Biomedicines最新文献

Neutrophils are very important cells of the immune system, and every year, new nuances of their functional activity in the body and participation in various pathological processes are discovered [...].

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) are a hallmark of MS and reflect intrathecal IgG synthesis and inflammation. This study aims to analyze the temporal distribution of IgG OCBs in the CSF of patients with a definitive diagnosis of MS. Methods: This retrospective study included 500 patients with diagnosed MS. Patients were divided into four groups according to diagnostic epochs: Group 1 (Pre-2001 or Pre-McDonald), Group 2 (2001-2010 or McDonald 2001-Polman 2010), Group 3 (2010-2018 or Polman 2010), and Group 4 (Post-2018 or Thompson 2017). Statistical analyses examined temporal and sex differences in OCB positivity rates. Results: OCB positivity was lower in Group 4 (69.2%) compared to Group 1 (85.4%) in the overall population (p = 0.0022). A decrease in OCB positivity was observed in Groups 3 (62.5%) and 4 (71.8%) compared to Group 1 (92.5%) among males (p = 0.0117 and p = 0.0198, respectively) and in Group 4 (68.1%) compared to Group 1 (82.5%) among females (p = 0.0274). Conclusions: The present study provides valuable insights into temporal trends in CSF positivity among patients diagnosed with MS. There was an overall decrease in OCB positivity rates over the years, particularly in the post-2018 period.

Background/Objectives: Beneficial effects of neurosteroid dehydroepiandrosterone sulphate (DHEAS) on cognition, emotions and behavior have been previously reported, suggesting its potential in the prevention and treatment of various neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease (AD). This study aimed to investigate the potential neuroprotective actions of DHEAS against Aβ toxicity in both cellular and animal models of AD. Methods: After optimizing the AD model in vitro, we investigated the DHEAS effects on the viability and death of primary mouse neurons exposed to toxic Aβ₄₂ oligomers for 24 h. In order to extend our research to an in vivo study, we further tested the acute effects of intraperitoneal DHEAS administration on the Aβ plaque density in different brain regions of 3xTg-AD mice, an animal model of AD. Results: In cell culture, DHEAS hampered the decrease in the neuronal viability caused by toxic Aβ oligomers, primarily by influencing mitochondrial function and apoptosis. DHEAS also counteracted the increase in the mRNA expression of selected genes (PI3K, Akt, Bcl2, Bax), induced in neuronal culture by treatment with Aβ₄₂ oligomers. Obtained data suggested the involvement of mitochondria, caspases 3 and 7, as well as the PI3K/Akt and Bcl2 signaling network in the antiapoptotic properties of DHEAS in neurons. Forty-eight hours after DHEAS treatment, a significantly lower number of Aβ plaques was observed in the motor cortex but not in other brain areas of 3xTg-AD mice. Conclusions: Results indicated potential neuroprotective effects of DHEAS against Aβ toxicity and accumulation, suggesting that DHEAS supplementation should be further studied as a novel option for AD prevention and/or treatment.

Background/Objectives: The PowerMag system (PM) is a platform for the isolation of circulating tumor cells (CTCs) by the depletion of CD45⁺-leukocytes. However, an EpCAM^-CD45^- cell population is present in large numbers in the cell filtrates collected by PM. This lowers the purity of the CTCs and negatively impacts their molecular characterization. The aims of this study are to characterize the cellular properties of the EpCAM^-CD45^- cells and to upgrade the system to improve CTC purity. Methods: A real-time RT-PCR assay, Liu's stain analysis, and Annexin V (AnxV) binding assay were used to define the cellular properties of the EpCAM^-CD45^- cells. An upgraded system was developed to remove the EpCAM^-CD45^- cells and improve the CTC purity. Clinical blood samples were used to evaluate the performance of the system. Results: The EpCAM^-CD45^- cells were defined as apoptotic cells, which displayed apoptotic body-like morphology and elicited AnxV binding activity. AnxV beads developed in-house can effectively bind and remove EpCAM^-CD45^- cells from the cell filtrates. An improved generation of a CTCs isolation platform, designated as PM II, was developed by integration of AnxV beads into the workflow to remove the apoptotic cells. PM II recovered CTCs with improved CTC purity by effective removal of the background apoptotic cells. The improved performance of PM II allowed for direct profiling of cancer-related gene mutations by next-generation sequencing without cell picking and further purification. Conclusions: PM II holds great promise as a platform for isolating CTCs with improved purity and for exploring its application in cancer diagnosis and monitoring in a clinical setting.

