Design and evaluation of oseltamivir phosphate dual-phase extended-release tablets for the treatment of influenza.

In this study, once-daily extended-release tablets with dual-phase release of oseltamivir phosphate were developed for the treatment of influenza. The goal was to improve patient adherence and offer more therapeutic choices. The tablets were manufactured using wet granulation, bilayer tablet compression, and enteric membrane-controlled coating processes. Various polymers, such as hydroxypropyl methylcellulose (HPMC K100MCR, K15MCR, K4MCR, K100LV), enteric polymers (HPMC AS-LF, Eudragit L100-55) and membrane-controlled polymers (OPADRY® CA), were used either individually or in combination with other common excipients. The formulations include enteric-coated extended-release tablet (F1), hydrophilic matrix extended-release tablet (F2), semipermeable membrane-controlled release tablet (F3) and a combination extended-release tablet containing both enteric and hydrophilic matrix (F4). The in vitro drug release profile of each formulation was fitted to the first-order model, and the Ritger-Peppas model suggested that Fickian diffusion was the primary mechanism for drug release. Comparative bioequivalence studies with Tamiflu® (oseltamivir phosphate) capsules revealed that formulations F1, F2, and F3 did not achieve bioequivalence. However, under fed conditions, formulation F4 achieved bioequivalence with a relative bioavailability of 95.30% (90% CI, 88.83%-102.15%). This suggests that the formulation F4 tablet could potentially be a new treatment option for patients with influenza.

Comprehensive evaluation of the mechanism of Banxia Baizhu Tianma Decoction in ameliorating posterior circulation ischemia vertigo based on integrating fecal short-chain fatty acids and 16S rRNA sequencing.

Posterior circulation ischemia vertigo (PCIV) is vertebrobasilar insufficiency resulting in vertigo. Banxia Baizhu Tianma Decoction (BBTD) is broadly applied to treat PCIV in China, but its efficacy and detailed mechanism remains unclear. Therefore, this study aims to investigate the effects of BBTD on PCIV, and identify important gut microbiota and its derived short-chain fatty acid (SCFA) changes and the detailed mechanism through 16 S rRNA sequencing with SCFAs profiling. In this study, the model of PCIV was established by surgical ligation of the right subclavian artery (RSCA) and right common carotid artery (RCCA). We found that BBTD administration effectively reduced the volume of cerebral infarction and improved neurologic functions, reduced neuronal apoptosis and neuroinflammatory. Moreover, BBTD significantly modulated the diversity and composition of the gut microbiota, including increasing the relative abundance of Lactobacillus, Prevotella and Akkermansia and decreasing relative abundances of Lachnospiraceae, Bacteroidetes (S24-7) and Ruminococcaceae. BBTD treatment also increased propionate content. Propionate mediates the the recovery of neurological functions and anti-apoptotic effects of BBTD in PCIV rat. Our findings wish to discover the potential mechanism of BBTD treatment on PCIV and promote its clinical application.

Characterization of key odorants in 'Baimaocha' black teas from different regions.

'Baimmaocha' is a distinctive resource for production of high-quality black tea, and its processed black tea has unique aroma characteristics. 190 volatile compounds were identified by comprehensive two-dimensional gas chromatography-olfactometry-quadrupole-time-of-flight mass spectrometry(GC × GC-O-Q-TOMS), and among them 23 compounds were recognized as key odorants contributing to forming different aroma characteristics in 'Baimaocha' black teas of Rucheng, Renhua, and Lingyun (RCBT, RHBT, LYBT). The odor activity value coupled with GC-O showed that methyl salicylate (RCBT), geraniol (RHBT), trans-ß-ionone and benzeneacetaldehyde (LYBT) might be the most definitive aroma compounds identified from their respective regions. Furthermore, PLS analysis revealed three odorants as significant contributors to floral characteristic, four odorants related to fruity attribute, four odorants linked to fresh attribute, and three odorants associated with roasted attribute. These results provide novel insights into sensory evaluation and chemical substances of 'Baimaocha' black tea and provide a theoretical basis for controlling and enhancement tea aroma quality.

