Study on the differential hepatotoxicity of raw polygonum multiflorum and polygonum multiflorum praeparata and its mechanism.

BACKGROUND: Polygonum multiflorum (PM), a widely used traditional Chinese medicine herb, is divided into two forms, namely raw polygonum multiflorum (RPM) and polygonum multiflorum praeparata (PMP), according to the processing procedure. Emerging data has revealed the differential hepatotoxicity of RPM and PMP, however, its potential mechanism is still unclear. METHODS: In our study, we investigated the differential hepatotoxicity of RPM and PMP exerted in C57BL/6 mice. First, sera were collected for biochemical analysis and HE staining was applied to examine the morphological alternation of the liver. Then we treated L02 cells with 5 mg / mL of RPM or PMP. The CCK8 and EdU assays were utilized to observe the viability and proliferation of L02 cells. RNA sequencing was performed to explore the expression profile of L02 cells. Western blotting was performed to detect the expression level of ferroptosis-related protein. Flow cytometry was used to evaluate ROS accumulation. RESULTS: In our study, a significant elevation in serum ALT, AST and TBIL levels was investigated in the RMP group, while no significant differences were observed in the PMP group, compared to that of the CON group. HE staining showed punctate necrosis, inflammatory cell infiltration and structural destruction can be observed in the RPM group, which can be significantly attenuated after processing. In addition, we also found RPM could decrease the viability and proliferation capacity of L02 cells, which can be reversed by ferroptosis inhibitor. RNA sequencing data revealed the adverse effect of PM exerted on the liver is closely associated with ferroptosis. Western blotting assay uncovered the protein level of GPX4, HO-1 and FTL was sharply decreased, while the ROS content was dramatically elevated in L02 cells treated with RPM, which can be partially restored after processing. CONCLUSIONS: The hepatotoxicity induced by RPM was significantly lower than the PMP, and its potential mechanism is associated with ferroptosis.

UNVEILING THE PROTECTIVE MECHANISMS OF PUERARIN AGAINST ACUTE LUNG INJURY: A COMPREHENSIVE EXPLORATION OF THE ROLES AND MECHANISMS OF MST1/ERS SIGNALING.

OBJECTIVES: Puerarin, the principal active constituent extracted from Pueraria, is believed to confer protection against sepsis-induced lung injury. The study aimed to elucidate the role and mechanism of Mst1/ERS in puerarin-mediated protection against acute lung injury (ALI). METHODS: Monolayer vascular endothelial cell permeability was assessed by gauging the paracellular flow of FITC-dextran 40,000 (FD40). ELISA was employed for the quantification of inflammatory cytokines. Identification of target proteins was conducted through Western blotting. Histological alterations and apoptosis were scrutinized using H&E staining and TUNEL staining, respectively. The ultrastructure of the endoplasmic reticulum was observed via transmission electron microscopy. RESULTS: Puerarin significantly protected mice from LPS-induced ALI, reducing lung interstitial width, neutrophil and lymphocyte infiltration, pulmonary interstitial and alveolar edema, and lung apoptosis. Puerarin treatment also markedly attenuated levels of TNF-α and IL-1ß in both alveolar lavage fluid and serum. Furthermore, puerarin significantly attenuated LPS-induced increases in Mst1, GRP78, CHOP, and Caspase12 protein expression and blunted LPS-induced decrease in ZO-1 protein expression in lung tissues. Puerarin obviously reduced endoplasmic reticulum expansion and vesiculation. Similarly, puerarin significantly mitigated the LPS-induced reduction in HUVEC cell viability and ZO-1 expression. Puerarin also attenuated LPS-induced increase in apoptosis, TNF-α and IL-1ß, FD40 flux, and Mst1, GRP78, CHOP, and Caspase12 expression in HUVEC cells. Nevertheless, the inhibitory impact of puerarin on vascular endothelial cell injury, lung injury, and endoplasmic reticulum stress (ERS) was diminished by Mst1 overexpression. CONCLUSION: These findings demonstrated that the Mst1/ERS signaling pathway played a pivotal role in the development of LPS-induced vascular endothelial cell dysfunction and ALI. Puerarin exhibited the ability to attenuate LPS-induced vascular endothelial cell dysfunction and ALI by inhibiting the Mst1/ERS signaling pathway.

