Search Results (56,991)

Polymorphous Light Eruption (PLE) is a prevalent UV-induced photodermatosis characterized by abnormal immune responses, oxidative stress, and cutaneous inflammation. Alpha-glucosylrutin (AGR), a chemically modified flavonoid widely used for its antioxidant and photoprotective effects, has shown clinical efficacy; however, its synthetic origin and classification as a potential skin sensitizer and aquatic toxin raise safety and environmental concerns. These limitations underscore the need for safer, naturally derived alternatives. In this study, we investigated the comparative efficacy of quercetin (QC) and hesperidin (HPN)—two plant-based flavonoids—against AGR in in vitro and ex vivo models of sun-induced skin damage. An optimized QC:HPN 8:1 (w/w) complex significantly restored antioxidant enzyme activities (SOD: 4.11 ± 0.32 mU/mg; CAT: 1.88 ± 0.04 mU/mg) and suppressed inflammatory cytokine production (IL-6: 155.95 ± 3.17 pg/mL; TNF-α: 62.34 ± 0.72 pg/mL) more effectively than AGR. β-hexosaminidase secretion, a marker of allergic response, was reduced to 99.02 ± 1.45% with QC:HPN 8:1, compared to 121.33 ± 1.15% with AGR. QC alone exhibited dose-dependent cytotoxicity at ≥10 μg/mL, whereas HPN maintained >94% cell viability at all tested concentrations. These findings highlight the QC:HPN 8:1 complex as a safe, natural, and effective alternative to synthetic AGR for preventing and managing PLE and UV-induced dermal inflammation. Further research should focus on clinical validation and formulation development for topical use. Full article

Over the past four decades, cardioprotective research has revealed an extraordinary complexity of cellular and molecular mechanisms capable of mitigating ischemia/reperfusion injury (IRI). Among these, ischemic conditioning has emerged as one of the most influential discoveries: brief episodes of ischemia followed by reperfusion activate protective programs that reduce myocardial damage. These effects can be elicited locally (pre- or postconditioning) or remotely (remote conditioning), acting mainly through paracrine signaling and mitochondria-linked kinase pathways, with both early and delayed windows of protection. We have contributed to clarifying the roles of mitochondria, oxidative stress, prosurvival kinases, connexins, extracellular vesicles, and sterile inflammation, particularly via activation of the NLRP3 inflammasome. Despite robust preclinical evidence, clinical translation of these approaches has remained disappointing. The challenges largely stem from experimental models that poorly reflect real-world clinical settings—such as advanced age, comorbidities, and multidrug therapy—as well as the reliance on surrogate endpoints that do not reliably predict clinical outcomes. Nevertheless, interest in multi-target protective strategies remains strong. New lines of investigation are focusing on emerging mediators—such as gasotransmitters, extracellular vesicles, and endogenous peptides—as well as targeted modulation of inflammatory responses. Future perspectives point toward personalized cardioprotection tailored to patient metabolic and immune profiles, with special attention to high-risk populations in whom IRI continues to represent a major clinical challenge. Full article

The Carbohydrate-Responsive Element-Binding Protein (ChREBP) is a glucose-sensitive transcription factor that regulates the carbohydrate and lipid metabolism. We investigated its cell-type-specific role in hepatocarcinogenesis using a chemically induced mouse model. Additionally, we examined the functions of its isoforms, ChREBPα and ChREBPβ. After the diethylnitrosamine (DEN) administration, we analyzed hepatocellular adenomas and carcinomas in systemic ChREBP-knockout (KO), hepatocyte-specific ChREBP-KO (L-KO), and wildtype (WT) mice at 4, 12, and 36 weeks using histology, morphometry, proliferation measurements, immunohistochemistry, a Western blot, and a quantitative PCR. Tumors developed 36 weeks after the DEN administration in 27% of WT mice but less frequently in KO (18%) and L-KO (9%) mice. However, preneoplastic foci were less common in KO mice but not in L-KO mice (39% vs. 9%; p < 0.05). L-KO hepatocytes exhibited lower proliferation, while KO tumors showed the downregulation of AKT/mTOR signaling, glycolysis, and lipogenesis compared to WT tumors. Our results showed that the liver-specific loss of ChREBPα, while ChREBPβ remained active, significantly reduced the tumor progression, suggesting an oncogenic role for ChREBPα. In contrast, the systemic knockout of both ChREBPα and ChREBPβ reduced the tumor initiation but did slightly prevent tumor progression, indicating that ChREBPβ may exert tumor-suppressive functions. Full article

