Bosnian Journal of Basic Medical Sciences (BJBMS)
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Nogo-A exacerbates sepsis-associated encephalopathy by modulating microglial SHP-2/NLRP3 balance and inducing ROS and M1 polarization
Get PDFSepsis, a systemic inflammatory response caused by infection, can lead to sepsis-associated encephalopathy (SAE), characterized by brain dysfunction without direct central nervous system infection. The pathogenesis of SAE involves blood-brain barrier disruption, neuroinflammation and neuronal death, with neuroinflammation being the core process. Nogo-A, a neurite growth-inhibitory protein in the central nervous system, is not well understood in sepsis. This study explores Nogo-A\u27s mechanisms in sepsis, focusing on SAE. Using in vivo and in vitro methods, healthy SPF C57BL/6J male mice were divided into Sham, Nogo-A-NC-Model, and Nogo-A-KD-Model groups, with sepsis induced by abdominal ligation and puncture. Morris water maze tests assessed learning and memory, and brain tissues underwent hematoxylin-eosin (HE) staining, Nissl staining, and Western blot analysis. In vitro, Nogo-A gene knockdown models were constructed using BV-2 microglia cells to study inflammation and oxidative stress. Results showed Nogo-A expression affected learning and memory in septic mice, with knockdown reducing neuronal damage. Bioinformatics analysis suggested Nogo-A may activate reactive oxygen species (ROS) to inhibit p-SHP2, activating mitochondrial autophagy and promoting neuronal apoptosis. Western blot results confirmed that Nogo-A affects mitochondrial autophagy and neuronal survival by inhibiting SHP2 and activating ROS. Nogo-A\u27s role in neuroinflammation and neuroprotection was emphasized, revealing its impact on endoplasmic reticulum (ER) stress, mitochondrial autophagy, and NLRP3 inflammasome activation. This study provides a theoretical basis for SAE treatment, suggesting further multi-gene and multi-pathway analyses and validation in clinical samples. Developing gene therapy and drug interventions targeting Nogo-A pathways will offer more effective treatment strategies
CDKN2B-AS1 polymorphism rs1333049 is associated with advanced carotid artery atherosclerosis in a Slovenian population
Get PDFSeveral studies have reported an association between the 9p21 region in the human genome and atherosclerosis. The rs1333049 polymorphism is a single nucleotide polymorphism (SNP) in CDKN2B-AS1, located in the 9p21 region. The aim of our study was to investigate the association between the rs1333049 polymorphism and advanced carotid atherosclerosis, as well as its effect on CDKN2B expression in endarterectomy sequesters. In our case-control study, we included 881 participants, divided into two groups. The case group comprised 308 participants with advanced atherosclerosis of the internal or common carotid artery (stenosis > 75 %) who underwent a revascularization procedure. The control group included 573 participants without hemodynamically significant carotid atherosclerosis. We analyzed the rs1333049 polymorphism using the StepOne real-time polymerase chain reaction (PCR) and TaqMan SNP genotyping assay. We found a statistically significant association according to the co-dominant (P=0.014, OR=3.29, 95% CI: 1.32-8.91, and P=0.015, OR=2.50, 95% CI: 1.22-5.37) and dominant (P=0.006, OR=2.74, 95% CI: 1.36-5.71) models. We performed immunohistochemical analysis of CDKN2B expression on 26 endarterectomy sequesters. The C allele of rs1333049 was associated with a lower numerical area density of CDKN2B-positive cells in atherosclerotic plaques. In conclusion, the C allele of the rs1333049 SNP is associated with an increased risk of developing advanced carotid atherosclerosis and lower CDKN2B expression in the plaques
Hsa_circ_0023179 modulated the processes of proliferation, apoptosis, and EMT in non-small cell lung cancer cells via the miR-615-5p/CDH3 axis
