Sea buckthorn extract mitigates chronic obstructive pulmonary disease by suppression of ferroptosis via scavenging ROS and blocking p53/MAPK pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Sea buckthorn (Hippophae rhamnoides), a traditional Tibetan medicinal herb, exhibits protective effects against cardiovascular and respiratory diseases. Although Sea buckthorn extract (SBE) has been confirmed to alleviate airway inflammation in mice, its therapeutic effect and underlying mechanism on chronic obstructive pulmonary disease (COPD) requires further clarification. AIM OF THE STUDY: To elucidate the alleviative effect and molecular mechanism of SBE on lipopolysaccharides (LPS)/porcine pancreatic elastase (PPE)-induced COPD by blocking ferroptosis. METHODS: The anti-ferroptotic effects of SBE were evaluated in human BEAS-2B bronchial epithelial cells using CCK8, RT-qPCR, western blotting, and transmission electron microscopy. Transwell was employed to detect chemotaxis of neutrophils. COPD model was induced by intranasally administration of LPS/PPE in mice and measured by alterations of histopathology, inflammation, and ferroptosis. RNA-sequencing, western blotting, antioxidant examination, flow cytometry, DARTS, CETSA, and molecular docking were then used to investigate its anti-ferroptotic mechanisms. RESULTS: In vitro, SBE not only suppressed erastin- or RSL3-induced ferroptosis by suppressing lipid peroxides (LPOs) production and glutathione (GSH) depletion, but also suppressed ferroptosis-induced chemotactic migration of neutrophils via reducing mRNA expression of chemokines. In vivo, SBE ameliorated LPS/PPE-induced COPD phenotypes, and inhibited the generation of LPOs, cytokines, and chemokines. RNA-sequencing showed that p53 pathway and mitogen-activated protein kinases (MAPK) pathway were implicated in SBE-mediated anti-ferroptotic action. SBE repressed erastin- or LPS/PPE-induced overactivation of p53 and MAPK pathway, thereby decreasing expression of diamine acetyltransferase 1 (SAT1) and arachidonate 15-lipoxygenase (ALOX15), and increasing expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). Mechanistically, erastin-induced elevation of reactive oxygen species (ROS) was reduced by SBE through directly scavenging free radicals, thereby contributing to its inhibition of p53 and MAPK pathways. CETSA, DARTS, and molecular docking further showed that ROS-generating enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) may be the target of SBE. Overexpression of NOX4 partially impaired the anti-ferroptotic activity of SBE. CONCLUSION: Our results demonstrated that SBE mitigated COPD by suppressing p53 and MAPK pro-ferroptosis pathways via directly scavenging ROS and blocking NOX4. These findings also supported the clinical application of Sea buckthorn in COPD therapy.

Radiomic features on multiparametric MRI for differentiating pseudoprogression from recurrence in high-grade gliomas.

BACKGROUND: Distinguishing between tumor recurrence and pseudoprogression (PsP) in high-grade glioma postoperatively is challenging. This study aims to enhance this differentiation using a combination of intratumoral and peritumoral radiomics. PURPOSE: To assess the effectiveness of intratumoral and peritumoral radiomics in improving the differentiation between high-grade glioma recurrence and pseudoprogression after surgery. MATERIAL AND METHODS: A total of 109 cases were randomly divided into training and validation sets, with 1316 features extracted from intratumoral and peritumoral volumes of interest (VOIs) on conventional magnetic resonance imaging (MRI) and apparent diffusion coefficient (ADC) maps. Feature selection was performed using the mRMR algorithm, resulting in intratumoral (100 features), peritumoral (100 features), and combined (200 features) subsets. Optimal features were then selected using PCC and RFE algorithms and modeled using LR, SVM, and LDA classifiers. Diagnostic performance was compared using area under the receiver operating characteristic curve (AUC), evaluated in the validation set. A nomogram was established using radscores from intratumoral, peritumoral, and combined models. RESULTS: The combined model, utilizing 14 optimal features (8 peritumoral, 6 intratumoral) and LR as the best classifier, outperformed the single intratumoral and peritumoral models. In the training set, the AUC values for the combined model, intratumoral model, and peritumoral model were 0.938, 0.921, and 0.847, respectively; in the validation set, the AUC values were 0.841, 0.755, and 0.705. The nomogram model demonstrated AUCs of 0.960 (training set) and 0.850 (validation set). CONCLUSION: The combination of intratumoral and peritumoral radiomics is effective in distinguishing high-grade glioma recurrence from pseudoprogression after surgery.

