Zafirlukast ameliorates lipopolysaccharide and bleomycin-induced lung inflammation in mice.

Acute lung injury (ALI) is the result of damage to the capillary endothelia and the alveolar epithelial cell caused by various direct and indirect factors, leading to significant pulmonary interstitial and alveolar edema and acute hypoxic respiratory insufficiency. A subset of ALI cases progresses to irreversible pulmonary fibrosis, a condition with fatal implications. Zafirlukast is a leukotriene receptor antagonist licensed for asthma prevention and long-term treatment. This study demonstrated a significant improvement in lung tissue pathology and a reduction in inflammatory cell infiltration in models of lipopolysaccharide (LPS)-induced ALI and bleomycin (BLM)-induced lung inflammation following zafirlukast administration, both in vivo and in vitro. Moreover, zafirlukast was found to suppress the inflammatory response of alveolar epithelial cells in vitro and lung inflammation in vivo by reducing the activation of the TLR4/NF-κB/NLRP3 inflammasome pathway. In conclusion, zafirlukast relieved lung injury and the infiltration of inflammatory cells in the lung by regulating the TLR4/NF-κB/NLRP3 pathway.

The mitigating role of social capital on the association between food insecurity and psychological distress among Chinese adults.

BACKGROUND: Food insecurity, a pervasive global issue exacerbated by the COVID-19 pandemic, has been linked to adverse mental health outcomes. However, the role of social capital in mitigating this relationship remains understudied, particularly in the Chinese context. AIMS: This study investigated the associations between food insecurity and psychological distress (depressive and anxiety symptoms) and examined the potential moderating effects of bonding and bridging social capital among Chinese adults in Shanghai. METHODS: This cross-sectional study included 3,220 Chinese adults (mean age: 34.45; 51.5% male) in Shanghai. Food insecurity was assessed using the modified Household Food Insecurity Access Scale, psychological distress was measured using the Patient Health Questionnaire-9 and the Generalized Anxiety Disorder-7, and social capital was evaluated using the Revised Personal Social Capital Scale. RESULTS: Multivariable linear regression analyses revealed that food insecurity was significantly positively associated with both depressive (ß = 0.449, SE = 0.024) and anxiety symptoms (ß = 0.391, SE = 0.022), after adjusting for sociodemographic characteristics, health status, and COVID-19-related factors. Higher levels of bonding and bridging social capital were significantly associated with fewer depressive and anxiety symptoms. Significant interactions (p < .001) between bonding social capital and food insecurity indicated that the associations between food insecurity and psychological distress were less pronounced among adults with higher bonding social capital. CONCLUSIONS: These findings highlight the critical role of food insecurity as a risk factor for psychological distress and the importance of bonding social capital in mitigating its impact on mental health. Policies and interventions targeting food insecurity prevention and bonding social capital enhancement may promote better mental health outcomes among Chinese adults.

Natural killer cells promote neutrophil extracellular traps and restrain macular degeneration in mice.

Neovascular age-related macular degeneration (nvAMD) is the leading cause of blindness in the elderly population. Although it is known that nvAMD is associated with focal inflammation, understanding of the precise immune components governing this process remains limited. Here, we identified natural killer (NK) cells as a prominent lymphocyte population infiltrating the perivascular space of choroidal neovascularization (CNV) lesions in patients with nvAMD and in mouse models. Olink proteomic analysis and single-cell RNA sequencing combined with knockout studies demonstrated the involvement of C-C chemokine receptor 5 (CCR5) in NK cell recruitment and extravasation at the CNV sites of mice. Depletion of NK cells or inhibition of activating receptor NK group 2, member D (NKG2D) inhibited the formation of neutrophil extracellular traps, increased vascular leakage, and exacerbated pathological angiogenesis, indicating that NK cells restrain pathogenesis in this mouse model. Age is the strongest risk factor for AMD, and we show that NK cells from aged human donors exhibited a less cytotoxic phenotype. NK cells from old mice exhibited compromised protective effects in the CNV mouse model. In addition, interleukin-2 complex-mediated expansion of NK cells improved CNV formation in mice. Collectively, our study highlights NK cells as a potential therapeutic target for patients with nvAMD.