Exploring the potential applications of amphiphilic carbon dots based nanocomposite hydrogel in liquid chromatographic separations.

BACKGROUND: Due to their excellent stability, low toxicity, flexible modification and adjustable functionality, carbon dots (CDs) have a promising application prospect in the field of chromatographic stationary phases. Hydrogels are new functional polymer materials with three-dimensional network structure that have excellent hydrophilicity, high porosity and unique mechanical properties, which are also good candidate materials for liquid chromatography. Nevertheless, a review of the literature reveals that CDs based nanocomposite hydrogels have not yet been reported as HPLC stationary phases. RESULTS: In this work, amphiphilic CDs with multiple functional groups and polyacrylic acid hydrogel were grafted to the surface of silica gel by an in-situ polymerization method, and a CDs/polyacrylic acid nanocomposite hydrogel stationary phase (CDs/hydrogel@SiO2) was prepared. CDs act as the macroscopic cross-linking agents to form a cross-linked network with polyacrylic acid chains through physical cross-linking by hydrogen bonding and chemical cross-linking by amidation and esterification reactions, which not only improve the swelling property of the hydrogel but also increase its stability. Additionally, the introduction of CDs with multifunctional groups modulates the hydrophilic-hydrophobic balance of the hydrogel that also imparts good hydrophobicity to the composite hydrogel. Through the study of retention mechanism and influencing factors, it is certificate that the CDs/hydrogel@SiO2 has mixed-mode chromatographic performance. Furthermore, the CDs/hydrogel@SiO2 column shows great potential for the determination of organic contaminants in environmental water samples. SIGNIFICANCE: This work confirms the potential application of CDs/hydrogel composite for the separation of various samples and provides the possibility of developing CDs based nanocomposite hydrogel in the field of liquid chromatography. Introducing CDs into hydrogel can open up a new way for nanocomposite hydrogels to be used in HPLC, which expands the advance of hydrogel and CDs in separation field.

Stress stimulation promotes the injury repair process of airway epithelial cells through the [Cl-]i-FAK signaling axis.

The airway epithelium serves as a critical interface with the external environment, making it vulnerable to various external stimuli. Airway epithelial stress acts as a catalyst for the onset of numerous pulmonary and systemic diseases. Our previous studies have highlighted the impact of acute stress stimuli, especially bacterial lipopolysaccharide (LPS) and hydrogen peroxide (H2O2), on the continuous elevation of intracellular chloride concentration ([Cl-]i). However, the precise mechanism behind this [Cl-]i elevation and the consequential effects of such stress on the injury repair function of airway epithelial cells remain unclear. Our findings indicate that H2O2 induces an elevation in [Cl-]i by modulating the expression of CF transmembrane conductance regulator (CFTR) and Ca-activated transmembrane protein 16 A (TMEM16A) in airway epithelial cells (BEAS-2B), whereas LPS achieves this solely through CFTR. Subsequently, the elevated [Cl-]i level facilitated the injury repair process of airway epithelial cells by activating focal adhesion kinase (FAK). In summary, the [Cl-]i-FAK axis appears to play a promoting effect on the injury repair process triggered by stress stimulation. Furthermore, our findings suggest that abnormalities in the [Cl-]i-FAK signaling axis may play a crucial role in the pathogenesis of chronic airway diseases. Therefore, controlling the structure and function of airway epithelial barriers through the modulation of [Cl-]i holds promising prospects for future applications in managing and treating such conditions.

Metformin Protects Against Acute Kidney Injury Induced by Lipopolysaccharide via Up-Regulating the MCPIP1/SIRT1 Pathway.

