The Application of Drugs and Nano-Therapies Targeting Immune Cells in Hypoxic Inflammation.

Immune cells are pivotal in the dynamic interplay between hypoxia and inflammation. During hypoxic conditions, HIF-1α, a crucial transcription factor, facilitates the adaptation of immune cells to the hypoxic micro-environment. This adaptation includes regulating immune cell metabolism, significantly impacting inflammation development. Strategies for anti-inflammatory and hypoxic relief have been proposed, aiming to disrupt the hypoxia-inflammation nexus. Research extensively focuses on anti-inflammatory agents and materials that target immune cells. These primarily mitigate hypoxic inflammation by encouraging M2-macrophage polarization, restraining neutrophil proliferation and infiltration, and maintaining Treg/TH17 balance. Additionally, oxygen-releasing nano-materials play a significant role. By alleviating hypoxia and clearing reactive oxygen species (ROS), these nano-materials indirectly influence immune cell functions. This paper delves into the response of immune cells under hypoxic conditions and the resultant effects on inflammation. It provides a comprehensive overview of various therapies targeting specific immune cells for anti-inflammatory purposes and explores nano-materials that either carry or generate oxygen to alleviate anoxic micro-environments.

Isolation, identification and osteogenic capability analysis of mesenchymal stem cells derived from different layers of human maxillary sinus membrane.

AIM: To discover the populations of mesenchymal stem cells (MSCs) derived from different layers of human maxillary sinus membrane (hMSM) and evaluate their osteogenic capability. MATERIALS AND METHODS: hMSM was isolated into a monolayer using the combined method of physical separation and enzymatic digestion. The localization of MSCs in hMSM was performed by immunohistological staining and other techniques. Lamina propria layer-derived MSCs (LMSCs) and periosteum layer-derived MSCs (PMSCs) from hMSM were expanded using the explant cell culture method and identified by multilineage differentiation assays, colony formation assay, flow cytometry and so on. The biological characteristics of LMSCs and PMSCs were compared using RNA sequencing, reverse transcription and quantitative polymerase chain reaction, immunofluorescence staining, transwell assay, western blotting and so forth. RESULTS: LMSCs and PMSCs from hMSMs were both CD73-, CD90- and CD105-positive, and CD34-, CD45- and HLA-DR-negative. LMSCs and PMSCs were identified as CD171+/CD90+ and CD171-/CD90+, respectively. LMSCs displayed stronger proliferation capability than PMSCs, and PMSCs presented stronger osteogenic differentiation capability than LMSCs. Moreover, PMSCs could recruit and promote osteogenic differentiation of LMSCs. CONCLUSIONS: This study identified and isolated two different types of MSCs from hMSMs. Both MSCs served as good potential candidates for bone regeneration.

[Multi-modal physiological time-frequency feature extraction network for accurate sleep stage classification].

Sleep stage classification is essential for clinical disease diagnosis and sleep quality assessment. Most of the existing methods for sleep stage classification are based on single-channel or single-modal signal, and extract features using a single-branch, deep convolutional network, which not only hinders the capture of the diversity features related to sleep and increase the computational cost, but also has a certain impact on the accuracy of sleep stage classification. To solve this problem, this paper proposes an end-to-end multi-modal physiological time-frequency feature extraction network (MTFF-Net) for accurate sleep stage classification. First, multi-modal physiological signal containing electroencephalogram (EEG), electrocardiogram (ECG), electrooculogram (EOG) and electromyogram (EMG) are converted into two-dimensional time-frequency images containing time-frequency features by using short time Fourier transform (STFT). Then, the time-frequency feature extraction network combining multi-scale EEG compact convolution network (Ms-EEGNet) and bidirectional gated recurrent units (Bi-GRU) network is used to obtain multi-scale spectral features related to sleep feature waveforms and time series features related to sleep stage transition. According to the American Academy of Sleep Medicine (AASM) EEG sleep stage classification criterion, the model achieved 84.3% accuracy in the five-classification task on the third subgroup of the Institute of Systems and Robotics of the University of Coimbra Sleep Dataset (ISRUC-S3), with 83.1% macro F1 score value and 79.8% Cohen's Kappa coefficient. The experimental results show that the proposed model achieves higher classification accuracy and promotes the application of deep learning algorithms in assisting clinical decision-making.