Background/Objectives: Gouty arthritis (GA) is a chronic inflammatory disorder frequently linked to systemic inflammation and impaired kidney function. Growth differentiation factor-15 (GDF-15) has been suggested as a potential biomarker involved in both inflammatory responses and renal dysfunction. Studies on GDF-15 serum levels and renal function decline in GA patients are limited. This study aimed to investigate serum GDF-15 levels in patients with GA and to evaluate the relationship between GDF-15 and renal function parameters. Methods: This prospective case–control study included 60 (intercritical group: 30; acute attack group: 30) patients with gout arthritis and 60 healthy controls, matched for body mass index and sex. The enzyme-linked immunosorbent assay measured serum GDF-15, and renal function and inflammatory markers were also assessed. Group comparisons used non-parametric tests, Spearman’s analysis evaluated correlations, and receiver operating characteristic (ROC) analysis assessed diagnostic performance. Results: Serum GDF-15 levels were significantly higher in GA patients than controls (p < 0.001), especially during acute attacks. GDF-15 correlated moderately with renal function markers. ROC analysis showed high diagnostic accuracy for both acute (area under the curve (AUC) = 0.98) and intercritical gout phases (AUC = 0.96). Conclusions: Serum GDF-15 levels are increased in patients with gouty arthritis and are associated with impaired renal function. GDF-15 may serve as a helpful biomarker for disease activity and renal involvement in GA, but its interpretation should be considered in conjunction with other clinical and laboratory parameters. Full article

This article re-examines Julio Cortázar’s “Continuity of Parks” (1956) and “Instructions for John Howell” (1963) through the lens of reader-response theory, hermeneutics, and cognitive narratology. Traditionally viewed as examples of the fantastic, these stories are interpreted here as complementary explorations of passive and active reading, offering a literary dialectic that parallels the reflections articulated in Cortázar’s Rayuela [Hopscotch] (1963). Drawing on Wolfgang Iser’s theories of textual gaps and reader cooperation, Paul Ricoeur’s hermeneutics of appropriation, and more recent approaches to cognitive immersion and narrative engagement, this study argues that both stories dramatize reading as an ethical and political act. “Continuity of Parks” illustrates the dangers of uncritical textual consumption, culminating in the protagonist’s epistemic and existential annihilation, while “Instructions for John Howell” presents a model of insurgent readership, where the spectator’s appropriation of the play foregrounds the risks and possibilities of narrative intervention. By analyzing the use of metalepsis, destabilized focalization, and narrative layering in these stories, this article highlights how Cortázar anticipates contemporary concerns regarding reader agency, interpretive autonomy, and the sociopolitical implications of literary engagement. Full article

The formation of acidic goaf water in abandoned coal mines poses significant environmental threats, especially in karst regions where the risk of groundwater contamination is heightened. This study investigates the geochemical processes responsible for the generation of acidic water through batch and column leaching experiments using coal mine surrounding rocks (CMSR) from Yangquan, China. The coal-bearing strata, primarily composed of sandstone, mudstone, shale, and limestone, contain high concentrations of pyrite (up to 12.26 wt%), which oxidizes to produce sulfuric acid, leading to a drastic reduction in pH (approximately 2.5) and the mobilization of toxic elements. The CMSR samples exhibit elevated levels of arsenic (11.0 mg/kg to 18.1 mg/kg), lead (69.5 mg/kg to 113.5 mg/kg), and cadmium (0.6 mg/kg to 2.6 mg/kg), all of which exceed natural crustal averages and present significant contamination risks. The fluorine content varies widely (106.1 mg/kg to 1885 mg/kg), with the highest concentrations found in sandstone. Sequential extraction analyses indicate that over 80% of fluorine is bound in residual phases, which limits its immediate release but poses long-term leaching hazards. The leaching experiments reveal a three-stage release mechanism: first, the initial oxidation of sulfides rapidly lowers the pH (to between 2.35 and 2.80), dissolving heavy metals and fluorides; second, slower weathering of aluminosilicates and adsorption by iron and aluminum hydroxides reduce the concentrations of dissolved elements; and third, concentrations stabilize as adsorption and slow silicate weathering regulate the long-term release of contaminants. The resulting acidic goaf water contains extremely high levels of metals (with aluminum at 191.4 mg/L and iron at 412.0 mg/L), which severely threaten groundwater, particularly in karst areas where rapid cross-layer contamination can occur. These findings provide crucial insights into the processes that drive the acidity of goaf water and the release of contaminants, which can aid in the development of effective mitigation strategies for abandoned mines. Targeted management is essential to safeguard water resources and ecological health in regions affected by mining activities. Full article

