Current molecular medicine最新文献

Introduction: The expression dynamics of Toll-like receptors (TLRs) in response to SARS-CoV-2, particularly regarding disease severity, remain poorly understood. This study aimed to investigate the gene expression of TLR3, TLR4, and TLR7 in COVID-19 patients and correlate them with disease severity and gender.

Methods: This case-control study enrolled 470 COVID-19 patients (categorized as moderate, severe, and critical) and 100 healthy controls. The mRNA expression levels of these genes in peripheral blood leukocytes were quantified using RT-qPCR.

Results: Expression of all three TLRs was significantly higher in patients than in the control group. Overall, male patients exhibited higher expression than females. Notably, a significant decrease in TLR3, TLR4, and TLR7 expression was observed in the critical group compared with the moderate and severe groups.

Discussion: This paradoxical downregulation of TLRs in critical patients, reported for the first time in such a large cohort (N=470), aligns with reports of 'immunoparalysis' or 'immune exhaustion' observed in other severe inflammatory conditions. This phenomenon might represent a negative feedback mechanism to prevent overwhelming systemic inflammation, although it may concurrently compromise pathogen clearance.

Conclusion: The findings suggest that while TLR expression is upregulated in COVID-19, its downregulation in critical stages may be associated with an unfavorable disease outcome. Therefore, TLR expression levels could be considered potential biomarkers for identifying patients at risk of progressing to the critical phase of the disease.

Introduction: This study aimed to investigate the regulatory mechanism of the LncRNA HULC/miR-556-5p axis in endothelial cell injury associated with heart failure and its impact on endothelial cell function. Specifically, we explored how HULC interacts with miR-556-5p to modulate cell survival, apoptosis, inflammation, and autophagy in response to Ang II-induced injury.

Methods: Human cardiac microvascular endothelial cells (HCMECs) were utilized as the study model. Ang II-induced HCMEC injury was simulated by treating cells with 100 nM Ang II for 24 hours. The expression levels of HULC, miR-556-5p, and related proteins were assessed using techniques, such as real-time quantitative PCR and Western blot. Cell apoptosis was detected using flow cytometry, and inflammatory cytokine release (TNF-α, IL-1β, and IL-6) was analyzed via ELISA. Cell viability was assessed using MTT assays. Immunoblotting was employed to evaluate the phosphorylation status of key signaling molecules, including AMPK and FOXO3.

Results: We observed a crucial role of the LncRNA HULC/miR-556-5p axis in Ang IIinduced HCMEC injury. Overexpression of HULC significantly suppressed miR-556-5p activity, thereby reducing cell apoptosis and the release of inflammatory cytokines while promoting cell survival. Further experimental results indicated that miR-556-5p regulated cell function by reducing the expression level of FOXO3 and modulating the AMPK signaling pathway. Additionally, miR-556-5p markedly decreased cellular autophagy levels, further supporting its regulatory role in endothelial cell injury associated with heart failure.

Conclusion: This study elucidates the important role of the LncRNA HULC/miR-556- 5p axis in endothelial cell injury associated with heart failure. Our findings provide new insights into the pathophysiological mechanisms of heart failure and highlight the potential therapeutic value of targeting this axis to improve endothelial cell function.

Phosphatidylethanolamine (PE) is a major phospholipid in biological membranes and plays essential roles in autophagy, cell signaling, protein function, and membrane integrity. Its dynamic, conical structure supports membrane fluidity and curvature, which are crucial for processes such as signaling, autophagosome formation, membrane fusion, vesicle trafficking, and proper protein folding. Although PE is abundant, its significance for human health and disease has only recently come to light. Altered PE levels or disruptions in its metabolism have been associated with various conditions, including metabolic disorders such as non-alcoholic fatty liver disease (NAFLD), neurodegenerative diseases like Alzheimer's and Parkinson's, and several cancers. PE is synthesized primarily via two pathways: the CDP-ethanolamine (Kennedy) pathway and the mitochondrial phosphatidylserine decarboxylase (PSD) pathway, both of which are critical for maintaining lipid homeostasis. Advances in lipidomics now allow comprehensive profiling of PE species, facilitating the identification of disease-specific lipid biomarkers. This review expands current knowledge on the physiological roles of PE and elucidates mechanisms underlying PErelated lipid dysregulation in human disease.

Intervertebral disc degeneration (IDD) is a common spinal disease that imposes a significant economic burden on healthcare systems. Understanding the biological processes involved in IDD development and degeneration is critical for developing potential therapeutic approaches. Single-cell RNA sequencing (scRNAseq) technology has revolutionized our understanding of cellular heterogeneity at the single-cell level and provided profound insights into the transcriptional landscape of IDD. This review provides an overview of research progress on the cellular biological characteristics of IDD occurrence and degeneration using scRNA-seq. It systematically summarizes the applications and key findings of scRNA-seq in subtyping cell populations, detecting transcriptomic changes, regulating signaling pathways, and elucidating cell-cell interactions in IDD. Additionally, it emphasizes the potential role of scRNA-seq in maintaining and repairing intervertebral disc tissues, from both preventive and therapeutic perspectives. In summary, this study underscores the extensive application of scRNA-seq in degenerative disc research and provides a foundation for future investigations and potential treatment strategies.