Baricitinib alleviates cardiac fibrosis and inflammation induced by chronic sympathetic activation.

Cardiac fibrosis is characterized by the over-proliferation, over-transdifferentiation and over-deposition of extracellular matrix (ECM) of cardiac fibroblasts (CFs). Cardiac sympathetic activation is one of the leading causes of myocardial fibrosis. Meanwhile, cardiac fibrosis is often together with cardiac inflammation, which accelerates fibrosis by mediating inflammatory cytokines secretion. Recently, the Janus kinase/signal transducer and activator of transcription (JAK/STAT3) signaling pathway has been confirmed by its vital role during the progression of cardiac fibrosis. Thus, JAK/STAT3 signaling pathway is thought to be a potential therapeutic target for cardiac fibrosis. Baricitinib (BR), a novel JAK1/2 inhibitor, has been reported excellent effects of anti-fibrosis in multiple fibrotic diseases. However, little is known about whether and how BR ameliorates cardiac fibrosis caused by chronic sympathetic activation. Isoproterenol (ISO), a ß-Adrenergic receptor (ß-AR) nonselective agonist, was used to modulate chronic sympathetic activation in mice. As expected, our results proved that BR ameliorated ISO-induced cardiac dysfunction. Meanwhile, BR attenuated ISO-induced cardiac fibrosis and cardiac inflammation in mice. Moreover, BR also inhibited ISO-induced cardiac fibroblasts activation and macrophages pro-inflammatory secretion. As for mechanism studies, BR reduced ISO-induced cardiac fibroblasts by JAK2/STAT3 and PI3K/Akt signaling, while reduced ISO-induced macrophages pro-inflammatory secretion by JAK1/STAT3 and NF-κB signaling. In summary, BR alleviates cardiac fibrosis and inflammation caused by chronic sympathetic activation. The underlying mechanism involves BR-mediated suppression of JAK1/2/STAT3, PI3K/Akt and NF-κB signaling.

Estimating the risk of major adverse cardiac events following radiotherapy for left breast cancer using a modified generalized Lyman normal-tissue complication probability model.

BACKGROUND: We introduced an adapted Lyman normal-tissue complication probability (NTCP) model, incorporating clinical risk factors and censored time-to-event data, to estimate the risk of major adverse cardiac events (MACE) following left breast cancer radiotherapy (RT). MATERIALS AND METHODS: Clinical characteristics and MACE data of 1100 women with left-side breast cancer receiving postoperative RT from 2005 to 2017 were retrospectively collected. A modified generalized Lyman NTCP model based on the individual left ventricle (LV) equivalent uniform dose (EUD), accounting for clinical risk factors and censored data, was developed using maximum likelihood estimation. Subgroup analysis was performed for low-comorbidity and high-comorbidity groups. RESULTS: Over a median follow-up 7.8 years, 64 patients experienced MACE, with higher mean LV dose in affected individuals (4.1 Gy vs. 2.9 Gy). The full model accounting for clinical factors identified D50 = 43.3 Gy, m = 0.59, and n = 0.78 as the best-fit parameters. The threshold dose causing a 50 % probability of MACE was lower in the high-comorbidity group (D50 = 30 Gy) compared to the low-comorbidity group (D50 = 45 Gy). Predictions indicated that restricting LV EUD below 5 Gy yielded a 10-year relative MACE risk less than 1.3 and 1.5 for high-comorbidity and low-comorbidity groups, respectively. CONCLUSION: Patients with comorbidities are more susceptible to cardiac events following breast RT. The proposed modified generalized Lyman model considers nondosimetric risk factors and addresses incomplete follow-up for late complications, offering comprehensive and individualized MACE risk estimates post-RT.

Remdesivir alleviates skin fibrosis by suppressing TGF-ß1 signaling pathway.