Association of the Number of Concurrent Metabolic Syndrome Risk Factors with Textbook Outcomes Following Liver Resection for Patients with Hepatocellular Carcinoma: A Multicenter Study.

BACKGROUND: There is little information regarding the impact of the number of concurrent metabolic syndrome (MetS) risk factors on the textbook outcomes (TO) in patients with hepatocellular carcinoma (HCC) following liver resection. PATIENTS AND METHODS: Data from patients who underwent liver resection between 2015 and 2023 in a multicenter database were retrospectively reviewed (N = 3156). According to the guidelines, MetS risk factors include obesity, hypertension, diabetes, and dyslipidemia. RESULTS: In this study, 2056 (65.1%) patients achieved TO. The incidence of TO was 63.1% in patients with ≥ 1 MetS risk factor, which was lower than that in patients without any MetS risk factors (67.5%, P = 0.011). As the number of MetS risk factors increased, the probability of not achieving TO gradually increased. The non-TO rates in patients with no, 1, 2, and ≥ 3 MetS risk factors were 32.5%, 35.9%, 37.6% and 40.2%, respectively (Ptrend = 0.005). Multivariate logistic regression confirmed that the number of MetS risk factors (0 as a reference; 1, OR 1.220, 95% CI 1.029-1.447, P = 0.022; 2, OR 1.397, 95% CI 1.113-1.755, P = 0.004; ≥ 3, OR 1.647, 95% CI 1.197-2.264, P = 0.002) independently contributed to non-TO in patients with HCC after liver resection. Both the 5-year recurrence-free survival (TO: 50.7% versus non-TO: 43.9%, P < 0.001) and overall survival rates (TO: 71.0% versus non-TO: 58.7%, P < 0.001) of TO patients were significantly better than those of non-TO patients. CONCLUSIONS: Concurrent MetS risk factors can adversely impact TO achievement in patients with HCC after liver resection. The more risk factors patients have, the less likely they are to achieve TO.

Selective Generation of Reactive Oxygen Species in Photocatalytic Oxidation by Tuning Porphyrin-Based COFs' Dimensionality.

Regulating the selective generation of reactive oxygen species (ROS) is a significant challenge in the field of photocatalytic oxidation, with successful approaches still being limited. Herein, we present a strategy to selectively generate singlet oxygen (1O2) and superoxide radicals (O2•-) by tuning the dimensionality of porphyrin-based covalent organic frameworks (COFs). The transformation of COFs from three-dimensional (3D) solids to two-dimensional (2D) sheets was achieved through the reversible protonation of the imine bond. Upon irradiation, both bulk and thin-layer COF-367 can transfer energy to O2 to generate 1O2. However, thin-layer COF-367 exhibited a superior performance compared to its bulk counterpart in activating O2 to form the O2•- radicals via electron transfer. After excluding the influences of the band structure, O2 adsorption energy, and frontier orbital composition attributed to the dimensionality of the COFs, it is reasonably speculated that the variance in ROS generation arises from the differential exposure ratios of the active surfaces, leading to distinct reaction pathways between the carrier and O2. This study is the first to explore the modulation mechanism of COF dimensionality on the activation of the O2 pathway, underscoring the importance of considering COF dimensionality in photocatalytic reactions.

Demethylzeylasteral alleviates inflammation and colitis via dual suppression of NF-κB and STAT3/5 by targeting IKKα/ß and JAK2.