Despite widespread use of general anaesthesia (GA) in neonatal procedures, its effects on the developing brain are still not fully understood, raising ongoing questions in both research and clinical practice. Experimental studies have demonstrated that GA can cause neuronal cell injury, and neonates may be vulnerable due to their physiological immaturity, necessitating exact dosing and constant monitoring. To optimise anaesthesia protocols and minimise risks in this vulnerable population, it is imperative to thoroughly evaluate the mechanisms underlying anaesthesia-induced neuronal cell damage in neonates. This review article will explore the following mechanisms: apoptosis, pyroptosis, gamma-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA), oxidative stress and mitochondrial damage, calcium imbalance, neural circuit impairment, and neuroinflammation, with particular focus on studies utilising animal models. It will also highlight recent studies on therapeutic strategies against reducing neuronal cell damage. However, as most of these findings remain preclinical, their translational potential requires cautious interpretation. In conclusion, although current evidence highlights plausible mechanisms and emerging neuroprotective approaches, more clinical trials are needed to ensure the reliability and efficacy of the treatment strategies to confirm their effects on neonatal anaesthesia-induced cell damage.

Introduction: Menstrual hygiene practices are a critical health concern, and if neglected, they may lead to reproductive tract infections (RTIs), toxic shock syndrome, and other vaginal diseases. To prevent these conditions, antiseptic and antibacterial properties must be incorporated into sanitary napkins.

Methods: In this study, nanolayered topsheets were synthesized by embedding silver nanoparticles (AgNPs) into PVA in Aloe vera extract, which was then coated onto a non-woven fabric. The polymer-entrapped AgNPs in Aloe vera (AgNPs + PVA + Aloe vera) were characterized using UV-visible spectrometry, dynamic light scattering (DLS), zeta potential, FTIR, and SEM analyses.

Results: The release kinetics of AgNPs from the coated fabric were studied in simulated vaginal fluid (SVF), showing an initial burst release followed by sustained release. The toxicity of the released nanosilver was evaluated both in vitro using A375 cells and in vivo using zebrafish embryos, establishing a safe dose of 3 μM. The antimicrobial effect of the coated fabric was tested against S. aureus and E. coli, showing clear zones of inhibition.

Discussion: The AgNPs and the coated fabric demonstrated comparable antimicrobial activity.

Conclusion: This product has potential for use in coating sanitary napkins to provide skin-soothing and antimicrobial effects.

Introduction: Stem cells play a pivotal role in immunomodulation and tissue repair, and their functions can be influenced by TLR signaling. The Toll/interleukin-1 receptor domain-containing protein C (TcpC), secreted by Uropathogenic Escherichia coli, can inhibit host immunity by interfering with TLR pathways. As mitochondria are crucial for stem cell function, there may be links between TcpC and mitochondrial homeostasis.

Methods: We isolated MSC mitochondria using magnetic beads coated with a monoclonal antibody against the outer mitochondrial membrane protein OMP25 and conducted a proteomic study to examine the MSC mitochondrial proteome with or without TcpC. Bioinformatics analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and proteinprotein interaction (PPI) network analysis, were employed.

Results: A total of 33 proteins with significant changes in abundance were identified: 4 increased in abundance, including glycolytic enzymes (Pkm [FC=1.6599, p=0.0217]) and stress response proteins (Ywhaq [FC=1.4666, p=0.04502]); and 29 decreased, mainly related to mitochondrial oxidative phosphorylation (e.g., Atp5f1e [FC=0.001, p=0.00120], Ndufa11 [FC=0.001, p=0.00674]) and protein quality control (e.g., Grpel1 [FC=0.46663, p=0.02083], Hspa9 [FC=0.48089, p=0.0435], Pitrm1 [FC=0.12764, p=0.01388]).

Discussion: The possible effects of TcpC on the MSC mitochondrial proteome are reported here for the first time. This information provides a clearer understanding of MSCs in the context of infectious disease and offers a scientific basis for future stem cell therapy research.

Conclusion: TCP-C intervention leads to a series of differentially expressed proteins in MSC mitochondria, which are involved in several functional clusters, including oxidative phosphorylation, respiratory electron transport, the tricarboxylic acid cycle, glyoxylate and dicarboxylate metabolism, branched-chain amino acid catabolism, and cristae formation.

Introduction: SLC39A8 has been implicated in various cancers; however, its specific role in osteosarcoma (OS) remains poorly understood. This study aims to elucidate the functional significance of SLC39A8 in OS progression.

