Bosnian Journal of Basic Medical Sciences (BJBMS)
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Jianpi Yiqi Busui prescription alleviates myasthenia gravis by regulating Th17 through the TAK1/P38 MAPK/eIF-4E signaling pathway
Get PDFJianpi Yiqi Busui Prescription (JYBP), a traditional Chinese medicine formula (TCM), is used in the treatment of myasthenia gravis (MG). However, its mechanisms of action still require further clarification. In this study, an experimental autoimmune MG (EAMG) rat model was established for research. Changes in body weight, forelimb grip strength, Lennon clinical score, and antifatigue ability of EAMG model rats were recorded to evaluate the effectiveness of JYBP. Flow cytometry was utilized to count Th17, Th1, Th2, and Treg cells in lymphocytes. ELISA and RT-qPCR were used to measure acetylcholine receptor antibody (AChR-Ab) and Th17-related cytokines, including IL-17, IL-21, IL-23, TNF-α, TGF-β, IL-1β, and IL-6. Western blot and immunofluorescence staining were used to detect the expression levels of key proteins and their phosphorylated forms, such as transforming growth factor beta-activated kinase 1 (TAK1), P38 mitogen-activated protein kinase (P38 MAPK), and eukaryotic initiation factor 4E (eIF-4E). The results indicate that JYBP can increase the body weight of EAMG model rats, improve grip strength and antifatigue ability, and reduce the Lennon clinical score and AChR-Ab concentration. Mechanistic studies indicate that JYBP can inhibit the differentiation of CD4+ T cells into Th17 and Th1, promote their differentiation into Th2 and Treg, and regulate the expression of Th17-related cytokines. Further research shows that JYBP can reduce the expression of related proteins in the TAK1/P38 MAPK/eIF-4E signaling pathway. In conclusion, JYBP can alleviate the condition of EAMG model rats, positively affecting MG treatment. The inhibitory effect of JYBP on the differentiation of CD4+ T cells into Th17 may be related to the TAK1/P38 MAPK/eIF-4E signaling pathway
Prediction of post-insertion infections related to totally implantable subcutaneous venous access ports in tumor patients using a nomogram
Get PDFTotally implantable subcutaneous venous access ports (TISVAPs) are essential for long-term central venous chemotherapy, delivering medication directly into the central veins of patients. While they play a critical role in reducing patient discomfort, TISVAPs pose a notable risk of post-insertion infections—particularly concerning for oncology patients with compromised immune systems due to aggressive treatment regimens. Our research addresses this issue by developing a predictive nomogram to estimate the risk of TISVAP-associated infections. The model is based on independent risk factors identified in our study: a history of diabetes, the type of chemotherapy, peripheral blood leukocyte count (WBC), and serum albumin levels. Using retrospective clinical data from 309 oncology patients who underwent TISVAP implantation at a tertiary A-grade comprehensive hospital, we divided the dataset into training (n = 246) and validation (n = 63) subsets. Through logistic and Lasso regression analyses, we identified the independent risk factors associated with infections. The resulting interactive nomogram demonstrated strong accuracy and reliability, with C-indexes of 0.82 and 0.835 for the training and validation sets, respectively. This tool equips healthcare providers to proactively identify high-risk patients and tailor preventive strategies accordingly. Ultimately, our research aims to enhance patient outcomes and improve the quality of life for those undergoing long-term venous chemotherapy
Glioblastoma induces CAF-like astrocyte activation via the AKT/mTOR–SERPINH1/COL5A1 axis
Get PDFGlioblastoma multiforme (GBM), the most aggressive form of glioma, remains the most malignant tumor of the central nervous system. Despite a range of therapeutic strategies, the prognosis for GBM patients remains poor, underscoring the urgent need for novel treatments to inhibit GBM progression. The tumor microenvironment (TME) plays a critical role in tumor development, with cancer-associated fibroblasts (CAFs) acting as key components. However, the origin, composition, and spatial distribution of CAFs within the GBM microenvironment remain poorly understood. To address this gap, our research aims to investigate the etiology, cellular composition, and precise localization of CAFs in GBM, with the goal of elucidating their role in oncogenesis and tumor progression, thereby providing new avenues for therapeutic intervention. In this study, we developed a novel CAF-related prognostic model using data from the TCGA and GEO databases and identified SERPINH1 and COL5A1 as CAF-related genes in GBM. We established a GBM mouse model as well as a GBM cell and astrocyte co-culture system to examine the expression of SERPINH1 and COL5A1 in astrocytes under a simulated tumor microenvironment. Our findings revealed that these genes were more highly expressed in peritumoral tissue compared to normal brain tissue and showed strong co-localization with astrocytes. Furthermore, we found that normal astrocytes can be induced by GBM cells to activate the AKT/mTOR signaling pathway, migrate to the peritumoral region, and upregulate CAF-associated proteins (SERPINH1/COL5A1). These results suggest that astrocytes may serve as a potential source of CAF precursor cells within the GBM tumor microenvironment
