Bosnian Journal of Basic Medical Sciences (BJBMS)
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Roxadustat: Do we know all the answers?
Get PDFAnemia is a common complication of chronic kidney disease (CKD), and its prevalence rises as the disease progresses. Intravenous or subcutaneous erythropoiesis-stimulating agents (ESAs) are advised to treat CKD-associated anemia, since shortage of erythropoietin (EPO) and iron are the main cause of anemia. However, ESA resistance and safety have spurred a lot of interest in the development of alternate anemia therapies. Roxadustat, an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that increases erythropoiesis and may modulate iron metabolism, was recently licensed in China, Chile, South Korea, Japan and the European Union for the treatment of CKD-related anemia. Despite this, clinical trials have shown a number of adverse effects, including cardiovascular disease, hyperkalemia, and infections. In addition, of concern is roxadustat\u27s possible effects on other organs and systems. In this review, based on clinical evidence, we discuss the potentially detrimental effects of roxadustat to the known biology on systems other than kidney, and the need for long-term follow-up in order for roxadustat to be approved in more countries in the future
Identification of new biomarkers and immune infiltration characteristics of sepsis in very low birth weight infants
Get PDFSepsis is a life-threatening condition, especially in very low birth weight (VLBW) infants, and its pathogenesis remains unclear. Effective biomarkers need to be found to diagnose and treat the disease at an early stage. The Gene Expression Omnibus (GEO) database was screened and analyzed for differentially expressed genes (DEGs) in VLBW infants with sepsis. DEGs were then analyzed for functional enrichment. A weighted gene co-expression network analysis (WCGNA) was performed to identify the key modules and genes. The optimal feature genes (OFGs) were created using three machine learning algorithms. The single-sample Gene Set Enrichment Analysis (ssGSEA) scored the degree of immune cell enrichment between septic and control patients, and the correlation between OFGs and immune cells was evaluated. A total of 101 DEGs were identified between the sepsis and control samples. DEGs were mainly associated with immune responses and inflammatory signaling pathways in the enrichment analysis. In the WGCNA analysis, the MEturquoise module was significantly correlated with sepsis in VLBW infants (cor = 0.57, P < 0.001). By intersecting OFGs derived from three machine learning algorithms, two biomarkers were identified: glycogenin 1 (GYG1) and resistin (RETN). The area under the curves of GYG1 and RETN was greater than 0.97 in the testing set. The ssGSEA indicated immune cells infiltration in septic VLBW infants, and GYG1 and RETN revealed close correlations with immune cells. New biomarkers offer promising insights into the diagnosis and treatment of sepsis in VLBW infants
Lipoprotein(a): Role in atherosclerosis and new treatment options
Get PDFAtherosclerosis is a chronic process characterized by inflammation and the progressive accumulation of inflammatory cells and lipids in the blood vessel wall, resulting in narrowing of the blood vessel’s circumference. Treatment of people with dyslipidemia aims to reduce the risk of developing atherosclerotic disease and prevent major adverse cardiovascular events (MACE). The results of previous studies indicated that lipoprotein(a) (Lp(a)) is a critical causal factor in the estimated risk of developing a cardiovascular (CV) incident even after achieving desirable low-density lipoprotein (LDL) cholesterol levels. Lp(a) is a low-density lipoprotein particle, like LDL cholesterol. The levels of Lp(a) in plasma are genetically determined. Lp(a) catabolism is still controversial. The pathogenic potential of Lp(a) can be divided into three categories: promotion of plaque formation, thrombogenicity, and proinflammatory effects. Lp(a) levels above the 75th percentile reduced the risk of aortic valve stenosis and myocardial infarction, whereas higher levels (above 90th percentile) were associated with an increased risk of heart failure. However, no hypolipidemic agents have been approved for targeted use in patients with high Lp(a) levels. There are insufficient randomized controlled trials assessing CV outcomes that would support the evidence that current treatment options, which effectively lower Lp(a) levels, also effectively prevent CV event. However, according to some studies, there is strong evidence that better CV outcome is one of the benefits of such therapy. The results of ongoing clinical trials are eagerly awaited