Factors influencing methotrexate pharmacokinetics highlight the need for individualized dose adjustment: a systematic review.

PURPOSE: To develop a population pharmacokinetic (PPK) model for methotrexate (MTX) dosage for all ages, assess the association between concentration and clearance, and determine covariates affecting MTX disposition. METHODS: We compared MTX PK profiles among neonates, children, and adults by performing a systematic literature search for published population MTX models and conducted a Monte Carlo-based meta-analysis. Subsequently, we evaluated study quality and covariates significantly affecting dosage regimens and compared LDMTX and HDMTX PK profiles. RESULTS: Of the total 40 studies included, 34 were HDMTX, and six were LDMTX studies. For HDMTX, three studies involving neonates reported estimated apparent clearances (median, range) of 0.53 (0.27-0.77) L/kg/h; for 14 studies involving children, 0.23 (0.07-0.23) L/kg/h; and for 13 involving adults, 0.11 (0.03-0.22) L/kg/h. Neonates had a higher volume of distribution than children and adults. For LDMTX studies, apparent clearance was 0.085 (0.05-1.68) L/kg/h, and volume of distribution was 0.25 (0.018-0.47) L/kg, lower than those of HDMTX studies, with large between-subject variability. Bodyweight significantly influenced apparent clearance and volume of distribution, whereas renal function mainly influenced clearance. Mutations in certain genes reduced MTX clearance by 8-35.3%, whereas those in others increased it by 15-48%. Body surface area (BSA) significantly influenced apparent clearance with a median reduction of 51% when BSA increased in pediatric patients. CONCLUSIONS: Methotrexate dosage regimens were primarily based on body surface area and renal function. Further studies are needed to evaluate MTX pharmacokinetics and pharmacodynamics in both children (especially infants) and adults.

Progress of SARS-CoV-2 Main protease peptide-like inhibitors.

The pneumonia outbreak caused by Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) infection poses a serious threat to people worldwide. Although vaccines have been developed, antiviral drugs are still needed to combat SARS-CoV-2 infection due to the high mutability of the virus. SARS-CoV-2 main protein (Mpro ) is a special cysteine protease that is a key enzyme for SARS-CoV-2 replication. It is encoded by peptides and is responsible for processing peptides into functional proteins, making it an important drug target. The paper reviews the structure and peptide-like inhibitors of SARS-CoV-2 Mpro , also the binding mode and structure-activity relationship between the inhibitors and Mpro are introduced in detail. It is hoped that this review can provide ideas and help for the development of anti-coronavirus drugs such as COVID-19, and help to develop broad-spectrum antiviral drug for the treatment of coronavirus diseases as soon as possible.

Gender-specific lncRNA-miRNA-mRNA regulatory network to reveal potential genes for primary open-angle glaucoma.

BACKGROUND: Investigation of biomarkers may facilitate understanding the mechanisms of primary open-angle glaucoma (POAG) and developing therapeutic targets. This study aimed to identify potential genes based on competing endogenous RNA (ceRNA) network for POAG. METHODS: Based on long noncoding RNAs (lncRNAs), microRNAs (miRNAs) and messenger RNAs (mRNAs) from the Gene Expression Omnibus (GEO) database, we identified differential expressed lncRNAs (DELs), differential expressed miRNAs (DEMis) and differential expressed mRNAs (DEMs) and then constructed a ceRNA network. Through weighted gene co-expression network analysis (WGCNA), we identified gender-specific genes for gender-associated ceRNA network construction, followed by the protein-protein interaction (PPI) network and functional enrichment analysis to screen hub genes and reveal their functions. The expression levels of hub genes were measured in steroid-induced ocular hypertension (SIOH) mice. RESULTS: A total of 175 DELs, 727 DEMs and 45 DEMis were screened between control and POAG samples. Seven modules were identified through WGCNA and one module was associated with gender of POAG patients. We discovered 41 gender-specific genes for gender-associated ceRNA construction and then identified 8 genes (NAV3, C1QB, RXRB, P2RY4, ADAM15, VAV3, ZNF207 and TOP1), which were enriched in cell cycle-related pathways and immune-related pathways. C1QB, RXRB, Top1 and ZNF207 were highly interacted with other proteins. The expression levels of NAV3 and C1QB were downregulated in SIOH, while the levels of RXRB, P2RY4, ADAM15, VAV3, ZNF207 and TOP1 were upregulated in SIOH. CONCLUSION: This study identifies hub genes associated with the pathogenesis of gender-specific POAG and provides potential biomarkers for POAG.

