As Aboriginal women, Registered Nurses, and health promotion and public health academics, our perspectives are shaped by both our lived experiences and our professional practice. We have worked across clinical care, health promotion, public health, research, and academia, partnering with Aboriginal and Torres Strait Islander communities, health services, and organisations to improve health and wellbeing. These experiences have reinforced our understanding that meaningful and sustainable health promotion is built on relationships, trust, and shared decision-making, rather than simply the application of participatory methods. We wrote this commentary because we have become increasingly concerned that the term co-design is being used widely across research, policy and practice without always reflecting the principles it was intended to represent. Too often, co-design is reduced to consultation, workshops or the collection of community feedback, while decision-making power, and control remain with researchers, institutions or health services. In our experience, this not only undermines the intent of co-design but also risks reinforcing the very inequities that health promotion seeks to address. Our understanding of authentic co-design is informed by Aboriginal ways of knowing, being and doing, which recognise that relationships are not peripheral to the work; they are the work. Genuine partnership requires time to build trust, reciprocal relationships, mutual accountability, respect for community knowledge, and a willingness to share power throughout every stage of a project. These principles are not unique to Aboriginal and Torres Strait Islander contexts; rather, we believe they represent the foundations of effective health promotion with all communities. As nurses and health promoters, we have seen firsthand that programs developed with communities are more relevant, culturally safe, acceptable and sustainable than those developed for communities. Conversely, we have also witnessed the consequences of tokenistic engagement, where communities are invited to participate after key decisions have already been made. These experiences have shaped our conviction that authentic co-design is not a methodology to be applied, but a way of working that is grounded in humility, reciprocity and respect. We acknowledge that our perspectives are informed by our identities as Aboriginal women and by our professional experiences. While we do not claim to speak for all Aboriginal and Torres Strait Islander peoples or communities, we offer this commentary from a position of shared experience and commitment to strengthening health promotion practice. We hope this paper contributes to an ongoing conversation about moving beyond co-design as a buzzword and toward approaches that genuinely redistribute power, privilege community expertise and foster authentic relationships capable of creating meaningful and lasting health change.
The superficial circumflex iliac artery (SCIA) perforator flap is supplied by the SCIA, which consists of superficial and deep branches. In this study, the feasibility of using a flap based solely on the superficial branch of the SCIA for reconstruction surgery in the head and neck region was explored. During flap harvesting, the deep branch of the SCIA was discarded, and the superficial branch was dissected as the vascular pedicle; this technique is referred to as the 'simplified SCIA flap. This simplified SCIA flap was used to repair head and neck defects in 16 patients, all of whom were followed up for at least 3 months postoperatively. The superficial branch of the SCIA was successfully identified in all 16 patients. The mean pedicle length of the superficial branch of the artery was 7.2 cm (range 6.2-8.2 cm). The mean diameter of the superficial branch of the artery was 0.7 mm (range 0.6-0.9 mm), while the mean diameter of the accompanying vein was 1.2 mm (range 1.0-1.3 mm). The reconstruction was successful in 15 of the 16 patients. The remaining patient ultimately underwent reconstruction with a left radial forearm free flap. In this case, the skin paddle of the simplified SCIA flap was used as a full thickness skin graft to repair the defect in the forearm donor site. All patients completed speech and swallowing assessments during postoperative follow-up. Compared with the traditional SCIA flap, the simplified SCIA flap is easier to harvest, offers lower donor site morbidity, and results in a well-concealed scar in the iliac region. This flap warrants clinical promotion.
Replacing high-performance synthetic fibers with sustainable bio-derived alternatives is critical for mitigating microplastic pollution but remains limited by the inferior mechanical performance of biomass-derived fibers. Here, we present bioinspired cellulose metafibers (Meta-CFs) enabled by a scalable hydrodynamic twisting strategy, wherein an asymmetric microfluidic field precisely guides the formation of continuously twisted architectures within a chemically cross-linked network, thereby locking in the ordered configuration and markedly suppressing defect accumulation. Multiscale experiments and simulations reveal that this strategy promotes efficient stress delocalization and cooperative load transfer. The resulting Meta-CFs achieve an unprecedented maximum tensile strength of 3.29 GPa (average 3.06 ± 0.23 GPa) and a toughness of 349.5 MJ m-3, simultaneously rivaling the strength of high-performance synthetic fibers and the toughness of natural spider silk. Furthermore, encapsulating multiple individual Meta-CFs with calcium alginate effectively scales up the bundle diameter while preserving GPa-level strength and full biodegradability. This upscaling strategy enables large-diameter structural applications, as demonstrated by durable trimmer lines that avoid the generation of persistent agricultural microplastic residues, thereby establishing a viable pathway toward high-performance, sustainable material alternatives.
