Biomolecules & biomedicine最新文献

Ferroptosis plays a crucial role in the secondary pathophysiological damage to brain tissue surrounding hematomas after intracerebral hemorrhage (ICH). While platelet factor 4 (PF4) is known to promote regeneration following peripheral nerve injury, its role in brain tissue repair after cerebral hemorrhage remains unclear. In this study, Hemin-induced PC12 cells were treated with various inhibitors and assessed for viability, oxidative stress, and ferroptosis using a combination of assays, including CCK-8 (Cell Counting Kit-8), EdU (5-Ethynyl-2'-deoxyuridine), flow cytometry, and immunofluorescence. ICH cells were also treated with recombinant PF4 (Rm-PF4) and a CXCR3 antagonist (AMG487) to investigate the mechanism by which Rm-PF4 influences Hemin-induced PC12 cell injury and inflammation. Subsequently, ICH mouse models were established via collagenase injection. Neurological function in these mice was evaluated using the Cylinder and Corner tests. Histopathological damage to brain tissue was analyzed through HE, TUNEL, and Nissl staining, as well as immunohistochemistry, to further explore the role of Rm-PF4 in controlling neuroinflammation in vivo. Results showed that Rm-PF4 inhibited Hemin-mediated ferroptosis-induced PC12 cell damage and inflammation by activating the CXCR3/AKT1/SLC7A11 signaling pathway. Blocking the CXCR3/AKT1/SLC7A11 pathway partially reversed PF4's protective effects on Hemin-induced PC12 cells.In ICH mice, pro-inflammatory marker CD16 (3rd day) and anti-inflammatory marker Arg1 (7th day) were significantly decreased and increased, respectively (p<0.05). IL-6, TNF-α, and IL-1β levels were down-regulated in brain tissues after Rm-PF4 injection, which was significantly reversed by AMG487. PF4 inhibits ferroptosis after ICH reduced PC12 cell damage and the inflammatory response via activating the CXCR3/AKT1/SLC7A11 pathway.

Cardiac arrest (CA) remains a critical global health issue with high rates of mortality and morbidity. Accurate prediction of neurological outcomes in post-CA patients is essential for optimizing management strategies. Optic nerve sheath diameter (ONSD) and near-infrared spectroscopy (NIRS) are emerging as promising tools for evaluating brain oxygenation and intracranial pressure. However, the potential benefits of combining these methods for improved prognostic accuracy have not been thoroughly explored. This study investigates whether the combined use of ultrasonographic ONSD and NIRS measurements enhances the prediction of neurological outcomes after CA. In this prospective study, ONSD measurements were obtained three times at 24-hour intervals, while regional hemoglobin oxygen saturation (rSO2) using NIRS was recorded twice. Neurological outcomes were assessed using the Full Outline of Unresponsiveness (FOUR) and Cerebral Performance Categories (CPC) scores for both early and late evaluations. Results indicated that 47.5% of patients had poor outcomes and 52.5% had good outcomes based on the FOUR score, while 65% had poor outcomes and 35% had good outcomes according to the CPC score. The combination of ONSD and NIRS measurements showed superior prognostic performance compared to either method alone. While standalone NIRS measurements taken after 24 hours exhibited limited predictive value, combining ONSD and NIRS provided a more reliable approach for neurological assessment in the short term following CA. This integrated method may improve prognostic accuracy and support better clinical decision-making.

The Wnt signaling pathway is one of the most important and critical signaling pathways for maintaining cellular functions, such as cell proliferation and differentiation. Increasing evidence substantiates that the Wnt signaling pathway also plays a significant role in the regulation of bone formation in osteoporosis. Accordingly, inhibitors of this pathway, such as sclerostin, Dickkopf-1 (DKK1), WNT inhibitory factor 1 (WIF1), and secreted frizzled-related proteins (SFRPs), have a negative regulatory role in bone formation and may serve as effective therapeutic targets for osteoporosis. This review examines the mechanisms of action of Wnt signaling pathway inhibitors in osteoporosis, the relationship between the Wnt pathway and its inhibitors, and new molecular targets for osteoporosis treatment. Overall, the regulatory mechanisms of Wnt pathway inhibitors are summarized to provide scientific and theoretical guidance for the treatment and prevention of osteoporosis.

