Cancer cell membrane-coated nanoparticles: a promising anti-tumor bionic platform.

Nanoparticle (NP) drug delivery systems have shown promise in tumor therapy. However, limitations such as susceptibility to immune clearance and poor targeting in a complex intercellular environment still exist. Recently, cancer cell membrane-encapsulated nanoparticles (CCM-NPs) constructed using biomimetic nanotechnology have been developed to overcome these problems. Proteins on the membrane surface of cancer cells can provide a wide range of activities for CCM-NPs, including immune escape and homologous cell recognition properties. Meanwhile, the surface of the cancer cell membrane exhibits obvious antigen enrichment, so that CCM-NPs can transmit tumor-specific antigen, activate a downstream immune response, and produce an effective anti-tumor effect. In this review, we first provided an overview of the functions of cancer cell membranes and summarized the preparation techniques and characterization methods of CCM-NPs. Then, we focused on the application of CCM-NPs in tumor therapy. In addition, we summarized the functional modifications of cancer cell membranes and compiled the patent applications related to CCM-NPs in recent years. Finally, we proposed the future challenges and directions of this technology in order to provide guidance for researchers in this field.

Effects of the Glucocorticoid-Mediated Mitochondrial Translocation of Glucocorticoid Receptors on Oxidative Stress and Pyroptosis in BV-2 Microglia.

Microglia are resident macrophages within the central nervous system, serving as the first responders to neuroinflammation. Glucocorticoids (GCs) may cause damage to brain tissue, but the specific mechanism remains unclear. This study was divided into two parts: a glucocorticoid receptor (GR) mitochondrial translocation intervention experiment and a mitochondrial oxidative stress inhibition experiment. BV-2 microglia were stimulated with dexamethasone (DEX) and treated with either tubastatin-A or mitoquinone (MitoQ) for 24 h. Our results showed that DEX increased the translocation of GRs to mitochondria, and this effect was accompanied by decreases in the expression of mitochondrially encoded cytochrome c oxidase 1 (MT-CO1) and mitochondrially encoded cytochrome c oxidase 3 (MT-CO3) and increases in the expression of NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), caspase-1, and Gasdermin D (GSDMD). The level of mitochondrial respiratory chain complex IV (MRCC IV) and adenosine triphosphate (ATP) was decreased. An elevation in the level of mitochondrial oxidative stress and the opening of the mitochondrial permeability transition pore (mPTP) was also observed. Mechanistically, tubastatin-A significantly suppressed the mitochondrial translocation of GRs, improved the expression of mitochondrial genes, promoted the restoration of mitochondrial function, and inhibited pyroptosis. MitoQ significantly prevented mitochondrial oxidative stress, improved mitochondrial function, and reduced apoptosis and pyroptosis. Both tubastatin-A and MitoQ suppressed DEX-induced pyroptosis. This study substantiates that the increase in the mitochondrial translocation of GRs mediated by GCs exacerbates oxidative stress and pyroptosis in microglia, which indicates that the regulation of mitochondrial pathways by GCs is pathogenic to microglia.

TME-Related Biomimetic Strategies Against Cancer.

The tumor microenvironment (TME) plays an important role in various stages of tumor generation, metastasis, and evasion of immune monitoring and treatment. TME targeted therapy is based on TME components, related pathways or active molecules as therapeutic targets. Therefore, TME targeted therapy based on environmental differences between TME and normal cells has been widely studied. Biomimetic nanocarriers with low clearance, low immunogenicity, and high targeting have enormous potential in tumor treatment. This review introduces the composition and characteristics of TME, including cancer­associated fibroblasts (CAFs), extracellular matrix (ECM), tumor blood vessels, non-tumor cells, and the latest research progress of biomimetic nanoparticles (NPs) based on TME. It also discusses the opportunities and challenges of clinical transformation of biomimetic nanoparticles.

Recent advances in cancer cell bionic nanoparticles for tumour therapy.

Nanoparticle-based drug delivery systems have found extensive use in delivering oncology therapeutics; however, some delivery vehicles still exhibit rapid immune clearance, lack of biocompatibility and insufficient targeting. In recent years, bionanoparticles constructed from tumour cell membranes have gained momentum as tumour-targeting therapeutic agents. Cancer cell membrane-coated nanoparticles (CCMCNPs) typically consist of a drug-loaded nanoparticle core coated with cancer cell membrane. CCMCNPs retain homologous tumour cell surface antigens, receptors and proteins, and it has been shown that the modified nanoparticles exhibit better homologous targeting, immune escape and biocompatibility. CCMCNPs are now widely used in a variety of cancer treatments, including photothermal, photodynamic and sonodynamic therapies, chemotherapy, immunotherapy, chemodynamical therapy or other combination therapies. This article presents different therapeutic approaches using multimodal antitumour therapy-combination of two or more therapies that treat tumours synergistically-based on tumour cell membrane systems. The advantages of CCMCNPs in different cancer treatments in recent years are summarised, thus, providing new strategies for cancer treatment research.

