A radiogenomic clinical decision support system to inform individualized treatment in advanced nasopharyngeal carcinoma.

Both concurrent chemoradiotherapy (CCRT) and induction chemotherapy (ICT) followed by CCRT are standard care of advanced nasopharyngeal carcinoma (NPC). However, tailoring personalized treatment is lacking. Herein, we established a radiogenomic clinical decision support system to classify patients into three subgroups according to their predicted disease-free survival (DFS) with CCRT and ICT response. The CCRT-preferred group was suitable for CCRT since they achieved good survival with CCRT, which could not be improved by ICT. The ICT-preferred group was suitable for ICT plus CCRT since they had poor survival with CCRT; additional ICT could afford an improved DFS. The clinical trial-preferred group was suitable for clinical trials since they exhibited poor survival regardless of receiving CCRT or ICT plus CCRT. These findings suggest that our radiogenomic clinical decision support system could identify optimal candidates for CCRT, ICT plus CCRT, and clinical trials, and may thus aid in personalized management of advanced NPC.

Epicardial adipose tissue volume and density are associated with heart failure with improved ejection fraction.

BACKGROUND: Heart failure (HF) with improved ejection fraction (EF, HFimpEF) is a distinct HF subtype, characterized by left ventricular (LV) reverse remodeling and myocardial functional recovery. Multiple cardiometabolic factors are implicated in this process. Epicardial adipose tissue (EAT), emerging as an endocrine and paracrine organ, contributes to the onset and progression of HF. However, the relation between EAT and the incidence of HFimpEF is still unclear. METHODS: A total of 203 hospitalized HF patients with reduced EF (HFrEF, LVEF ≤ 40%) who underwent coronary CT angiography (CCTA) during index hospitalization were consecutively enrolled between November 2011 and December 2022. Routine follow-up and repeat echocardiograms were performed. The incidence of HFimpEF was defined as (1) an absolute LVEF improvement ≥ 10% and (2) a second LVEF > 40% (at least 3 months apart). EAT volume and density were semiautomatically quantified on non-enhanced series of CCTA scans. RESULTS: During a median follow-up of 8.6 (4.9 ~ 13.3) months, 104 (51.2%) patients developed HFimpEF. Compared with HFrEF patients, HFimpEF patients had lower EAT volume (115.36 [IQR 87.08 ~ 154.78] mL vs. 169.67 [IQR 137.22 ~ 218.89] mL, P < 0.001) and higher EAT density (-74.92 ± 6.84 HU vs. -78.76 ± 6.28 HU, P < 0.001). Multivariate analysis showed lower EAT volume (OR: 0.885 [95%CI 0.822 ~ 0.947]) and higher density (OR: 1.845 [95%CI 1.023 ~ 3.437]) were both independently associated with the incidence of HFimpEF. Subgroup analysis revealed that the association between EAT properties and HFimpEF was not modified by HF etiology. CONCLUSIONS: This study reveals that lower EAT volume and higher EAT density are associated with development of HFimpEF. Therapies targeted at reducing EAT quantity and improving its quality might provide favorable effects on myocardial recovery in HF patients.

Rechargeable Seawater-Based Chloride-Ion Batteries Enabled by Covalent Surface Chemistry in MXenes.

Rechargeable aqueous chloride-ion batteries (ACIBs) using Cl- ions as charge carriers represent a promising energy-storage technology, especially when natural seawater is introduced as the electrolyte, which can bring remarkable advantages in terms of cost-effectiveness, safety, and environmental sustainability. However, the implementation of this technology is hindered by the scarcity of electrodes capable of reversible chloride-anion storage. Here, we show that a Ti3C2Clx MXene with Cl surface terminations enables reversible Cl- ion storage in aqueous electrolytes. Further, we developed seawater-based ACIBs that show a high specific capacity and an exceptionally long lifespan (40000 cycles, more than 1 year) in natural seawater electrolyte. The pouch-type cells achieve a high energy density (50 Wh Lcell-1) and maintain stable performance across a broad temperature range (-20 to 50 °C). Our investigations reveal that the covalent interaction between Cl- ions and Cl-terminated MXene facilitates Cl- ion intercalation into the MXene interlayer, promoting rapid ion migration with a low energy barrier (0.10 eV). Moreover, this MXene variant also enables the reversible storage of Br- ions in an aqueous electrolyte with a long cycle life. This study may advance the design of anion storage electrodes and enable the development of sustainable aqueous batteries.