Identifying ALOX15-initiated lipid peroxidation increases susceptibility to ferroptosis in asthma epithelial cells.

Ferroptosis is a programmed form of cell death regulated by iron and has been linked to the development of asthma. However, the precise mechanisms driving ferroptosis in asthma remain elusive. To gain deeper insights, we conducted an analysis of nasal epithelial and sputum samples from the GEO database using three machine learning methods. Our investigation identified a pivotal gene, Arachidonate 15-lipoxygenase (ALOX15), associated with ferroptosis in asthma. Through both in vitro and in vivo experiments, we further confirmed the significant role of ALOX15 in ferroptosis in asthma. Our results demonstrate that ferroptosis manifests in an HDM/LPS-induced allergic airway inflammation (AAI) mouse model, mimicking human asthma, and in HDM/LPS-stimulated 16HBE cells. Moreover, we observed an up-regulation of ALOX15 expression in HDM/LPS-induced mice and cells. Notably, silencing ALOX15 markedly decreased HDM/LPS-induced ferroptosis in 16HBE cells. These findings indicate that ferroptosis may be implicated in the onset and progression of asthma, with ALOX15-induced lipid peroxidation raising the susceptibility to ferroptosis in asthmatic epithelial cells.

The efficacy of cognitive behavioral therapies for depression in China in comparison with the rest of the world: A systematic review and meta-analysis.

OBJECTIVE: There is consistent evidence that cognitive behavioral therapies (CBTs) are effective interventions for adult depression. While some evidence has compared these effects in different countries, no prior systematic review and meta-analysis has compared the efficacy of CBTs between Chinese and people from the rest of the world. The current meta-analysis addressed this gap by a systematic review of eligible studies from Chinese and worldwide databases. METHOD: Hedges' g was calculated using a random-effects model. Subgroup analyses and multilevel meta-analytic models were conducted to examine the relationship among effect sizes and the characteristics in Chinese studies. Metaregression analyses were conducted to explore the difference of the efficacy of CBTs between Chinese studies and non-Chinese studies after controlling for the moderators. RESULTS: A total of 34 (n = 3,710) studies in China and 307 (n = 30,333) studies from the rest of the world were included. The effect size of CBTs on depression for Chinese participants was 1.19 (95% CI [0.86, 1.52]), which was higher (Q = 4.63, p = .03) than the effect size of the rest of the world (0.82, 95% CI [0.74, 0.90]). After controlling for moderators, the effect size of Chinese studies was still higher than non-Chinese studies (ß = 0.351, p = .011). CONCLUSIONS: CBTs are effective interventions for adult depression and deserve more attention in China for depression management. Moderators related to study design, clinical features, and cultural factors need to be considered in the interpretation of the results. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Exploring the inhibitory potential of KPHs-AL-derived GLLF peptide on pancreatic lipase and cholesterol esterase activities.

The effective modulation of pancreatic lipase and cholesterol esterase activities proves critical in maintaining circulatory triglycerides and cholesterol levels within physiological boundaries. In this study, peptides derived from KPHs-AL, produced through the enzymatic hydrolysis of skipjack tuna dark muscle using alkaline protease, have a specific inhibitory effect on pancreatic lipase and cholesterol esterase. It is hypothesized that these peptides target and modulate the activities of enzymes by inducing conformational changes within their binding pockets, potentially impacting the catalytic functions of both pancreatic lipase and cholesterol esterase. Results revealed these peptides including AINDPFIDL, FLGM, GLLF and WGPL, were found to nestle into the binding site groove of pancreatic lipase and cholesterol esterase. Among these, GLLF stood out, demonstrating potent inhibition with IC50 values of 0.1891 mg/mL and 0.2534 mg/mL for pancreatic lipase and cholesterol esterase, respectively. The kinetics studies suggested that GLLF competed effectively with substrates for the enzyme active sites. Spectroscopic analyses, including ultraviolet-visible, fluorescence quenching, and circular dichroism, indicated that GLLF binding induced conformational changes within the enzymes, likely through hydrogen bond formation and hydrophobic interactions, thereby increasing structural flexibility. Molecular docking and molecular dynamics simulations supported these findings, showing GLLF's stable interaction with vital active site residues. These findings position GLLF as a potent inhibitor of key digestive enzymes, offering insights into its role in regulating lipid metabolism and highlighting its potential as functional ingredient.