Methods: Using qRT-PCR and Western blot analysis, we analyzed SLC39A8 expression in osteosarcoma cells. Functional assays, including CCK-8, colony formation, and transwell assays, were employed to assess the impact of SLC39A8 on cell proliferation, migration, and invasion. Ferroptosis was evaluated by measuring lipid peroxidation, labile iron pool (LIP), Fe²⁷, malondialdehyde (MDA), reactive oxygen species (ROS), glutathione (GSH), and GPX4 expression.

Results: Our results revealed that SLC39A8 is upregulated in osteosarcoma cells. The knockdown of SLC39A8 significantly suppressed cell proliferation, migration, and invasion while inducing ferroptosis, as evidenced by increased levels of LIP, Fe²⁷, MDA, and ROS, and decreased GSH and GPX4 expression. These effects were reversed by the ferroptosis inhibitor ferrostatin-1 (Fer-1). Furthermore, SLC39A8 overexpression activated the Wnt/β-catenin signaling pathway and upregulated GPX4 expression, effects that were abrogated by silencing β-catenin or TCF4. In vivo experiments confirmed that SLC39A8 knockdown inhibited tumor growth.

Discussion: SLC39A8 is a key zinc and iron transporter. Studies have reported that SLC39A8 was significantly dysregulated in some cancers and was associated with their prognosis. SLC39A8 has been identified as an iron metabolism- and ferroptosisrelated gene related to the prognosis of esophageal squamous cell carcinoma. Our study showed that SLC39A8 promotes osteosarcoma cell proliferation, migration, and invasion while suppressing ferroptosis by regulating β-catenin signaling. Our study further indicated that LF3 reversed SLC39A8-mediated ferroptosis in osteosarcoma cells by reducing GPX4 expression. Although our study shows that SLC39A8 regulates the β-catenin signaling pathway, the upstream regulatory mechanism remains to be investigated.

Conclusion: Our findings demonstrate that SLC39A8 plays a pivotal role in osteosarcoma progression by modulating ferroptosis via the β-catenin/TCF4/GPX4 signaling pathways.

Aim & objectives: Sorafenib is a first-line drug for hepatocellular carcinoma (HCC). Understanding the regulatory mechanisms of sorafenib resistance is critical to inhibit sorafenib resistance and develop novel therapeutic strategies. Here, we aimed to study the role of SSR2 (signal sequence receptor subunit 2) in sorafenib resistance of HCC.

Methods: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay, and cell viability assay were used to determine the role of SSR2 in sorafenib resistance of HCC. Co-immunoprecipitation (CoIP) was used to determine the interacting protein of SSR2.

Results: We found SSR2 was upregulated in sorafenib-resistant HCC tissues. In addition, in HCC patients, SSR2 was associated with both poor response to sorafenib and poor clinical outcomes. Functional assay showed that SSR2 promoted sorafenib resistance in HCC cells. Mechanistically, SSR2 suppressed ferroptosis. Further analysis showed that SSR2 interacted with ferroptosis master regulator glutathione peroxidase 4 (GPX4) and increased the catalytic activity of GPX4, leading to inhibition of ferroptosis. Induction of ferroptosis could reverse the promotion effect of SSR2 overexpression on sorafenib resistance.

Discussion: SRR2 plays a critical role in sorafenib resistance generation. However, the detailed mechanism of SRR2 increasing the catalytic activity of GPX4 will be further studied.

Conclusions: In summary, we reveal that SSR2 enhances sorafenib resistance of HCC via interacting with GPX4 and inhibiting ferroptosis, providing a potential target for HCC treatment. The molecular mechanism of GPX4-SSR2 interaction in ferroptosis will be further studied.

Background: Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer, and there have been disputes over its prognostic biomarker and clinical outcome. Cuproptosis, a novel form of regulated cell death (RCD), has been insufficiently explored in terms of its potential role in LUAD.

Methods: In this study, we developed a machine learning-based integrative procedure for constructing a consensus cuproptosis-related lncRNA signature (CTLNS) using TCGA data and validated it with external datasets.

Results: The CTLNS was identified as an independent predictor of overall survival, showing stable and accurate performance across multiple cohorts. Patients classified into high- and low-risk groups exhibited significant differences in survival outcomes. Functional analyses revealed that the low-risk group was enriched in DNA replication and immune-related pathways, while the high-risk group was associated with oncogenic signaling and cell cycle regulation. Notably, high-risk patients showed increased sensitivity to several chemotherapy agents, including Docetaxel, Cisplatin, Gefitinib, and Paclitaxel, while low-risk patients were more responsive to Nilotinib.

Conclusion: These findings suggest that CTLNS is a reliable biomarker for prognostic prediction and treatment stratification in LUAD, offering potential utility in personalized therapy.