As the largest freshwater lake in China, Poyang Lake plays a crucial role in hydrological processes. Conventional models often fail to capture the time-lagged relationships between meteorological drivers and runoff responses, while lacking regional generalization capability. To address these limitations, this study proposes a novel XAJ-LSTM-TFM hybrid model that accounts for time-lagged hydrological responses and enhances the regional applicability of the Xinanjiang model. The model innovatively integrates the physical mechanisms of the Xinanjiang model with the temporal learning capacity of LSTM networks. By incorporating intermediate hydrological variables (including interflow and groundwater flow) along with 1–3 day lagged meteorological features, the model achieves an average 15.3% improvement in Nash–Sutcliffe Efficiency (NSE) across five sub-basins, with the Ganjiang Basin attaining an NSE of 0.812 and a 25.7% reduction in flood peak errors. The results demonstrate superior runoff simulation performance and reliable generalization capability under intensive anthropogenic activities. Full article

Background: Electroencephalography (EEG) systems based on textile electrodes are increasingly being developed to address the need for more wearable sensor systems for brain function monitoring. Blink-related oscillations (BROs) are a new measure of brain function that corresponds to brainwave responses occurring after spontaneous blinking, and indexes neural processes as the brain evaluates new visual information appearing after eye re-opening. Prior studies have reported BRO utility as both a clinical and non-clinical biomarker of cognition, but no study has demonstrated BRO measurement using textile-based EEG devices that facilitate user comfort for real-world applications. Methods: We investigated BRO measurement using a four-channel EEG system with textile electrodes by extracting BRO responses using existing, publicly available EEG data (n = 9). We compared BRO effects derived from textile-based electrodes with those from standard dry Ag/Ag-Cl electrodes collected at the same locations (i.e., Fp1, Fp2, F7, F8) and using the same EEG amplifier. Results: Results showed that BRO effects measured using textile electrodes exhibited similar features in both time and frequency domains compared to dry Ag/Ag-Cl electrodes. Data from both technologies also showed similar performance in artifact removal and signal capture. Conclusions: These findings provide the first demonstration of successful BRO signal capture using four-channel EEG with textile electrodes, providing compelling evidence toward the development of a comfortable and user-friendly EEG technology that uses the simple activity of blinking for objective brain function assessment in a variety of settings. Full article

Phenothiazines, mainly known for their antipsychotic activity, have recently attracted attention as potential compounds with anticancer and immunomodulatory activity In this study, 20 new quinobenzothiazines (MJ1–MJ20) were synthesized and their effects on normal cell lines (BEAS-2B, NHDF) and cancer cell lines (HCT116, MCF7, A549, SH-SY5Y, U2OS) were investigated. The studies included cytotoxicity assessment, analysis of the expression of genes (BCL2, AIFM2, MDM2) and pro-inflammatory cytokines (IL6, IL8) using the RT-qPCR method, and prediction of biological activity using the PASS platform. The results indicate that the compounds MJ19 and MJ20 have the greatest effect on the induction of pro-inflammatory (IL6, IL8) and antiapoptotic (BCL2, MDM2) genes, suggesting their potential use in therapies for inflammatory and autoimmune diseases. Gene expression analysis showed that compound MJ2 in BEAS-2B cells significantly induced the expression of AIFM2, a protein responsible for protecting against ferroptosis, while moderately increasing the expression of BCL2 and MDM2, suggesting a potential role for MJ2 in the modulation of protective mechanisms of healthy cells, e.g., avoiding apoptosis death. These results emphasize the potential of quinobenzothiazines as multifunctional bioactive compounds, which require further studies to determine their mechanisms of action and specificity. Full article