Tumour cells commonly exhibit aerobic glycolysis and produce lactate despite oxygen availability. Lactate dehydrogenase (LDH) catalyses pyruvate-lactate interconversion and regulates intracellular lactate levels. Endothelial cells also depend on glycolysis for ATP production, which prompted us to investigate LDH in canine hemangiosarcoma (HSA), a malignant endothelial tumour. We inhibited LDH with (R)-GNE-140 or sodium oxamate in two canine HSA cell lines (HU-HSA-2 and HU-HSA-3) and generated HU-HSA-3 clones with knockout of LDHA or LDHB to evaluate the effects of LDH perturbation. (R)-GNE-140 and sodium oxamate suppressed proliferation and reduced global histone lactylation levels in both cell lines. mRNA-sequencing (mRNA-seq) of (R)-GNE-140-treated HU-HSA-2 cells identified cholesterol/lipid metabolism-related gene sets among the top negatively enriched pathways. Representative cholesterol/lipid metabolism genes such as SREBF2, SQLE and LDLR responded differently depending on cell lines and inhibitors. (R)-GNE-140 decreased these genes in HU-HSA-2 but not HU-HSA-3, whereas sodium oxamate decreased them in HU-HSA-3 with limited effects in HU-HSA-2. In HU-HSA-3, LDHA and LDHB knockout clones decreased SREBP2 expression and reduced the number of lipid droplets. Fluvastatin, a cholesterol metabolism inhibitor, inhibited HSA cell growth in vitro but did not significantly suppress tumour growth in two HSA patient-derived xenograft (PDX) models. In contrast, combined fluvastatin and dipyridamole treatment inhibited proliferation in vitro and tumour growth in PDX models. Collectively, these results suggest a context-dependent association between LDH and cholesterol/lipid metabolism in canine HSA cell lines and provide a rationale for further evaluation of combined cholesterol pathway inhibition.
Anterior Gradient 2 (AGR2) is an endoplasmic reticulum (ER)-resident protein that belongs to the protein disulphide isomerase (PDI) family, and whose expression and secretion are induced by stress. Extracellular (secreted) AGR2 has been proposed as a marker of ER stress-related proteostasis alterations. Cancer cells frequently overexpress intracellular AGR2 (iAGR2) and secrete extracellular AGR2 (eAGR2). These features are associated with tumour progression and may serve as potential biomarkers in epithelial ovarian cancer (EOC). To investigate the roles of both iAGR2 and eAGR2 in EOC, we first generated EOC cells overexpressing iAGR2 and secreting eAGR2. Antibodies blocking eAGR2 reduced the proliferation and migration of these overexpressing cells. Concurrently, supplementation of parental cells with recombinant eAGR2 partially rescued these properties, further supporting a functional extracellular role for AGR2 in EOC. Quantitative proteomics, complemented by analysis of the TCGA database, revealed that eAGR2 modulated the expression of proteins involved in autophagy. This suggests that eAGR2-induced signalling may enhance catabolic activity under stress conditions, thereby increasing nutrient availability and, in turn, facilitating protein synthesis. This was reflected in the increased translational activity observed in AGR2-overexpressing and eAGR2-stimulated cells. Our results highlight two distinct, compartmentalised roles for AGR2. Specifically, iAGR2 acts as an ER-resident PDI, enhancing protein folding and ER quality control. In a complementary manner, eAGR2 functions as a metabolic regulator that may relieve constraints on tumour cell aggressiveness by maintaining autophagic flux and promoting protein synthesis. Overall, these findings support a dual-compartment model in which iAGR2 couples ER proteostasis with the metabolic and translational stimulation mediated by eAGR2.