Combination of ferroptosis and pyroptosis dual induction by triptolide nano-MOFs for immunotherapy of Melanoma.

Immunotherapy has good potential to eradicate tumors in the long term. However, due to the low immunogenicity of tumor cells, current cancer immunotherapies are not effective. To address this limitation, we constructed a BSA-FA functionalized iron-containing metal-organic framework (TPL@TFBF) that triggers a potent systemic anti-tumor immune response by inducing ferroptosis and pyroptosis in tumor cells and releasing large quantities of damage-associated molecular patterns (DAMPs) to induce immunogenicity, and showing excellent efficacy against melanoma lung metastases in vivo. This nanoplatform forms a metal-organic framework through the coordination between tannic acid (TA) and Fe3+ and is then loaded with triptolide (TPL), which is coated with FA-modified BSA. The nanoparticles target melanoma cells by FA modification, releasing TPL, Fe3+ and TA. Fe3+ is reduced to Fe2+ by TA, triggering the Fenton reaction and resulting in ROS production. Moreover, TPL increases the production of intracellular ROS by inhibiting the expression of nuclear factor erythroid-2 related factor (Nrf2). Such simultaneous amplification of intracellular ROS induces the cells to undergo ferroptosis and pyroptosis, releasing large amounts of DAMPs, which stimulate antigen presentation of dendritic cells (DCs) and the proliferation of cytotoxic T lymphocytes (CD4+/CD8 + T cells) to inhibit tumor and lung metastasis. In addition, combining nanoparticle treatment with immune checkpoint blockade (ICB) further inhibits melanoma growth. This work provides a new strategy for tumor immunotherapy based on various combinations of cell death mechanisms.

Pyrimidine metabolism regulator-mediated molecular subtypes display tumor microenvironmental hallmarks and assist precision treatment in bladder cancer.

Background: Bladder cancer (BLCA) is a common urinary system malignancy with a significant morbidity and death rate worldwide. Non-muscle invasive BLCA accounts for over 75% of all BLCA cases. The imbalance of tumor metabolic pathways is associated with tumor formation and proliferation. Pyrimidine metabolism (PyM) is a complex enzyme network that incorporates nucleoside salvage, de novo nucleotide synthesis, and catalytic pyrimidine degradation. Metabolic reprogramming is linked to clinical prognosis in several types of cancer. However, the role of pyrimidine metabolism Genes (PyMGs) in the BLCA-fighting process remains poorly understood. Methods: Predictive PyMGs were quantified in BLCA samples from the TCGA and GEO datasets. TCGA and GEO provided information on stemness indices (mRNAsi), gene mutations, CNV, TMB, and corresponding clinical features. The prediction model was built using Lasso regression. Co-expression analysis was conducted to investigate the relationship between gene expression and PyM. Results: PyMGs were overexpressed in the high-risk sample in the absence of other clinical symptoms, demonstrating their predictive potential for BLCA outcome. Immunological and tumor-related pathways were identified in the high-risk group by GSWA. Immune function and m6a gene expression varied significantly between the risk groups. In BLCA patients, DSG1, C6orf15, SOST, SPRR2A, SERPINB7, MYBPH, and KRT1 may participate in the oncology process. Immunological function and m6a gene expression differed significantly between the two groups. The prognostic model, CNVs, single nucleotide polymorphism (SNP), and drug sensitivity all showed significant gene connections. Conclusions: BLCA-associated PyMGs are available to provide guidance in the prognostic and immunological setting and give evidence for the formulation of PyM-related molecularly targeted treatments. PyMGs and their interactions with immune cells in BLCA may serve as therapeutic targets.

Liposomal Silybin Improves Glucose and Lipid Metabolisms in Type 2 Diabetes Mellitus Complicated with Non-Alcoholic Fatty Liver Disease via AMPK/TGF-ß1/Smad Signaling.