ERBB4 as a therapeutic target in aortic dissection: Implications for cell-based therapies in vascular regeneration
Get PDFThis study investigates the role of Erb-B2 receptor tyrosine kinase 4 (ERBB4) in aortic dissection (AD) pathogenesis and its potential as a therapeutic target in cell-based therapies. Using immunohistochemical (IHC) staining, we examined the phenotypic transition of vascular smooth muscle cells (VSMCs) in thoracic aortic tissue from AD patients. RNA sequencing identified differentially expressed genes (DEGs), highlighting ERBB4 as a key regulator. In vitro, ERBB4 knockdown in human aortic smooth muscle cells (HASMCs) was assessed using cell counting kit-8 (CCK-8 assays), wound healing, transwell migration, colony formation, flow cytometry, and tube formation assays. Our results showed significant inhibition of cell viability, migration, proliferation, and angiogenesis. In vivo, ERBB4 knockdown reduced inflammatory cell infiltration and enhanced collagen fiber contractility, as demonstrated by Masson staining. Mechanistically, ERBB4 silencing suppressed integrin-binding proteins (CD151, ITGAE, ITGB5) and inhibited NF-κB signaling (p-IκBα, p-NF-κB-65). These findings suggest that ERBB4 is critical in AD progression and that its knockdown mitigates pathological changes in HASMCs, reduces inflammation, and restores collagen contractility. ERBB4 may serve as a promising target for cell-based therapies aimed at restoring vascular integrity and function, providing potential new treatment strategies for AD patients
SOX-9 as a prognostic marker in gastric adenocarcinoma
Get PDFSRY-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
Role of Fascin-1 in cervical cancer metastasis via Wnt/β-catenin pathway activation
Get PDFThis investigation delves into the impact of Fascin-1, a protein known for its role in actin bundling and its association with metastatic enhancement, on the advancement of cervical cancer (CC). Elevated levels of Fascin-1 have been observed in metastatic carcinomas, but its impact on gene regulation in CC has not been thoroughly studied. Our research demonstrates a marked elevation in the expression of Fascin-1 within tissues affected by CC. Experiments employing both overexpression and knockdown methods revealed that Fascin-1 plays a critical role in promoting the proliferation and mobility of CC cells in vitro. Correspondingly, reducing Fascin-1 levels led to a marked decrease in tumor growth and metastatic spread in vivo. At the molecular level, diminishing Fascin-1 expression resulted in decreased β-catenin and C-myc RNA and protein levels. This implies that Fascin-1 could intensify the progression of CC by influencing the Wnt/β-catenin signaling cascade. This study not only elucidates the mechanism by which Fascin-1 contributes to the advancement of CC but also proposes a novel approach for therapeutic intervention
Serum ferritin as a prognostic biomarker in CAR-T therapy for multiple myeloma: A meta-analysis
Get PDFSerum ferritin, a marker of systemic inflammation and iron metabolism, has been implicated in the outcomes of patients with relapsed/refractory multiple myeloma (R/R MM). However, its prognostic significance in R/R MM patients undergoing chimeric antigen receptor-modified T-cell (CAR-T) therapy remains unclear. This meta-analysis aimed to evaluate the association between pre-infusion serum ferritin levels and survival outcomes in R/R MM patients treated with CAR-T therapy. We systematically searched PubMed, Embase, and Web of Science for relevant studies. Studies reporting progression-free survival (PFS) and/or overall survival (OS) based on serum ferritin levels were included. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. Eight retrospective cohort studies, encompassing 1077 patients, met the inclusion criteria. High pre-infusion serum ferritin levels were significantly associated with worse PFS (HR: 2.15, 95% CI: 1.74–2.66, P < 0.001) and OS (HR: 2.86, 95% CI: 2.20–3.72, P < 0.001), with mild heterogeneity (I² = 9% for PFS and 0% for OS). Sensitivity analyses, conducted by excluding one study at a time, confirmed the robustness of these findings. Subgroup analyses showed consistent results across different CAR-T product sources (commercial vs academic), ferritin cutoffs, and follow-up durations (P for subgroup differences all >0.05). In conclusion, elevated serum ferritin levels before CAR-T infusion predict poorer survival outcomes in R/R MM patients. These findings highlight the potential prognostic value of ferritin and its role in optimizing patient selection and management strategies in CAR-T therapy
TUDCA combined with Syndopa protects the midbrain and gut from MPTP toxicity in a Parkinson’s disease mouse model: Immunohistochemical evidence