Mechanism of adipose tissue-derived stromal cell-extracellular vesicles in treating oral submucous fibrosis by blocking the TGF-β1/Smad3 pathway via the miR-760-3p/IGF1R axis
Get PDFOral submucous fibrosis (OSF) is a prevalent chronic condition, and understanding its pathogenesis is crucial for developing effective therapeutic strategies. This study explores the potential of adipose tissue-derived stromal cell-extracellular vesicles (ADSC-EVs) in mitigating OSF and investigates the underlying molecular mechanisms. OSF was induced in mice by arecoline feeding. Adipose tissue-derived stromal cells (ADSCs), fibrotic buccal mucosal fibroblasts (fBMFs) isolated from OSF mice, and ADSC-EVs were comprehensively characterized. The treatment effects of extracellular vesicles (EVs) and pcDNA3.1-IGF1R on fBMF proliferation, migration, and invasion were assessed using Cell Counting Kit-8 (CCK-8) assay, transwell assay, and flow cytometry assay. The expression levels of alpha-smooth muscle actin (α-SMA), collagen I, collagen III, and insulin-like growth factor 1 receptor (IGF1R) were evaluated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot. The interaction between miR-760-3p and IGF1R was investigated. In fBMFs and OSF mice treated with a miR-760-3p inhibitor and/or EVs, the expression patterns of miR-760-3p, IGF1R, and proteins related to the TGF-β1/Smad3 pathway were determined. ADSC-EVs demonstrated the ability to upregulate miR-760-3p, impede cell proliferation, migration, and invasion, and reduce α-SMA, collagen I, and collagen III levels in fBMFs. The expression of miR-760-3p was diminished in ADSC-EVs treated with a miR-760-3p inhibitor. However, silencing miR-760-3p or overexpressing IGF1R partially counteracted the beneficial effects of ADSC-EVs on fBMF fibrosis. miR-760-3p directly targets IGF1R. Significantly, ADSC-EVs exert their suppressive effects on the TGF-β1/Smad3 pathway through the miR-760-3p/IGF1R axis. In summary, ADSC-EVs, by transferring miR-760-3p and inhibiting IGF1R expression, effectively block the TGF-β1/Smad3 pathway, thereby alleviating fibrosis in fBMFs and preventing the progression of OSF
Evaluation of TyG index and TG/HDL-C ratio in HBeAg negative chronic hepatitis B infected patients
Get PDFPatients with hepatitis B e antigen (HBeAg) negative chronic HBV infection are regularly followed up. This study investigates the presence of insulin resistance and the relationship between hepatosteatosis and insulin resistance in patients with HBeAg negative chronic HBV infection using the TyG index and TG/HDL-C ratio. Patients with HBeAg negative chronic HBV infection who applied to the Infectious Diseases and Clinical Microbiology outpatient clinic between January 2019 and December 2020 were included in the study. Glucose, lipid panel, alanine amino transferase (ALT), acetyl amino transferase (AST), body mass index (BMI), TyG index, TG/HDL-C and hepatobiliary ultrasonography (USG) results were evaluated. The data were compared with the control group consisting of 308 HBsAg negative individuals. The study included 132 patients with a median age of 52 years. There was no significant difference between the patient and control groups regarding age, gender and BMI. Glucose, total cholesterol, TG, LDL, AST, ALT, TyG index and TG/HDL-C ratio were significantly higher in patient than in the control group. At the same time, the HDL value was significantly lower in the patients. There was a strong positive correlation between the TG and BMI, and a strong negative correlation between HDL levels and both TyG index and TG/HDL-C ratio. Our findings showed that the TyG index and TG/HDL-C ratio are helpful in the diagnosis of insulin resistance and hepatosteatosis in patients with HBeAg negative chronic HBV infection
Circulating cytokine profile and modulation of regulatory T cells in chronic hepatitis B patients with type 2 diabetes mellitus
