutic avenues for the clinical management of heart diseases.

Background and objectives: The incidence of idiopathic membranous nephropathy (IMN) has been increasing in recent years and is closely correlated with fine particulate matter particulate matter (PM) 2.5. Thus, the relationship between polycyclic aromatic hydrocarbons (PAHs), one of the main components of PM2.5, and IMN should be explored.

Methods: Patients with IMN and healthy control (HC) individuals were screened, and the concentrations and clinical indicators of blood PAHs were detected in these two groups for statistical analysis. Immortalized mouse podocyte cells were treated with 6.25, 12.5, and 25 μg/mL Benzo[b]fluoranthene (BbF) for 72 h. The cell morphology was observed, and the expressions of nephrin and synaptopodin (Synpo) were detected. On days 0 and 2, 1.25 mg/kg BbF was intratracheally administered to the rats. The rats were sacrificed on day 0, day 3, day 7, and day 14. The glomerulus was observed under a microscope, and the nephrin expression was detected.

Results: Compared with the HC group, the total concentration of PAHs in the IMN group was significantly increased (P < 0.001), and the between-group diference was -3.031 μg/mL (95% confidence interval, -3.739 to -2.324). The total concentration of PAHs in the IMN group was significantly negatively correlated with total protein (TP) and albumin (ALB) and significantly positively correlated with β2 microglobulin (β2-MG) and 24-hour urine TP (24hTP). Among them, BbF was not only negatively correlated with TP and ALB but also positively correlated with cystatin C, β2-MG, and 24hTP and was positively correlated with anti-phospholipase A2 receptor (P < 0.05). In cell experiments, the cell morphology became irregular, the cytoplasm started to shrink, the number of cells decreased with increasing BbF concentration, and the expressions of nephrin and Synpo decreased with increasing BbF concentration. In animal experiments, glomeruli had marked inflammatory cell infiltration in hematoxylin and eosin staining, mesangial cell proliferation and increased mesangial matrix in periodic acid-Schif staining, and deposition of a small number of immune complexes in Masson staining over time, and the nephrin expression gradually decreased.

Conclusion: This study showed that the total concentration of PAHs in the blood of patients with IMN significantly increased, and BbF is significantly correlated with the disease severity of IMN, suggesting that PAHs are correlated with IMN occurrence and development and may play a certain role in IMN.

Background and objectives: The conventional diagnostic process for cardiovascular autonomic neuropathy (CAN) is often time-consuming and lacks standardization. The Cardiovascular Autonomic Nervous Function Multi-Parameter Evaluation System is the first intelligent device designed for CAN diagnosis, featuring wireless wearable modules and human‒computer interaction. This study aims to evaluate the accuracy and eficiency of the novel device.

Methods: A two-part, paired-design multicenter study involving a total of 200 subjects (122 with diabetes) from three centers was conducted. Cardiovascular autonomic reflex tests (CARTs) and 5-min heart rate variability (HRV) analyses were performed via the study device. Concurrent manual measurements with physician diagnoses and nonstandardized conventional methods served as controls in Part I and Part II, respectively.

Methods: In Part I, the study device diagnosed 19.3% (29/150) of the subjects with CAN, demonstrating 96.6% sensitivity and 100% specificity. There was excellent agreement with the physician's CAN diagnosis for CARTs (Cohen's kappa of 0.979, P < 0.001) and with the control device for HRV parameters (intraclass correlations [ICCs] > 0.9). Part II showed weak to moderate intermethod correlations with the nonstandardized conventional method (ICCs = 0.193‒0.632). Repeated tests revealed high reproducibility (coefficients of variation = 3%‒20%). The investigational device required only one examiner to perform a standardized assessment and saved 33 minutes compared with manual methods.

Conclusions: The proposed system provides eficient and standardized testing with excellent accuracy and reproducibility for CAN assessment. This novel device will facilitate the evaluation of therapeutic efficacy and promote streamlined clinical workflows.

Background and objectives: Haploidentical stem cell transplantation (haplo-HSCT) has demonstrated promising results in patients without severe comorbidities. There is also an increasing need for haplo-HSCT in patients with severe comorbidities. However, the high risk of treatment-related mortality (TRM) hindered its extensive application. We aimed to investigate a novel conditioning regimen (Bu/Flu/Cy/ATG) followed by haplo-HSCT in patients with severe comorbidities.