Fibrotic skin diseases, such as keloids, are pathological results of aberrant tissue healing and are characterized by overgrowth of dermal fibroblasts. Remdesivir (RD), an antiviral drug, has been reported to have pharmacological activities in a wide range of fibrotic diseases. However, whether RD function on skin fibrosis remains unclear. Therefore, in our study, we explored the potential effect and mechanisms of RD on skin fibrosis both in vivo and in vitro. As expected, the results demonstrated that RD alleviated BLM-induced skin fibrosis and attenuates the gross weight of keloid tissues in vivo. Further studies suggested that RD suppressed fibroblast activation and autophagy both in vivo and in vitro. In addition, mechanistic research showed that RD attenuated fibroblasts activation by the TGF-ß1/Smad signaling pathway and inhibited fibroblasts autophagy by the PI3K/Akt/mTOR signaling pathway. In summary, our results demonstrate therapeutic potential of RD for skin fibrosis in the future.

A mouse model of TB-associated lung fibrosis reveals persistent inflammatory macrophage populations during treatment.

Post-TB lung disease (PTLD) causes a significant burden of global disease. Fibrosis is a central component of many clinical features of PTLD. To date, we have a limited understanding of the mechanisms of TB-associated fibrosis and how these mechanisms are similar to or dissimilar from other fibrotic lung pathologies. We have adapted a mouse model of TB infection to facilitate the mechanistic study of TB-associated lung fibrosis. We find that the morphologies of fibrosis that develop in the mouse model are similar to the morphologies of fibrosis observed in human tissue samples. Using Second Harmonic Generation (SHG) microscopy, we are able to quantify a major component of fibrosis, fibrillar collagen, over time and with treatment. Inflammatory macrophage subpopulations persist during treatment; matrix remodeling enzymes and inflammatory gene signatures remain elevated. Our mouse model suggests that there is a therapeutic window during which adjunctive therapies could change matrix remodeling or inflammatory drivers of tissue pathology to improve functional outcomes after treatment for TB infection.

Multi-model analysis of gallbladder cancer reveals the role of OxLDL-absorbing neutrophils in promoting liver invasion.

BACKGROUND: Gallbladder cancer (GBC) is the most common and lethal malignancy of the biliary tract that lacks effective therapy. In many GBC cases, infiltration into adjacent organs or distant metastasis happened long before the diagnosis, especially the direct liver invasion, which is the most common and unfavorable way of spreading. METHODS: Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), proteomics, and multiplexed immunohistochemistry (mIHC) were performed on GBC across multiple tumor stages to characterize the tumor microenvironment (TME), focusing specifically on the preferential enrichment of neutrophils in GBC liver invasion (GBC-LI). RESULTS: Multi-model Analysis reveals the immunosuppressive TME of GBC-LI that was characterized by the enrichment of neutrophils at the invasive front. We identified the context-dependent transcriptional states of neutrophils, with the Tumor-Modifying state being associated with oxidized low-density lipoprotein (oxLDL) metabolism. In vitro assays showed that the direct cell-cell contact between GBC cells and neutrophils led to the drastic increase in oxLDL uptake of neutrophils, which was primarily mediated by the elevated OLR1 on neutrophils. The oxLDL-absorbing neutrophils displayed a higher potential to promote tumor invasion while demonstrating lower cancer cytotoxicity. Finally, we identified a neutrophil-promoting niche at the invasive front of GBC-LI that constituted of KRT17+ GBC cells, neutrophils, and surrounding fibroblasts, which may help cultivate the oxLDL-absorbing neutrophils. CONCLUSIONS: Our study reveals the existence of a subset of pro-tumoral neutrophils with a unique ability to absorb oxLDL via OLR1, a phenomenon induced through cell-cell contact with KRT17+ GBC cells in GBC-LI.

Machine learning assisted mid-infrared spectrochemical fibrillar collagen imaging in clinical tissues.