Get PDFThe risk of hepatitis B virus (HBV) infection is higher in patients with diabetes mellitus, and diabetes mellitus is one of the metabolic complications of HBV infection. However, the cytokine profile of chronic hepatitis B (CHB) patients with type 2 diabetes mellitus (T2DM) is not fully understood. The aim of this study was to investigate the cytokine expression profile in CHB patients with T2DM, and to assess the regulatory function of cytokines to regulatory T cells (Tregs). Forty-four T2DM patients, 39 CHB patients, 17 patients with CHB and T2DM, and 21 control subjects were enrolled. Cytokine levels in the plasma were measured by Luminex multiplex assay. CD4+CD25+CD127dim/- Tregs were detected by flow cytometry. Tregs were purified and stimulated with recombinant human interleukin-15 (IL-15). The regulation of IL-15 on Tregs function was investigated by measuring cell number, IL-10/IL-35 secretion, and mRNA expression of immune checkpoint molecules in a Tregs+PBMC co-culture system. We found that levels of IL-1α, IL-6, and IL-33 were upregulated, while IFN-α, IL-2, IL-7, and IL-15 were downregulated in T2DM and CHB patients. CHB patients with T2DM had even lower plasma IL-7 and IL-15 levels. Tregs percentage was elevated in T2DM and CHB patients. CHB patients with T2DM had increased levels of Tregs, which correlated negatively with IL-15. Tregs showed stronger inhibitory activity in CHB patients with T2DM than in controls, T2DM, and CHB patients, which presented as reduction in cellular proliferation and induction of IL-10/IL-35 secretion. IL-15 suppressed Tregs function and inhibited the expression of immune checkpoint molecules in Tregs. The current data suggest that insufficient IL-15 levels and decreased responsiveness of Tregs to IL-15 signaling might contribute to strong immune dysfunction in CHB patients with T2DM
Cytotoxic T-lymphocyte-associated protein 4 +49A/G polymorphism in Down syndrome children with Hashimoto’s thyroiditis
Get PDFThyroid dysfunction is the most common endocrine disorder in Down syndrome (DS) children. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is one of the immune regulatory genes that correlates with Hashimoto’s thyroiditis (HT). However, studies on CTLA-4 +49A/G in DS children with HT are still limited. We aimed to evaluate CTLA-4 +49A/G gene polymorphism in DS children with HT. This case-control study, conducted from February 2020 to February 2022 at Dr. Soetomo General Hospital, Surabaya, enrolled 40 DS children with HT and 50 healthy children. The DNA sequencing was performed to identify the polymorphism (Sanger sequencing). Thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb), thyroid-stimulating hormone (TSH), and free thyroxine (FT4) levels were analyzed by enzyme-linked immunosorbent assay (ELISA). The mean age of DS children with HT was 1.78 years. Males predominated in the study population. Subjects with GG genotype were diagnosed earliest with hypothyroidism (8 months) compared with other studies. The most common thyroid dysfunction was central hypothyroidism, with TgAb positivity present in all patients. The AA genotype (odds ratio [OR] 0.265, 95% confidence interval [CI] 0.094–0.746; P = 0.012) and A allele (OR 0.472, 95% CI 0.309–0.721; P = 0.0002) were significantly more frequent in the control group. The AG genotype (OR 2.65, 95% CI 0.094–0.746; P = 0.003) and G allele (OR 2.116, 95% CI 1.386–3.23; P = 0.003) were more frequent in the DS with HT group. The age of the subjects in this study was younger than in previous studies. The AG genotype and the G allele were more prevalent in the DS with HT group and may be a risk factor in HT development in DS children. Furthermore, the AA genotype may act as a protective factor against HT in DS children
A prognostic nomogram for predicting overall survival in colorectal mucinous adenocarcinoma patients based on the SEER database
Get PDFA nomogram was constructed to predict the survival of patients with colorectal mucinous adenocarcinoma based on data extracted from the Surveillance, Epidemiology and End Result (SEER) database. Data collected between 2010 and 2018 were obtained from the SEER database. The log-rank test and multivariate Cox regression were performed to identify the independent prognostic factors for overall survival, which were further used to construct a nomogram model to predict 1-, 3-, and 5-year overall survival. In total, 10846 patients diagnosed with colorectal mucinous adenocarcinoma were enrolled in the study. The following 11 variables were associated with survival and were further incorporated into the nomogram: age at diagnosis, primary site, grade, tumour size, lymph node dissection, T stage, N stage, M stage, surgery for primary site, chemotherapy, and