BACKGROUND: Ulcerative colitis (UC) is a common inflammatory bowel disease and a risk factor of colorectal cancer. Demethylzeylasteral (DZT), a bioactive component mainly isolated from Tripterygium wilfordii, has been shown to inhibit inflammation and cancer. However, its anti-UC function and molecular mechanisms have not been well characterized. This study aims to explore the therapeutic effect and functional targets of demethylzeylasteral against UC. METHODS: RT-qPCR, Western blot and ELISA were used to detect the generation of pro-inflammatory cytokines and chemokines in murine macrophage cells. Luciferase reporter gene, Western blot, pull-down, CETSA, DARTS, and virtual docking were employed to detect the anti-inflammatory targets and molecular mechanisms of demethylzeylasteral. The anti-inflammatory and anti-colitis effects of demethylzeylasteral were further determined in DSS-challenged mice. RESULTS: In vitro, demethylzeylasteral inhibited NO and PGE2 production by suppressing the mRNA and protein expression of iNOS and COX-2, and suppressed the mRNA expression of TNF-α, IL-1ß, IL-6, MCP-1, CXCL9, and CXCL10 in RAW264.7 macrophages stimulated by LPS/IFNγ. Furthermore, demethylzeylasteral was not only capable of inhibiting IKKα/ß-NF-κB activation, but also able to block JAKs-STAT3/5 activation in LPS/INFγ-incubated RAW264.7 cells or DSS-exposed colon tissues of mice. Mechanistically, demethylzeylasteral was found to directly bind to IKKα/ß and JAK2 kinases, leading to inactivation of pro-inflammatory signaling cascades and reduced generation of cytokines and chemokines. In vivo, oral administration of demethylzeylasteral significantly attenuated DSS-induced colitis, which was mainly manifested as mitigated symptoms of colitis, colonic mucosal barrier damage, and colonic inflammation. CONCLUSION: We demonstrated that demethylzeylasteral alleviated UC pathology by blocking NF-κB and STAT3/5 pathways via targeting IKKα/ß and JAK2 kinases, raising the possibility that demethylzeylasteral could act as a candidate for the treatment of UC.

Study on the metabolism of Xiao-Jian-Zhong-Tang in rats with chronic atrophic gastritis coupled with bioinformatics.

Xiao-Jian-Zhong-Tang (XJZT) has the effect of warming the middle and tonifying the deficiency, easing the urgency and relieving pain according to the theory of traditional Chinese medicine (TCM), and is able to treat spleen deficiency type chronic atrophic gastritis (CAG). Metabolites of TCM in cecum contents are common metabolites of intestinal bacteria and hosts, which can reflect the metabolic status in disease states. The present work was performed to study the effect of XJZT against CAG coupled with the cecal metabolites analysis and bioinformatics. A total of nine prototypical components and 144 metabolites were firstly identified in the cecum metabolites of XJZT using ultra-high performance liquid chromatography added to the quadrupole-time of flight mass spectrometry (UHPLC-Q-TOF/MS), which underwent the metabolism of oxidation, reduction, methylation, and glucuronic acid reaction Furthermore, different prototypical compounds might metabolize into identical metabolites in the presence of intestinal flora. Bioinformatics was further used to correlate these metabolites with the disease and intestinal flora. Components and targets were screened by Cytoscape, and molecular docking of key targets and core components showed good binding ability. This study provided important information for exploring the mechanism of TCM formulae.

Design and structure-activity relationships of ether-linked alkylides: Hybrids of 3-O-descladinosyl macrolides and quinolone motifs.

Ketolides (3-keto) such as TE-802 and acylides (3-O-acyl) like TEA0929 are ineffective against constitutively resistant pathogens harboring erythromycin ribosomal methylation (erm) genes. Following our previous work on alkylides (3-O-alkyl), we explored the structure-activity relationships of hybrids combining (R/S) 3-descladinosyl erythromycin with 6/7-quinolone motifs, featuring extended ether-linked spacers, with a focus on their efficacy against pathogens bearing constitutive erm gene resistance. Optimized compounds 17a and 31f not only reinstated efficacy against inducibly resistant pathogens but also demonstrated significantly augmented activities against constitutively resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes, which are typically refractory to existing C-3 modified macrolides. Notably, hybrid 31f (coded ZN-51) represented a pioneering class of agents distinguished by its dual modes of action, with ribosomes as the primary target and topoisomerases as the secondary target. As a novel chemotype of macrolide-quinolone hybrids, alkylide 31f is a valuable addition to our armamentarium against macrolide-resistant bacteria.

Geranylgeraniol: Bio-based platform for teprenone, menaquinone-4, and α-tocotrienol synthesis.