Propeller vs Quasi-Planar 6-Cantilever Small Molecular Platforms with Extremely Two-Dimensional Conjugated Extension.

Two exotic 6-cantilever small molecular platforms, characteristic of quite different molecular configurations of propeller and quasi-plane, are established by extremely two-dimensional conjugated extension. When applied in small molecular acceptors, the only two cases of CH25 and CH26 that could contain six terminals and such broad conjugated backbones have been afforded thus far, rendering featured absorptions, small reorganization and exciton binding energies. Moreover, their distinctive but completely different molecular geometries result in sharply contrasting nanoscale film morphologies. Finally, CH26 contributes to the best device efficiency of 15.41 % among acceptors with six terminals, demonstrating two pioneered yet highly promising 6-cantilever molecular innovation platforms.

Preparation of Enzyme-Soluble Swim Bladder Collagen from Sea Eel (Muraenesox cinereus) and Evaluation Its Wound Healing Capacity.

In the present research, the enzyme-facilitated collagen from sea eel (Muraenesox cinereus) swim bladder was isolated, and the collagen characteristics were analyzed. Then, the collagen sponge was prepared and its potential mechanism in promoting skin wound healing in mice was further investigated. Collagen was obtained from the swim bladder of sea eels employing the pepsin extraction technique. Single-factor experiments served as the basis for the response surface method (RSM) to optimize pepsin concentration, solid-liquid ratio, and hydrolysis period. With a pepsin concentration of 2067 U/g, a solid-liquid ratio of 1:83 g/mL, and a hydrolysis period of 10 h, collagen extraction achieved a yield of 93.76%. The physicochemical analysis revealed that the extracted collagen belonged to type I collagen, and the collagen sponge displayed a fibrous structure under electron microscopy. Furthermore, in comparison to the control group, mice treated with collagen sponge dressing exhibited elevated activities of superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (T-AOC), and glutathione peroxidase (GSH-Px), and decreased levels of malondialdehyde (MDA), interleukin (IL)-1ß, interleukin (IL)-6, and tumor necrosis factor (TNF)-α. The collagen sponge dressing effectively alleviated inflammation in the wound area, facilitating efficient repair and rapid healing of the skin tissue. During the initial phase of wound healing, the group treated with collagen sponge dressing exhibited an enhancement in the expressions of cluster of differentiation (CD)31, epidermal growth factor (EGF), transforming growth factor (TGF)-ß1, and type I collagen, leading to an accelerated rate of wound healing. In addition, this collagen sponge dressing could also downregulate the expressions of CD31, EGF, and type I collagen to prevent scar formation in the later stage. Moreover, this collagen treatment minimized oxidative damage and inflammation during skin wound healing and facilitated blood vessel formation in the wound. Consequently, it exhibits significant potential as an ideal material for the development of a skin wound dressing.

Functional and structural MRI based obsessive-compulsive disorder diagnosis using machine learning methods.

BACKGROUND: The success of neuroimaging in revealing neural correlates of obsessive-compulsive disorder (OCD) has raised hopes of using magnetic resonance imaging (MRI) indices to discriminate patients with OCD and the healthy. The aim of this study was to explore MRI based OCD diagnosis using machine learning methods. METHODS: Fifty patients with OCD and fifty healthy subjects were allocated into training and testing set by eight to two. Functional MRI (fMRI) indices, including amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo), degree of centrality (DC), and structural MRI (sMRI) indices, including volume of gray matter, cortical thickness and sulcal depth, were extracted in each brain region as features. The features were reduced using least absolute shrinkage and selection operator regression on training set. Diagnosis models based on single MRI index / combined MRI indices were established on training set using support vector machine (SVM), logistic regression and random forest, and validated on testing set. RESULTS: SVM model based on combined fMRI indices, including ALFF, fALFF, ReHo and DC, achieved the optimal performance, with a cross-validation accuracy of 94%; on testing set, the area under the receiver operating characteristic curve was 0.90 and the validation accuracy was 85%. The selected features were located both within and outside the cortico-striato-thalamo-cortical (CSTC) circuit of OCD. Models based on single MRI index / combined fMRI and sMRI indices underperformed on the classification, with a largest validation accuracy of 75% from SVM model of ALFF on testing set. CONCLUSION: SVM model of combined fMRI indices has the greatest potential to discriminate patients with OCD and the healthy, suggesting a complementary effect of fMRI indices on the classification; the features were located within and outside the CSTC circuit, indicating an importance of including various brain regions in the model.