Structural basis of SecA-mediated protein translocation.

Secretory proteins are cotranslationally or posttranslationally translocated across lipid membranes via a protein-conducting channel named SecY in prokaryotes and Sec61 in eukaryotes. The vast majority of secretory proteins in bacteria are driven through the channel posttranslationally by SecA, a highly conserved ATPase. How a polypeptide chain is moved by SecA through the SecY channel is poorly understood. Here, we report electron cryomicroscopy structures of the active SecA-SecY translocon with a polypeptide substrate. The substrate is captured in different translocation states when clamped by SecA with different nucleotides. Upon binding of an ATP analog, SecA undergoes global conformational changes to push the polypeptide substrate toward the channel in a way similar to how the RecA-like helicases translocate their nucleic acid substrates. The movements of the polypeptide substrates in the SecA-SecY translocon share a similar structural basis to those in the ribosome-SecY complex during cotranslational translocation.

Electroencephalograph-Based Emotion Recognition Using Brain Connectivity Feature and Domain Adaptive Residual Convolution Model.

In electroencephalograph (EEG) emotion recognition research, obtaining high-level emotional features with more discriminative information has become the key to improving the classification performance. This study proposes a new end-to-end emotion recognition method based on brain connectivity (BC) features and domain adaptive residual convolutional network (short for BC-DA-RCNN), which could effectively extract the spatial connectivity information related to the emotional state of the human brain and introduce domain adaptation to achieve accurate emotion recognition within and across the subject's EEG signals. The BC information is represented by the global brain network connectivity matrix. The DA-RCNN is used to extract high-level emotional features between different dimensions of EEG signals, reduce the domain offset between different subjects, and strengthen the common features between different subjects. The experimental results on the large public DEAP data set show that the accuracy of the subject-dependent and subject-independent binary emotion classification in valence reaches 95.15 and 88.28%, respectively, which outperforms all the benchmark methods. The proposed method is proven to have lower complexity, better generalization ability, and domain robustness that help to lay a solid foundation for the development of high-performance affective brain-computer interface applications.

Hierarchical Spatiotemporal Electroencephalogram Feature Learning and Emotion Recognition With Attention-Based Antagonism Neural Network.

Inspired by the neuroscience research results that the human brain can produce dynamic responses to different emotions, a new electroencephalogram (EEG)-based human emotion classification model was proposed, named R2G-ST-BiLSTM, which uses a hierarchical neural network model to learn more discriminative spatiotemporal EEG features from local to global brain regions. First, the bidirectional long- and short-term memory (BiLSTM) network is used to obtain the internal spatial relationship of EEG signals on different channels within and between regions of the brain. Considering the different effects of various cerebral regions on emotions, the regional attention mechanism is introduced in the R2G-ST-BiLSTM model to determine the weight of different brain regions, which could enhance or weaken the contribution of each brain area to emotion recognition. Then a hierarchical BiLSTM network is again used to learn the spatiotemporal EEG features from regional to global brain areas, which are then input into an emotion classifier. Especially, we introduce a domain discriminator to work together with the classifier to reduce the domain offset between the training and testing data. Finally, we make experiments on the EEG data of the DEAP and SEED datasets to test and compare the performance of the models. It is proven that our method achieves higher accuracy than those of the state-of-the-art methods. Our method provides a good way to develop affective brain-computer interface applications.