Get PDFCircular RNA (circRNA) has been widely studied as a competitive endogenous RNA targeting microRNA (miRNA)/messenger RNA to regulate cancer progression. However, the regulatory mechanism of circ_0023179 in non-small cell lung cancer (NSCLC) remains unclear. The expression levels of circ_0023179, miR-615-5p and Cadherin 3 (CDH3) in NSCLC were detected using quantitative real-time polymerase chain reaction. The stability of circ_0023179 was verified using ribonuclease R enzyme, actinomycin D and agarose gel electrophoresis. Colony formation and thymidine analog 5-ethynyl-2’-deoxyuridine assays were performed to examine proliferation changes in NSCLC cells. Western blot was used to assess the levels of CDH3 and epithelial-mesenchymal transition (EMT)–related marker proteins to evaluate EMT. Dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays were performed to explore the potential mechanisms of circ_0023179 in regulating NSCLC progression. Finally, the effects of circ_0023179 on NSCLC tumour growth in vivo were explored using a nude mouse subcutaneous tumour model. The results showed that the expression of circ_0023179 was remarkably higher in NSCLC tissues and cells, and it had a significant effect on NSCLC cell proliferation. Additionally, the knockdown of circ_0023179 significantly inhibited tumour growth in NSCLC mice. Mechanistically, circ_0023179 alleviated its inhibition of downstream CDH3 through the sponge-like adsorption of miR-615-5p. The downregulation of miR-615-5p and the upregulation of CDH3 mitigated the inhibitory effect of silencing circ_0023179 on NSCLC cell proliferation. In conclusion, silencing circ_0023179 inhibited NSCLC cell proliferation by targeting the miR-615-5p/CDH3 axis involved in NSCLC progression
Prognostic value of Naples Prognostic Score in locally advanced cervical cancer patients undergoing concurrent chemoradiotherapy
Get PDFThis study aimed to investigate the prognostic value of the Naples Prognostic Score (NPS) in patients with locally advanced cervical cancer (LACC) who received curative concurrent chemoradiotherapy (CCRT). Clinicopathological data from 213 (training set) and 106 (validation set) LACC cases undergoing CCRT were retrospectively analyzed. The receiver operating characteristic curve (ROC) was used to compare the predictive ability of NPS and other indicators for survival. Cox proportional hazard regression was conducted for overall survival (OS) and progression-free survival (PFS). A prediction model using a nomogram was developed with independent prognostic factors in the training set and validated in the validation set. The 5-year OS for the NPS = 1, 2, and 3 groups was 56.8%, 45.4%, and 28.9% (P < 0.001), and the 5-year PFS for the NPS = 1, 2, and 3 groups was 44.9%, 36.7%, and 28.4% (P = 0.001), respectively. NPS showed better predictive ability for OS and PFS compared to other indicators. Multivariate regression analysis identified NPS as an independent prognostic factor for OS (P < 0.001) and PFS (P < 0.001). A predictive nomogram based on NPS was established and validated. The C-indices of the nomogram in the training set were 0.722 for OS and 0.683 for PFS, while in the validation set the C-indices were 0.731 for OS and 0.693 for PFS. This study confirmed that preoperative NPS could serve as a useful independent prognostic factor in LACC patients treated with CCRT
Screening and validating genes associated with cuproptosis in systemic lupus erythematosus by expression profiling combined with machine learning
Get PDFCell death has long been a focal point in life sciences research, and recently, scientists have discovered a novel form of cell death induced by copper, termed cuproptosis. This paper aimed to identify genes associated with cuproptosis in systemic lupus erythematosus (SLE) through machine learning, combined with single-cell RNA sequencing (scRNA-seq), to screen and validate related genes. The analytical results were then experimentally verified. Two published microarray gene expression datasets (GSE65391 and GSE61635) from SLE and control peripheral blood samples were downloaded from the GEO database. The GSE65391 dataset was used as the training group, while the GSE61635 dataset served as the validation group. Differentially expressed genes from GSE65391 identified 12 differential genes. Nine diagnostic genes, considered potential biomarkers, were selected using the least absolute shrinkage and selection operator and support vector machine recursive feature elimination analysis. The receiver operating characteristic (ROC) curves for both the training and validation groups were used to calculate the area under the curve to assess discriminatory properties. CIBERSORT was used to assess the relationship between these diagnostic genes and a reference set of infiltrating immune cells. scRNA-seq data (GSE162577) from SLE patients were also obtained from the GEO database and analyzed. Experimental validation of the most important SLE biomarkers was performed. Twelve significantly different