A comparison of 'not just right experiences' in obsessive-compulsive disorder, anxiety and depressive disorders and non-clinical controls in China.

OBJECTIVE: The aim of this study is to investigate the characteristics of 'not just right experiences' (NJREs) in patients with obsessive-compulsive disorder (OCD), anxiety disorders (ADs) or major depressive disorder (MDD), compared with those of healthy controls (HCs). METHOD: One hundred adults with OCD, 86 adults with ADs, 57 adults with MDD and 60 HCs were enrolled in the study. The Not Just Right Experiences Questionnaire Revised (NJRE-QR), Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) were used to evaluate clinical symptoms in patients with OCD, ADs or MDD. The Obsessive Belief Questionnaire-44 (OBQ-44) was used to evaluate OC beliefs in the OCD patients. The HCs only received assessment using the NJRE-QR. Analysis of variance (ANOVA) and covariance (ANCOVA) were performed to compare the NJREs scores across the groups, while Pearson correlation and partial correlation analyses were used to examine the association between NJREs and other clinical features. The contribution of NJREs to predict OC symptoms was determined by multiple stratified linear regression. RESULTS: Individuals with OCD had significantly higher scores for the number of NJREs than ADs, but not MDD. The severity of NJREs was also significantly higher in patients with OCD than those with MDD or ADs (F = 5.23 and F = 19.79, respectively, P < 0.01). All the clinical scores in the NJRE-QR were significantly higher than those in the HC group. The number and severity of NJREs correlated significantly with the Y-BOCS total score (r = 0.29 and r = 0.39, respectively, P < 0.01). NJREs showed an independent contribution to OC symptoms, which alone explained 8% of the variation (F = 16.49, ΔR2 = 0.08; P < 0.01). CONCLUSION: NJREs are related closely to OC symptoms, with their severity discriminating between OCD patients and those with ADs or MDD. NJREs were more specific for OCD in the Chinese population and are therefore worthy of further study in the future.

Multilevel resistive switching memory in lead-free double perovskite La[Formula: see text]NiFeO[Formula: see text] films.

Dense and flat La[Formula: see text]NiFeO[Formula: see text] (LNFO) films were fabricated on the indium tin oxide-coated glass (ITO/glass) substrate by sol-gel method. The bipolar resistive switching behavior (BRS) could be maintained in 100 cycles and remained after 30 days, indicating that the LNFO-based RS device owned good memory stability. Surprisingly, the multilevel RS characteristics were firstly observed in the Au/LNFO/ITO/glass device. The high resistance states (HRSs) and low resistance state (LRS) with the maximum ratio of [Formula: see text] 500 could be remained stably in 900 s and 130 cycles, demonstrating the fine retention and endurance ability of this LNFO-based RS device. The BRS behavior of Au/LNFO/ITO/glass devices primarily obeyed the SCLC mechanism controlled by oxygen vacancies (OVs) dispersed in the LNFO layer. Under the external electric field, injected electrons were captured or discharged by OVs during trapping or detrapping process in the LNFO layer. Thus, the resistive state switched between HRS and LRS reversibly. Moreover, the modulation of Schottky-like barrier formed at the Au/LNFO interface was contributed to the resistive states switchover. It was related to the change in OVs located at the dissipative region near the Au/LNFO interface. The multilevel RS ability of LNFO-based devices in this work provides an opportunity for researching deeply on the high density RS memory in lead-free double perovskite oxides-based devices.