Objectives: We conducted a retrospective study to investigate the effectiveness of angiotensin receptor blockers (ARBs) in preventing moderate-to-severe cerebral vasospasm, which may influence patient outcomes in cases of subarachnoid hemorrhage resulting from aneurysmal rupture. Methods: Between 2016 and 2020, we treated 210 patients with aneurysmal subarachnoid hemorrhage (aSAH) caused by a ruptured cerebral aneurysm. We obtained the clinical and radiological characteristics of patients through medical records and divided them into two groups: those who were administered ARBs (ARB group) and those who were not (no-ARB group). Results: A total of 181 patients aged 19 years or older with aSAH, without vascular abnormalities (including vascular malformations and moyamoya disease), were enrolled in this study. The age of the enrolled patients was 59.01 ± 12.98 (mean ± standard deviation), and the sex ratio of males to females was 66:115, with a higher proportion of females. The ARB group had 29 and the no-ARB group had 152 participants. The overall incidence of moderate-to-severe vasospasm was 33.7%. The incidence of moderate-to-severe vasospasm in each group was 13.8% (4 patients) and 37.5% (57 patients), respectively. The Fisher grade (III-IV) [odds ratio (OR) of 2.732 (95% confidence interval [CI]: 1.343-5.560; p = 0.006)] independently increases the risk of moderate-to-severe vasospasm, while older age [OR = 0.963; 95% CI: 0.938-0.989; p = 0.006] and ARB administration [OR = 0.246; 95% CI: 0.079-0.771; p = 0.016] independently decrease this risk. Conclusions: Despite the potential adverse impacts associated with hypotension, the administration of ARBs may provide therapeutic benefits in preventing moderate-to-severe vasospasm. A multicenter randomized double-blind controlled trial is needed to further investigate the efficacy and safety of ARBs in preventing moderate-to-severe vasospasm in aSAH patients who have undergone interventions and are experiencing acute hypertension.

Objective: To evaluate the differences in overall survival (OS) and progression-free survival (PFS) between men and women with non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) in second-line and later treatments. Methods: A retrospective, single-center observational study was conducted on patients with advanced NSCLC treated with ICIs (nivolumab, pembrolizumab, and atezolizumab) from January 2015 to December 2019 (with follow-up until December 2021). Demographic, clinical, and treatment-related variables were collected. OSand PFSwere analyzed using the Kaplan-Meier method and compared between genders using the log-rank test.A multivariate Cox regression analysis was performed to adjust for confounders. Results: A total of 189 patients were included, and 47 (25%) were women. The most common histology was adenocarcinoma (61%). Women began treatment at a younger age (59.8 vs. 66 years, p < 0.001) and had higher rates of active smoking (46.8% vs. 38%, p = 0.001). The median OS was similar between men (9.5 months, 95% CI: 7.1-11.8) and women (9.2 months, 95% CI: 3.3-15.2; p = 0.382) while PFS was significantly higher in males (3.2 months, 95% CI: 2.5-4.0) than in females (2.1 months; 95% CI = 1.6-2.5) (p = 0.002).Women had higher rates of tumor cachexia (BMI < 20).Worse PFS was observed for women both in the <20 kg/m² (median PFS: 1.8 vs. 2.7 months, p = 0.016) and 20-24.9 kg/m² groups (median PFS: 2.2 vs. 3.3 months, p = 0.077), while in patients with a BMI >= 25 kg/m², median OS was higher in women than in men (14.7 months vs. 10.1 months). Women had also a significantly worse PFS than men among those with a cumulative tobacco consumption of <30 packs-year (median PFS: 2.2 vs. 3.2, p = 0.038. In the multivariate analysis, the male sex was significantly associated with a better PFS(HR = 0.59; p = 0.009), without significant differences between sexes in OS (HR = 0.90; p = 0.618). Among the other variables analyzed, only an ECOG >= 2 was significantly associated with both worse OS (HR = 3.53; 95% CI = 1.93-6.47) and PFS (HR = 2.19; 95% CI = 1.23-3.89). Women who discontinued due to toxicity (n = 7) had a median OS of 41.4 months (95% CI: 14.7-68.1) after discontinuation, whereas men (n = 15) had a median OS of 8.8 months (95% CI: 6.9-10.8), (p = 0.045). Conclusions: Sex-based differences were observed in the ICI outcomes. Women had worse PFS, particularly with lower BMI and lower tobacco exposure, despite similar OS between sexes. Women discontinued ICIs due to toxicity earlier but showed longer OS after discontinuation. Poor ECOG status was linked to worse outcomes across all the patients.

Background: This study investigates the impact of fermentation supernatants (FSs) from Pleurotus eryngii whole mushrooms (PEWS), as well as its subcomponents, digested (PEWSD) and extracted (PEWSE) forms, on intestinal barrier function and immune modulation in lipopolysaccharide (LPS) -stimulated Caco-2 cells. Methods: Gene expression of tight junction (TJs) genes, cytokines, and key immune/metabolic receptors was assessed via qRT-PCR, while cytokine protein levels were measured using ELISA to explore post-transcriptional regulation. Results: LPS challenge significantly downregulated TJs zonula occludens-1 (ZO-1,) occludin, and claudin-1, compromising epithelial integrity. Treatment with FS-PEWS notably restored ZO-1 and occludin expression, outperforming FS-PEWSD and FS-PEWSE, which only partially mitigated the LPS-induced damage. FS-PEWS further demonstrated potent immunomodulatory effects, upregulating anti-inflammatory IL-10 and pro-inflammatory cytokines such as IL-8 and TNF-α. The activation of key receptors like TLR-2 and mTOR suggests that FS-PEWS modulates critical immune and metabolic pathways, such as NF-kB signaling, to maintain immune homeostasis. Although mRNA expression of pro-inflammatory cytokines was altered, no corresponding protein release was detected, suggesting potential post-transcriptional regulation. Conclusions: FS-PEWS preserves intestinal barrier integrity and modulates immune responses, particularly in low-grade inflammation, highlighting the whole food matrix's role in enhancing its bioactivity and functional food potential.