In the present study, we aimed to explore the effect and underlying mechanism of metformin on lipopolysaccharide (LPS)-induced acute kidney injury (AKI). A total of 24 BALB/C mice were randomly divided into four groups: control group, LPS group and metformin group (50 or 100 mg/kg). The histological changes and cell apoptosis in kidney tissues were detected by hematoxylin-eosin staining and terminal-deoxynucleotidyl transferase-mediated nick end labeling assay, respectively. Enzyme-linked immunosorbent assay was applied to determine serum levels of blood urea nitrogen (BUN), kidney injury molecule-1 (Kim-1), creatinine (Cre), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß). Western blotting analysis were carried out to confirm the expressions of monocyte chemotactic protein-inducible protein 1 (MCPIP1), silent information regulator sirtuin 1 (SIRT1), and NF-κB p65 (acetyl K310). Compared with the control group, the mice in LPS group had glomerular capillary dilatation, renal interstitial edema, tubular cell damage and apoptosis. The serum levels of BUN, KIM-1, Cre, TNF-α, and IL-1ß in LPS group were significantly higher than those in control group. Moreover, LPS also elevated the expressions of MCPIP1 and NF-κB p65 (acetyl K310) but decreased the expression of SIRT1 in kidney tissues. However, metformin distinctly decreased LPS-induced renal dysfunction, the serum levels of BUN, KIM-1, Cre, TNF-α, and IL-1ß. In addition, metformin markedly increased the expressions of MCPIP1 and SIRT1 but decreased the expression of NF-κB p65 (acetyl K310) in kidney tissues. Metformin prevented LPS-induced AKI by up-regulating the MCPIP1/SIRT1 signaling pathway and subsequently inhibiting NF-κB-mediated inflammation response.

Characterised intron retention profiles in muscle tissue of idiopathic inflammatory myopathy subtypes.

OBJECTIVES: Idiopathic inflammatory myopathies (IIMs) are a group of heterogeneous autoimmune diseases. Intron retention (IR) serves as an important post-transcriptional and translational regulatory mechanism. This study aims to identify changes in IR profiles in IIM subtypes, investigating their influence on proteins and their correlations with clinical features. METHODS: RNA sequencing and liquid chromatography-tandem mass spectrometry were performed on muscle tissues obtained from 174 patients with IIM and 19 controls, following QC procedures. GTFtools and iREAD software were used for IR identification. An analysis of differentially expressed IRs (DEIs), exons and proteins was carried out using edgeR or DEP. Functional analysis was performed with clusterProfiler, and SPIRON was used to assess splicing factors. RESULTS: A total of 6783 IRs located in 3111 unique genes were identified in all IIM subtypes compared with controls. IIM subtype-specific DEIs were associated with the pathogenesis of respective IIM subtypes. Splicing factors YBX1 and HSPA2 exhibited the most changes in dermatomyositis and immune-mediated necrotising myopathy. Increased IR was associated with reduced protein expression. Some of the IIM-specific DEIs were correlated with clinical parameters (skin rash, MMT-8 scores and muscle enzymes) and muscle histopathological features (myofiber necrosis, regeneration and inflammation). IRs in IFIH1 and TRIM21 were strongly correlated with anti-MDA5+ antibody, while IRs in SRP14 were associated with anti-SRP+ antibody. CONCLUSION: This study revealed distinct IRs and specific splicing factors associated with IIM subtypes, which might be contributing to the pathogenesis of IIM. We also emphasised the potential impact of IR on protein expression in IIM muscles.

Network-based pharmacology-based research on the effect and mechanism of the Hedyotis diffusa-Scutellaria Barbata pair in the treatment of hepatocellular carcinoma.