Integrated biomarker profiling of the metabolome associated with type 2 diabetes mellitus among Tibetan in China.

INTRODUCTION: Metabolomic signatures of type 2 diabetes mellitus (T2DM) in Tibetan Chinese population, a group with high diabetes burden, remain largely unclear. Identifying the serum metabolite profile of Tibetan T2DM (T-T2DM) individuals may provide novel insights into early T2DM diagnosis and intervention. METHODS: Hence, we conducted untargeted metabolomics analysis of plasma samples from a retrospective cohort study with 100 healthy controls and 100 T-T2DM patients by using liquid chromatography-mass spectrometry. RESULTS: The T-T2DM group had significant metabolic alterations that are distinct from known diabetes risk indicators, such as body mass index, fasting plasma glucose, and glycosylated hemoglobin levels. The optimal metabolite panels for predicting T-T2DM were selected using a tenfold cross-validation random forest classification model. Compared with the clinical features, the metabolite prediction model provided a better predictive value. We also analyzed the correlation of metabolites with clinical indices and found 10 metabolites that were independently predictive of T-T2DM. CONCLUSION: By using the metabolites identified in this study, we may provide stable and accurate biomarkers for early T-T2DM warning and diagnosis. Our study also provides a rich and open-access data resource for optimizing T-T2DM management.

Advances in Genetics and Epigenetics of Developmental Coordination Disorder in Children.

Developmental coordination disorder (DCD) is a developmental disorder characterized by impaired motor coordination, often co-occurring with attention deficit disorder, autism spectrum disorders, and other psychological and behavioural conditions. The aetiology of DCD is believed to involve brain changes and environmental factors, with genetics also playing a role in its pathogenesis. Recent research has identified several candidate genes and genetic factors associated with motor impairment, including deletions, copy number variations, single nucleotide polymorphisms, and epigenetic modifications. This review provides an overview of the current knowledge in genetic research on DCD, highlighting the importance of continued research into the underlying genetic mechanisms. While evidence suggests a genetic contribution to DCD, the evidence is still in its early stages, and much of the current evidence is based on studies of co-occurring conditions. Further research to better understand the genetic basis of DCD could have important implications for diagnosis, treatment, and our understanding of the condition's aetiology.

Schisandrin A ameliorates airway inflammation in model of asthma by attenuating Th2 response.

Asthma is a persistent respiratory ailment that displays periodicity and is linked to the equilibrium of T cells. Several compounds obtained from Chinese herbal medicines display beneficial impacts on T cell regulation and the attenuation of inflammatory mediator synthesis. Schisandrin A, an active lignan derived from the Schisandra fruit, exhibits anti-inflammatory characteristics. In the present study, the network analysis conducted revealed that the nuclear factor-kappaB (NF-κB) signaling pathway is likely a prominent contributor to the anti-asthmatic effects of schisandrin A. In addition, it has been established that the inhibition of cyclooxygenase 2 (COX-2/PTGS2) is likely a significant factor in this process. The results of in vitro experiments have substantiated that schisandrin A can effectively lower the expression of COX-2 and inducible nitric oxide synthase (iNOS) in 16 HBE cells and RAW264.7 cells in a manner that is dependent on the dosage administered. It was able to effectively reduce the activation of the NF-κB signaling pathway while simultaneously improving the injury to the epithelial barrier function. Furthermore, an investigation utilizing immune infiltration as a metric revealed an inequity in Th1/Th2 cells and a surge in Th2 cytokines in asthma patients. In the OVA-induced asthma mice model, it was observed that schisandrin A treatment effectively suppressed inflammatory cell infiltration, reduced the Th2 cell ratio, inhibited mucus secretion, and prevented airway remodeling. To summarize, the administration of schisandrin A has been found to effectively alleviate the symptoms of asthma by impeding the production of inflammation, which includes reducing the Th2 cell ratio and improving the integrity of the epithelial barrier function. These findings offer valuable insights into the potential therapeutic applications of schisandrin A for the treatment of asthma.

