European Journal of Medical Research最新文献

Sepsis remains a leading cause of morbidity and mortality in intensive care units worldwide, driven by a dysregulated host response to infection that culminates in multi-organ dysfunction. Current diagnostic biomarkers and therapeutic strategies lack the needed sensitivity, specificity and efficacy, underscoring an urgent need for novel molecular insights. Long non-coding RNAs (lncRNAs), a diverse class of transcripts exceeding 200 nucleotides without protein-coding capacity, have emerged as pivotal regulators of sepsis pathophysiology. They orchestrate immune responses, inflammatory cascades, cellular apoptosis, metabolic reprogramming and the lethal cross-talk among diverse cell death pathways. Through intricate interactions with DNA, RNA and proteins, lncRNAs also drive organ-specific injury via distinct cell-type specific mechanisms. Specific lncRNAs, including NEAT1, MALAT1 and GAS5, are deeply implicated in disease onset, progression and prognosis, highlighting their potential as both biomarkers and therapeutic targets. In this review, we synthesize current evidence on the roles of lncRNAs in immune modulation, organ dysfunction and metabolic regulation during sepsis. We also evaluate their promise in diagnosis, prognosis and therapy, and discuss major translational barriers, such as physicochemical instability, poor permeability and disease heterogeneity, that must be overcome for clinical application. A deeper understanding of these molecules may unlock novel strategies for the early diagnosis, prognosis, and treatment of sepsis.

Objective: This study aims to investigate the molecular mechanisms by which ECRG4 regulates breast cancer progression, with a focus on its tumor-suppressive effects mediated through the NFIC/PTEN and SHP2/PI3K/SP1 signaling pathways.

Methods: Bioinformatics analysis was used to identify genes associated with ECRG4. Subcutaneous tumor transplantation experiments in nude mice were conducted to assess breast cancer progression; immunohistochemical staining was used to detect the expression of p-SHP2, ECRG4, and NFIC in tumor tissues; Western blot analysis was employed to assess the expression levels of relevant proteins. Scratch assays, Transwell assays, and plate colony formation assays were conducted to evaluate the migration and invasion capabilities of human breast cancer cell line MCF-7, while flow cytometry was used to analyze the cell cycle and apoptosis status of MCF-7 cells.

Results: Bioinformatics analysis revealed significant associations between ECRG4 and the NFIC/PTEN and SHP2/PI3K/SP1 pathways. Under hypoxic and low-serum conditions, p-SHP2 activates the PI3K/AKT pathway and induces SP1 expression, thereby upregulating the DNA methyltransferase DNMT1 and suppressing the expression of the tumor suppressor gene ECRG4. ECRG4 positively regulates the transcription factor NFIC, leading to increased expression of its downstream target gene PTEN. PTEN negatively feeds back to inhibit the activity of the PI3K/AKT pathway. The activated PI3K/AKT pathway phosphorylates the transcription factor CREB, driving the expression of the E3 ubiquitin ligase SKP2, thereby promoting cell survival. Meanwhile, the pro-apoptotic factors FOXO1/FOXO3a and SKP2 form a bidirectional antagonistic interaction: SKP2 mediates the ubiquitination and degradation of FOXO1/FOXO3a, while FOXO1/FOXO3a can transcriptionally inhibit SKP2 expression, jointly regulating the dynamic balance between apoptosis and survival.

Conclusion: ECRG4 inhibits breast cancer progression by positively regulating NFIC/PTEN to suppress the SHP2/PI3K/SP1 signaling pathway. Targeting this signaling axis may provide a new strategy for breast cancer treatment.

Background: The Coronary Slow Flow Phenomenon (CSF) is increasingly recognized as a distinct phenotype of Ischemia with Non-Obstructive Coronary Arteries (INOCA). However, debate persists regarding whether CSF represents fixed structural microvascular remodeling or functional dysregulation. Conventional Left Ventricular Ejection Fraction (LVEF) is often insensitive to the subtle subendocardial mechanics associated with this condition.

Objectives: This study aimed to interrogate the functional reserve of the left ventricle in patients with angiographically defined CSF using Two-Dimensional Speckle-Tracking Echocardiography (2D-STE) during physiological exercise stress.

Methods: We conducted a prospective case-control study enrolling 63 patients evaluated for angina pectoris. The cohort comprised 33 patients with angiographically defined CSF (Corrected TIMI Frame Count > 27) and 30 age- and sex-matched controls with normal coronary flow. All participants underwent symptom-limited treadmill exercise testing (Bruce protocol). Left ventricular Global Longitudinal Strain (GLS) was quantified at rest and at peak stress.