Bees are key pollinators in natural and agricultural ecosystems, yet they are increasingly affected by the intensive use of pesticides. Although not primary targets of these compounds, bees may be exposed during foraging activities. Thiamethoxam and fipronil are widely used insecticides and have been implicated in pollinator decline. Stingless bees are essential pollinators in Neotropics, making the assessment of pesticide effects on these species particularly important. This study evaluated the sublethal effects of thiamethoxam and fipronil on neural and detoxification-related enzymes in the stingless bee Melipona scutellaris. Forager bees were exposed to fipronil (LC₅₀/2 = 0.0055 and LC₅₀/5 = 0.0022 ng a.i./μL) and thiamethoxam (LC₅₀/2 = 0.027 and LC₅₀/5 = 0.010 ng a.i./μL). AChE and CaE-3 activities were assessed in the heads, while GST activity was measured in the abdomens after 1, 6, 12, 24, 48, and 96 h of exposure. Thiamethoxam promoted more pronounced alterations in AChE, CaE-3, and GST activities than fipronil, particularly at longer exposure periods. Significant Treatment vs Time interactions demonstrated that enzymatic modulation varied according to insecticide type and exposure duration, although response profiles differed among biomarkers. Alterations in AChE activity indicate disruption of cholinergic regulation, whereas changes in CaE-3 and GST activities suggest activation of detoxification and oxidative stress-related pathways. The results demonstrate that M. scutellaris exhibits marked enzymatic sensitivity to sublethal concentrations of thiamethoxam and fipronil, reinforcing the importance of incorporating sublethal endpoints into pesticide risk assessments and highlight the potential of enzymatic biomarkers as early indicators of pesticide-induced stress in stingless bees.
Fibrosing interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF), are frequently associated with abnormalities in telomere homeostasis. Heterozygous pathogenic variants in telomere-related genes (TRGs) are found in 20-35% of patients with familial pulmonary fibrosis. These genetic defects are associated with impaired telomere homeostasis, which can lead to cellular senescence. Type II pneumocytes, the progenitor cells of the alveolar epithelium, are particularly sensitive to these genetic defects. Their senescence disrupts alveolar regeneration and promotes fibrosis by the production of profibrotic mediators. Autosomal dominant PARN deficiency provides a model for understanding the molecular mechanisms underlying pulmonary fibrosis associated with monogenic defects in telomere homeostasis, and developing targeted therapies.
Metabolically dysfunction-associated steatotic liver disease (MASLD), a globally prevalent metabolic condition, is increasingly linked to impaired mitophagy. However, its regulatory mechanisms in MASLD are not fully elucidated. This study investigated the role of Zinc finger protein 143 (ZNF143) in regulating hepatocyte mitophagy during MASLD development and the mechanisms involved. We employed two complementary MASLD models: (1) C57BL/6J mice fed a high-fat diet (HFD) for 16 weeks and (2) Huh-7 cells exposed to free fatty acid (FFA). Pathological changes were detected by H&E Staining. Cellular lipid deposition and mitochondrial damage were assessed using Oil Red O, JC-1 staining and transmission electron microscope (TEM), respectively. The intermolecular interaction was identified by dual-luciferase reporter assay, ChIP, and Co-IP. ZNF143 was upregulated in MASLD models, and its knockdown mitigated lipid accumulation and liver injury by activating hepatocyte mitophagy. ZNF143 promoted SMAD-specific E3 ubiquitin-protein ligase 1 (SMURF1) transcription by binding to its promoter region. Moreover, SMURF1 mediated transient receptor potential vanilloid type 1 (TRPV1) ubiquitination and degradation. Finally, knockdown of TRPV1 or overexpression of SMURF1 reversed the promoting effect of ZNF143 knockdown on mitophagy in FFA-treated Huh-7 cells. In short, ZNF143 upregulation exacerbated MASLD progression by mediating TRPV1 ubiquitination and degradation through transcriptionally activating SMURF1.