Four three-dimensional rare earth metal - organic framework fluorescent sensor for efficient detection of gentamicin sulfate and Fe3.

Excessive use of gentamicin sulfate can cause severe nephrotoxicity and ototoxicity, abnormal levels of Fe3+ intake can also cause serious damage to body. Therefore, establishing a fast and accurate detection method for the above-mentioned substances is of great significance. However, traditional detection methods such as high-performance liquid chromatography still have certain problems such as high cost and complex operation. Fluorescent MOFs are favored by analysts due to their high specific surface area, high porosity, adjustable pore size, and good stability. In this paper, we have synthesized four rare earth MOFs based on the pyridinecarboxylic acid ligand (H2L), which are [Eu(L)1/2H2O]n, [Gd(L)1/2H2O]n, [Sm(L)1/2H2O]n, [Y(L)3/2H2O·DMF]n. The structures of four MOFs were confirmed by single crystal X-ray diffraction, which proved that MOF-1, MOF-2 and MOF-3 were isostructural, and all the four MOFs were three-dimensional structures. In the fluorescence test, gentamicin sulfate and Fe3+ can cause significant fluorescence quenching of MOF-1 and MOF-4 respectively, and show good selectivity and anti-interference performance, as well as low detection limit and wide detection range. This work may provide a possibility for the detection of gentamicin sulfate and iron ions in complex environments.

Energetic demands regulate sleep-wake rhythm circuit development.

Sleep and feeding patterns lack strong daily rhythms during early life. As diurnal animals mature, feeding is consolidated to the day and sleep to the night. In Drosophila, circadian sleep patterns are initiated with formation of a circuit connecting the central clock to arousal output neurons; emergence of circadian sleep also enables long-term memory (LTM). However, the cues that trigger the development of this clock-arousal circuit are unknown. Here, we identify a role for nutritional status in driving sleep-wake rhythm development in Drosophila larvae. We find that in the 2nd instar larval period (L2), sleep and feeding are spread across the day; these behaviors become organized into daily patterns by the 3rd instar larval stage (L3). Forcing mature (L3) animals to adopt immature (L2) feeding strategies disrupts sleep-wake rhythms and the ability to exhibit LTM. In addition, the development of the clock (DN1a)-arousal (Dh44) circuit itself is influenced by the larval nutritional environment. Finally, we demonstrate that larval arousal Dh44 neurons act through glucose metabolic genes to drive onset of daily sleep-wake rhythms. Together, our data suggest that changes to energetic demands in developing organisms trigger the formation of sleep-circadian circuits and behaviors.

Like most young animals, babies must obtain enough nutrients and energy to grow, yet they also need to rest for their brains to mature properly. As many exhausted new parents know first-hand, balancing these conflicting needs results in frequent, rapid switches between eating and sleeping. Eventually, new-borns' internal biological clock system, which is aligned with the 24-hour light cycle, becomes fully operational. Exactly how this then translates into allowing them to stay alert during the day and be sleepy at night is still unclear. Like humans, the larvae of fruit flies first sleep haphazardly before developing a circadian pattern whereby they sleep at night and eat during the day. This shift occurs when a group of nerve cells called DN1a, whose job is to 'keep time', connects with Dh44, a subset of neurons which, when active, promote wakefulness. The trigger for these changes, however, has remained elusive. In response, Poe et al. hypothesized that feeding behaviour and nutrient availability coordinated the emergence of sleep rhythms in fruit flies. Forcing fruit fly larvae to keep feeding in an 'immature' pattern ­ by either genetic manipulations or reducing the sugar content of their food ­ not only prevented them from developing 'mature' sleeping rhythms but also resulted in memory problems. These experiments also showed that the DN1a-Dh44 connection depends on nutrient availability, as it did not form in larvae raised on the low-sugar food. Further genetic experiments showed that the Dh44 cells themselves act like nutrient sensors during the emergence of sleeping patterns. These results shed new light on the factors triggering sleep rhythm development. Poe et al. hope that the understanding gained can be extended to humans and eventually help manage nervous system disorders and health problems associated with disrupted sleep during early life.