Aitongxiao improves pain symptoms of rats with cancer pain by reducing IL-1, TNF-α, and PGE2.

OBJECTIVE: To explore the mechanism of Aitongxiao in improving pain symptoms of rats with cancer pain. METHODS: Walker 256 breast cancer cells were injected into the right tibial bone marrow cavity of normal female rats to establish a rat model of tibial cancer pain. The rats with successful model replication were randomly divided into normal group (NG), Hank solution group (HSG), cancer pain model group (CPMG), and Aitongxiao+cancer pain model group (ATX+CPMG). The pain response score, mechanical pain hindpaw withdrawal threshold, and latent heat pain of rats were evaluated, and the changes of serum IL-1ß, TNF-α, PGE2 and blood cell counts of rats were detected. RESULTS: Compared with the NG, the pain response score was increased, the mechanical pain hindpaw withdrawal threshold and latent heat pain were decreased, and IL-1ß, TNF-α, and PGE2 were increased in CPMG. Compared with the CPMG, the pain response score was decreased, the mechanical pain hindpaw withdrawal threshold and latent heat pain were increased, and IL-1ß, TNF-α, and PGE2 were decreased in ATX+CPMG. There was no significant change in blood cell count in each group. CONCLUSION: Aitongxiao can improve the pain symptoms of rats with tibial cancer pain. Its mechanism may be related to the reduction of IL-1ß, TNF-α, and PGE2 levels.

Liubao Insect tea polyphenols prevent HCl/ethanol induced gastric damage through its antioxidant ability in mice.

The aim of this study was to study the preventive effects of polyphenols extracted from Liubao Insect tea on gastric injury. The content of Liubao Insect tea polyphenols (LITP) was 72.36% by ion precipitation extraction method. HCl/ethanol-induced gastric injury in mice led to increased gastric juice volume and decreased pH. LITP increased the gastric juice pH value and reduced the gastric juice volume at slightly lower quantities than ranitidine. Visual observation of gastric tissue showed that LITP could effectively reduce the area of gastric injury, and higher concentrations of LITP had a greater effect. Pathological observation also confirmed that LITP can reduce the cell damage and inflammatory effects, and play a role in preventing gastric injury. Serum cytokine assays showed that LITP could reduce the levels of IL-6 (interleukin 6), TNF-α (tumor necrosis factor alpha) and IFN-γ (interferon gamma) induced by gastric injury, and the effects of higher concentration of LITP were similar to those of ranitidine. The results showed that LITP could increase SOD (superoxide dismutase) and GSH (glutathione) levels; decrease MDA (malondialdehyde) and MPO (myeloperoxidase) levels; up-regulate the expression of Cu/Zn-SOD (cuprozinc-superoxide dismutase), Mn-SOD (manganese superoxide dismutase), CAT (catalase), nNOS (neuronal nitric oxide synthase), eNOS (endothelial nitric oxide synthase); and down-regulate the expression of iNOS (inducible nitric oxide synthase), COX-2 (cyclooxygenase-2), TNF-α, and IL-1ß (interleukin-1 beta) in mice with gastric injury, thus inhibiting gastric injury. We demonstrate that LITP is an active substance which could prevent gastric injury in experimental animals. With the increase of LITP concentration, its effects on preventing gastric injury were stronger and similar to those of ranitidine.

Protection of tight junction between RPE cells with tissue factor targeting peptide.