The incidence of atrial fibrillation (AF) increases with age and is particularly high in individuals with diabetes. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), such as dapagliflozin, show promise in treating heart failure (HF) and reducing the risk of AF. Sirtuin 1 (SIRT1), a key enzyme in metabolic regulation, may be influenced by SGLT2i and play a role in the development of AF. This study investigates the relationship between dapagliflozin therapy and atrial tachyarrhythmia in diabetic cardiomyopathy, with a focus on the role of SIRT1. A streptozotocin (STZ)-induced diabetes mellitus (DM) rat model was used to assess AF across four groups: sham, STZ, STZ with dapagliflozin, and STZ with dapagliflozin + sirtinol (a SIRT1 inhibitor). Additionally, HL-1 cardiomyocytes were cultured under high glucose (HG) conditions and treated with dapagliflozin, with or without sirtinol. In the rat model, dapagliflozin improved atrial fibrosis and reduced AF inducibility and duration-effects that were partially reversed by sirtinol. These findings suggest that dapagliflozin may alleviate cardiac fibrosis and atrial arrhythmia by modulating SIRT1. In HL-1 cells under HG conditions, dapagliflozin reduced apoptosis, restored autophagy and mitophagy, and improved calcium channel activity. However, sirtinol negated these protective effects. Dapagliflozin helped normalize autophagy, mitophagy, and calcium handling, while sirtinol diminished its protective effects, highlighting the key role of SIRT1 in regulating calcium handling under HG conditions. Overall, SIRT1 plays a protective role in diabetic cardiomyopathy by reducing apoptosis, regulating autophagy and mitophagy, and modulating calcium channel activity. Dapagliflozin reduces AF duration and inducibility in the STZ model, likely through SIRT1 upregulation and calcium channel modulation.

Esophageal cancer (EC) is a highly aggressive malignancy with limited treatment options. Nei like DNA glycosylase 3 (NEIL3) and DNA topoisomerase II alpha (TOP2A) have been identified as potential therapeutic targets, though their roles in EC remain unclear. This study investigates the effects of NEIL3 overexpression and TOP2A knockdown, focusing on the WNT signaling pathway. ECA109 esophageal cancer cells were used to assess the impact of NEIL3 overexpression and TOP2A knockdown on proliferation, colony formation, migration, invasion, and apoptosis. The involvement of the WNT signaling pathway was also explored. NEIL3 overexpression significantly enhanced proliferation, colony formation, migration, and invasion while reducing apoptosis. In contrast, TOP2A knockdown suppressed these functions and promoted apoptosis, independent of NEIL3. NEIL3 overexpression could not reverse the effects of TOP2A knockdown. Both NEIL3 and TOP2A acted through the WNT signaling pathway. In vivo, NEIL3 knockdown reduced tumor size and weight via WNT pathway modulation. NEIL3 and TOP2A play key roles in EC progression through the WNT signaling pathway. Targeting these molecules may offer promising therapeutic strategies for EC.

SRY-box transcription factor 9 (SOX9) has been reported to be overexpressed in a wide variety of gastrointestinal malignancies. While its role has been studied in gastric cancer (GC), the results remain conflicting. This study aimed to evaluate the relationship between SOX9 immunohistochemistry results and the pathological and clinical characteristics of gastric adenocarcinoma, assessing its potential as a prognostic marker. Gastric tissue samples from 150 patients with gastric cancer were included in the study. Tissue sections were stained using an anti-SOX9 antibody, and relevant data were retrospectively collected from digital records. Immunostaining results were scored based on the proportion and intensity of stained nuclei throughout the tumor. A final immunostaining score was calculated by multiplying the SOX9 intensity score by the proportion score. Strong SOX9 nuclear staining was observed in 68 patients (45.3%), while moderate staining was seen in 60 patients (40%). SOX9 nuclear staining was absent in three patients (2%). A final SOX9 immunostaining score of ≥10, classified as high expression, was identified in 60 patients (40%). Patients with higher SOX9 expression or strong intensity scores exhibited significantly larger tumor sizes, higher rates of perineural and vascular invasion, more advanced T or lymph node staging, and greater likelihoods of lymphatic or distant metastases compared to those with lower SOX9 expression or intensity scores (all P < 0.05). These findings suggest that SOX9 staining intensity and expression are associated with increased tumor malignancy and disease progression. Therefore, SOX9 may serve as a prognostic pathological indicator in GC patients.

SWItch/sucrose non-fermentable (SWI/SNF) is a large protein complex with a central role in chromatin remodeling and genome transcription. The catalytic subunits of the SWI/SNF related BAF chromatin remodeling complex subunit ATPase 2 (SWI/SNF SMARCA2; also called BRM) and SWI/SNF related BAF chromatin remodeling complex subunit ATPase 4 (SMARCA4; also called BRG1) are encoded by the SMARCA2 and SMARCA4 genes, respectively, and are mutually exclusive. Loss of either SMARCA2 and/or SMARCA4 has been previously reported in several types of malignant solid tumors of the gastrointestinal and genitourinary tract. So far, their absence in non-small cell lung cancer (SCLC) has been observed in a series of studies involving primary tumors and cell lines, where it is associated with loss of differentiation and heightened tumorigenic potential leading to an unfavorable prognosis. SMARCA2 and SMARCA4 deficiency is frequent in solid predominant adenocarcinomas and tumors with low levels of bronchial epithelial markers, including thyroid transcription factor 1. A rare case of SMARCA4 deficiency in SCLC is described. A 57-year-old male patient, with no medical history of past illness, was admitted to our center for the investigation and management of a space-occupying lesion in the right upper lung lobe with tracheal and mediastinal infiltration. Biopsy of a lymph node in the right supraclavicular region was diagnostic for SCLC with regional loss of SMARCA4. The patient demonstrated progressive respiratory failure and clinical deterioration and eventually deceased despite intubation and transfer to the intensive care unit. This case indicates that SMARCA4-deficient SCLC may present with an aggressively deteriorating phenotype with poor outcomes for the patients.