Fabrication of a Terbium-Functionalized Cadmium Organic Framework with Proper Energy Levels as a Ratiometric Probe of an Anthrax Biomarker.

Anthrax bacillus is a very dangerous zoonotic pathogen that seriously endangers public health. Rapid and accurate qualitative and quantitative detection of its biomarkers, 2,6-dipicolinic acid (DPA), is crucial for the prevention and treatment of this pathogenic bacterium. In this work, a novel Cd-based MOF (TTCA-Cd) has been synthesized from a polycarboxylate ligand, [1,1':2',1″-terphenyl]-4,4',4″,5'-tetracarboxylic acid (H4TTCA), and further doped with Tb(III), forming a dual-emission lanthanide-functionalized MOF hybrid (TTCA-Cd@Tb). TTCA-Cd@Tb can be developed as a high-performance ratiometric fluorescent sensor toward DPA with a very low detection limit of 7.14 nM and high selectivity in a wide detection range of 0-200 µM, demonstrating a big advancement and providing a new option for the detection of DPA.

Comparison of immediate vs. delayed guided tissue regeneration in Infrabony defect of second molars after adjacent third molar extraction: a retrospective study.

BACKGROUND: The distal aspect of the second molar (d-M2) often exhibits infrabony defects due to the adjacent third molar. Although the defects can be treated by guided tissue regeneration (GTR) after removing the third molar, the optimal timing remains uncertain following third molar removal in clinical decision-making. This study aimed to compare delayed and immediate GTR treatments to assist in clinical decision-making. METHODS: D-M2 infrabony defects with a minimum 1-year follow-up were collected and divided into three groups: Immediate GTR group, which underwent third molar extraction and received GTR simultaneously; Delayed GTR group, which underwent delayed GTR at least 3 months after third molar extraction; and Control group, which underwent only scaling and root planing during third molar extraction. The clinical and radiographic parameters related to the infrabony defect before GTR and post-surgery were evaluated using the Kruskal-Wallis test or one-way ANOVA, followed by post-hoc Dunn's test or the Bonferroni test for pairwise comparisons. RESULTS: A total of 109 d-M2 infrabony defects were assessed. No significant differences were found between the two GTR groups, although both of them showed significant reductions in infrabony defect depth: the immediate GTR group (2.77 ± 1.97 mm vs. 0.68 ± 1.03 mm, p < 0.001) and the delayed GTR group (2.98 ± 1.08 mm vs. 0.68 ± 1.03 mm, p < 0.001) compared to the control group. CONCLUSION: GTR can effectively improve d-M2 infrabony defects when the third molar is removed, whether simultaneously or delayed. Patients may experience less discomfort with immediate GTR treatment as it requires only one surgery.

Personalized, parcel-guided non-invasive transcranial magnetic stimulation for the treatment of post-concussive syndrome: safety and proof of concept.

OBJECTIVE: To determine the safety and proof of concept of a parcel-guided, repetitive Transcranial Magnetic Stimulation (rTMS) in patients who develop a heterogeneous array of symptoms, known collectively as post-concussive syndrome (PCS), following traumatic brain injury (TBI). METHODS: We performed a retrospective review of off-label, individualized, parcel-guided rTMS in 19 patients from December 2020 to May 2023. Patients had at least one instance of mild, moderate, or severe TBI and developed symptoms not present prior to injury. rTMS targets were identified based on machine learning connectomic software using functional connectivity anomaly matrices compared to healthy controls. EuroQol (EQ-5D), as a measurement of quality of life, and additional questionnaires dependent on individual's symptoms were submitted prior to, after, and during follow-up from rTMS. RESULTS: Nineteen patients showed improvement in EQ-5D and Rivermead Post Concussion Symptoms Questionnaires - 3 after treatment and follow-up. For nine patients who developed depression, five (55%) attained response and remission based on the Beck Depression Inventory after treatment. Eight of ten patients with anxiety had a clinically significant reduction in Generalized Anxiety Disorder-7 scores during follow-up. CONCLUSION: Parcel-guided rTMS is safe and may be effective in reducing PCS symptoms following TBI and should incite further controlled studies.