Methods: This prospective, single-arm clinical trial was performed at Peking University Institute of Hematology, China. Patients were enrolled if they were (1) diagnosed with acute leukemia, myelodysplastic syndrome (MDS), or chronic myelomonocytic leukemia (CMML); (2) patients with no HLA-matched sibling donor or matched unrelated donor available but with a haplo-HSCT donor; (3) patients with hematopoietic cell transplantation comorbidity index (HCT-CI) scores ≥3. The primary endpoint was 2-year TRM.

Results: From June 2018 to November 2022, a total of 72 patients were enrolled. All patients achieved neutrophil engraftment. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) at day 100 was 20.8%. The cumulative incidences of cytomegalovirus (CMV) viremia and Epstein‒Barr (EB) viremia at day 100 were 72.2% and 31.9%, respectively. The cumulative incidence of 2-year TRM was 25.1%. The cumulative incidence of 2-year relapse was 8.6%. The probabilities of 2-year overall survival and leukemia-free survival were 71.9% and 65.6%, respectively.

Conclusion: This study suggested that a novel conditioning regimen followed by haploidentical HSCT might be a promising option for patients with severe comorbidities. The study was registered as a clinical trial (NCT03412409).

Background and objectives: Cancer continues to be a predominant cause of mortality worldwide, underscoring the critical need to identify and develop novel biomarkers to improve prognostic accuracy and therapeutic approaches. The dysregulation of ELAVL1 is linked to various diseases, including cancer. Nevertheless, its role across different cancer types remains insufficiently investigated.

Methods: We conducted a systematic investigation into the expression patterns, prognostic significance, genomic alterations, modifications, and functional implications of ELAVL1 in pan-cancer types. Besides, we performed in vitro and in vivo experiments to confirm the role of ELAVL1 in nasopharyngeal carcinoma (NPC).

Results: By utilizing multi-omics datasets, we found obvious overexpression of ELAVL1 in various cancer types at both the mRNA and protein levels, with predominant expression in malignant cells. Survival analysis revealed that increased ELAVL1 expression was linked to unfavorable outcomes in certain cancers; however, its effect difers among various cancer types. Additionally, we found that the genomic alterations and modifications of ELAVL1 were related to tumor progression. We discovered that ELAVL1 was elevated in NPC tissues. In addition, survival analysis indicated that NPC patients with higher ELAVL1 expression had worse prognoses. Functional assays demonstrated that ELAVL1 suppression led to decreased proliferation and migration in NPC cell lines. Moreover, ELAVL1 knockdown effectively inhibited NPC progression in the lymph node and lung metastasis models.

Conclusions: In summary, ELAVL1 exhibits diverse and complex involvement in tumor progression. Targeting it might inhibit tumor progression, making it a promising biomarker and therapeutic target for enhancing cancer treatment outcomes.

Background and objectives: Aberrant upregulation or mutations of EZH2 frequently occur in human cancers. However, the clinical benefits of EZH2 inhibitors (EZH2i) remain unsatisfactory for majority of solid tumors. Therefore, there is an urgent need to develop new strategies to expand the therapeutic benefits of EZH2i. Nanocarriers have gained increased attention due to their advantages of prolonged blood circulation, enhanced cellular uptake, and active targeting capabilities. This study aims to address the challenges of EZH2i GSK126's limited efficacy and severe adverse effects against solid tumors.

Methods: A nano delivery system was developed by encapsulating GSK126 within albumin nanoparticles (GSK126 NPs).

Results: The prepared GSK126 NPs exhibited a small spherical core with an average diameter of 30.09 nm ± 1.55 nm, high drug loading capacity (16.59% ± 2.86%) and good entrapment efficiency (99.53% ± 0.208%). GSK126 NPs decreased tumor weight and volume in the B16F10 xenograft mice, while such effects were not observed in the free GSK126 group. Subsequently, histological analysis demonstrated that GSK126 NPs significantly alleviated lipid-associated liver toxicity. Additionally, GSK126 NPs can partially counteract the effects of GSK126 on MDSCs, particularly by decreasing the infiltration of M-MDSCs into tumors.

Conclusions: Albumin-based EZH2i NPs have potent anti-cancer efficacy with tolerable adverse effects, providing promising opportunity for future clinical translation in treating solid tumors.

Eupatilin, a flavonoid found in Artemisia argyi (Compositae) leaves, exhibits robust anti-inflammatory, antioxidant, and anti-tumor properties. Numerous investigations have demonstrated remarkable efficacy of eupatilin across various disease models, spanning digestive, respiratory, nervous, and dermatological conditions. This review aims to provide an overview of recent studies elucidating the mechanistic actions of eupatilin across a spectrum of disease models and evaluate its clinical applicability. The findings herein provide valuable insights for advancing the study of novel Traditional Chinese Medicine compounds and their clinical utilization.