The Hedyotis diffusa-Scutellaria officinalis pair (HD-SB) has therapeutic effects on a variety of cancers. Our study was to explore the mechanism of HD-SB in the treatment of hepatocellular carcinoma (HCC). A total of 217 active ingredients of HD-SB and 1196 HCC-related targets were reserved from the TCMSP and the SwissTarget Prediction database, and we got 63 intersection targets from GeneCards. We used a Venn diagram, and Cytoscape found that the three core ingredients were quercetin, luteolin, and baicalein. The PPI analysis showed that the core targets were TP53, CDK2, XPO1, and APP. Molecular docking results showed that these core ingredients had good binding potential with the core targets. HD-SB acts simultaneously on various HCC-related signaling pathways, including proteoglycans in cancer and the P53 signaling pathway. In vitro experiments confirmed that HD-SB can inhibit HepG2 cell proliferation by increasing TP53 and APP levels and decreasing XPO1 and CDK2 levels. This study analyzed active ingredients, core targets, and central mechanisms of HD-SB in the treatment of HCC. It reveals the role of HD-SB in targeting the P53 signaling pathway in the treatment of HCC. We hope that our research could provide a new perspective to the therapy of HCC and find new anticancer drugs.

[Corrigendum] Azurocidin 1 inhibits the aberrant proliferation of triple­negative breast cancer through the regulation of pyroptosis.

Following the publication of the above article, the authors drew to our attention that they had made a couple of inadvertent errors in assembling Figs. 4 and 5; first, for the BT­549 cell line, the data shown for the Pro­caspase­1/Cleaved caspase­1 in Fig. 5 and the GSDMD­F/GSDMD­N data in Fig. 4B were identical, and had been derived from the same original source; secondly, in Fig. 4A, the data shown correctly for the GSDMD BT­549 cell line had also inadvertently been included in this figure to represent the MDA­MB­231 cell line. The revised and corrected versions of Figs. 4 and 5, showing the correct western blotting data for the GSDMD experiment in Fig. 4A and the Pro­caspase­1/Cleaved caspase­1 data for the BT­549 cell line in Fig. 5, are shown in the next two pages. The authors regret that these errors in the assembly of Figs. 4 and 5 went unnoticed before the article was published, and thank the Editor of Oncology Reports for granting them the opportunity to publish this corrigendum. All the authors agree with the publication of this corrigendum; furthermore, they apologize to the readership of the journal for any inconvenience caused.[Oncology Reports 50: 188, 2023; DOI: 10.3892/or.2023.8625].

Facile synthesis of a novel polymer/covalent organic framework@silica composite material in deep eutectic solvent for mixed-mode liquid chromatographic separation.

The solvothermal synthesis of covalent organic framework (COF) modified silica gel usually requires the use of harmful organic solvents, tedious steps, and harsh reaction conditions. In pursuit of green chemistry, a new strategy for the facile preparation of COF@SiO2 composite material was realized in this work by using a low-toxicity and low-cost deep eutectic solvent as the reaction medium. Additionally, a flexible polyacrylic acid (PAA) was introduced for the purpose of improving the hydrophilic selectivity and separation efficiency of COF@SiO2. Based on the above ideas, a novel PAA/COF@SiO2 composite was successfully developed as a liquid chromatographic packing material. Performance evaluation of the slurry-packed PAA/COF@SiO2 column showed that diverse types of analytes were effectively separated, and the retention behavior of polar nucleosides showed a U-shaped trend, indicating mixed-mode of hydrophobic/hydrophilic retention mechanisms. Thermodynamic studies revealed that the separation mechanism was largely independent of temperature. This work verifies the feasibility of synthesizing polymer/COF@SiO2 composite material in the deep eutectic solvent. This strategy provides a theoretical reference for the green and facile preparation of COF@SiO2 as an efficient liquid chromatographic stationary phase.

Exploring the potential mechanism of Xuebijing injection against sepsis based on metabolomics and network pharmacology.