Physiological traits related to water status and photosynthesis biophysically link plant performance to environmental conditions like light and water availability. By approaching the concept of species' niches from a trait-based perspective, physiological traits can be used to characterize how trait syndromes diverge to limit direct resource competition and promote resource partitioning in sympatric species. Such traits could also inform broader studies of changing community composition in an era of drastic shifts in climate or disturbance regimes. However, the extent of inter/intraspecies trait variation and how such traits vary along local environmental gradients remains an open question in understanding physiological traits as species-level characteristics. To address this, we quantified hydraulic and gas exchange traits in four co-occurring Viburnum species while also quantifying local canopy coverage and soil conditions. All species displayed significant variation in gas-exchange traits, turgor loss point, and heavy carbon isotope discrimination along gradients of canopy openness. Specifically, plants in shadier environments exhibited higher photosynthetic rates at low light levels while individuals growing in gaps demonstrated higher drought tolerance and stricter stomatal regulation. Soil texture explained little variation in traits assessed. V. acerifolium displayed a more conservative, shade-tolerant trait syndrome, yet little significant difference was found in traits between the congeners, highlighting the potentially limited resolution of physiological traits to differentiate trait syndromes of closely related, co-occurring species.
Accurate assessment of the critical view of safety (CVS) is essential for preventing bile duct injuries during laparoscopic cholecystectomy. Existing artificial intelligence approaches primarily rely on static frame-level analysis and often fail to capture the temporal evolution of surgical scenes, limiting their ability to provide reliable and context-aware safety assessment. To address this challenge, we propose TempoSafe-CVS, a temporal multi-scale framework for automated CVS assessment in surgical videos. The proposed architecture integrates complementary visual representations through a Swin Transformer-based global context encoder, a ResNet-based local feature extractor, and a structure-aware convolutional module. These multi-scale features are combined and processed using temporal sequence modelling and spatio-temporal reasoning to capture both visual and temporal dependencies across surgical sequences. Furthermore, a unified multi-task prediction framework jointly estimates CVS safety status, procedural progression, anatomical structure visibility, and clinically relevant C1/C2/C3 criteria. Experiments conducted on the Endoscapes benchmark dataset demonstrate the effectiveness of the proposed approach, achieving 79.6% AUC-ROC for safety assessment, 81.5% average balanced accuracy for C1/C2/C3 criteria classification, and a mean absolute error of 0.187 for progression estimation. Comparative evaluations show consistent improvements over existing CVS assessment methods, highlighting the benefits of temporal reasoning and multi-scale visual representation learning. Qualitative analyses further demonstrate the interpretability of the framework through temporally consistent and anatomically grounded predictions. The proposed framework advances intelligent surgical video understanding by combining temporal sequence reasoning with multi-scale visual analysis, offering a potential solution for explainable and context-aware decision support in safety-critical surgical environments.
BYSL gene encodes the bystin-like (BYSL) protein, a nucleolar protein involved in eukaryotic ribosome biogenesis and essential for 40S ribosomal subunit synthesis. Although BYSL upregulation has been implicated in hepatocellular carcinoma, its mechanistic contribution to tumor progression remains undefined. We observed that BYSL is consistently upregulated across multiple cancer types and is associated with adverse clinicopathological features and poor prognosis, with the strongest clinical relevance observed in hepatocellular carcinoma through the integrative transcriptomic and proteomic analyses. BYSL-knockout suppresses malignant phenotypes, including proliferation, migration, and invasion, and induced G1/S arrest and apoptosis. Mechanistically, loss of BYSL disrupts nucleolar homeostasis and reduces global protein synthesis, thereby activating the RPL5/RPL11-MDM2-p53 axis, leading to p53 stabilization and tumor suppression. Importantly, MYC directly bound to the BYSL promoter and transcriptionally activated its expression, whereas co-targeting BYSL and MYC produced more synergistic antitumor effects than either intervention alone. Collectively, our study reveals that BYSL acts as a pivotal downstream mediator of MYC-regulated ribosome biogenesis and promotes hepatocellular carcinoma progression. Our findings suggest that BYSL may represent a potential therapeutic target for hepatocellular carcinoma; nevertheless, additional in vivo preclinical studies are warranted to validate its translational prospects.