Disentangled Representation Learning.

Disentangled Representation Learning (DRL) aims to learn a model capable of identifying and disentangling the underlying factors hidden in the observable data in representation form. The process of separating underlying factors of variation into variables with semantic meaning benefits in learning explainable representations of data, which imitates the meaningful understanding process of humans when observing an object or relation. As a general learning strategy, DRL has demonstrated its power in improving the model explainability, controlability, robustness, as well as generalization capacity in a wide range of scenarios such as computer vision, natural language processing, and data mining. In this article, we comprehensively investigate DRL from various aspects including motivations, definitions, methodologies, evaluations, applications, and model designs. We first present two well-recognized definitions, i.e., Intuitive Definition and Group Theory Definition for disentangled representation learning. We further categorize the methodologies for DRL into four groups from the following perspectives, the model type, representation structure, supervision signal, and independence assumption. We also analyze principles to design different DRL models that may benefit different tasks in practical applications. Finally, we point out challenges in DRL as well as potential research directions deserving future investigations. We believe this work may provide insights for promoting the DRL research in the community.

Sodium thiosulfate: A donor or carrier signaling molecule for hydrogen sulfide?

Sodium thiosulfate has been used for decades in the treatment of calciphylaxis and cyanide detoxification, and has recently shown initial therapeutic promise in critical diseases such as neuronal ischemia, diabetes mellitus, heart failure and acute lung injury. However, the precise mechanism of sodium thiosulfate remains incompletely defined and sometimes contradictory. Although sodium thiosulfate has been widely accepted as a donor of hydrogen sulfide (H2S), emerging findings suggest that it is the executive signaling molecule for H2S and that its effects may not be dependent on H2S. This article presents an overview of the current understanding of sodium thiosulfate, including its synthesis, biological characteristics, and clinical applications of sodium thiosulfate, as well as the underlying mechanisms in vivo. We also discussed the interplay of sodium thiosulfate and H2S. Our review highlights sodium thiosulfate as a key player in sulfide signaling with the broad clinical potential for the future.

The micro-ecological feature of colonies is a potential strategy for Phaeocystis globosa bloom formation.

Phaeocystis globosa is among the dominant microalgae associated with harmful algal blooms. P. globosa has a polymorphic life cycle and its ecological success has been attributed to algal colony formation, however, few studies have assessed differences in microbial communities and their functional profiles between intra- and extra-colonies during P. globosa blooms. To address this, environmental and metagenomics tools were used to conduct a time-series analysis of the bacterial composition and metabolic characteristics of intra- and extra-colonies during a natural P. globosa bloom. The results show that bacterial composition, biodiversity, and network interactions differed significantly between intra- and extra-colonies. Dominant extra-colonial bacteria were Bacteroidia and Saccharimonadis, while dominant intra-colonial bacteria included Alphaproteobacteria and Gammaproteobacteria. Despite the lower richness and diversity observed in the intra-colonial bacterial community, relative to extra-colonies, the complexity and interconnectedness of the intra-colonial networks were higher. Regarding bacterial function, more functional genes were enriched in substance metabolism (polysaccharides, iron element and dimethylsulfoniopropionate) and signal communication (quorum sensing, indoleacetic acid-IAA) pathways in intra- than in extra-colonies. Conceptual model construction showed that microbial cooperative synthesis of ammonium, vitamin B12, IAA, and siderophores were strongly related to the P. globosa bloom, particularly in the intra-colonial environment. Overall, our data highlight the differences in bacterial structure and functions within and outside the colony during P. globosa blooms. These findings represent fundamental information indicating that phenotypic heterogeneity is a selective strategy that improves microbial population competitiveness and environmental adaptation, benefiting P. globosa bloom formation and persistence.

