Background/Objectives: Biologic therapies are the cornerstone of severe asthma management. However, evidence regarding switching between biologics in children with severe asthma remains limited. Methods: Retrospective observational study including patients aged 6–17 years with severe asthma, followed at our tertiary referral center, who switched biologic therapy. Clinical, laboratory, and lung function data were collected at the initiation of the second biologic (T0) and after 4 (T1) and 12 months (T2). Changes in asthma control, exacerbation rate, inhaled corticosteroid dose, FeNO and lung function were evaluated. Results: Eight patients who switched and had been treated with a second biologic for at least 12 months were included. Switching occurred from omalizumab to dupilumab (n = 1), mepolizumab to dupilumab (n = 5), and mepolizumab to omalizumab (n = 2). The main reason for switching was inadequate asthma control, while one patient switched because of poorly controlled comorbidity. At T2, exacerbations significantly decreased (p = 0.03), with significant improvements in FEV1 (p = 0.002) and FEV1/FVC (p = 0.015). The daily fluticasone-equivalent dose decreased from a median of 500 μg to 425 μg. Conclusions: In this cohort, switching biologic therapy was associated with improved clinical and functional outcomes, with a significant response already detectable after 4 months. These findings highlight the importance of close clinical and functional monitoring to identify children who may benefit from a change in biologic therapy. Larger prospective studies are needed to define standardized criteria and optimal timing for biologic switching in pediatric severe asthma.
Background: Psoriasis is a chronic, immune-mediated inflammatory skin disorder that frequently exhibits spontaneous clinical remission during pregnancy. However, the underlying cell-type-specific transcriptomic alterations—particularly the involvement of dermal fibroblasts and hormone receptor signaling—remain poorly understood. Methods: We established an imiquimod (IMQ)-induced psoriasis-like dermatitis model in BALB/c mice comparing pregnant and non-pregnant cohorts. Multi-omics profiling combing bulk and single-cell RNA sequencing was integrated with computational intercellular communication and trajectory analysis. In vitro hormone-stimulation assays with ELISA quantification and in situ multiplex immunofluorescence were performed for experimental evaluation. Results: Compared with non-pregnant IMQ-treated mice, pregnant mice exhibited reduced psoriasis area and severity index scores and diminished epidermal thickening. Bulk RNA sequencing revealed downregulated Th1/Th17 inflammatory transcripts and upregulated hormone-associated genes (e.g., Pgr, Esr1, Ghr). Single-cell RNA sequencing identified 11 distinct cell types, with fibroblasts displaying distinct hormone receptor profiles and functional heterogeneity. Fibroblasts displayed transcripts encoding both anti-inflammatory factors (e.g., Tgfb2, Gas6, Grn) and pro-inflammatory factors (e.g., Fgf7, Mif). Keratinocytes exhibited an anti-inflammatory transcriptional phenotype with attenuated proliferation signatures. Monocytes/macrophages shifted toward M2-like transcriptional signatures and displayed computationally predicted communication with fibroblasts via candidate pathways including GRN and Gas6. Experimentally, primary mouse dermal fibroblasts stimulated with estradiol, progesterone, and growth hormone in vitro significantly increased secretion of PGRN. Gas6 secretion was significantly augmented by estradiol and growth hormone, whereas progesterone induced a modest elevation with borderline significance (p = 0.060). In contrast, TGF-β2 protein remained undetectable in culture supernatants. Furthermore, multiplex immunofluorescence demonstrated significantly increased expression of the Gas6 receptor MerTK on dermal macrophages in the IMQ + pregnancy group. Conclusions: Pregnancy-induced hormonal fluctuations may be associated with the amelioration of IMQ-induced psoriatic dermatitis, which correlates with a fibroblast-involved immunoregulatory network. These findings highlight the association of stromal-immune crosstalk in disease remission and suggest the GRN and Gas6 pathways as candidate pathways for future functional validation.
Obesity has become a major global public health concern, with prevalence rates rising dramatically over the past several decades and affecting more than one billion people worldwide. The increasing burden of obesity has been largely driven by sedentary lifestyles and the consumption of energy-dense, nutrient-poor diets, although its etiology is multifactorial, involving complex interactions among genetic, metabolic, endocrine, and environmental factors. Beyond excess adiposity, obesity is closely associated with numerous chronic diseases, including cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), hypertension, cancer, and chronic inflammatory disorders. Emerging evidence indicates that oxidative stress plays a pivotal role in the pathogenesis of obesity and its related metabolic complications. Reactive oxygen species (ROS) and reactive nitrogen species (RNS), which are generated during normal cellular metabolism, serve important physiological functions in cell signaling and redox regulation. However, excessive production of these reactive species or impairment of endogenous antioxidant defense systems disrupts redox homeostasis, leading to oxidative damage to lipids, proteins, and nucleic acids. Such alterations contribute to cellular dysfunction, chronic inflammation, and disease progression. In this context, dietary antioxidants have attracted considerable attention due to their ability to neutralize free radicals, inhibit lipid peroxidation, and restore redox balance. Natural antioxidants derived from fruits, vegetables, and other plant-based foods may act individually or synergistically to enhance cellular defense mechanisms against oxidative stress. Furthermore, growing evidence suggests that antioxidant-rich dietary patterns may offer protective effects against obesity-associated metabolic disturbances and chronic diseases. However, clinical benefits of isolated antioxidant supplementation remain inconsistent and appear to depend on dose, bioavailability, baseline redox status, disease stage, and the preservation of physiological redox signaling. Understanding the molecular mechanisms underlying antioxidant-mediated regulation of redox homeostasis may facilitate the development of nutritional strategies for obesity prevention and management, while contributing to the reduction in oxidative stress and obesity-related disease burden and the promotion of long-term health.