Background: Ovarian cancer (OC) is the third most common and second most lethal onco-gynecological disease in the world, with high-grade serous ovarian cancer (HGSOC) making up the majority of OC cases worldwide. The current serological biomarkers used for OC diagnosis are lacking sensitivity and specificity, thus new biomarkers are greatly needed. Recently, the chromatin remodeling complex gene ARID1A, Notch and Wnt pathway gene expression, as well as HOX-related gene promoter methylation have been linked with promoting OC. Methods: In this pilot study, 10 gene expression biomarkers and 4 promoter methylation biomarkers were examined as potential diagnostic and prognostic indicators of OC in 65 fresh-frozen gynecologic tumor tissues. Results: Out of 10 genes analyzed, the expression of eight biomarkers was significantly reduced in OC cases compared to benign, and HOX-related gene promoter methylation significantly increased in OC tumors. Out of 14 biomarkers, CTNNB1 showed the best single biomarker separation of HGSOC from benign cases (AUC = 0.97), while a combination of the seven Notch pathway-related gene expressions (NOTCH1, NOTCH2, NOTCH3, NOTCH4, DLL1, JAG2, and HES1) demonstrated the best separation of HGSOC from the benign cases (AUC = 1). Conclusions: The combination of multiple gene expression or gene promoter methylation biomarkers shows great promise for the development of an effective biomarker-based diagnostic approach for OC.

Background/Objectives: Type 2 diabetes mellitus (T2DM) and its macro- and microvascular complications are major health concerns with multiple factors, like advanced end glycation products (AGEs), in the background. AGEs induce long-lasting functional modification of the proteins and collagen in the vascular wall and nerve tissue. We investigated the effect of alpha-lipoic acid (ALA) treatment on AGEs, soluble AGE receptor (sRAGE), the AGE/sRAGE ratio, and the parameters of endothelial dysfunction and their correlations. Methods: In our 6-month intervention study, 54 T2DM patients with neuropathy treated according to the actual therapeutic guidelines with unchanged oral antidiabetic drugs were included and treated by daily oral administration of 600 mg ALA. A total of 24 gender and age-matched T2DM patients without neuropathy served as controls. Results: In our work, we first demonstrated the attenuating effect of alpha lipoic acid therapy on AGEs in humans (11.89 (9.44-12.88) to 10.95 (9.81-12.82) AU/μg (p = 0.017)). sRAGE levels or the AGEs/sRAGE ratio were not affected by ALA treatment or by the presence of neuropathy. We found a correlation between the changes of AGEs and the improvement of current perception threshold and progranulin levels, and an inverse correlation with the change of asymmetric dimethylarginine. Conclusions: According to our results, ALA decreases AGEs, which may contribute to the clinically well-known beneficial effect in diabetic neuropathy and improvement of endothelial function.

Background and Objectives: Orofacial pain corresponds to pain sensitization originating from the facial and oral regions, often accompanied by diagnostic complexity due to a multitude of contributory factors, leading to significant patient distress and impairment. Here, we have reviewed current mechanistic pathways and biochemical aspects of complex orofacial pain pathology, highlighting recent advancements in understanding its multifactorial regulation and signaling and thus providing a holistic approach to challenging it. Materials and Methods: Studies were identified from an online search of the PubMed database without any search time range. Results: We have discussed neuron-glia interactions and glial cell activation in terms of immunomodulatory effects, metabolism reprogramming effects and epigenetic modulatory effects, in response to orofacial pain sensitization comprising different originating factors. We have highlighted the fundamental role of oxidative stress affecting significant cellular pathways as well as cellular machinery, which renders pain pathology intricate and multidimensional. Emerging research on the epigenetic modulation of pain regulatory genes in response to molecular and cellular environmental factors is also discussed, alongside updates on novel diagnostic and treatment approaches. Conclusions: This review deliberates the integrative perspectives and implications of modulation in the immune system, glucose metabolism, lipid metabolism and redox homeostasis accompanied by mitochondrial dysfunction as well as epigenetic regulation accommodating the effect of dysregulated non-coding RNAs for an interdisciplinary understanding of pain pathology at the molecular level, aiming to improve patient outcomes with precise diagnosis offering improved pain management and treatment.