Significance: Label-free multimodal imaging methods that can provide complementary structural and chemical information from the same sample are critical for comprehensive tissue analyses. These methods are specifically needed to study the complex tumor-microenvironment where fibrillar collagen's architectural changes are associated with cancer progression. To address this need, we present a multimodal computational imaging method where mid-infrared spectral imaging (MIRSI) is employed with second harmonic generation (SHG) microscopy to identify fibrillar collagen in biological tissues. Aim: To demonstrate a multimodal approach where a morphology-specific contrast mechanism guides a mid-infrared spectral imaging method to detect fibrillar collagen based on its chemical signatures. Approach: We trained a supervised machine learning (ML) model using SHG images as ground truth collagen labels to classify fibrillar collagen in biological tissues based on their mid-infrared hyperspectral images. Five human pancreatic tissue samples (sizes are in the order of millimeters) were imaged by both MIRSI and SHG microscopes. In total, 2.8 million MIRSI spectra were used to train a random forest (RF) model. The remaining 68 million spectra were used to validate the collagen images generated by the RF-MIRSI model in terms of collagen segmentation, orientation, and alignment. Results: Compared to the SHG ground truth, the generated MIRSI collagen images achieved a high average boundary F-score (0.8 at 4 pixels threshold) in the collagen distribution, high correlation (Pearson's R 0.82) in the collagen orientation, and similarly high correlation (Pearson's R 0.66) in the collagen alignment. Conclusions: We showed the potential of ML-aided label-free mid-infrared hyperspectral imaging for collagen fiber and tumor microenvironment analysis in tumor pathology samples.

A novel base substitution mutation of the CRYBA2 gene is associated with autosomal dominant congenital cataract.

Congenital cataract is one of the leading causes of vision loss in children, and a large proportion of cases are related to genetics. In a Chinese family, we reported a new missense mutation in CRYBA2 (c.223T>C: p.Tyr75His), which can cause autosomal dominant congenital bilateral cataract. We collected blood samples from family members (mother and two sons) and extracted DNA. Through whole-exome sequencing, we discovered a novel unreported mutation. According to relevant ACMG guidelines, this mutation was determined to be a variant of unknown clinical significance. This article further expands the site information on the CRYBA2 mutations.

Selpercatinib attenuates bleomycin-induced pulmonary fibrosis by inhibiting the TGF-ß1 signaling pathway.

IPF is a chronic, progressive, interstitial lung disease with high mortality. Current drugs have limited efficacy in curbing disease progression and improving quality of life. Selpercatinib, a highly selective inhibitor of receptor tyrosine kinase RET (rearranged during transfection), was approved in 2020 for the treatment of a variety of solid tumors with RET mutations. In this study, the action and mechanism of Selpercatinib in pulmonary fibrosis were evaluated in vivo and in vitro. In vivo experiments demonstrated that Selpercatinib significantly ameliorated bleomycin (BLM)-induced pulmonary fibrosis in mice. In vitro, Selpercatinib inhibited the proliferation, migration, activation and extracellular matrix deposition of fibroblasts by inhibiting TGF-ß1/Smad and TGF-ß1/non-Smad pathway, and suppressed epithelial-mesenchymal transition (EMT) like process of lung epithelial cells via inhibiting TGF-ß1/Smad pathway. The results of in vivo pharmacological tests corroborated the results obtained from the in vitro experiments. Further studies revealed that Selpercatinib inhibited abnormal phenotypes of lung fibroblasts and epithelial cells in part by regulating its target RET. In short, Selpercatinib inhibited the activation of fibroblasts and EMT-like process of lung epithelial cells by inhibiting TGF-ß1/Smad and TGF-ß1/non-Smad pathways, thus alleviating BLM-induced pulmonary fibrosis in mice.

Development of an individualized model for predicting postoperative delirium in elderly patients with hepatocellular carcinoma.

Postoperative delirium (POD) is a common complication in older patients with hepatocellular carcinoma (HCC) that adversely impacts clinical outcomes. We aimed to evaluate the risk factors for POD and to construct a predictive nomogram. Data for a total of 1481 older patients (training set: n=1109; validation set: n=372) who received liver resection for HCC were retrospectively retrieved from two prospective databases. The receiver operating characteristic (ROC) curve, calibration plot, and decision curve analysis (DCA) were used to evaluate the performance. The rate of POD was 13.3% (148/1109) in the training set and 16.4% (61/372) in the validation set. Multivariate analysis of the training set revealed that factors including age, history of cerebrovascular disease, American Society of Anesthesiologists (ASA) classification, albumin level, and surgical approach had significant effects on POD. The area under the ROC curves (AUC) for the nomogram, incorporating the aforementioned predictors, was 0.798 (95% CI 0.752-0.843) and 0.808 (95% CI 0.754-0.861) for the training and validation sets, respectively. The calibration curves of both sets showed a degree of agreement between the nomogram and the actual probability. DCA demonstrated that the newly established nomogram was highly effective for clinical decision-making. We developed and validated a nomogram with high sensitivity to assist clinicians in estimating the individual risk of POD in older patients with HCC.