household income. The concordance index (C-index) value was 0.725 (95% confidence interval 0.716-0.734), and the receiver operating characteristic curves and calibration curves showed satisfactory predictive accuracy. Both the C-index and time-independent area under the curve values were greater than those of the American Joint Committee on Cancer 7th TNM classification system (both P < 0.001). In the validation group, the results were consistent with those of the training group, with a C-index value of 0.726 (95% confidence interval 0.713-0.739). This study constructed a practical nomogram to predict 1-, 3-, and 5-year OS for patients with colorectal colorectal mucinous adenocarcinoma based on SEER data
Sivelestat sodium attenuates acute lung injury by inhibiting JNK/NF-κB and activating Nrf2/HO-1 signaling pathways
Get PDFSivelestat sodium (SIV), a neutrophil elastase inhibitor, is mainly used for the clinical treatment of acute respiratory distress syndrome (ARDS) or acute lung injury (ALI). However, studies investigating the effects of SIV treatment of ALI are limited. Therefore, this study investigated the potential molecular mechanism of the protective effects of SIV against ALI. Human pulmonary microvascular endothelial cells (HPMECs) were stimulated with tumor necrosis factor α (TNF-α), and male Sprague-Dawley rats were intratracheally injected with Klebsiella pneumoniae (KP) and treated with SIV, ML385, and anisomycin (ANI) to mimic the pathogenetic process of ALI in vitro and in vivo, respectively. The levels of inflammatory cytokines and indicators of oxidative stress were assessed in vitro and in vivo. The wet/dry (W/D) ratio of lung tissues, histopathological changes, inflammatory cells levels in bronchoalveolar lavage fluid (BALF), and survival rates of rats were analyzed. The JNK/NF-κB (p65) and Nrf2/HO-1 levels in the HPMECs and lung tissues were analyzed by western blot and immunofluorescence analyses. Administration of SIV reduced the inflammatory factors levels, intracellular reactive oxygen species (ROS) production, and malondialdehyde (MDA) levels and increased the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in lung tissues. Meanwhile, SIV alleviated pathological injuries, decreased the W/D ratio, and inflammatory cell infiltration in lung tissue. In addition, SIV also inhibited the activation of JNK/NF-κB signaling pathway, promoted nuclear translocation of Nrf2, and upregulated the expression of heme oxygenase 1 (HO-1). However, ANI or ML385 significantly reversed these changes. SIV effectively attenuated the inflammatory response and oxidative stress. Its potential molecular mechanism was related to the JNK/NF-κB activation and Nrf2/HO-1 signaling pathway inhibition. This further deepened the understanding of the protective effects of SIV against ALI
Incorporating ultrasound-based lymph node staging significantly improves the performance of a clinical nomogram for predicting preoperative axillary lymph node metastasis in breast cancer
Get PDFModels for predicting axillary lymph node metastasis (ALNM) in breast cancer patients are lacking. We aimed to develop an efficient model to accurately predict ALNM. Three hundred fifty-five breast cancer patients were recruited and randomly divided into the training and validation sets. Univariate and multivariate logistic regressions were applied to identify predictors of ALNM. We developed nomograms based on these variables to predict ALNM. The performance of the nomograms was tested using the receiver operating characteristic curve and calibration curve, and a decision curve analysis was performed to assess the clinical utility of the prediction models. The nomograms that included clinical N stage (cN), pathological grade (pathGrade), and hemoglobin accurately predicted ALNM in the training and validation sets (area under the curve [AUC] 0.80 and 0.80, respectively). We then explored the importance of the cN and pathGradesignatures used in the integrated model and developed new nomograms by removing the two variables. The results suggested that the combine-pathGrade nomogram also accurately predicted ALNM in the training and validation sets (AUC 0.78 and 0.78, respectively), but the combine-cN nomogram did not (AUC 0.64 and 0.60, in training and validation sets, respectively). We described a cN-based ALNM prediction model in breast cancer patients, presenting a novel efficient clinical decision nomogram for predicting ALNM