By utilizing the conformational selectivity of biosynthesis and the flexibility of chemical synthesis, researchers have formulated metabolic engineering-based semi-synthetic approaches that initiate with the final product's structure and identify key biosynthesis intermediates. Nonetheless, these tailored semi-synthetic routes focused on end-products, neglecting the possibility of biobased intermediates as a platform for derivatization. To address this challenge, this studyproposed a novel strategy resembling chemosynthesis-style divergent exploration to amplify the significance of biobased intermediates, in the case of geranylgeraniol (GGOH). Using the novel bifunctional terpene synthase PTTC066 and systematic metabolic engineering modifications, the engineered yeast straindemonstrated high GGOH production levels (3.32 g/L, 0.039 g/L/h). This platformenabled the semi-synthesis of various pharmaceuticals, including the anti-ulcer drug teprenone, the osteoporosis treatment drug menaquinone-4, and introduced a novel route for synthesizingα-tocotrienol. This study offers a fresh outlook on semi-synthetic approaches, opening avenues for improvements, substitutions, and innovations in industrial production processes.

Photodegradation of Organic Solar Cells under Visible Light and the Crucial Influence of Its Spectral Composition.

While wavelength-dependent photodegradation of organic solar cells (OSCs) under visible light is typically discussed in terms of UV/blue light-activated phenomena, we recently demonstrated wavelength-dependent degradation rates up to 660 nm for PM6:Y6. In this study, we systematically investigated this phenomenon for a broad variety of devices based on different donor:acceptor combinations. We found that the spectral composition of the light used for degradation, tuned in a spectral range from 457 to 740 nm and under high irradiances of up to 30 suns, has a crucial influence on the device stability of almost all tested semiconductors. The relevance of this phenomenon was investigated in the context of simulated AM1.5 illumination with metal halide lamps and white LEDs. It is concluded that the current stability testing protocols in OSC research have to be adjusted to account for this effect to reveal the underlying physics of this still poorly understood mechanism.

Increased adrenal steroidogenesis and suppressed corticosteroid responsiveness in critical COVID-19.

BACKGROUND: The effect of coronavirus disease 2019 (COVID-19) on adrenal endocrine metabolism in critically ill patients remains unclear. This study aimed to investigate the alterations in adrenal steroidogenic activity, elucidate underlying mechanisms, provide in situ histopathological evidence, and examine the clinical implications. METHODS: The comparative analyses of the adrenal cortices from 24 patients with fatal COVID-19 and 20 matched controls were performed, excluding patients previously treated with glucocorticoids. SARS-CoV-2 and its receptors were identified and pathological alterations were examined. Furthermore, histological examinations, immunohistochemical staining and ultrastructural analyses were performed to assess corticosteroid biosynthesis. The zona glomerulosa (ZG) and zona fasciculata (ZF) were then dissected for proteomic analyses. The biological processes that affected steroidogenesis were analyzed by integrating histological, proteomic, and clinical data. Finally, the immunoreactivity and responsive genes of mineralocorticoid and glucocorticoid receptors in essential tissues were quantitatively measured to evaluate corticosteroid responsiveness. FINDINGS: The demographic characteristics of COVID-19 patients were comparable with those of controls. SARS-CoV-2-like particles were identified in the adrenocortical cells of three patients; however, these particles did not affect cellular morphology or steroid synthesis compared with SARS-CoV-2-negative specimens. Although the adrenals exhibited focal necrosis, vacuolization, microthrombi, and inflammation, widespread degeneration was not evident. Notably, corticosteroid biosynthesis was significantly enhanced in both the ZG and ZF of COVID-19 patients. The increase in the inflammatory response and cellular differentiation in the adrenal cortices of patients with critical COVID-19 was positively correlated with heightened steroidogenic activity. Additionally, the appearance of more dual-ZG/ZF identity cells in COVID-19 adrenals was in accordance with the increased steroidogenic function. However, activated mineralocorticoid and glucocorticoid receptors and their responsive genes in vital tissues were markedly reduced in patients with critical COVID-19. INTERPRETATION: Critical COVID-19 was characterized by potentiated adrenal steroidogenesis, associated with increased inflammation, enhanced differentiation and elevated dual-ZG/ZF identity cells, alongside suppressed corticosteroid responsiveness. These alterations implied the reduced effectiveness of conventional corticosteroid therapy and underscored the need for evaluation of the adrenal axis and corticosteroid sensitivity.