Background and Objectives: The Hippo pathway, via Yes-associated protein 1 (YAP1), regulates cell proliferation, apoptosis, and tissue regeneration. Aberrant YAP1 activation is linked to tumor progression and immune evasion in various cancers, including breast carcinoma, despite conflicting evidence on its prognostic value. Preclinical studies have explored drugs targeting YAP1–TEAD interactions, but therapeutic application is limited. Materials and Methods: This study included 50 patients with locally advanced breast cancer, who were assessed by a multidisciplinary tumor board and underwent neoadjuvant treatment per tumor subtype and clinical guidelines. Eligibility required both pre-treatment core biopsy and post-treatment surgical resection samples. Due to the absence of residual tumor in some patients achieving complete pathological response, post-treatment tissue was available and analyzable in 30 patients. YAP1 expression was evaluated immunohistochemically for nuclear and cytoplasmic staining patterns. ROC analysis identified a cutoff for YAP1 expression, defining tumors with ≥70% nuclear and ≥80% cytoplasmic staining. Results: YAP1 expression had a significant relationship with tumor subtype (p = 0.001), being most frequent in HER-2-positive tumors (55.6%) and least frequent in luminal tumors (11.1%). YAP1 positivity significantly predicted axillary pathological complete response (pCR) (p = 0.01). In YAP1-positive patients, 77.8% achieved axillary pCR compared to 31.7% in YAP1-negative patients, though the YAP1 status and breast pCR association were insignificant (p = 0.07). The Mann–Whitney U test indicated that higher Ki-67 values were significantly associated with positive YAP1 expression (p = 0.028). In contrast, there was no association between ER, PR status, age, and tumor size. Following treatment, there was a statistically significant change in YAP1 expression, with nuclear staining decreasing (p = 0.004) while cytoplasmic staining increased (p = 0.002). YAP1 was significantly linked to axillary pCR, HER-2 status, and Ki-67. Conclusions: Post treatment, nuclear YAP1 decreased, whereas cytoplasmic expression increased, showing a localization shift. These results suggest that YAP1 may predict treatment response and become a future therapeutic target. Full article

Universities in severely cold regions face the dual challenge of adapting to seasonal climate variations while enhancing outdoor thermal comfort in outdoor leisure plazas. This study takes a university in Hohhot as a case study. Through field investigations conducted in summer and winter, thermal benchmarks were established. Based on this, an orthogonal experimental design was developed considering greenery layout, plant types, and surface albedo. ENVI-met was used to simulate and analyze the seasonal regulatory effects of landscape elements on the microclimate. The results show that: (1) the lower limit of the neutral PET range in Hohhot in winter is −11.3 °C, and the upper limit in summer is 31.3 °C; (2) the seasonal contribution of landscape elements to PET ranks as follows: plant types > greenery layout > surface albedo; and (3) the proposed optimization plan achieved a weighted increase of 6.0% in the proportion of activity area within the neutral PET range in both summer and winter. This study is the first to construct outdoor thermal sensation categories for both summer and winter in Hohhot and to establish a thermal comfort optimization evaluation mechanism that considers both diurnal and seasonal weightings. It systematically reveals the comprehensive regulatory effects of landscape elements on the thermal environment in severely cold regions and provides a nature-based solution for the climate-responsive design of campus plazas in such areas. Full article

Acute lymphoblastic leukemia (ALL) is the most common cancer affecting children, making up about 80% of all acute leukemia cases in the pediatric population. While treatment with L-asparaginase (ASNase) has greatly improved survival rates, its bacterial origin often causes immune reactions in some patients, which can reduce how well the therapy works. To overcome this challenge, previous in silico studies designed a humanized chimeric ASNase by swapping out the predicted immunogenic parts of the bacterial enzyme with similar, less immunogenic segments from the human version—while keeping the enzyme’s active site intact. In this study, the chimeric L-asparaginase designed was successfully cloned, expressed, and purified using the Escherichia coli Rosetta strain. The production conditions (37 °C, 0.01 mM IPTG, 2–4 h) were optimized, and we purified the enzyme in a single step with nickel-affinity chromatography. The enzyme’s activity was confirmed in vitro, showing that it is possible to produce a functional humanized variant in a bacterial system. These results lay important groundwork for future research to assess the immune response and therapeutic potential of this novel chimeric enzyme. Full article

