Biology subjects

Erzurum, S.

Publications and source records attributed to Erzurum, S..

5 recordsLinked to original sources

bioRxiv2026

High-Dimensional Immunophenotyping Identifies Circulating Immune Signatures Associated with FeNO-Defined Asthma Phenotypes

Background: Asthma is a heterogeneous inflammatory airway disease traditionally classified into T2 high (eosinophilic) and T2 low inflammatory phenotypes. Fractional exhaled nitric oxide (FeNO) is commonly used as a biomarker of T2 inflammation, although nitric oxide also regulates monocyte maturation and T cell polarization. We hypothesized that FeNO identifies distinct systemic immune phenotypes in asthma. Methods: Peripheral immune cell subsets were characterized using OMIP - 69, a 40 - color high dimensional immunophenotyping panel encompassing innate and adaptive immune populations. Adults with asthma and healthy controls underwent peripheral blood immunophenotyping. FeNO was dichotomized at 25 ppb (FeNO - high [≥] 25 vs FeNO - low <25). Immune-cell subset proportions were summarized as medians (IQRs) and compared using the Wilcoxon rank-sum test. Logistic regression was used to evaluate associations between immune subsets and FeNO status. Results: Eighteen participants with asthma and seven healthy controls were enrolled. Asthmatic participants had higher BMI than healthy controls (median [IQR] asthma: 35.1 [28.9 - 37.7] vs healthy: 25.4 [22.6 - 26.7] kg/m2; p=0.003), although demographics were otherwise similar. Among asthmatics, 10 participants had FeNO - low asthma, and eight had FeNO - high asthma. FeNO - high asthma demonstrated increased classical monocytes (CD14++CD16 -) and compared with healthy controls (p=0.027), whereas FeNO - low asthma more closely resembled healthy controls. Intermediate monocytes (CD14++CD16+) were increased in FeNO - high versus FeNO - low (p= 0.08); a similar association was noted for classical monocytes (p = 0.13). In contrast, CCR7+ TCR; T - cells were significantly enriched in FeNO - low asthma (p=0.002). Logistic regression demonstrated positive associations between high - FeNO and classical monocytes (OR 16.06, 95% CI 1.56 - 1304.69; p=0.007) and intermediate monocytes (OR 4.19, 1.22 - 132.30; p=0.017), whereas CCR7+ {gamma} {delta} T - cells were negatively associated with high FeNO (OR 0.06, 0.00 - 0.47; p=0.001). Conclusions: Distinct systemic immune signatures identified by high-dimensional cytometry support the existence of biologically divergent FeNO - defined asthma endotypes and may inform future biomarker-driven approaches to patient stratification and precision therapy.

immunology↗

bioRxiv2026

Metabolomic Network Analysis Reveals Reorganization of Lipid and Steroid Programs Linked to Right Ventricular-Pulmonary Vascular Function in Pulmonary Hypertension

BackgroundPulmonary arterial hypertension (PAH) is characterized by circulating metabolic alterations, but whether these reflect disease-specific metabolic programs or reorganization of normal metabolic architecture, and how they relate to right ventricular-pulmonary vascular function (RV-PV), remains unclear. We hypothesized that the PAH metabolome is organized into biologically coherent, co-regulated metabolic modules whose relationships to RV-PV function would provide insight into known and novel metabolic pathways. MethodsWe applied weighted gene co-expression network analysis (WGCNA) to untargeted metabolomic data from 412 PAH patients enrolled in the multicenter PVDOMICS study. Module preservation analysis was performed in 85 healthy controls, with external replication in an independent single-center pulmonary hypertension cohort of 89 patients. ResultsWGCNA identified 16 distinct metabolic modules organized around biologically coherent programs. A coherent fatty acid axis, spanning substrate pools, {beta}-oxidation intermediates, and conjugated fatty acid disposal products, formed a central organizing structure, with downstream fatty acid oxidation modules strongly associated with adverse hemodynamics and worse RV-pulmonary artery (PA) coupling. Acylcholine-enriched and 5-reduced androgen metabolite modules were associated with favorable hemodynamic indices. Module architecture was largely preserved in healthy controls, with subtle disease-associated modular reorganization, rather than emergence of novel modules, observed in PAH. Core modules were recovered in the replication cohort with conserved hub metabolites. ConclusionsThese findings establish a systems-level framework demonstrating that PAH involves structured intensification and reorganization of interconnected metabolic programs associated with favorable and adverse RV-PV phenotypes. This work provides new insight into the metabolic architecture underlying PAH and identifies coordinated metabolic pathways linked to pulmonary vascular and right ventricular function.