Objectives: This study aimed to identify ferro-aging-related hub genes in chronic kidney disease (CKD) and elucidate their potential roles in proximal tubular (PT) cells. Methods: Differential expression analysis was performed using GSE104954, and the differentially expressed genes were intersected with a set of ferro-aging-related genes. Feature selection was conducted using the least absolute shrinkage and selection operator (LASSO), support vector machine–recursive feature elimination (SVM-RFE), and random-forest algorithms. The findings were externally validated in GSE180394. Single-cell transcriptomic data from GSE183276 were then used to define the cellular localization and expression profile of the hub genes, and their regulatory networks were investigated using scTenifoldKnk-based in silico knockout and gene set enrichment analysis (GSEA). Results: Fourteen candidate genes were identified, of which IRF7 and SOCS2 were consistently selected by all three machine-learning algorithms. SOCS2 was significantly downregulated in both the discovery and validation cohorts and showed strong tissue-level discriminatory performance in the discovery cohort, with more modest performance in the external cohort. Single-cell analysis showed that SOCS2 downregulation occurred predominantly in PT cells; CKD PT cells also exhibited increased ACSL4 expression and the enrichment of the ferroptosis pathway. In silico SOCS2 knockout further identified 77 significantly perturbed genes, primarily associated with mitochondrial oxidative phosphorylation, oxidative stress, and metabolic homeostasis. Conclusions: Collectively, these findings identify SOCS2 as a candidate gene associated with a ferro-aging-related transcriptomic signature in CKD PT cells. The observed changes in ACSL4, ferroptosis-related pathways, mitochondrial oxidative phosphorylation, and oxidative stress networks are compatible with, but do not establish, a ferro-aging phenotype. Further functional validation is required to determine whether SOCS2 contributes causally to iron–lipid dysregulation and tubular injury in CKD.
Background: Transforming growth factor beta 1 (TGF-β1) is a master regulator of fibrogenesis and extracellular matrix (ECM) remodeling. Among molecules involved in profibrotic signaling, periostin (POSTN) and the Snail family transcriptional repressor 2 (SLUG, SNAI2) have emerged as potential regulators of tissue remodeling and fibroblast activation. However, the temporal relationship between TGF-β1-induced expression of SLUG and periostin in human dermal fibroblasts remains poorly understood. Objectives: This study aimed to evaluate the effect of TGF-β1 stimulation on SNAI2/SLUG and POSTN/periostin expression dynamics in normal human dermal fibroblasts (NHDFs) and characterize their association with profibrotic responses. Methods: NHDFs were stimulated with recombinant human TGF-β1 (20 ng/mL) for 24, 48, and 72 h. SNAI2 and POSTN mRNA expression was quantified by RT-qPCR, intracellular SLUG protein levels were assessed by Western blotting, and periostin accumulation in the culture medium was measured by enzyme-linked immunosorbent assay (ELISA). The RT-qPCR and ELISA data were analyzed using two-way ANOVA with Bonferroni correction; because of the small number of replicates (n = 2), the Western blot data are presented descriptively. Results: TGF-β1 significantly increased POSTN mRNA expression after 24 and 48 h (both p < 0.001); at 72 h, POSTN mRNA levels remained numerically elevated relative to the control, although this difference did not reach statistical significance. Periostin accumulation in the culture medium increased progressively and was significantly higher than in the control group after 48 and 72 h (p < 0.001). In contrast, SNAI2/SLUG exhibited transient expression kinetics, with increased SNAI2 mRNA at 48 h (p < 0.05) and the highest SLUG protein levels also observed after 48 h of stimulation, followed by a decline at 72 h. Conclusions: TGF-β1 induced time-dependent changes in SNAI2/SLUG and POSTN/periostin expression in human dermal fibroblasts. As fibroblast activation and ECM remodeling were not directly assessed, the present conclusions are restricted to the expression changes in the two investigated molecules, whose concurrent yet temporally distinct regulation may indicate potential relevance in the fibroblast response to profibrotic signaling. Further studies are required to determine whether they participate in common regulatory mechanisms or independently contribute to fibrotic processes.