Neuropathic pain is a significant global clinical issue that poses substantial challenges to both public health and the economy due to its complex underlying mechanisms. It has emerged as a serious health concern worldwide. Recent studies involving dorsal root ganglion (DRG) stimulation have provided strong evidence supporting its effectiveness in alleviating chronic pain and its potential for sustaining long-term pain relief. In addition to that, there has been ongoing research with clinical evidence relating to the role of small non-coding ribonucleic acids known as microRNAs in regulating gene expressions affecting pain signals. The signal pathway involves alterations in neuronal excitation, synaptic transmission, dysregulated signaling, and subsequent pro-inflammatory response activation and pain development. When microRNAs are dysregulated in the dorsal root ganglia neurons, they polarize macrophages from anti-inflammatory M2 to inflammatory M1 macrophages causing pain signal generation. By reversing this polarization, a therapeutic activity can be induced. However, the direct delivery of these nucleotides has been challenging due to limitations such as rapid clearance, degradation, and reduction in half-life. Therefore, safe and efficient carrier vehicles are fundamental for microRNA delivery. Here, we present a comprehensive analysis of miRNA-based nano-systems for chronic neuropathic pain, focusing on their impact in dorsal root ganglia. This review provides a critical evaluation of various delivery platforms, including viral, polymeric, lipid-based, and inorganic nanocarriers, emphasizing their therapeutic potential as well as their limitations in the treatment of chronic neuropathic pain. Innovative strategies such as hybrid nanocarriers and stimulus-responsive systems are also proposed to enhance the prospects for clinical translation. Serving as a roadmap for future research, this review aims to guide the development and optimization of miRNA-based therapies for effective and sustained neuropathic pain management. Full article

In this paper, physics students’ experiences of a flipped, active learning physics class are explored through the lens of transactional distance theory (TDT). Transactional distance (TD) is the psychological and communicative distance that may arise between students and their teacher in learning environments such as large classes. TD has been shown to have a negative impact on students’ satisfaction, engagement, and learning outcomes, yet there is lack of research on how pedagogical approaches, such as the flipped classroom and active learning, may ameliorate the impacts of TD. In this paper, I use a qualitative methodology to gain an in-depth understanding of the ways in which a flipped class can impact the experience of transactional distance for first year physics students. Eleven students took part in semi-structured interviews about their experience of the class, from which three themes were developed: (a) creating connections; (b) stimulating engagement; and (c) supporting responsiveness. These themes are interpreted through the lens of TDT to understand the ways in which the flipped class and active learning pedagogics reduced students’ experience of TD. This gives new insights into students’ experiences of small group discussions, pre-class quizzes, and in-class ‘clicker’ questions. The implications for the pedagogical design of flipped classes will be discussed. Full article

There is a present need to develop alternative biotherapeutic drugs to mitigate the exacerbated inflammatory immune responses characteristic of sepsis. The potent endotoxin lipopolysaccharide (LPS), a major component of Gram-negative bacterial outer membrane, activates the immune system via Toll-like receptor 4 (TLR4), triggering macrophages and a persistent cascade of inflammatory mediators. Our previous studies have demonstrated that Fh15, a recombinant member of the Fasciola hepatica fatty acid binding protein family, can significantly increase the survival rate by suppressing many inflammatory mediators induced by LPS in a septic shock mouse model. Although Fh15 has been proposed as a TLR4 antagonist, the specific mechanisms underlying its immunomodulatory effect remained unclear. In the present study, we employed a quantitative proteomics approach using tandem mass tag (TMT) followed by LC-MS/MS analysis to identify and quantify differentially expressed proteins that participate in signaling pathways downstream TLR4 of macrophages, which can be dysregulated by Fh15. Data are available via ProteomeXchange with identifier PXD065520. Based on significant fold change (FC) cut-off of 1.5 and p-value ≤ 0.05 criteria, we focused our attention to 114 proteins that were upregulated by LPS and downregulated by Fh15. From these proteins, TNFα, IL-1α, Lck, NOS2, SOD2 and CD36 were selected for validation by Western blot on murine bone marrow-derived macrophages due to their relevant roles in the NF-κB, iNOS, oxidative stress, and phagosome signaling pathways, which are closely associated with sepsis pathogenesis. These results suggest that Fh15 exerts a broad spectrum of action by simultaneously targeting multiple downstream pathways activated by TLR4, thereby modulating various aspects of the inflammatory responses during sepsis. Full article