AIM: To investigate the effect of tissue factor targeting peptide (TF-TP) on retinal pigment epithelium (RPE) cells tight junctions. METHODS: Cell counting kit-8 (CCK-8) was used to measure the proliferation of ARPE-19 cells. Expression of tight junction, ZO-1 in ARPE-19 cells was measured by Western blot and immunofluorescent staining. Western blot was also used to detect the expression of tissue factor (TF). CEC Transmigration Assay was used to measure the migration of ARPE-19 cells. The transport of fluorescent markers [fluorescein isothiocyanate dextrans of 4, 10, 20 (FD4, FD10, FD20)] and the transepithelial electrical resistance (TEER) were used to measure in ARPE-19 cell. RESULTS: CCK-8 assay showed that 5 µmol/L TF-TP can inhibit ARPE-19 cells abnormally proliferation stimulated by lipopolysaccharide (LPS; P<0.05). LPS increased the transport of fluorescent markers (FD4, FD10, FD20) and decreased TEER levels in ARPE-19 cells, respectively, which were prevented by 5 µmol/L TF-TP pretreatment (P<0.05). Furthermore, LPS significantly up-regulated the expression of TF and downregulated the expression of ZO-1 (P<0.05) in ARPE-19 cell which was inhibited by the TF-TP (P<0.05). In addition, TF-TP inhibited the abnormal migration induced by LPS in ARPE-19 cell (P<0.05). CONCLUSION: Our findings suggest that TF-TP suppressed proliferation and migration of ARPE-19 cells induced by LPS, and maintained the RPE tight junctions through inhibition of TF expression and increased expression of ZO-1.

Correction: High ECT2 expression is an independent prognostic factor for poor overall survival and recurrence-free survival in non-small cell lung adenocarcinoma.

[This corrects the article DOI: 10.1371/journal.pone.0187356.].

SPC25 upregulation increases cancer stem cell properties in non-small cell lung adenocarcinoma cells and independently predicts poor survival.

In this study, we investigated the functional role and prognostic value of spindle pole body component 25 (SPC25) in non-small cell lung cancer (NSCLC). SPC25 expression profile in lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC) and normal lung tissues was examined by using data from the Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA). LUAD A549 cells and LUSC H520 cells were used to investigate the influence of SPC25 on cancer stem cell (CSC) properties in terms of the proportion of CD133+ cells, tumorsphere formation and CSC markers, including CD133, ALDH1 and Sox2. Data mining was also performed in the Kaplan-Meier plotter and TCGA-NSCLC to assess the independent prognostic value of SPC25. Results showed SPC25 was significantly upregulated in LUAD and LUSC tissues compared with normal lung tissues. SPC25 overexpression significantly increased the CSC properties and invasion of A549 cells, but not H520 cells. In comparison, SPC25 knockdown impaired the CSC properties and invasion of A549 cells, but not H520 cells. Univariate and multivariate analysis confirmed that high SPC25 expression was an independent prognostic factor for poor overall survival (OS) (HR: 1.622, 95%CI: 1.207-2.178, p = .001) and recurrence-free survival (RFS) (HR: 1.726, 95%CI: 1.242-2.399, p = .001) in LUAD patients. However, no independent prognostic value of SPC25 was observed in LUSC patients even under the best cut-off model. Based on these findings, we infer that SPC25 upregulation can increase CSC properties in LUAD and independently predict poor survival in this histological subtype.

High ECT2 expression is an independent prognostic factor for poor overall survival and recurrence-free survival in non-small cell lung adenocarcinoma.

Different subtypes of non-small cell lung cancer (NSCLC) have distinct sites of origin, histologies, genetic and epigenetic changes. In this study, we explored the mechanisms of ECT2 dysregulation and compared its prognostic value in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). In addition, we also investigated the enrichment of ECT2 co-expressed genes in KEGG pathways in LUAD and LUSC. Bioinformatic analysis was performed based on data from the Cancer Genome Atlas (TCGA)-LUAD and TCGA-LUSC. Results showed that ECT2 expression was significantly upregulated in both LUAD and LUSC compared with normal lung tissues. ECT2 expression was considerably higher in LUSC than in LUAD. The level of ECT2 DNA methylation was significantly lower in LUSC than in LUAD. ECT2 mutation was observed in 5% of LUAD and in 51% of LUSC cases. Amplification was the predominant alteration. LUAD patients with ECT2 amplification had significantly worse disease-free survival (p = 0.022). High ECT2 expression was associated with unfavorable overall survival (OS) (p<0.0001) and recurrence-free survival (RFS) (p = 0.001) in LUAD patients. Nevertheless, these associations were not observed in patients with LUSC. The following univariate and multivariate analysis showed that the high ECT2 expression was an independent prognostic factor for poor OS (HR: 2.039, 95%CI: 1.457-2.852, p<0.001) and RFS (HR: 1.715, 95%CI: 1.210-2.432, p = 0.002) in LUAD patients, but not in LUSC patients. Among 518 genes co-expressed with ECT2 in LUAD and 386 genes co-expressed with ECT2 in LUSC, there were only 98 genes in the overlapping cluster. Some of the genes related KEGG pathways in LUAD were not observed in LUSC. These differences might help to explain the different prognostic value of ECT2 in LUAD and LUSC, which are also worthy of further studies.