Improving hepatic glucose and lipid metabolisms is an important strategy to treat type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease (T2DM-NAFLD). Silybin (SLB) has the potential hepatoprotection, while its oral bioavailability is poor. This study aims to investigate the functional role and mechanism of liposomal SLB in modulating glucose/lipid metabolism in T2DM-NAFLD. SLB was prepared by thin film dispersion method and characterized using dynamic light scattering, scanning electron microscope, high performance liquid chromatography and zeta potential analyzer. A rat model of T2DM-NAFLD was used to determine the role of liposomal SLB in regulating glycolipid metabolism and hepatic damage. Rat primary hepatocytes were used to demonstrate the hepatoprotection mechanism of liposomal SLB. The encapsulation efficiency was more than 80%, which showed the average particle size of 119.76 nm. Also, the average Zeta potential was -4.76 mV. These liposomes were spherical. In rats with T2DM-NAFLD, liposomal SLB alleviated insulin resistance and lipid metabolism, thereby improving hepatic lipid accumulation, inflammation and fibrosis. Besides, liposomal SLB elevated AMPK phosphorylation, and decreased collagen I/III, α-smooth muscle actin (α-SMA), transforming growth factor-ß1 (TGF-ß1) and the phosphorylation of Smad2/3. In hepatocyte model, compound C partially reversed the effects of liposomal SLB on cell viability, glycolipid metabolism and AMPK/TGF-ß1/Smad pathway activation. Liposomal SLB ameliorates hepatic glucose and lipid metabolisms in T2DM-NAFLD via activating AMPK/TGF-ß1/Smad pathway, providing an efficient strategy for treating T2DM-NAFLD.

[Mechanism of Huangjing Qianshi Decoction in treatment of prediabetic mice based on transcriptome sequencing].

Based on transcriptome sequencing technology, the mouse model of prediabetes treated with Huangjing Qianshi Decoction was sequenced to explore the possible mechanism of treating prediabetes. First of all, transcriptome sequencing was performed on the normal BKS-DB mouse group, the prediabetic model group, and the Huangjing Qianshi Decoction treatment group(treatment group) to obtain differentially expressed genes in the skeletal muscle samples of mice. The serum biochemical indexes were detected in each group to screen out the core genes of Huangjing Qianshi Decoction in prediabetes. Gene Ontology(GO) database and Kyoto Encyclopedia of Genes and Genomes(KEGG) database were used to conduct signaling pathway enrichment analysis of differentially expressed genes, and real-time quantitative polymerase chain reaction(RT-qPCR) was used to verify them. The results showed that the levels of fasting blood glucose(FBG), fasting insulin(FINS), insulin resistance index(HOMA-IR), total cholesterol(TC), triglycerides(TG), and low-density lipoprotein cholesterol(LDL-C) in the mouse model were significantly decreased after treatment with Huangjing Qianshi Decoction. In the results of differential gene screening, there were 1 666 differentially expressed genes in the model group as compared with the normal group, and there were 971 differentially expressed genes in the treatment group as compared with the model group. Among them, interleukin-6(IL-6) and NR3C2 genes, which were closely related to the regulation of insulin resis-tance function, were significantly up-regulated between the model group and the normal group, and vascular endothelial growth factor A(VEGFA) genes were significantly down-regulated between the model group and the normal group. However, the expression results of IL-6, NR3C2, and VEGFA genes were adverse between the treatment group and the model group. GO functional enrichment analysis found that the biological process annotation mainly focused on cell synthesis, cycle, and metabolism; cell component annotation mainly focused on organelles and internal components; and molecular function annotation mainly focused on binding molecular functions. KEGG pathway enrichment analysis found that it involved the protein tyrosine kinase 6(PTK6) pathway, CD28-dependent phosphoinositide 3-kinase/protein kinase B(PI3K/AKT) pathway, p53 pathway, etc. Therefore, Huangjing Qianshi Decoction can improve the state of prediabetes, and the mechanism may be related to cell cycle and apoptosis, PI3K/AKT pathway, p53 pathway, and other biological pathways regulated by IL-6, NR3C2, and VEGFA.

Use of different ligand modification liposomes to evaluate the anti-liver tumor activity of cantharidin.

In this study, cantharidin(CTD), a bioactive terpenoid in traditional Chinese medicine cantharidin, was selected as a model component to construct novel nano liposome delivery systems for hepatocellular carcinoma therapy. Previous studies have shown that although cantharidin has definite curative effects on primary liver cancer, it is associated with numerous toxic and side effects. Therefore, based on the glycyrrhetinic acid (GA) binding site and the asialoglycoprotein receptor (ASGPR) on the hepatocyte membrane, the surface of CTD liposomes was modified with stearyl alcohol galactoside (SA-Gal) or/and the newly synthesized 3-succinic-30-stearyl deoxyglycyrrhetinic acid (11-DGA-Suc) ligands, and the physicochemical properties, pharmacokinetics, in vivo and in vitro anti-liver tumor activity and its mechanism of modified liposomes were investigated. Compared to CTD-lip, SA-Gal-CTD-lip, and 11-DGA-Suc + SA-Gal-CTD-lip, 11-DGA-Suc-CTD-lip showed stronger cytotoxicity and increased inhibition of HepG2 cell migration had the highest apoptosis rate. The cell cycle results indicated that HepG2 cells was arrested mainly at G0/G1phase and G2/M phase. The results of in vivo pharmacokinetic experiments revealed that the distribution of modified liposomes in the liver was significantly increased compared with that of unmodified liposome. In vivo tumor inhibition experiment showed that 11-DGA-Suc-CTD-lip had excellent tumor inhibition, and the tumor inhibition rates was 80.96%. The 11-DGA-Suc-CTD-lip group also displayed the strongest proliferation inhibition with the lowest proliferation index of 7% in PCNA assay and the highest apoptotic index of 49% in TUNEL assay. Taken together, our findings provide a promising solution for improving the targeting of nano liposomes and further demonstrates the encouraging potential of poor solubility and high toxicity drugs applicable to tumor therapy.