Sepsis is a major contributor to the death of critically ill patients globally, in which metabolic disturbance is observed. Xuebijing injection (XBJ), a well-known traditional Chinese medicine, has received approval by the State Food and Drug Administration (SFDA) of China owing to its satisfactory clinical therapeutic effect. Nowadays, it has been applied clinically to the treatment of sepsis, but its effect on metabolic disorders remains unclear. In the present study, we sought to explore its underlying mechanism by employing a combination of network pharmacology and metabolomics. Initially, its protective effects were validated using a sepsis rat model created through cecal ligation puncture (CLP). Subsequently, the metabonomic strategy was utilized to discriminate the differential metabolic markers. Meanwhile, a comprehensive view of the potential ingredient-target-disease network was constructed based on a network pharmacology analysis. Next, the network diagram was constructed by integrating the results of network pharmacology and metabonomics. Finally, qRT-PCR together with Western blot was used to validate the expression levels of the associated genes. Based on our findings, we identified 34 differential metabolites in the sepsis group and 26 distinct metabolites in the XBJ group, with 8 common biological metabolites predominantly associated with arginine and proline metabolism. Through comprehensive analysis, we identified 21 genes that regulate metabolites, and qRT-PCR validation was conducted on six of these genes in both liver and kidney tissues. Additionally, XBJ demonstrated the capability to inhibit the activation of the NF-kB signaling pathway in both liver and kidney tissues, leading to a reduction in the occurrence of inflammatory responses. In summary, our study has validated the complexity of the natural compounds within XBJ and elucidated their potential mechanisms for addressing CLP-induced metabolic disturbances. This work contributes to our understanding of the bioactive compounds and their associated targets, providing insights into the potential molecular mechanisms involved.

Azurocidin 1 inhibits the aberrant proliferation of triple­negative breast cancer through the regulation of pyroptosis.

Azurocidin 1 (AZU1) is a heparin­binding protein which has been reported to be aberrantly expressed in various tumors, but its definite role in breast cancer (BC) has not been clarified. The aim of the present study was to explore the associations between AZU1 and BC. In the present study, bioinformatics and western blot analyses were applied to detect the expression level of AZU1 in BC tissues. The effect of AZU1 on cell proliferation and apoptosis was analyzed using Cell Counting Kit­8 assay, colony formation assay and flow cytometry. Based on bioinformatics analysis, AZU1 exhibited low expression in tissues and was negatively associated with the survival rate of patients with triple­negative BC (TNBC). Exogenous AZU1 stimuli significantly inhibited the proliferation and colony formation of TNBC cell lines. Furthermore, the data of flow cytometry revealed that exogenous AZU1 stimuli enhanced apoptosis in MDA­231 and BT­549 cells. As pyroptosis is a new type of cell death, the effects AZU1 played on the expression of gasdermin D (GSDMD), a specific biomarker of pyroptosis, were also investigated. The findings of the present study revealed that GSDMD, as well as its upstream regulators [NF­κB, NLR family pyrin domain containing 3 (NLRP3) and caspase­1], were significantly increased in TNBC cell lines when treated with exogenous AZU1, indicating that AZU1 contributed to the inhibition of pyroptosis of TNBC cell lines through the NF­κB/NLRP3/caspase­1 axis. Collectively, it was revealed for the first time, that AZU1 exposure promoted pyroptosis through the modulation of the pNF­κB/NLRP3/caspase­1/GSDMD axis in TNBC in vitro. The findings of the present study unveiled a novel mechanism of AZU1­induced pyroptosis in TNBC, which may aid in developing new strategies for therapeutic interventions in TNBC. breast cancer is the most commone form of cancer in women and is second only to lung cancer in terms of cancer­related mortality.

Hydrophobic/hydrophilic separation performance evaluation of a mixed-mode ionic liquid embedded stearyl thioglycolate functionalized silica stationary phase.