Multi-omics analysis reveals key regulatory defense pathways and genes involved in salt tolerance of rose plants.

Salinity stress causes serious damage to crops worldwide, limiting plant production. However, the metabolic and molecular mechanisms underlying the response to salt stress in rose (Rosa spp.) remain poorly studied. We therefore performed a multi-omics investigation of Rosa hybrida cv. Jardin de Granville (JDG) and Rosa damascena Mill. (DMS) under salt stress to determine the mechanisms underlying rose adaptability to salinity stress. Salt treatment of both JDG and DMS led to the buildup of reactive oxygen species (H2O2). Palisade tissue was more severely damaged in DMS than in JDG, while the relative electrolyte permeability was lower and the soluble protein content was higher in JDG than in DMS. Metabolome profiling revealed significant alterations in phenolic acid, lipids, and flavonoid metabolite levels in JDG and DMS under salt stress. Proteome analysis identified enrichment of flavone and flavonol pathways in JDG under salt stress. RNA sequencing showed that salt stress influenced primary metabolism in DMS, whereas it substantially affected secondary metabolism in JDG. Integrating these datasets revealed that the phenylpropane pathway, especially the flavonoid pathway, is strongly enhanced in rose under salt stress. Consistent with this, weighted gene coexpression network analysis (WGCNA) identified the key regulatory gene chalcone synthase 1 (CHS1), which is important in the phenylpropane pathway. Moreover, luciferase assays indicated that the bHLH74 transcription factor binds to the CHS1 promoter to block its transcription. These results clarify the role of the phenylpropane pathway, especially flavonoid and flavonol metabolism, in the response to salt stress in rose.

ZNF692 promotes the migration and response to immunotherapy of clear cell renal cell carcinoma cells by targeting metabolic pathway.

Clear cell renal cell carcinoma (ccRCC), with high mortality and poor prognosis, is the most common type of renal malignancy. It is necessary to identify new biomarkers that can serve as indicators for the detection of ccRCC at its early stages. In this study, we analyzed the role of classical zinc finger protein 692 (ZNF692) in ccRCC using datasets from The Cancer Genome Atlas (TCGA) and Single Cell Portal and immunohistochemical (IHC) staining of a tissue-microarray, and analyzed the function of ZNF692 in ccRCC cells. The analyses indicated that ZNF692 was upregulated in ccRCC samples compared with normal or paracancerous control samples (P < 0.001) and that the expression of this gene was linked to poor overall survival (HR = 2.1, P < 0.0001). The knockdown of ZNF692 inhibited the proliferation and migration of ccRCC cells by target GTPase-activating protein (SH3 domain)-binding protein 2 (G3BP2), and transmembrane 9 superfamily member 2 (TM9SF2)). T, B, proximal, and collecting tubule cells are the dominant cell types in normal kidney tissue where ZNF692 is expressed. In addition, immune checkpoint blockade (ICB) therapy dramatically changed the expression patterns of ZNF692. Collectively, these data indicate that ZNF692 may serve as prognosis, and as a potential indicator of the response to ICB therapy, a possibility needs to be verified by a case‒control study.

Application and configuration analysis of electric muck transfer equipment in plateau railway tunnel: a case study in southwest China.