Results: At rest, despite comparable LVEF between groups (CSF: 65.6 ± 3.5% vs. Control: 66.3 ± 3.6%; P = 0.423), the CSF group exhibited significantly impaired GLS compared with controls (-18.37 ± 0.85% vs. -20.07 ± 1.33%; P < 0.001), indicating subclinical systolic dysfunction. Upon peak exercise, both groups demonstrated significant augmentation in GLS (P < 0.001). Although peak stress GLS remained numerically lower in the CSF group (-22.10 ± 2.08% vs. -23.27 ± 1.74%; P = 0.020), the magnitude of functional recruitment (ΔGLS) was fully preserved in CSF patients (3.73 ± 1.54% vs. 3.19 ± 1.41%; P = 0.154).

Conclusions: Patients with CSF exhibit distinct subclinical longitudinal dysfunction at rest, likely attributable to elevated resting microvascular resistance. However, the preservation of contractile reserve during physiological stress suggests that the underlying microvascular dysfunction is predominantly functional and reversible. 2D-STE provides incremental diagnostic value over conventional angiography in stratifying the pathophysiology of INOCA.

Background: Lenvatinib is the first-line therapy for advanced hepatocellular carcinoma (HCC). Nevertheless, drug resistance is a challenge for improving the outcomes of these patients. Discs Large Homolog Associated Protein 5 (DLGAP5) belongs to cell-cycle-regulated proteins, associated with poor prognosis in cancer. However, its biological roles and mechanisms in lenvatinib sensitivity of HCC remain unclear.

Methods: We analyzed the expression level of DLGAP5 by public database. A sixty HCC patients' cohort was used to investigate the prognostic potential after lenvatinib treatment. Cell growth, metastasis, apoptosis, and animal experiments were used to explore the specific function of DLGAP5. Differentially expressed genes of DLGAP5-knockdown cells were analyzed by RNA-seq data.

Results: DLGAP5 was upregulated in HCC tissues, especially in lesions of patients with metastasis. Overexpression of DLGAP5 correlated with poor prognosis and lower response to lenvatinib treatment. We found that the downregulation of DLGAP5 inhibited malignancy and increased the sensitivity of HCC cells to lenvatinib both in vitro and in vivo. Mechanistically, DLGAP5 might function by regulating AKT/mTOR/NF-κB signaling pathway.

Conclusions: DLGAP5 promotes malignancy of HCC and reduces cell lenvatinib sensitivity by positively regulating the AKT/mTOR/NF-κB pathway, indicating that DLGAP5 functions as a potential biomarker for clinical prognosis and lenvatinib treatment in HCC.

Acute respiratory distress syndrome (ARDS) presents significant challenges in critical care medicine due to its complex pathophysiology and diverse etiologies. Critical care ultrasound (CCUS), also known as point-of-care ultrasound in the critical care setting, encompasses a variety of ultrasound applications tailored specifically to manage critically ill patients. In recent years, comprehensive critical care ultrasound evaluations, including pulmonary, cardiac, and diaphragmatic ultrasound, have improved the understanding of ARDS pathophysiology by visualizing respiratory dynamics and supporting diagnostic investigations. These modalities provide valuable information for etiology identification, severity assessment, and prognostic evaluation in ARDS patients, while recognizing that therapeutic decisions require integration with clinical context and established diagnostic standards. This narrative review aims to synthesize the current evidence and expert consensus on the use of critical care ultrasound in the management of ARDS. We will explore its role in diagnosis, monitoring, and prognostication, while critically evaluating its strengths and limitations as an adjunct to conventional imaging methods. We also outline future directions for research and development in this field, emphasizing the need for standardized protocols and additional training to maximize the benefits of CCUS in the critical care management of ARDS.

Background: Heart failure (HF) is a global health burden, affecting millions of people worldwide. This prospective study aimed to investigate the prognostic value of the red blood cell distribution width-albumin ratio (RAR) in HF patients.

Methods: This two-center cohort study included patients with symptomatic HF (NYHA functional class III-IV) from 2014 to 2016. Survival analysis, logistic regression, and Kaplan-Meier curves were employed to assess the association between RAR and prognosis.

Results: The study included 2151 HF patients. Significant differences in clinical profiles were observed across RAR groups. Patients with higher RAR were more likely to be female and had a greater prevalence of comorbidities such as atrial fibrillation, renal insufficiency, and hypoproteinemia. During the 6-year follow-up period, higher RAR was significantly associated with reduced survival probability (P < 0.001). Elevated RAR was independently associated with a higher risk of HF re-hospitalization [HR(95% confidence interval; CI): 1.848 (1.502-2.275), P < 0.001], cardiac death [HR (95% CI): 1.334 (1.074-1.657), P = 0.009], and all-cause death [HR(95%CI): 1.575 (1.283-1.933), P < 0.001] at 3 months. Furthermore, elevated RAR independently predicted a higher risk of HF re-hospitalization at 6 years [HR(95%CI): 1.457(1.271-1.671), P < 0.001] and all-cause mortality [HR(95%CI): 1.507 (1.318-1.723), P < 0.001].