Serum S100A12 levels are associated with the presence and severity of obstructive sleep apnea syndrome in male patients.

PURPOSE: Inflammation plays a critical role in the pathogenesis of obstructive sleep apnea syndrome (OSAS). S100A12 is a newly identified inflammatory biomarker. This study aims to investigate whether serum S100A12 levels are associated with the presence and severity of OSAS in male patients. METHODS: A total of 126 male patients with OSAS and 74 controls were enrolled in this study. The presence and severity of OSAS was assessed by apnea-hypopnea index (AHI). Serum S100A12 levels were detected by enzyme-linked immunosorbent assay. RESULTS: Serum S100A12 levels were significantly higher in the OSAS group than in the control group (132.17 (range 101.86 to 174.49) ng/ml vs. 78.40 (range 58.35 to 129.44) ng/ml, P < 0.01). Multivariate logistic regression demonstrated that S100A12 was the only significant and independent predictor of OSAS (odds ratio 1.012, 95% confidence interval 1.006 to 1.017; P < 0.01). Serum S100A12 levels elevated with the increase in the severity of OSAS (S100A12 levels of 106.04 (range 83.92 to 135.13) ng/ml in mild OSAS group, 133.51 (range 109.64 to 208.95) ng/ml in moderate OSAS group, and 173.04 (range 131.88 to 275.77) ng/ml in severe OSAS group; P < 0.001). Serum S100A12 levels were independently correlated with AHI scores (r = 0.324, P < 0.001) CONCLUSIONS: Serum S100A12 levels were independently associated with the presence and severity of OSAS. These findings suggest that serum S100A12 level could be a potential biomarker for reflecting the presence and severity of OSAS.

[Research progress of tumor microenvironment and non-Hodgkin's lymphomas].

Non-Hodgkin's lymphoma cells including lymphoma stem cells reside in a specific microenvironment in which a series of nonmalignant bystander cells and cytokines play a crucial role in the genesis and development of non-Hodgkin's lymphomas. In addition, tumor microenvironment has important prognostic significance in Non-Hodgkin's lymphomas. Blocking the cross-talk between the tumor microenvironment and lymphoma cells may thus represent a promising new strategy for treating Non-Hodgkin's lymphomas. This review summarizes the current advance in studies of the tumor microenvironment and non-Hodgkin's lymphomas, including cells in tumor microenvironment, role of mesenchymal stem cells and stromal cells, auxiliary role of T cell subsets, macrcphage and dentritic cells, cytokines, immune surveillance and so on.

BSA-modified polyethersulfone membrane: preparation, characterization and biocompatibility.

A polyethersulfone (PES) membrane was modified by blending with a co-polymer of acrylic acid (AA) and N-vinyl pyrrolidone (VP), followed by immobilization of bovine serum albumin (BSA) onto the surface. The scanning electron microscopy results showed that PES had good miscibility with the co-polymer. X-ray photoelectron spectroscopy confirmed the existence of P(VP-AA) co-polymer on the surface of the blended membrane and the existence of BSA after the immobilization process. The amount of BSA immobilized on the surface of the membranes was determined. It was found that the protein adsorption amounts from BSA, human plasma fibrinogen and diluted human plasma solutions decreased significantly after modification. According to the circular dichroism results, the proteins kept more alpha-helix conformation in the modified membranes than in the pure PES membrane. The number of the adhered platelets was reduced, and the morphology change for the adherent platelets was also suppressed by the modification with BSA. The SEM morphological observation of the cells and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay demonstrated that the BSA-modified PES membrane surface promoted endothelial cell adhesion and proliferation.