The impact of deep-inspiration breath-hold total-body PET/CT imaging on thoracic 18F-FDG avid lesions compared with free-breathing.

OBJECTIVES: To investigate PET/CT registration and quantification accuracy of thoracic lesions of a single 30-second deep-inspiration breath-hold (DIBH) technique with a total-body PET (TB-PET) scanner, and compared with free-breathing (FB) PET/CT. METHODS: 137 of the 145 prospectively enrolled patients finished a routine FB-300 s PET/CT exam and a 30-second DIBH TB-PET with chest to pelvis low dose CT. The total-body FB-300 s, FB-30 s, and DIBH-30 s PET images were reconstructed. Quantitative assessment (SUVmax and SUVmean of lung and other organs), PET/CT registration assessment and lesion analysis (SUVmax, SUVpeak, SUVmean and tumor-background ratio) were compared with Wilcoxon signed-rank tests. RESULTS: The SUVmax and SUVmean of the lung with DIBH-30 s were significantly lower than those with FB. The distances of the liver dome between PET and CT were significantly smaller with DIBH-30 s than with FB. 195 assessable lesions in 106 patients were included, and the detection sensitivity was 97.9 % and 99.0 % in FB-300 s, and DIBH-30 s, respectively. For both small co-identified lesions (n = 86) and larger co-identified lesions with a diameter ≥ 1 cm (n = 91), the lesion SUVs were significantly greater with DIBH-30 s than with FB-300 s. Regarding lesion location, the differences of the SUVs for the lesions in the lower thorax area (n = 97, p < 0.001) were significant between DIBH-30 s and FB-300 s, while these differences were not statistically significant in the upper thorax (n = 80, p > 0.05). The lesion tumor-to-surrounding-background ratio (TsBR) was significantly increased, both in the upper and lower thorax. CONCLUSION: The TB DIBH PET/CT technique is feasible in clinical practice. It reduces the background lung uptake and achieves better registration and lesion quantification, especially in the lower thorax.

Discernible interindividual patterns of global efficiency decline during theoretical brain surgery.

The concept of functional localization within the brain and the associated risk of resecting these areas during removal of infiltrating tumors, such as diffuse gliomas, are well established in neurosurgery. Global efficiency (GE) is a graph theory concept that can be used to simulate connectome disruption following tumor resection. Structural connectivity graphs were created from diffusion tractography obtained from the brains of 80 healthy adults. These graphs were then used to simulate parcellation resection in every gross anatomical region of the cerebrum by identifying every possible combination of adjacent nodes in a graph and then measuring the drop in GE following nodal deletion. Progressive removal of brain parcellations led to patterns of GE decline that were reasonably predictable but had inter-subject differences. Additionally, as expected, there were deletion of some nodes that were worse than others. However, in each lobe examined in every subject, some deletion combinations were worse for GE than removing a greater number of nodes in a different region of the brain. Among certain patients, patterns of common nodes which exhibited worst GE upon removal were identified as "connectotypes". Given some evidence in the literature linking GE to certain aspects of neuro-cognitive abilities, investigating these connectotypes could potentially mitigate the impact of brain surgery on cognition.

The influence of sleep disorders on perioperative neurocognitive disorders among the elderly: A narrative review.