Recent studies identify amyloidogenic human amylin, secreted by the pancreas, as a potential link between type-2 diabetes and Alzheimer's disease. Evidence suggests that pathogenic amylin signaling impairs cerebral bioenergetics, promoting tau hyperphosphorylation and neurodegeneration. Selective targeting of circulating amyloidogenic amylin and its pathogenic signaling may enable biomarker development and disease-modifying therapies.
Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy, and its intrinsic variability contributes to aggressive progression, recurrence, and therapeutic resistance. Exosomes are key mediators of intercellular communication among tumor cells with different malignant potentials, while N6-methyladenosine (m6A) modification has emerged as a critical epigenetic regulator of tumorigenesis. However, the mechanisms by which exosome-mediated m6A regulation contributes to HCC progression and heterogeneity remain poorly understood. Exosomal microRNA (miRNA) profiles from HCC cells with distinct malignant phenotypes were analyzed using microarray analysis, and the clinical relevance of miR-769-3p was evaluated in samples of HCC patients. Gain- and loss-of-function assays were performed to assess its effects on HCC proliferation and metastasis both in vitro and in vivo. AlkB homolog 5 (ALKBH5) was identified as a downstream target of miR-769-3p, and its m6A-dependent regulatory mechanism was investigated using methylated RNA immunoprecipitation sequencing and subsequent validation assays. In addition, a liposome-based drug delivery system targeting miR-769-3p was developed and evaluated for therapeutic efficacy. Exosomal miR-769-3p was significantly enriched in highly malignant HCC cells and was associated with poor clinical outcomes. Functional studies demonstrated that exosomal miR-769-3p promoted HCC proliferation and metastasis by suppressing ALKBH5 expression. Mechanistically, ALKBH5 inhibited the expression of the oncogene G protein subunit alpha z (GNAZ) in an m6A-dependent manner, while ALKBH5-mediated destabilization of GNAZ transcripts required the m6A reader insulin-like growth factor 2 mRNA-binding protein 1. Importantly, in vivo experiments revealed that a liposomal delivery system targeting miR-769-3p markedly suppressed HCC tumor growth and metastatic dissemination. Exosomal miR-769-3p mediates malignant intercellular communication between HCC subtypes by regulating the ALKBH5/m6A/GNAZ axis. Targeting miR-769-3p using a liposome-based delivery strategy represents a promising therapeutic approach for HCC. These findings provide novel mechanistic insights into HCC progression and identify a potential therapeutic target for HCC treatment.
Mounting evidence has shown that histone acetyltransferase binding to ORC1 (HBO1) serves as an oncoprotein, warranting the use of the small molecule inhibitor WM-3835 for cancer therapy. However, HBO1 is ubiquitously expressed in both tumor and normal tissues, with potential to increase the risk of systemic toxicity. This unmet need highlights the importance of identifying suitable biomarkers to predict the sensitivity to HBO1 inhibitor. Here, we show that ATR, a key regulator of DNA replication stress, is a novel interacting partner of HBO1. Additionally, we reveal a regulatory function of HBO1 in DNA replication stress responses, in an ATR-dependent manner. Mechanistically, ATR mediated HBO1 Ser50/53 phosphorylation interferes with the genomic binding of HBO1 and regulates gene expression. Notably, overexpression of HBO1 mutated at the ATR phosphorylation site (S50/53A) dampens the expression of DNA repair related genes and suppresses tumor colony formation, consistent with the observations of WM-3835 treatment. Inhibition of ATR significantly antagonized the sensitivity to WM-3835 treatment. Collectively, our findings uncovered a previously unidentified role of HBO1 in the regulation of replication stress and discovered ATR as a potential biomarker for WM-3835 treatment.