FKBP11 upregulation promotes proliferation and migration in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related deaths world over. Early diagnosis and effective treatment monitoring significantly improves patients' outcomes. FKBP11 gene is highly expressed in HCC and could play a role in its development, early diagnosis and treatment. OBJECTIVE: This study aimed to evaluate the expression of FKBP11 in HCC, its correlation with patients' clinical characteristics and potential role in HCC development. METHODS: Expression was determined by bioinformatics analysis, quantitative real-time PCR, western blot, and immunohistochemistry. CCK-8, Transwell and wound healing assays were used to investigate involvement in HCC development. RESULTS: FKBP11 was significantly upregulated in HCC cells, tissues and blood (all p< 0.001). Its receiver operator characteristic (ROC) curve had an AUC of 0.864 (95% CI: 0.823-0.904), at a sensitivity of 0.86 and specificity of 0.78 indicating a good diagnostic potential in HCC. Its expression was markedly reduced after surgery (p< 0.0001), indicating a potential application in HCC treatment follow-up. Knockdown of FKBP11 in HCC cells attenuated proliferation and migration, suggesting a possible role in HCC pathogenesis. CONCLUSION: This study thus found that FKBP11 is upregulated in HCC, and the upregulation promotes HCC development. FKBP11 levels are significantly reduced post-surgery and could be a potential diagnostic and prognostic marker for HCC.

Perineal nerve block versus periprostatic block for patients undergoing transperineal prostate biopsy (APROPOS): a prospective, multicentre, randomised controlled study.

Background: We aimed to investigate perineal nerve block versus periprostatic block in pain control for men undergoing a transperineal prostate biopsy. Methods: In this prospective, randomised, blinded and parallel-group trial, men in six Chinese hospitals with suspected prostate cancer were randomly assigned (1:1) at the point of local anaesthesia to receive a perineal nerve block or periprostatic block and followed by a transperineal prostate biopsy. Centres used their usual biopsy procedure. Operators who performed anaesthesia were trained in both techniques before the trial and were masked to the randomised allocation until the time of anaesthesia and were not involved in the subsequent biopsy procedure and any assessment or analysis. Other investigators and the patients were masked until trial completion. The primary outcome was the level of the worst pain experienced during the prostate biopsy procedure. Secondary outcomes included pain (post-biopsy at 1, 6 and 24 h), changes in blood pressure, heart rate and breathing rate during the biopsy procedure, external manifestations of pain during biopsy, anaesthesia satisfaction, the detection rate of PCa and clinically significant PCa. This trial is registered on ClinicalTrials.gov, NCT04501055. Findings: Between August 13, 2020, and July 20, 2022, 192 men were randomly assigned to perineal nerve block or periprostatic block, 96 per study group. Perineal nerve block was superior for the relief of pain during the biopsy procedure (mean 2.80 for perineal nerve block and 3.98 for periprostatic block; adjusted difference in means -1.17, P < 0.001). Although the perineal nerve block had a lower mean pain score at 1 h post-biopsy compared with the periprostatic block (0.23 vs 0.43, P = 0.042), they were equivalent at 6 h (0.16 vs 0.25, P = 0.389) and 24 h (0.10 vs 0.26, P = 0.184) respectively. For the change in vital signs during biopsy procedure, perineal nerve block was significantly superior to periprostatic block in terms of maximum value of systolic blood pressure, maximum value of mean arterial pressure and maximum value of heart rate. There are no statistical differences in average value of systolic blood pressure, average value of mean, average value of heart rate, diastolic blood pressure and breathing rate. Perineal nerve block was also superior to periprostatic block in external manifestations of pain (1.88 vs 3.00, P < 0.001) and anaesthesia satisfaction (8.93 vs 11.90, P < 0.001). Equivalence was shown for the detection rate of PCa (31.25% for perineal nerve block and 29.17% for periprostatic block, P = 0.753) or csPCa (23.96% for perineal nerve block and 20.83% for periprostatic block, P = 0.604). 33 (34.8%) of 96 patients in the perineal nerve block group and 40 (41.67%) of 96 patients in the periprostatic block group had at least one complication. Interpretation: Perineal nerve block was superior to periprostatic block in pain control for men undergoing a transperineal prostate biopsy. Funding: Grant 2019YFC0119100 from the National Key Research and Development Program of China.