Get PDFNeuro-inflammation plays a significant role in the neurodegenerative processes associated with Parkinson\u27s disease (PD). A hallmark of PD is the degeneration of dopaminergic neurons within the nigrostriatal pathway. The standard treatment for PD is Syndopa (a combination of levodopa and carbidopa). However, while Syndopa alleviates symptoms, it is also associated with numerous side effects in patients. Research has demonstrated the protective effects of Tauroursodeoxycholic acid (TUDCA) in mitigating the neuropathological consequences of PD in several preclinical studies. Nonetheless, further investigation is necessary to delineate the role of TUDCA in PD therapeutics. Although the efficacy of TUDCA monotherapy in PD has been explored, there is a lack of preclinical research examining the additive effects of TUDCA in conjunction with Syndopa therapy. In this study, we utilized an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of PD to evaluate the potential therapeutic benefits of TUDCA monotherapy and the combined effects of TUDCA and Syndopa therapy, compared to standard Syndopa treatment. We conducted immunohistochemical (IHC) assessments of α-synuclein expression in the gut and substantia nigra pars compacta (SNpc), as well as tyrosine hydroxylase and NF-kB expression in the striatum and SNpc regions, to investigate the efficacy of the test drugs. The immunohistochemical findings indicate that both TUDCA monotherapy and the combination therapy of TUDCA and Syndopa significantly reduced MPTP-induced alterations in the expression levels of α-synuclein, tyrosine hydroxylase, and NFκB in the striatum and SNpc regions. Additionally, the MPTP-induced changes in α-synuclein expression in the gut were notably reversed by these treatments. Collectively, these results suggest that incorporating TUDCA with Syndopa may represent a promising therapeutic strategy to address the pathophysiological challenges associated with PD
Is SARS-CoV-2 facing constraints in its adaptive evolution?
Get PDFThe ultimate measure of viral fitness is the ability to maintain high prevalence within its host species. Effective transmission, efficient replication, and rapid immune evasion all contribute to this outcome. Over the past five years, SARS-CoV-2 has successfully adapted to humans, establishing long-term reservoirs and enabling sustained coexistence with the human population. We have observed innovative, synergistic mutations in the spike (S) protein that enhance receptor binding. Adaptation to the upper respiratory tract has shortened the incubation period, thereby facilitating viral spread. These improvements have also enabled immune escape mutations, even when such changes compromise replicative fitness. Adaptive mutations have driven intermittent selective sweeps by dominant variants. However, there are limits to functional enhancement. The receptor binding affinity of the S protein appears to have peaked between 2022 and 2023. The accumulation of fixed mutations plateaued following the emergence of BA.2.86/JN.1 around late 2023 and early 2024. Purifying selection has been the dominant evolutionary force acting on nonsynonymous mutations in the Omicron lineage, and the overall fitness impact of missense mutations in key viral proteins has declined. Additionally, due to weak selection pressure on synonymous mutations, the codon adaptation index in humans has been decreasing among Omicron subvariants. As a result, Omicron lineages have replicated less efficiently in cell cultures compared to the original virus, and recent variants show further attenuation in animal models. In the human population, this attenuation is reflected in declining COVID-19-related mortality, despite persistently high infection rates
Prognostic impact of pan-immune inflammation value in small-cell lung cancer treated with chemoradiotherapy and prophylactic cranial irradiation
Get PDFDetermining prognosis is crucial for treatment selection, especially for prophylactic cranial irradiation (PCI), in patients with limited-stage small cell lung cancer (LS-SCLC). This study evaluates the prognostic value of the pan-immune inflammation value (PIV) in patients with LS-SCLC. We included patients who underwent thoracic chemoradiotherapy (TRT) and PCI at our clinic between July 2012 and April 2024. PIV was calculated as (neutrophil count × platelet count × monocyte count) / lymphocyte count. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal pre-treatment PIV cut-off to divide patients into two groups. Survival outcomes between these groups were compared using Kaplan-Meier analysis and log-rank tests. Multivariate analyses were conducted using Cox regression. Fifty-nine patients were included in the study. The optimal PIV cut-off was identified as 911 (AUC: 0.60, Sensitivity: 0.31, Specificity: 0.94, J-index: 0.26). Patients were grouped based on PIV levels: low (<911) and high (≥911). Lower PIV levels were significantly associated with improved overall survival (OS) (39 months vs. 10 months, p < 0.001) and intracranial progression-free survival (ICPFS) (not reached vs. 15 months, p < 0.001). The independent prognostic value of PIV was confirmed in multivariate analyses for both OS (p < 0.001) and ICPFS (p < 0.001). These findings suggest that pre-treatment PIV is an independent prognostic marker in LS-SCLC patients undergoing TRT and PCI.