In this work, a novel imidazolium ionic liquid embedded multifunctional chromatographic stationary phase (Sil-AVI-ST) was synthesized by the radical-mediated thiol-ene click reaction. A wide range of samples including hydrophilic sulfonamides, vitamins and nucleosides/bases as well as hydrophobic phthalates, bisphenols, alkylphenols and steroid hormones were selected to evaluate the separation ability of the newly obtained Sil-AVI-ST. As expected, an efficient separation of the above tested analytes was successfully achieved in different chromatographic modes. It was proved that multiple stationary phase-analyte interaction forces promoted the selective separation. The Sil-AVI-ST column provided multiple retention mechanisms, enabling the efficient separation of diverse analytes with different polarity. More importantly, embedding a polar ligand (1-allyl-3-vinyl-imidazolium) could improve the separation efficiency of long-chain alkyl bonded stationary phases for hydrophilic analytes, and the developed Sil-AVI-ST column could also realize the detection of hydrophobic analytes under water-rich conditions, which is impossible for the conventional hydrophobic columns. Therefore, the newly prepared Sil-AVI-ST stationary phase has a good practical application potential.

Preparation and application of a novel imine-linked covalent organic framework@silica composite for reversed-phase and hydrophilic interaction chromatographic separations.

The composites of covalent organic frameworks (COFs) and silica gel have been considered to be promising chromatographic separation materials due to the distinct advantages such as large specific surface area, good mechanical strength and high porosity. In the present study, a novel imine-linked COF@silica composite was prepared by in-situ growth of 2,4,6-tris(4-aminophenyl)-1,3,5-triazine (TAPT) and 2,5-dihydroxyterephthalaldehyde (DHTA) monomers on the surface of aminated silica gel (SiO2-NH2). The successful surface-modification of TAPT-DHTA-COF distinctly enhanced the separation selectivity and efficiency of SiO2-NH2. Multiple types of analyte-stationary phase interactions contributed to the selective retention of structurally similar analytes. The designed TAPT-DHTA-COF@SiO2 was observed to effectively separate hydrophobic phenyl ketones, phthalate esters and steroid hormones. Moreover, the polar amino and hydroxyl groups of TAPT-DHTA-COF facilitated the selective determination of hydrophilic nucleosides/bases. The kinetic performance and thermodynamic behavior of TAPT-DHTA-COF@SiO2 column were particularly explored. It was found that column efficiency was mainly affected by the mass transfer resistance, and the retention of nucleosides/bases on the TAPT-DHTA-COF@SiO2 column was temperature dependent. The developed versatile TAPT-DHTA-COF@SiO2 column was finally applied for detecting environmental hormones as well as water-soluble nicotinamide in real samples. In summary, the potential application of TAPT-DHTA-COF@SiO2 composite material for liquid chromatographic separations was first explored and verified. The TAPT-DHTA-COF@SiO2 was proved to be a promising chromatographic separation material.

Insight into the mechanisms of therapeutic hypothermia for asphyxia cardiac arrest using a comprehensive approach of GC-MS/MS and UPLC-Q-TOF-MS/MS based on serum metabolomics.

Cardiac arrest (CA) is a severe worldwide health problem. Therapeutic hypothermia is widely used to reduce the cardiac injury and improve the neurological outcomes after CA. However, a few studies have reported the changes of serum metabolic characteristics after CA. The healthy male New Zealand Rabbits successfully resuscitated from 10-min asphyxia-induced CA were divided randomly into the normothermia (NT) group and mild therapeutic hypothermia (HT) group. The sham group underwent sham-operation. Survival was recorded and neurological deficit score (NDS) was assessed. The serum non-targeted metabolomics were detected using ultra-high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) and gas chromatography tandem mass spectrometry (GC-MS/MS) at 15 min, 3 h, 6 h and 24 h after return of spontaneous circulation (ROSC). Our study showed that the heart rate (HR) significantly slowed down during 0.5-6 h post ROSC, consistent with the decreasing trend of body temperature in the HT group. Compared with the NT group, the levels of Lac and PCO2 at 24 h post ROSC were lower, while a significant increase in PO2 level at 24 h post ROSC was observed in the HT group. The survival rate of the HT group was significantly higher than that of the NT group, and NDS scores were remarkably increased at 24 h post ROSC in the NT group. Significant differences in metabolic profiles at 15 min, 3 h, 6 h and 24 h post ROSC were observed among the Sham, NT and HT groups. The differential metabolites detected by UPLC-Q-TOF-MS/MS and GC-MS/MS were screened for further study between every two groups (NT vs sham, HT vs sham and HT vs NT) at 15 min, 3 h, 6 h and 24 h post ROSC. Phenylalanine metabolism, alanine, aspartate and glutamate metabolism and tricarboxylic acid (TCA) cycle were enriched in NT vs sham, HT vs sham and HT vs NT respectively. Our study demonstrated that therapeutic hypothermia improves the survival and neurological outcomes in rabbit model of cardiac arrest, and firstly represents the dynamic metabolic changes in the hypothermia therapy for CA by comprehensive UPLC-Q-TOF-MS/MS- and GC-MS/MS-based metabolomics.