The combination of machine learning and untargeted metabolomics identifies the lipid metabolism -related gene CH25H as a potential biomarker in asthma.

BACKGROUND: Lipids, significant signaling molecules, regulate a multitude of cellular responses and biological pathways in asthma which are closely associated with disease onset and progression. However, the characteristic lipid genes and metabolites in asthma remain to be explored. It is also necessary to further investigate the role of lipid molecules in asthma based on high-throughput data. OBJECTIVE: To explore the biomarkers and molecular mechanisms associated with lipid metabolism in asthma. METHODS: In this study, we selected three mouse-derived datasets and one human dataset (GSE41665, GSE41667, GSE3184 and GSE67472) from the GEO database. Five machine learning algorithms, LASSO, SVM-RFE, Boruta, XGBoost and RF, were used to identify core gene. Additionally, we used non-negative matrix breakdown (NMF) clustering to identify two lipid molecular subgroups and constructed a lipid metabolism score by principal component analysis (PCA) to differentiate the subtypes. Finally, Western blot confirmed the altered expression levels of core genes in OVA (ovalbumin) and HDM+LPS (house dust mite+lipopolysaccharide) stimulated and challenged BALB/c mice, respectively. Results of non-targeted metabolomics revealed multiple differentially expressed metabolites in the plasma of OVA-induced asthmatic mice. RESULTS: Cholesterol 25-hydroxylase (CH25H) was finally localized as a core lipid metabolism gene in asthma and was verified to be highly expressed in two mouse models of asthma. Five-gene lipid metabolism constructed from CYP2E1, CH25H, PTGES, ALOX15 and ME1 was able to distinguish the subtypes effectively. The results of non-targeted metabolomics showed that most of the aberrantly expressed metabolites in the plasma of asthmatic mice were lipids, such as LPC 16:0, LPC 18:1 and LPA 18:1. CONCLUSION: Our findings imply that the lipid-related gene CH25H may be a useful biomarker in the diagnosis of asthma.

Machine learning revealed ferroptosis features and ferroptosis-related gene-based immune microenvironment in lung adenocarcinoma.

Ferroptosis has been identified as a novel type of programmed cell death that has a major effect on the development of lung adenocarcinoma. Nevertheless, there has yet to be a clear set of therapeutic targets based on ferroptosis. This study seeks to employ machine learning methods to determine the regulators of ferroptosis in LUAD. 318 LUAD samples were investigated to determine three ferroptosis molecular phenotypes in LUAD, and then Boruta dimensionality reduction combined with principal component analysis was used to measure the ferroptosis regulation score (FRS) of patients. We additionally presented DeepFerr, a deep learning neural network model, which used the transcriptome map of 11 ferroptosis regulators to predict ferroptosis in LUAD. LASSO, SVM-RFE and elastic net were used to dissect the differential ferroptosis regulators, and the eight pivotal ferroptosis regulators have considerable ferroptosis prediction ability. It was established that RRM2 and AURKA are key suppressors of ferroptosis, and the depletion of RRM2 and AURKA caused an increase in ferroptosis in H358 cells. In addition, not only did they act as pro-proliferative factors that hindered immune infiltration in LUAD, but they were also essential for anti-PD1 therapy and chemotherapy. In summary, this research confirms the regulatory role of RRM2 and AURKA in ferroptosis, and could be useful in predicting individualized treatment for patients with LUAD.

Clinical characteristics, risk factors and outcomes of Klebsiella pneumoniae pneumonia developing secondary Klebsiella pneumoniae bloodstream infection.