Design, synthesis and structure-activity relationships of novel non-ketolides: 9-Oxime clarithromycin featured with seven-to thirteen-atom-length diamine linkers at 3-OH.

We report here on the structure-activity relationships of hybrids combining 3-descladinosyl clarithromycin with quinolones linked by extended diamine connectors. Several hybrids, exemplified by 23Bc, 23Be, 23Bf, 26Be, and 30Bc, not only restored potency against inducibly resistant pathogens but also exhibited significantly enhanced activities against constitutively resistant strains of Staphylococcus pneumoniae and Staphylococcus pyogenes, which express high-level resistance independent of clarithromycin or erythromycin induction. Additionally, the novel hybrids showed susceptibility against Gram-negative Haemophilus influenzae. Notably, hybrid 23Be demonstrated dual modes of action by inhibiting both protein synthesis and DNA replication in vitro and in vivo. Given these promising characteristics, 23Be emerges as a potential candidate for the treatment of community-acquired bacterial pneumonia.

Synthetic macrolides overcoming MLSBK-resistant pathogens.

Conventional macrolide-lincosamide-streptogramin B-ketolide (MLSBK) antibiotics are unable to counter the growing challenge of antibiotic resistance that is conferred by the constitutive methylation of rRNA base A2058 or its G2058 mutation, while the presence of unmodified A2058 is crucial for high selectivity of traditional MLSBK in targeting pathogens over human cells. The absence of effective modes of action reinforces the prevailing belief that constitutively antibiotic-resistant Staphylococcus aureus remains impervious to existing macrolides including telithromycin. Here, we report the design and synthesis of a novel series of macrolides, featuring the strategic fusion of ketolide and quinolone moieties. Our effort led to the discovery of two potent compounds, MCX-219 and MCX-190, demonstrating enhanced antibacterial efficacy against a broad spectrum of formidable pathogens, including A2058-methylated Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and notably, the clinical Mycoplasma pneumoniae isolates harboring A2058G mutations which are implicated in the recent pneumonia outbreak in China. Mechanistic studies reveal that the modified quinolone moiety of MCX-190 establishes a distinctive secondary binding site within the nascent peptide exit tunnel. Structure-activity relationship analysis underscores the importance of this secondary binding, maintained by a sandwich-like π-π stacking interaction and a water-magnesium bridge, for effective engagement with A2058-methylated ribosomes rather than topoisomerases targeted by quinolone antibiotics. Our findings not only highlight MCX-219 and MCX-190 as promising candidates for next-generation MLSBK antibiotics to combat antibiotic resistance, but also pave the way for the future rational design of the class of MLSBK antibiotics, offering a strategic framework to overcome the challenges posed by escalating antibiotic resistance.

Whole-exome sequencing in a cohort of Chinese patients with isolated cervical dystonia.

Background: Dystonia is a kind of movement disorder but its pathophysiological mechanisms are still largely unknown. Recent evidence reveals that genetical defects may play important roles in the pathogenesis of dystonia. Objectives and Methods: -To explore possible causative genes in Chinese dystonia patients, DNA samples from 42 sporadic patients with isolated cervical dystonia were subjected to whole-exome sequencing. Rare deleterious variants associated with dystonia phenotype were screened out and then classified according to the American College of Medical Genetics and Genomics (ACMG) criteria. Phenolyzer was used for analyzing the most probable candidates correlated with dystonia phenotype, and SWISS-MODEL server was for predicting the 3D structures of variant proteins. Results: Among 42 patients (17 male and 25 female) recruited, a total of 36 potentially deleterious variants of dystonia-associated genes were found in 30 patients (30/42, 71.4 %). Four disease-causing variants including a pathogenic variant in PLA2G6 (c.797G > C) and three likely pathogenic variants in DCTN1 (c.73C > T), SPR (c.1A > C) and TH (c.56C > G) were found in four patients separately. Other 32 variants were classified as uncertain significance in 26 patients. Phenolyzer prioritized genes TH, PLA2G6 and DCTN1 as the most probable candidates correlated with dystonia phenotype. Although 3D prediction of DCTN1 and PLA2G6 variant proteins detected no obvious structural alterations, the mutation in DCTN1 (c.73C > T:p.Arg25Trp) was closely adjacent to its key functional domain. Conclusion: Our whole-exome sequencing results identified a novel variant in DCTN1 in sporadic Chinese patients with isolated cervical dystonia, which however, needs our further study on its exact role in dystonia pathogenesis.