The burgeoning development of railway construction in plateau regions of southwest China necessitates innovative and environmentally sustainable approaches, particularly in the realm of tunnel construction, where the transfer of muck poses significant operational and environmental challenges. This research, pivoting around the application and configuration of electric muck transfer equipment in plateau railway tunnels, seeks to dissect the potentialities and impediments of transitioning from conventional diesel-powered machinery to electric alternatives, with a spotlight on mitigating environmental impacts and enhancing operational efficiency. Through an analytical lens, the study employs a case study methodology, leveraging data and insights from existing electric equipment models and their applications, provided by major manufacturers in China, to weave a comprehensive narrative around the practicalities, specifications, and challenges embedded in the adoption of electric machinery in plateau environments. The findings unveil a nuanced landscape, where the environmental and operational advantages of electric equipment are juxtaposed against a backdrop of technological, financial, and infrastructural hurdles, thereby crafting a complex tapestry of opportunities and challenges. The research further extrapolates policy recommendations and practical guidelines, advocating for a harmonized amalgamation of governmental policies, technological advancements, and strategic planning to navigate through the identified challenges and optimize the integration of electric equipment in tunnel construction practices. Envisaging future research pathways, the study underscores the criticality of perpetuating technological innovations, policy adaptations, and interdisciplinary research to further refine and enhance the application of electric muck transfer equipment in plateau railway tunnel projects, thereby contributing to the broader narrative of sustainable construction practices in challenging terrains.

Base-promoted triple cleavage of CCl2Br: a direct one-pot synthesis of unsymmetrical oxalamide derivatives.

We present a novel, eco-friendly and one-pot approach for synthesizing unsymmetrical oxalamides with the aid of dichloroacetamide and amine/amides in the presence of CBr4 in a basic medium. The use of water as a potent supplement for the oxygen atom source and the detailed mechanism have been disclosed. Moreover, the protocol involves triple cleavage of CCl2Br and the formation of new C-O/C-N bonds, with the advantage of achieving selective bromination using CBr4 with good to excellent yield under mild conditions. The method also demonstrates promise for industrial use, as proven by its effective implementation in gram-scale synthesis conducted in a batch process, along with its utilization in a continuous-flow system.

Alkaloids from Fritillaria przewalskii Bulbs and Their Anti-Alzheimer's Disease Activities.

Three undescribed isosteroidal alkaloids, przewalskines A-C (1-3), as well as seven known alkaloids (4-10) were obtained from Fritillaria przewalskii bulbs. Their structures were deduced by extensive HRESIMS, 1D NMR, and 2D NMR analyses, and their bioactivities were evaluated involving the anti-inflammatory and inhibitory potencies on AChE, BChE, and Aß aggregation. Compound 4 revealed the potent effect on inhibiting Aß aggregation activity with IC50 value of 33.1 µM, AChE activity with IC50 value of 6.9 µM, and also showed NO release inhibitory acitivity with IC50 value of 32.6 µM. These findings contribute new multi-.target anti-AD agents and embody the chemical diversity of F. przewalskii.

Non-destructive detection of egg white and yolk morphology transformation and salt content of salted duck eggs in salting by hyperspectral imaging.

Salt content is a crucial indicator of the maturity and internal quality of salted duck eggs (SDEs) during the pickling process. However, there is currently no valid and rapid method available for accurately detecting salt content. In the present study, we utilized hyperspectral imaging to no-destructively determine the salt content in egg yolks, egg whites, and whole eggs during the curing period. Firstly, principal component analysis was applied to explain the characteristics of egg yolk and white morphology transformation of SDEs with different maturities during curing. Secondly, sensitive spectral factors representative of changes in the salt content of SDEs were extracted by three spectral transformations (Savitzky-Golay SG, continuum removal CR, and first-order derivation FD) and three approaches of selecting characteristic wavelengths (successive projection algorithm SPA, uninformative variables elimination UVE and competitive adaptive reweighting sampling algorithm CARS). The results of the PLSR model suggested that the optimal models for predicting salt content in egg yolks, whites, and whole eggs were SG-UVE-PLSR (predicted coefficient of determination Rp2=0.912, predicted standard deviation SEp=0.151, residual prediction deviation RPD = 3.371), CR-CARS-PLSR (Rp2=0.873, SEp=0.862, RPD = 2.806), and CR-UVE-PLSR (Rp2=0.877, SEp=0.680, RPD = 2.851), respectively. Eventually, the optimal prediction model for the salt content of the whole egg was employed to a pixel spectral matrix to calculate the salt content values of pixel points on the hyperspectral image of SDEs. Additionally, pseudo-color techniques were employed to visualize the spatial distribution of predicted salt content. This work will provide a theoretical foundation for rapidly detecting maturity and enabling high-throughput quality sorting of SDEs.