PURPOSE: The clinical characteristics of Klebsiella pneumoniae (KP) pneumonia and KP bloodstream infection (KP-BSI) are often reported, while the risk factors for KP pneumonia developing into secondary KP-BSI (KP-pneumonia/KP-BSI) are largely unknown. Therefore, this study attempted to investigate the clinical characteristics, risk factors and outcomes of KP-pneumonia/KP-BSI. METHODS: A retrospective observational study was conducted at a tertiary hospital between January 1, 2018, and December 31, 2020. The patients were divided into groups of KP pneumonia alone and KP pneumonia/KP-BSI, and the clinical information were collected from medical records electronic system. RESULTS: A total of 409 patients were finally recruited. According to the multivariate logistic regression analysis, male sex (adjusted odds ratio [aOR] 3.7; 95% CI, 1.44-9.5), immunosuppression (aOR, 13.52; 95% CI, 2.53,72.22), APACHE II score higher than 21 (aOR, 3.39; 95% CI, 1.41-8.12), serum procalcitonin (PCT) levels above 1.8 ng/ml (aOR, 6.37; 95% CI, 2.67-15.27), ICU stay of more than 2.5 days before pneumonia onset (aOR, 1.09; 95% CI, 1.02,1.17), mechanical ventilation (aOR, 4.96; 95% CI, 1.2,20.5), Klebsiella pneumoniae isolates producing extended spectrum ß-lactamase (ESBL-positive KP) (aOR, 12.93; 95% CI, 5.26-31.76), and inappropriate antibacterial therapy (aOR, 12.38; 95% CI, 5.36-28.58) were independent factors of KP pneumonia/KP BSI. In comparison with the patients with KP pneumonia alone, the patients with KP pneumonia/KP BSI showed an almost 3 times higher incidence of septic shock (64.4% vs. 20.1%, p < 0.01), a longer duration of mechanical ventilation, and longer lengths of ICU stay and total hospital stay (median days, 15 vs. 4,19 vs. 6, 34 vs. 17, respectively, both p < 0.01). Additionally, the overall in-hospital crude mortality rate in the patients with KP-pneumonia/KP-BSI was more than two times higher than that in those with KP pneumonia alone (61.5% vs. 27.4%, p < 0.01). CONCLUSION: Factors including male sex, immunosuppression, APACHE II score higher than 21, serum PCT levels above 1.8 ng/ml, ICU stay of more than 2.5 days before pneumonia onset, mechanical ventilation, ESBL-positive KP, and inappropriate antibacterial therapy are independent risk factors for KP pneumonia/KP-BSI. Of note, the outcomes in patients with KP pneumonia worsen once they develop secondary KP-BSI, which merits more attention.

SiNPs induce ferroptosis in HUVECs through p38 inhibiting NrF2 pathway.

Introduction: Despite of growing evidence linking silica nanoparticles (SiNPs), one of the global-top-three-produced and -used nanoparticle (NP), to human health risks, there remain many knowledge gaps over the adverse effects of SiNPs exposure on cardiovascular system and the underlying molecular mechanisms. Methods: In this study, the ferroptotic effects of SiNPs (20 nm; 0, 25, 50, and 100 µg/mL) on human umbilical vein endothelial cells (HUVECs) and the possible molecular mechanism were studied with the corresponding biochemical and molecular biology assays. Results and discussion: The results showed that at the tested concentrations, SiNPs could decrease HUVEC viability, but the deferoxamine mesylate (an iron ion chelator) might rescue this reduction of cell viability. Also, increased levels of intracellular reactive oxygen species and enhanced mRNA expression of lipid oxidation enzymes (ACSL4 and LPCAT3) with increase in lipid peroxidation (malondialdehyde), but decreased ratios of intracellular GSH/total-GSH and mitochondrial membrane potential as well as reduced enzymatic activities of anti-oxidative enzymes (CAT, SOD, and GSH-PX), were found in the SiNPs-treated HUVECs. Meanwhile, increase in p38 protein phosphorylation and decrease in NrF2 protein phosphorylation with reduced mRNA expressions of downstream anti-oxidative enzyme genes (CAT, SOD1, GSH-PX, and GPX4) was identified in the SiNPs-exposed HUVECs. These data indicated that SiNPs exposure might induce ferroptosis in HUVECs via p38 inhibiting NrF2 pathway. Ferroptosis of HUVECs will become a useful biomarker for assessing the cardiovascular health risks of environmental contaminants.