To assess how restricting open-label access to an off-label drug influences consent and trial enrolment in neonatal medicine. Multicentre, quasinatural experiment. Seventeen neonatal intensive care units in the Netherlands and Belgium participating in the DOXA-trial, a double-blind, randomised, placebo-controlled study of doxapram in extremely preterm infants. Infants born before 29 weeks' gestation whose parents were approached for DOXA-trial participation. Ten centres discontinued open-label doxapram outside the DOXA-trial (intervention centres), while seven continued its use (control centres). Parental consent rates (proportion of parents who provided written informed consent among those approached) and patient enrolment rates (proportion of infants randomised among those whose parents were approached), compared 12 months before and after the policy change in intervention centres and before and after a corresponding reference point in control centres. The reference point in control centres was defined as the mean discontinuation date across intervention centres RESULTS: Overall consent rates increased from 27.8% to 37.1% after the intervention or reference point (+9.3, 95% CI 3.3 to 15.4, p=0.003). In intervention centres, the consent rates rose from 27.1% to 42.9% (+15.8, 95% CI 8.6 to 23.0, p<0.001) and enrolment rates rose proportionally from 9.9% to 16.6% (+6.7, 95% CI 1.5 to 11.9, p=0.011), whereas in control centres, consent and enrolment rates remained unchanged. Restricting open-label access to an off-label investigational drug can substantially increase parental consent and patient enrolment in neonatal RCTs. To promote both ethical recruitment and optimal enrolment, future trials should explicitly discuss equipoise in each contributing unit and align local clinical practices with the trial design prior to initiation.
Activating mutations in PI3K are one of the most frequent mutations in breast cancer and are associated with worse patient outcomes in many breast cancer subtypes. Despite intense interest, cancer treatments that target the PI3K pathway have been only modestly effective due to intrinsic and acquired resistance mechanisms which reactivate PI3K signaling. Here, we characterize a feedback mechanism by which PI3K pathway inhibitors increase insulin receptor substrate 2 (IRS2) abundance and demonstrate the role of IRS2 in promoting resistance to these drugs. In PIK3CA mutant breast tumors and cell lines, there is a significant reduction in IRS2 mRNA and protein abundance which is reversed by PI3K pathway inhibition and mediated by the transcription factors FOXO1 and FOXO3. PIK3CA mutations do not alter IRS1 expression. IRS2 confers resistance to PI3K pathway inhibition by sustaining PI3K signaling in PIK3CA mutant, but not wild-type breast cancer cells. Increased IRS2 abundance also correlates with PI3K pathway inhibitor resistance across PIK3CA mutant cancer cell lines from a variety of tissues. The clinical relevance of these findings is highlighted by the frequency of PI3K mutations in cancer and the identification of a new target to address the challenges associated with prior efforts to block the reactivation of PI3K signaling during PI3K inhibition.
Lung cancer continues to be one of the deadliest malignancies worldwide, and its pathological progression is closely linked to a wide spectrum of environmental risk factors. Hexafluoropropylene oxide dimer acid (HFPO-DA), an emerging class of per- and polyfluoroalkyl substances (PFAS), has been extensively detected in global aquatic environments and biological samples in recent years. However, its potential role in lung cancer development and the underlying molecular events remain largely unexplored. In this work, we uncovered that HFPO-DA exposure notably boosted the growth, colony formation, and invasive capacity of human non-small cell lung cancer (NSCLC) celllines A549 and H1975. At the mechanistic level, HFPO-DA elevated the expression level of the deubiquitinatingenzyme OTUB1,reinforced the physical association between OTUB1 and STAT3, suppressed the ubiquitination-dependent breakdown of STAT3, and ultimately promoted STAT3 phosphorylation and functional activation. Upon translocation into the nucleus, activated STAT3 boosted the transcription of VEGF, strengthened VEGF autocrine signaling,and further triggered the VEGFR2 pathway through paracrine action, forming a self-reinforcing feedback loop.In vivo assays further confirmed that HFPO-DA administration (1, 5, 10 mg/kg/day) dose-dependentlyaccelerated the growth of subcutaneous tumor xenografts in nude mice, accompaniedby markedly elevated VEGF expression andVEGFR2 phosphorylation within tumor tissues. Collectively, our findings uncover a previously unrecognized molecular cascade by which HFPO-DA drives NSCLC progression via the OTUB1/STAT3/VEGF signaling axis. These resultsoffer key theoretical support for assessing the health risks posed by emerging PFAScontaminants and provide innovative directions for environmental etiology research and intervention development in lung cancer.