Conclusions: Elevated RAR levels are independently associated with a worse prognosis in HF patients, including higher risks of HF re-hospitalization and all-cause mortality. The RAR holds promise as a valuable tool for risk stratification and prognosis assessment in HF management.

Ferroptosis is a recently identified form of cell death caused by iron-dependent peroxidation of lipids. Altered lipid metabolism plays a crucial role in determining the vulnerability of hepatocellular carcinoma (HCC) cells to ferroptosis. Targeting lipid-peroxidation-driven ferroptosis has been increasingly recognized as a promising strategy in cancer therapy. Long-chain acyl-CoA synthetase family member 4 (ACSL4) is one of the key drivers of the ferroptosis process. ACSL4 modifies the phospholipid makeup of cell membranes, controls steroid production, and maintains a balance in eicosanoid biosynthesis. Moreover, metabolic reprogramming driven by ACSL4, along with its role in antitumor immunity, has attracted considerable interest in the field of cancer biology. Here, we present a summary of the diagnostic role of ACSL4 in HCC and the functions of ACSL4 in HCC initiation, development, metastasis, tumor immunity, and therapy resistance. Moreover, several possible therapeutic strategies based on ACSL4-mediated ferroptosis are discussed. Research on the molecular mechanisms of ACSL4 is critical for the development of targeted therapies for HCC.

Background: Pain symptoms are common in liver disease patients, but the temporal relationship between liver disease onset and pain development, as well as specific risk factors for pain in this population, remains poorly characterized.

Objective: This study aimed to examine the longitudinal trajectories of pain symptoms and identify risk factors for pain in patients with incident liver disease using a nationwide cohort.

Methods: We analyzed data from 16,159 participants without baseline liver disease in the China Health and Retirement Longitudinal Study (2011-2020). Incident liver disease was defined as new-onset physician-diagnosed liver disease during follow-up. Pain at 15 body sites was assessed dichotomously. Generalized estimating equations identified risk factors for pain symptoms post-diagnosis, adjusting for demographics, health status, lifestyle, and comorbidities. Time interactions, subgroup analysis by gender and residence, and sensitivity analysis including multiple imputation and different model specifications were performed.

Results: Among participants, 1150 (7.1%) developed incident liver disease over 9 years. At baseline, future incident cases showed significantly higher pain prevalence across all sites compared to those remaining disease-free (waist pain: 28.7% vs 17.9%, P < 0.001; leg pain: 20.7% vs 13.9%, P < 0.001; headache: 20.6% vs 12.4%, P < 0.001). Post-diagnosis pain prevalence increased substantially, with waist pain rising from 28.1% to 45.3%. Arthritis emerged as the strongest risk factor (OR range: 1.42-4.99), particularly for musculoskeletal pain. Depression (CESD-10) was consistently associated with increased pain risk (OR: 1.03-1.08, all P < 0.05), while self-rated health showed protective effects (OR: 0.72-0.82). Significant interactions revealed stronger depression-pain associations in males and urban residents. Kidney disease effects on back pain intensified over time (interaction OR = 1.47, P = 0.003).

Conclusions: Pain symptoms precede liver disease diagnosis and progressively worsen thereafter, with arthritis and depression as key modifiable risk factors requiring targeted management strategies in this vulnerable population.

Objectives: This study aimed to evaluate the association between maternal serum levels of vitamin D, calcium, and magnesium and the success of cervical ripening in pregnant women undergoing misoprostol induction.

Materials and methods: A prospective cohort study was conducted among 212 nulliparous pregnant women who received misoprostol for labor induction at Al-Zahra Hospital in Rasht, Iran, between 2022 and 2023. Based on their clinical response to misoprostol, participants were classified as responsive (n = 106) or unresponsive (n = 106). Serum concentrations of vitamin D, calcium, and magnesium were obtained before induction. These values were then analyzed in relation to cervical ripening outcomes, which were assessed using the Bishop score and the time interval to delivery.

Results: Serum magnesium levels were below 1.8 mg/dl in 20.8% of participants, and serum calcium levels were below 8.5 mg/dl in 28.8%. The majority of participants (76.4%) had low vitamin D levels. Significant differences in serum vitamin D, calcium, and magnesium levels were observed between groups with successful and unsuccessful cervical ripening (P < 0.05). Multiple logistic regression analysis revealed that higher serum levels of vitamin D, calcium, and magnesium were independently associated with increased likelihood of successful response to misoprostol treatment (P < 0.05).

Conclusions: Maternal vitamin D, calcium, and magnesium status appear to influence the body's readiness to respond to labor induction. Optimizing these micronutrient levels may improve clinical outcomes and support safer, more effective induction of labor.