The cysteine-rich epidermal growth factor ligand domain 2 protein (CRELD2) is associated with pathways that regulate epithelial-to-mesenchymal transition, a critical process driving cancer metastasis. This study aimed to determine the prognostic value of CRELD2 status on survival outcomes in triple-negative breast cancer (TNBC). Seventy patients were included in the study. Thirty-four patients were metastatic, and 36 patients were non-metastatic. CRELD2 protein expression in tumor tissue was determined by immunohistochemical staining (IHC). The patients were divided into two groups: CRELD2 positive and negative groups. Clinicopathological features and survival outcomes were compared between the groups. In the survival analysis of the non-metastatic patient group, five-year overall survival (OS) rate was 91.7% in the CRELD2-positive patient group and 91% in the negative group (P = 0.91). Median progression free survival (PFS) was 9.4 (95% confidence interval [CI]: 6.4-12.4) months in the CRELD2-positive group and 11.9 (95% CI: 8.2-18.6) months in the CRELD2-negative group (P = 0.04). The median OS was 17.2 (95% CI: 13.7-22.3) months in the CRELD2-positive group and 24.7 (95% CI: 21.8-29.6) months in the CRELD2-negative group (P = 0.02). In multivariate analysis, CRELD2 status (negative vs positive) (hazard ratio [HR]: 0.50, 95% CI: 0.38-0.96, P = 0.02) was determined to be a risk factor for OS and CRELD2 status (negative vs positive) (HR: 0.82, 95% CI: 0.33-0.96, P = 0.01) was defined as a risk factor for PFS in patients with metastatic TNBC. This is the first clinical study to determine the effect of CRELD2 on survival and as a prognostic marker in patients with triple metastatic breast cancer. These results need to be validated prospectively with a large sample size.

Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous metastatic lymphoma that can be treated by targeting angiogenesis. Apolipoprotein C1 (APOC1) plays a significant role in the proliferation and metastasis of various malignant tumors; however, its role in DLBCL-particularly its effects on angiogenesis-remains largely unexplored. This study investigates the correlation between APOC1 expression and patient prognosis in DLBCL. Using APOC1 gene knockdown, apoptosis, migration, and invasion were assessed through flow cytometry, the EDU assay, wound healing, and Transwell assays. Additionally, human umbilical vein endothelial cells (HUVEC) angiogenesis was evaluated. Advanced techniques, such as immunofluorescence, TUNEL assay, and immunohistochemical labeling were employed to analyze the effects of APOC1 knockdown on the PI3K/AKT/mTOR signaling pathway and tumor formation in nude mice. Results showed that APOC1 is overexpressed in DLBCL tissues and cells, with high APOC1 levels associated with poor patient prognosis. In vitro experiments revealed that APOC1 knockdown increased apoptosis and inhibited cell proliferation, migration, invasion, HUVEC angiogenesis, and PI3K/AKT/mTOR signaling pathway protein expression in DLBCL cells. Similarly, in vivo studies demonstrated that APOC1 knockdown significantly reduced tumor growth, angiogenesis-related proteins, and phosphorylated PI3K/AKT/mTOR pathway proteins in nude mice. APOC1 knockdown promotes apoptosis and suppresses angiogenesis in DLBCL cells by inhibiting the PI3K/AKT/mTOR pathway.

Mycoplasma pneumoniae (MP) is a common cause of community-acquired pneumonia (CAP) in children and can lead to severe complications, including respiratory failure. A retrospective analysis of 2084 children diagnosed with CAP and treated in our hospital from January 2022 to January 2023 was conducted. A comprehensive dataset of patient demographics, clinical symptoms, and laboratory findings was initially assembled. Subsequent statistical analyses were carried out to elucidate the clinical characteristics of MP pneumonia (MPP) in children. Additionally, the study identified high-risk factors for respiratory failure in the context of MPP. Among the hospitalized MPP cases, 15.8% progressed to respiratory failure. Statistical analysis identified D-dimer level as a significant risk factor for respiratory failure in children with MPP. A predictive model was developed using D-dimer levels, yielding an area under the curve (AUC) of 0.818 with a cutoff value of 1.015 mg/L. The model demonstrated a sensitivity of 62.4% and a specificity of 91.3%, proving effective in predicting respiratory failure caused by MPP. Respiratory failure remains a critical complication in children with MPP, and D-dimer levels serve as a key predictive risk factor. Vigilant monitoring of coagulation function, particularly D-dimer levels, is essential for the early identification of patients at risk of developing respiratory failure in MPP cases.