IgE-mediated food allergy and eosinophilic esophagitis (EoE) represent distinct yet interconnected manifestations of food-induced immune dysregulation. Rather than separate entities, emerging evidence supports a model that is on a continuum, in which clinical phenotypes are determined by antigen exposure patterns, dose, chronicity, and individual immune responses. This relationship has critical implications for food allergy immunotherapy, particularly oral immunotherapy. Among children with IgE-mediated food allergy, EoE prevalence is nearly 100-fold higher than the general population at 4.7%. During oral immunotherapy, gastrointestinal symptoms are common, with confirmed EoE developing in 1% to 10% of participants. Mechanistically, antigen avoidance favors IgE-mediated responses through T follicular helper cells, whereas sustained exposure promotes TH2-driven esophageal inflammation via pathogenic effector TH2 cells. Regulatory T-cell dysfunction appears central to this phenotypic switching. Clinical management requires risk stratification, systematic monitoring strategies, and individualized protocols that balance desensitization benefits against esophageal inflammation risks. Future directions include noninvasive diagnostic biomarkers, biologic therapies, and evidence-based prevention strategies. Understanding the food allergy-EoE continuum is essential for optimizing safety and efficacy of food allergen immunotherapy while minimizing complications.
Airway smooth muscle (ASM) is a key determinant of airway caliber and a major contributor to structural remodeling in obstructive lung diseases, including asthma and COPD. ASM proliferation is regulated by transcriptional and post-transcriptional mechanisms, including ubiquitin-dependent protein turnover mediated by E3 ubiquitin ligases. Here, we investigated the role of the RING-type E3 ligase RNF145 in mitogenic signaling and ASM cell proliferation. Human ASM cells were transfected with RNF145 shRNA or treated with the E3 ligase inhibitor SMER3, followed by stimulation with fetal bovine serum (FBS) or platelet-derived growth factor (PDGF). RNF145 knockdown or SMER3 treatment dose-dependently inhibited mitogen-induced ASM cell proliferation without inducing cytotoxicity, supporting a pro-mitogenic role for RNF145. Both interventions reduced phosphorylation of p70S6K at Thr421/Ser424 and Thr389 without affecting ERK MAPK signaling. Inhibition of PP2A and PP1 with okadaic acid or calyculin A restored p70S6K phosphorylation in RNF145-deficient cells, while SMER3 increased serine/threonine phosphatase activity. Mechanistically, RNF145 promoted K48-linked ubiquitination and proteasomal degradation of the PP2A scaffold subunit Aα, thereby limiting PP2A holoenzyme assembly during mitogenic signaling. Re-expression of RNF145 in RNF145-deficient cells reduced PP2A Aα abundance and restored p70S6K activation and ASM cell proliferation. These findings identify RNF145 as a positive regulator of ASM cell proliferation that sustains p70S6K signaling by suppressing PP2A. The RNF145-PP2A-p70S6K axis may therefore represent a therapeutic target for airway remodeling in chronic obstructive airway diseases.
The neuropeptide orexin/hypocretin regulates adaptive behaviors needed for survival, including food intake, sleep-wake regulation, mating, and maternal behavior. However, the orexinergic system plays a critical role in addictive behavior and promotes seeking and rewarding substances of abuse and palatable food. Plenty of orexin receptors exist in the medial prefrontal cortex (mPFC). The PFC input to the NAc mediates goal-directed behaviors such as seeking behavior and planning actions to obtain rewarding substances. This study investigated the role of mPFC orexin-2 receptors (Orx2Rs) in natural-and drug-reward-seeking behaviors. One hundred sixteen adult male Wistar rats received TCS OX2 29 (3, 10, and 30 nmol/0.5µl DMSO 12%) as an Orx2R antagonist in the mPFC during the acquisition and expression phases of two different CPP paradigms, morphine- and food-induced CPP protocols. Findings demonstrated that intra-mPFC administration of Orx2R antagonist reduced the acquisition and expression of morphine- and food-induced CPP in the rats. However, blockades of Orx2Rs in the mPFC have more inhibitory effects in food-induced CPP than in morphine-induced CPP. In conclusion, this study proposes a differential involvement of mPFC Orx2Rs in the acquisition and expression phases of CPP, suggesting distinguishable behavioral effects between food and morphine reward models. However, further mechanistic studies are required to clarify the underlying neural substrates.