Dynamic changes of serum metabolite profiling in septic mice based on high performance liquid chromatography of quadrupole time of flight mass spectrometry analysis.

The objective of this study is to gain insights into the underlying metabolic transformations that occurred during the whole progression of cecal ligation and puncture (CLP)-induced sepsis, thus providing new targets for its treatment. High-performance liquid chromatography of quadrupole time of flight mass spectrometry (HPLC-Q-TOF-MS/MS) combined with multivariate statistical techniques was used to detect the s in serum from septic mice. Fifty male mice were divided into two groups, including the sham group (n = 7) and the CLP-induced sepsis group (n = 43). Animals were sacrificed at 1, 3, 5, and 7 days post-CLP and then serum were collected for metabolomic analysis. Multivariate regression analysis was carried out through MetaboAnalyst 5.0, including principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA), to identify the s and screen out the related differential metabolites. Besides, the KEGG pathway analysis was used to analyze the related metabolic pathways in which the identified metabolites were involved. Based on the fold change (FC > 2.0 or <0.5), variable important in projection (VIP > 1.2), and P value (P < 0.05), we found 26, 17, 21, and 17 metabolites in septic mice at 1, 3, 5, and 7 days post-CLP, respectively, compared with that of the sham group. The PCA and PLS-DA pattern recognition showed a cluster-type distribution between the sham group and the CLP group. Dysregulated amino acid metabolism, as well as disturbed nucleotide metabolism, is observed. Several important metabolic pathways were identified between the sham group and the CLP group. Among them, phenylalanine metabolism, phenylalanine, tyrosine, and tryptophan biosynthesis showed striking at day 1 post-CLP. At day 3, phenylalanine, tyrosine, and tryptophan biosynthesis changed significantly. However, as the disease process, only pyrimidine metabolism showed the most significant alternation, compared to the sham group. Several differential metabolites were identified in the CLP group compared with that of the sham group and they were presented with dynamic alternation at different time points post-CLP, indicating metabolic disturbance occurred throughout the whole sepsis progression.

4H-SiC LDMOS Integrating a Trench MOS Channel Diode for Improved Reverse Recovery Performance.

In this paper, a 4H-SiC lateral gate MOSFET incorporating a trench MOS channel diode at the source side is explored to improve the reverse recovery characteristics. In addition, a 2D numerical simulator (ATLAS) is used to investigate the electrical characteristics of the devices. The investigational results have demonstrated that the peak reverse recovery current is reduced by 63.5%, the reverse recovery charge is reduced by 24.5%, and the reverse recovery energy loss is decreased by 25.8%, with extra complexity in the fabrication process.

Chromatographic separation performance of silica microspheres surface-modified with triazine-containing imine-linked covalent organic frameworks.