A time-resolved multi-omics atlas of transcriptional regulation in response to high-altitude hypoxia across whole-body tissues.

High-altitude hypoxia acclimatization requires whole-body physiological regulation in highland immigrants, but the underlying genetic mechanism has not been clarified. Here we use sheep as an animal model for low-to-high altitude translocation. We generate multi-omics data including whole-genome sequences, time-resolved bulk RNA-Seq, ATAC-Seq and single-cell RNA-Seq from multiple tissues as well as phenotypic data from 20 bio-indicators. We characterize transcriptional changes of all genes in each tissue, and examine multi-tissue temporal dynamics and transcriptional interactions among genes. Particularly, we identify critical functional genes regulating the short response to hypoxia in each tissue (e.g., PARG in the cerebellum and HMOX1 in the colon). We further identify TAD-constrained cis-regulatory elements, which suppress the transcriptional activity of most genes under hypoxia. Phenotypic and transcriptional evidence indicate that antenatal hypoxia could improve hypoxia tolerance in offspring. Furthermore, we provide time-series expression data of candidate genes associated with human mountain sickness (e.g., BMPR2) and high-altitude adaptation (e.g., HIF1A). Our study provides valuable resources and insights for future hypoxia-related studies in mammals.

The potential application and molecular mechanisms of natural products in the treatment of allergic rhinitis: A review.

BACKGROUNDS: Allergic rhinitis (AR) is a non-infectious chronic inflammation of the nasal mucosa mainly mediated by immunoglobulin E (IgE) in atopic individuals after exposure to allergens. The application of AR guideline-recommended pharmacotherapies can rapidly relieve symptoms of AR but with poor long-term efficacy, and many of these therapies have side effects. Many natural products and their derivatives have shown potential therapeutic effects on AR with fewer side effects. OBJECTIVES: This review aims to expand understanding of the roles and mechanisms of natural compounds in the treatment of AR and to highlight the importance of utilizing natural products in the treatment of AR. MATERIAL AND METHOD: We conducted a systematic literature search using PubMed, Web of Science, Google Scholar, and Clinical Trials. The search was performed using keywords including natural products, natural compounds, bioproducts, plant extracts, naturally derived products, natural resources, allergic rhinitis, hay fever, pollinosis, nasal allergy. Comprehensive research and compilation of existing literature were conducted. RESULTS: This article provided a comprehensive review of the potential therapeutic effects and mechanisms of natural compounds in the treatment of AR. We emphasized that natural products primarily exert their effects by modulating signalling pathways such as NF-κB, MAPKs, STAT3/ROR-γt/Foxp3, and GATA3/T-bet, thereby inhibiting the activation and expansion of allergic inflammation. We also discussed their toxicity and clinical applications in AR therapy. CONCLUSION: Taken together, natural products exhibit great potential in the treatment of AR. This review is also expected to facilitate the application of natural products as candidates for treating AR. Furthermore, drug discovery based on natural products has a promising prospect in AR treatment.

Efficient Electrosynthesis of Urea over Single-Atom Alloy with Electronic Metal Support Interaction.

Urea electrosynthesis from carbon dioxide (CO2) and nitrate (NO3 -) is an alternative approach to traditional energy-intensive urea synthesis technology. Herein, we report a CuAu single-atom alloy (SAA) with electronic metal support interaction (EMSI), achieving a high urea yield rate of 813.6 µg h-1 mgcat -1 at -0.94 V versus reversible hydrogen electrode (vs. RHE) and a Faradaic efficiency (FE) of 45.2 % at -0.74 V vs. RHE. In situ experiments and theoretical calculations demonstrated that single-atom Cu sites modulate the adsorption behavior of intermediate species. Bimetallic sites synergistically accelerate C-N bond formation through spontaneous coupling of *CO and *NO to form *ONCO as key intermediates. More importantly, electronic metal support interaction between CuAu SAA and CeO2 carrier further modulates electron structure and interfacial microenvironment, endowing electrocatalysts with superior activity and durability. This work constructs SAA electrocatalysts with EMSI effect to tailor C-N coupling at the atomic level, which can provide guidance for the development of C-N coupling systems.