This review comprehensively assesses the epidemiology, interaction, and impact on patient outcomes of perioperative sleep disorders (SD) and perioperative neurocognitive disorders (PND) in the elderly. The incidence of SD and PND during the perioperative period in older adults is alarmingly high, with SD significantly contributing to the occurrence of postoperative delirium. However, the clinical evidence linking SD to PND remains insufficient, despite substantial preclinical data. Therefore, this study focuses on the underlying mechanisms between SD and PND, underscoring that potential mechanisms driving SD-induced PND include uncontrolled central nervous inflammation, blood-brain barrier disruption, circadian rhythm disturbances, glial cell dysfunction, neuronal and synaptic abnormalities, impaired central metabolic waste clearance, gut microbiome dysbiosis, hippocampal oxidative stress, and altered brain network connectivity. Additionally, the review also evaluates the effectiveness of various sleep interventions, both pharmacological and nonpharmacological, in mitigating PND. Strategies such as earplugs, eye masks, restoring circadian rhythms, physical exercise, noninvasive brain stimulation, dexmedetomidine, and melatonin receptor agonists have shown efficacy in reducing PND incidence. The impact of other sleep-improvement drugs (e.g., orexin receptor antagonists) and methods (e.g., cognitive-behavioral therapy for insomnia) on PND is still unclear. However, certain drugs used for treating SD (e.g., antidepressants and first-generation antihistamines) may potentially aggravate PND. By providing valuable insights and references, this review aimed to enhance the understanding and management of PND in older adults based on SD.

Advantages and Challenges of Total-Body PET/CT at a Tertiary Cancer Center: Insights from Sun Yat-sen University Cancer Center.

In recent decades, researchers worldwide have directed their efforts toward enhancing the quality of PET imaging. The detection sensitivity and image resolution of conventional PET scanners with a short axial field of view have been constrained, leading to a suboptimal signal-to-noise ratio. The advent of long-axial-field-of-view PET scanners, exemplified by the uEXPLORER system, marked a significant advancement. Total-body PET imaging possesses an extensive scan range of 194 cm and an ultrahigh detection sensitivity, and it has emerged as a promising avenue for improving image quality while reducing the administered radioactivity dose and shortening acquisition times. In this review, we elucidate the application of the uEXPLORER system at the Sun Yat-sen University Cancer Center, including the disease distribution, patient selection workflow, scanning protocol, and several enhanced clinical applications, along with encountered challenges. We anticipate that this review will provide insights into routine clinical practice and ultimately improve patient care.

MMCA-NET: A Multimodal Cross Attention Transformer Network for Nasopharyngeal Carcinoma Tumor Segmentation Based on a Total-Body PET/CT System.

Nasopharyngeal carcinoma (NPC) is a malignant tumor primarily treated by radiotherapy. Accurate delineation of the target tumor is essential for improving the effectiveness of radiotherapy. However, the segmentation performance of current models is unsatisfactory due to poor boundaries, large-scale tumor volume variation, and the labor-intensive nature of manual delineation for radiotherapy. In this paper, MMCA-Net, a novel segmentation network for NPC using PET/CT images that incorporates an innovative multimodal cross attention transformer (MCA-Transformer) and a modified U-Net architecture, is introduced to enhance modal fusion by leveraging cross-attention mechanisms between CT and PET data. Our method, tested against ten algorithms via fivefold cross-validation on samples from Sun Yat-sen University Cancer Center and the public HECKTOR dataset, consistently topped all four evaluation metrics with average Dice similarity coefficients of 0.815 and 0.7944, respectively. Furthermore, ablation experiments were conducted to demonstrate the superiority of our method over multiple baseline and variant techniques. The proposed method has promising potential for application in other tasks.

Post-traumatic hyperoxia after pediatric TBI.

OBJECTIVE: Hyperoxia has been suggested as a mechanism for secondary injury following adult traumatic brain injury (TBI), but its effects have not been well described in pediatric patients. METHODS: Pediatric (≤18yo) TBI patients were identified in a prospective institutional registry from October 2008 to April 2022. The first, highest, and the Area Under the Curve (AUC) PaO2 in the first 24 hours were collected and calculated for each patient from arterial blood gas reports after admission to the ICU. Neurological outcome after 6 months was measured using dichotomized modified Rankin Scale (mRS) and Glasgow Outcome Scale - Extended (GOS-E). Multivariable logistic regression models were used to determine if the three measurements for hyperoxia predicted an unfavorable outcome after controlling for well-established clinical and imaging predictors of outcome. RESULTS: We identified 98 pediatric patients with severe accidental TBI during the study period. Hyperoxia (PaO2 > 300 mmHg) occurred in 33% of the patients. The presence of elevated PaO2 values, determined by all three evaluations of hyperoxia, was not associated with unfavorable outcome after 6 months. CONCLUSION: Utilizing multiple methods to assess exposure, hyperoxia was present in a substantial number of patients with severe TBI but was not associated with an unfavorable outcome.