cuproptosis-related genes were identified in the GSE65391 training set. Immune cell analysis revealed 12 immune cell types and identified nine signature genes, including PDHB, glutaminase (GLS), DLAT, LIAS, MTF1, DLST, DLD, LIPT1, and FDX1. In the GSE61635 validation set, seven genes were weakly expressed, and two genes were strongly expressed in the treatment group. According to the ROC curves, PDHB and GLS demonstrated significant diagnostic value. Additionally, correlation analysis was conducted on the nine characteristic genes in relation to immune infiltration. The distribution of key genes in immune cells was determined using scRNA-seq data. Finally, the mRNA expression of the nine diagnostic genes was validated using qPCR
Efficacy and mechanisms of curcumin in the treatment of osteoarthritis: A scoping review
Get PDFOsteoarthritis (OA) is a degenerative joint disease that primarily affects the elderly worldwide. It is characterized by local inflammation, which can be targeted therapeutically using natural anti-inflammatory compounds such as curcumin. This scoping review explores the therapeutic effects and mechanisms of curcumin in OA management. A total of 50 relevant original studies published in English were selected from PubMed, Web of Science, and Scopus using specific search strings, regardless of study type. These studies demonstrated curcumin’s anti-inflammatory, protective, and anti-apoptotic effects on chondrocytes. Curcumin has been shown to stimulate chondrocyte proliferation and collagen production while inhibiting matrix metalloproteinase activity. These mechanisms contribute to curcumin\u27s ability to alleviate pain and improve joint function in OA patients. While the findings highlight curcumin’s potential in OA management, further research is needed to enhance its bioavailability and determine optimal formulations, dosages, and administration routes
Molecular characterization and genotype of multi-drug resistant Staphylococcus epidermidis in nasal carriage of young population, Mahasarakham, Thailand
Get PDFStaphylococcus epidermidis, a coagulase-negative staphylococcus, is a prevalent skin commensal that has increasingly been recognized as a significant pathogen, particularly in hospital environments, where it is associated with device-related infections. The emergence of multi-drug resistance and its ability to form biofilms complicate the clinical management of infections caused by this organism, posing a growing public health concern. This study aimed to investigate the nasal carriage of S. epidermidis among healthy young individuals and to analyze its antibiotic resistance patterns, resistance genes, and biofilm formation capabilities. Nasal swabs were collected from 40 undergraduate students at Mahasarakham University, Thailand, aged between 20 and 22 years. A total of 38 isolates were confirmed as S. epidermidis through both phenotypic and molecular characterization. Antibiotic susceptibility testing demonstrated resistance to various classes of antimicrobials, including beta-lactams, macrolides, and tetracyclines. Notably, five isolates exhibited methicillin resistance S. epidermidis (MRSE). Resistance genes, such as mecA, ermA, tetM, tetL, and tetK, were identified across the isolates, contributing to the observed resistance profiles. Biofilm formation assays revealed that most isolates displayed weak to moderate biofilm formation, with only one isolate demonstrating strong biofilm-forming capacity. Genetic analysis indicated a significant correlation between biofilm formation and the presence of the icaA gene, which is crucial for biofilm production. This study suggests the necessity for ongoing surveillance of nasal carriage of S. epidermidis to enhance understanding of its role in the dissemination of antimicrobial resistance and biofilm-associated infections, particularly within healthcare settings
Role of MMP-2, MMP-9, TIMP-1, and TIMP-2 in children with ventricular septal defect