physiology↗

bioRxiv2025

Endothelial c-IAP2 Loss Amplifies P2X7 Receptor-Driven Inflammation and Worsens Infection-Associated Pulmonary Hypertension

Schistosomiasis-associated Pulmonary Hypertension (Sch-PH) is the most common form of group I PH worldwide. Recently, data revealed that the preclinical animal model of Sch-PH exhibited gut and lung microbiome dysbiosis linked to significant endothelial dysfunction and microvascular apoptosis, but the role of pro/anti-apoptosis sensors, such as the inhibitor of apoptosis protein 2 (c-IAP2) and purinergic receptor P2X7 (P2X7R), remained unclear. Using a novel Cdh5cre-ERT2;cIAP1-/-;cIAP2fl/fl animal model, this study investigated the contribution of endothelial c-IAP2 in this process, revealing P2X7R overexpression as a putative target in the onset of Sch-PH. Pharmacologically, inhibition of P2X7R function confirmed its role in promoting lung endothelial death and disease progression. Moreover, data suggest that microbiome-associated metabolic alterations in Sch-PH seem linked to microvascular endothelial apoptosis driven by ATP/P2X7R overactivation and suppressed c-IAP2 expression. Indeed, genetic ablation of endothelial c-IAP2 expression was sufficient to induce PH-like features in mice, with echocardiography indicating a higher pulmonary acceleration time (PAT), PAT/pulmonary ejection time (PET), and right ventricular free wall thickness after IP/IV-Egg challenge compared to controls. These findings suggest a significant contribution of lung endothelial P2X7R activation and c-IAP2 suppression to Sch-PH pathology, highlighting them as promising novel therapeutic targets for this life-threatening illness.

pharmacology and toxicology↗

bioRxiv2020

beta-blocker reverses inhibition of beta-2 adrenergic receptor resensitization by hypoxia

Ischemia/hypoxia is major underlying cause for heart failure and stroke. Although beta-adrenergic receptor ({beta}AR) is phosphorylated in response to hypoxia, less is known about the underlying mechanisms. Hypoxia results in robust GRK2-mediated {beta}2AR phosphorylation but does not cause receptor internalization. However, hypoxia leads to significant endosomal-{beta}2AR phosphorylation accompanied by inhibition of {beta}2AR-associated protein phosphatase 2A (PP2A) activity impairing resensitization. Phosphoinositide 3-kinase {gamma} (PI3K{gamma}) impedes resensitization by phosphorylating endogenous inhibitor of protein phosphatase 2A, I2PP2A that inhibits PP2A activity. Hypoxia increased PI3K{gamma} activity leading to significant phosphorylation of I2PP2A resulting in inhibition of PP2A and consequently resensitization. Surprisingly, {beta}-blocker abrogated hypoxia-mediated {beta}2AR phosphorylation instead of phosphorylation in normoxia. Subjecting mice to hypoxia leads to significant cardiac dysfunction and {beta}2AR phosphorylation showing conservation of non-canonical hypoxia-mediated pathway in vivo. These findings provide mechanistic insights on hypoxia-mediated {beta}AR dysfunction which is rescued by {beta}-blocker and will have significant implications in heart failure and stroke.

biochemistry↗

bioRxiv2020

No evidence that androgen regulation of pulmonary TMPRSS2 explains sex-discordant COVID-19 outcomes

The sex discordance in COVID-19 outcomes has been widely recognized, with males generally faring worse than females and a potential link to sex steroids. A plausible mechanism is androgen-induced expression of TMPRSS2 and/or ACE2 in pulmonary tissues that may increase susceptibility or severity in males. This hypothesis is the subject of several clinical trials of anti-androgen therapies around the world. Here, we investigated the sex-associated TMPRSS2 and ACE2 expression in human and mouse lungs and interrogated the possibility of pharmacologic modification of their expression with anti-androgens. We found no evidence for increased TMPRSS2 expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2. On the other hand, ACE2 and AR expression was sexually dimorphic and higher in males than females. ACE2 was moderately suppressible with enzalutamide therapy. Our work suggests that sex differences in COVID-19 outcomes attributable to viral entry are independent of TMPRSS2. Modest changes in ACE2 could account for some of the sex discordance.

physiology↗