Three undescribed dihydrostilbene glycosides from leaves of Camellia oleifera Abel. And their anti-inflammatory activity.

Three previously unidentified dihydrostilbene glycosides, named oleiferaside A (1), oleiferaside B (2), and oleiferaside C (3), were discovered through a phytochemical exploration on Camellia oleifera Abel. leaves. Additionally, nine known secondary metabolites (4-12) were also identified. The undescribed secondary metabolites 1-3 were elucidated as 3,5-dimethoxydihydrostilbene 4'-O-α-l-arabinofuranosyl-(1 â†’ 6)-ß-d- glucopyranoside, 3,5-dimethoxydihydrostilbene 4'-O-α-l-arabinopyranosyl-(1 â†’ 6)-ß-d- glucopyranoside and 3,5-dimethoxydihydrostilbene 4'-O-ß-d-apiofuranosyl-(1 â†’ 6)-ß-d- glucopyranoside, respectively. HR-MS and NMR spectroscopy were utilized for determining the structures of the isolates. The natural products were assessed for their anti-inflammatory effect using RAW264.7 macrophage stimulated by LPS. The findings demonstrated that compounds 1-4 exhibited inhibitory activities on NO and PGE2 production without causing cytotoxicity. These observations suggest that these compounds may have potential anti-inflammatory properties.

NBR1-p62-Nrf2 mediates the anti-pulmonary fibrosis effects of protodioscin.

BACKGROUND: Idiopathic pulmonary fibrosis is a persistent disease of the lung interstitium for which there is no efficacious pharmacological therapy. Protodioscin, a steroidal saponin, possesses diverse pharmacological properties; however, its function in pulmonary fibrosis is yet to be established. Hence, in this investigation, it was attempted to figure out the anti-pulmonary fibrosis influences of protodioscin and its pharmacological properties related to oxidative stress. METHODS: A mouse lung fibrosis model was generated using tracheal injections of bleomycin, followed by intraperitoneal injection of different concentrations of protodioscin, and the levels of oxidative stress and fibrosis were detected in the lungs. Multiple fibroblasts were treated with TGF-ß to induce their transition to myofibroblasts. It was attempted to quantify myofibroblast markers' expression levels and reactive oxygen species levels as well as Nrf2 activation after co-incubation of TGF-ß with fibroblasts and different concentrations of protodioscin. The influence of protodioscin on the expression and phosphorylation of p62, which is associated with Nrf2 activation, were detected, and p62 related genes were predicted by STRING database. The effects of Nrf2 inhibitor or silencing of the Nrf2, p62 and NBR1 genes, respectively, on the activation of Nrf2 by protodioscin were examined. The associations between p62, NBR1, and Keap1 in the activation of Nrf2 by protodioscin was demonstrated using a co-IP assay. Nrf2 inhibitor were used when protodioscin was treated in mice with pulmonary fibrosis and lung tissue fibrosis and oxidative stress levels were detected. RESULTS: In vivo, protodioscin decreased the levels of fibrosis markers and oxidative stress markers and activated Nrf2 in mice with pulmonary fibrosis, and these effects were inhibited by Nrf2 inhibitor. In vitro, protodioscin decreased the levels of myofibroblast markers and oxidative stress markers during myofibroblast transition and promoted Nrf2 downstream gene expression, with reversal of these effects after Nrf2, p62 and NBR1 genes were silenced or Nrf2 inhibitors were used, respectively. Protodioscin promoted the binding of NBR1 to p62 and Keap1, thereby reducing Keap1-Nrf2 binding. CONCLUSION: The NBR1-p62-Nrf2 axis is targeted by protodioscin to reduce oxidative stress and inhibit pulmonary fibrosis.