Get PDFVentricular septal defect (VSD) is the second most common congenital heart anomaly. In most cases, it closes spontaneously in the first year of life, but it sometimes requires surgical closure due to the risk of serious complications. This is why it is important to identify markers that could help predict its course. Findings that matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play an important role in the cleavage of the extracellular matrix were the reasons to investigate their role in cardiogenesis. In prior studies on this topic, their concentrations were studied in the blood. The aim of this prospective study was to investigate the role of MMP-2, MMP-9, TIMP-1, and TIMP-2 in the etiology and pathophysiology of VSD using urine samples, as an innovative non-invasive approach, and the enzyme-linked immunosorbent assay (ELISA) method. It involved 52 children with isolated VSD and 20 healthy children up to one year of age. We found that these MMPs and TIMPs are significantly (P = 0.000) higher in children with VSD, and the correlations between their concentrations and the size of the defect are positive, especially for MMP-9 and TIMP-1. MMP-9 was significantly (P = 0.044) higher in cases in which VSD did not close in the first year of life compared to cases in which it closed. Our results suggest the role of MMP-2, MMP-9, TIMP-1, and TIMP-2 in the aetiopathogenesis of VSD and that their urinary concentrations, especially of MMP-9, in combination with echocardiographic and clinical monitoring, could be useful in predicting its natural course
Mitochondrial dysfunction in myasthenia gravis: Exploring directions for future immunotherapy? A review
Get PDFMyasthenia gravis (MG) is an acquired autoimmune disease characterized by impaired transmission at the neuromuscular junction, primarily manifesting as fluctuating muscle weakness, fatigability, and partial paralysis. Due to its long disease course, treatment resistance, and frequent relapses, it places a significant burden on patients and their families. In recent years, advances in molecular biology have provided growing evidence that mitochondrial dysfunction impairs muscle function and affects immune cell proliferation and differentiation in patients. Mitochondria, as the cell\u27s energy source, play a critical role in various pathological processes in MG, including oxidative stress, dynamic abnormalities, mitophagy, and mitochondrial metabolism. The role of mitochondrial dysfunction in the pathogenesis of MG has garnered increasing attention. This manuscript primarily explores mitochondrial function and abnormal morphological changes in MG, as well as mitochondrial quality control, metabolic reprogramming, and their potential mechanisms in the pathological changes of the disease. It also reviews the current status of drug therapies aimed at improving mitochondrial function. The goal is to provide novel perspectives and strategies for future mitochondrial-targeted therapies in MG
The mechanism research of itraconazole combined with aspirin in the treatment of vulvovaginal candidiasis through NF-κB signaling pathway
Get PDFVulvovaginal candidiasis (VVC) is a common fungal infection caused primarily by Candida albicans, characterized by inflammation and discomfort, often requiring effective therapeutic strategies to reduce fungal load and inflammation. This study aimed to explore the therapeutic effects and underlying mechanisms of combining aspirin (ASP) and itraconazole (ITR) in treating VVC through the activation of the NF-κB signaling pathway. Clinical isolates of C. albicans were selected, and the M27-A4 microbroth dilution method was used for in vitro drug sensitivity testing. A VVC model was established, and after three days of continuous administration, fungal load, inflammatory factors, and pathway protein expression were analyzed using Gram staining, plate counting, glycogen (PAS) staining, ELISA, and qPCR. The results of the in vitro drug sensitivity tests revealed that the MIC50 values of ASP and ITR were significantly reduced when the two drugs were combined. In animal experiments, the VVC model group exhibited a substantial vaginal fungal load compared to the blank control group. This was accompanied by elevated levels of inflammatory factors (IL-1β, IL-6, and TNF-α) in serum and vaginal lavage fluid, increased phosphorylation of p65 and IκBα, and upregulation of p65 and IκBα mRNA expression in vaginal tissue. Treatment with the ASP and ITR combination significantly reduced vaginal fungal load, decreased levels of IL-1β, IL-6, and TNF-α, and suppressed the phosphorylation of p65 and IκBα in serum and vaginal lavage fluid. Additionally, the mRNA expression of p65 and IκBα in vaginal tissue was downregulated. These findings suggest that the combination of ASP and ITR is effective in treating VVC. The therapeutic effect may be attributed to the inhibition of IL-1β, IL-6, and TNF-α production by downregulating NF-κB signaling pathway proteins