Disorganized adrenocortical zonational structure in COVID-19 patients: Implications of critical illness duration.

Aberrant adrenal function has been frequently reported in COVID-19 patients, but histopathological evidence remains limited. This retrospective autopsy study aims to scrutinize the impact of COVID-19 duration on adrenocortical zonational architecture and peripheral corticosteroid reactivity. The adrenal glands procured from 15 long intensive care unit (ICU)-stay COVID-19 patients, 9 short ICU-stay COVID-19 patients, and 20 matched controls. Subjects who had received glucocorticoid treatment prior to sampling were excluded. Applying hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining, we disclosed that the adrenocortical zonational structure was substantially disorganized in COVID-19 patients, which long ICU-stay patients manifested a higher prevalence of severe disorganization (67%) than short ICU-stay patients (11%; P = 0.0058). The adrenal cortex of COVID-19 patients exhibited a 40% decrease in the zona glomerulosa (ZG) area and a 74% increase in the zona fasciculata (ZF) area (both P < 0.0001) relative to controls. Furthermore, among long ICU-stay COVID-19 patients, the ZG area diminished by 31% (P = 0.0004), and the ZF area expanded by 27% (P = 0.0004) in comparison to short ICU-stay patients. The zona reticularis (ZR) area remained unaltered. Nuclear translocation of corticosteroid receptors in the liver and kidney of long ICU-stay COVID-19 patients was at least 43% lower than in short ICU-stay patients (both P < 0.05). These findings underscore the necessity for clinicians to monitor adrenal function in long-stay COVID-19 patients.

VX-509 attenuates the stemness characteristics of colorectal cancer stem-like cells by regulating the epithelial-mesenchymal transition through Nodal/Smad2/3 signaling.

BACKGROUND: Colorectal cancer stem cells (CCSCs) are heterogeneous cells that can self-renew and undergo multidirectional differentiation in colorectal cancer (CRC) patients. CCSCs are generally accepted to be important sources of CRC and are responsible for the progression, metastasis, and therapeutic resistance of CRC. Therefore, targeting this specific subpopulation has been recognized as a promising strategy for overcoming CRC. AIM: To investigate the effect of VX-509 on CCSCs and elucidate the underlying mechanism. METHODS: CCSCs were enriched from CRC cell lines by in conditioned serum-free medium. Western blot, Aldefluor, transwell and tumorigenesis assays were performed to verify the phenotypic characteristics of the CCSCs. The anticancer efficacy of VX-509 was assessed in HCT116 CCSCs and HT29 CCSCs by performing cell viability analysis, colony formation, sphere formation, flow cytometry, and western blotting assessments in vitro and tumor growth, immunohistochemistry and immunofluorescence assessments in vivo. RESULTS: Compared with parental cells, sphere cells derived from HCT116 and HT29 cells presented increased expression of stem cell transcription factors and stem cell markers and were more potent at promoting migration and tumorigenesis, demonstrating that the CRC sphere cells displayed CSC features. VX-509 inhibited the tumor malignant biological behavior of CRC-stem-like cells, as indicated by their proliferation, migration and clonality in vitro, and suppressed the tumor of CCSC-derived xenograft tumors in vivo. Besides, VX-509 suppressed the CSC characteristics of CRC-stem-like cells and inhibited the progression of epithelial-mesenchymal transition (EMT) signaling in vitro. Nodal was identified as the regulatory factor of VX-509 on CRC stem-like cells through analyses of differentially expressed genes and CSC-related database information. VX-509 markedly downregulated the expression of Nodal and its downstream phosphorylated Smad2/3 to inhibit EMT progression. Moreover, VX-509 reversed the dedifferentiation of CCSCs and inhibited the progression of EMT induced by Nodal overexpression. CONCLUSION: VX-509 prevents the EMT process in CCSCs by inhibiting the transcription and protein expression of Nodal, and inhibits the dedifferentiated self-renewal of CCSCs.