In this work, 2,4,6-tris(4-aminophenyl)-1,3,5-triazine (TAPT) and 1,3,5-tris(4-formylphenyl)benzene (TFPB) were used as monomers to construct a triazine-containing imine-linked covalent organic framework (COF), which was then bonded onto the surface of aldehydized silica (SiO2-CHO), and finally a COF@silica composite material (TAPT-TFPB COF@SiO2) was successfully prepared. The chromatographic separation performance of SiO2-CHO, TAPT-TFPB COF@SiO2 and TAPT-TFPB COF@SiO2/SiO2-CHO (80/20, mass ratio) was evaluated and compared. It was found that separation efficiency was obviously enhanced by adding an appropriate amount of SiO2-CHO into TAPT-TFPB COF@SiO2. The obtained TAPT-TFPB COF@SiO2/SiO2-CHO showed more favorable separation ability than SiO2-CHO and TAPT-TFPB COF@SiO2. Various aromatic compounds including alkylbenzenes, polycyclic aromatic hydrocarbons, environmental endocrine disruptors, foodborne stimulants and phenyl ketones were effectively separated on the TAPT-TFPB COF@SiO2/SiO2-CHO column in reversed phase chromatography mode. The silica microspheres surface-modified with triazine-containing imine-linked COFs proved to be a new type of promising chromatographic packing materials.

Shengjiang San alleviated sepsis-induced lung injury through its bidirectional regulatory effect.

BACKGROUND: Sepsis is a life-threatening organ dysfunction caused by dysregulated host responses to infection, for which effective therapeutic strategies are still absent. Shengjiang San (SJS), a well-known Traditional Chinese Medicine formula, has been widely used clinically. However, its role in sepsis-induced lung injury remains unclear. METHODS: To explore its specific mechanism, we firstly established a sepsis animal model using cecal ligation and puncture (CLP) and treated MH-S cells with LPS plus ATP. Then, UPLC/Q-TOF-MS/MS was utilized to identify its active ingredients. Network pharmacology analysis was performed to uncover the potential mechanism. HE staining and biochemical analysis were conducted to validate its therapeutic effect. ELISA was applied to detect the release of pro-inflammatory and anti-inflammatory cytokines. Western blot was utilized to detect the protein levels of GSDMD, NLRP3, P65, ASC and caspase-1. RESULTS: SJS could dramatically increase the survival rate of sepsis. In addition, it is able to inhibit the pro-inflammatory cytokines release at day 1 post CLP while promote their production at day 7, indicating SJS could attenuate uncontrolled inflammatory response in the early stage and improve immunosuppression in the late phase. Network pharmacology analysis showed that pyroptosis is the crucial action SJS exerted in the protection of sepsis-induced lung injury. Western blot data implicated SJS could attenuate pyroptosis in early sepsis while enhance in the late phase. CONCLUSIONS: SJS acted to alleviate sepsis-induced lung injury through its bidirectional regulatory effect.

EZH2 inhibition dampens autoantibody production in lupus by restoring B cell immune tolerance.

OBJECTIVE: The aim of this study was to elucidate the role of enhancer of zeste homolog 2 (EZH2) in the breakdown of B cell immune tolerance and production of autoantibodies in systemic lupus erythematosus (SLE), and to explore the therapeutic effects of EZH2 inhibition on lupus. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from new-onset SLE patients for flow cytometric analysis. Pristane-induced lupus mice were constructed, and the EZH2 inhibitor was administrated by intraperitoneal injection to treat lupus mice. Blood and urine were collected from lupus mice to detect autoantibodies and proteinuria, and renal pathology scores were assessed. Mouse spleen B cells were sorted with magnetic beads and subjected to flow cytometric apoptosis detection, real time quantitative PCR (RT-qPCR), and western blotting (WB). RESULTS: EZH2 expression was elevated in diverse B-cell subsets in both SLE patients and pristane-induced lupus mice. The EZH2 inhibitor attenuated lupus-like symptoms and dampened autoantibody production in pristane-induced lupus mice. Inhibition of EZH2 also reduced autoantibody secretion by plasma cells from lupus patients. Mechanistically, EZH2 mediated the impaired apoptosis of autoreactive B cells and the differentiation of autoantibody producing plasma cells by inhibiting multiple cyclin-dependent kinase inhibitor (CKI) genes. CONCLUSION: EZH2 mediated the breakdown of B-cell peripheral immune tolerance by inhibiting CKI genes and participated in the generation of autoantibodies in SLE. EZH2 inhibition could serve as a promising drug intervention for the treatment of SLE.