[Construction of early warning indicators of in-hospital cardiac arrest in adult inpatients].

OBJECTIVE: To establish early warning indicators for Chinese nurses to recognize in-hospital cardiac arrest (IHCA) of adult inpatients. METHODS: Computer retrieval of Chinese and English databases such as CNKI, Wanfang Database, VIP, National Medical Library of the United States PubMed Database, Web of Science, Embase Database of the Netherlands Medical Abstracts, Cochrane Library Database and other international guidelines collaboration network (GIN), National Institute for Health and Clinical Optimization (NICE), Scottish Intercollegiate Guidelines Network (SIGN), BMJ best clinical practice and other guidelines was performed. The retrieval time limit for respiratory and cardiac arrest early warning indicators or risk identification related content of the adult inpatient in the professional website was until June 30, 2020. After literature research and expert group analysis, the research group drew up an expert correspondence questionnaire, and selected 32 medical and nursing experts from Beijing, Tianjin, Jilin, Shandong, Shaanxi, Sichuan, Zhejiang and other grade three first-class general hospitals from July to September 2022. The Delphi method was used to conduct two rounds of expert correspondence, forming the final version of the early warning index of cardiac arrest in adult inpatients. RESULTS: Five first-level indicators, 23 second-level indicators and 41 third-level indicators including vital signs, consciousness and pupils, postoperative blood drainage volume, lab results and other five aspects were initially formed. The effective response rates of the two rounds of expert correspondence were 100% (32/32) and 93.75% (30/32), respectively, the Kendall coordination coefficients W of the first round and the second round were 0.340 and 0.462, respectively, the expert authority coefficients Cr were 0.88 and 0.89, respectively, the mean value of importance assignment was 3.94-5.00, 4.07-5.00, and the coefficient of variation was 0-0.16, 0-0.14, with statistically significant differences (all P < 0.05). Finally, 5 primary indicators, 23 secondary indicators and 43 tertiary indicators were formed, including five aspects of vital signs, consciousness and pupils, postoperative blood drainage, lab results, symptoms and chief complaints. CONCLUSIONS: The expert consultation on the early warning indicators of IHCA for adult patients tends to be consistent and scientific, which is applicable to help nurses detect the changes of patients' condition as early as possible.

Buyang Huanwu decoction affects gut microbiota and lipid metabolism in a ZDF rat model of co-morbid type 2 diabetes mellitus and obesity: An integrated metabolomics analysis.

Type 2 diabetes mellitus (T2DM) is a chronic disease associated with many severe complications such as blindness, amputation, renal failure, and cardiovascular disease. Currently, the prevention and treatment of T2DM is a major global challenge as the number of aging and obese people is increasing. Traditional Chinese medicine offers the advantages of multi-target holistic and individual treatment for obesity and type 2 diabetes. However, most of the TCMs for T2DM are not scientifically evaluated. Here, Buyang Huanwu decoction (BYHWD), a widely used TCM formula, was used to explore scientific pharmacological activity against T2DM in rat models. First, BYHWD exhibited excellent inhibitory actions against body fat accumulation and increased blood triglyceride levels, and a high-fat diet (HFD) induced blood glucose elevation in diabetic rats. Moreover, 16S rDNA sequencing of fecal samples identified the distinct changes in the community composition of gut flora following BYHWD treatment, displayed as significantly increased Bacteroidetes and dramatically decreased Firmicutes at the phyla level, and the remarkable increase in the abundance of Lactobacillus and Blautia. Additionally, lipid metabolomics based on liquid chromatography-mass spectrometry revealed a significant shift of lipid metabolites in the liver after BYHWD treatment. Notably, these differential lipid metabolites were particularly involved in biological processes such as cholesterol metabolism, linoleic acid metabolism, glycerolipid metabolism, glycerophospholipid metabolism, insulin resistance, arachidonic acid metabolism, and alpha-linoleic acid metabolism. Importantly, Spearman correlation analyses suggested an association between disturbed gut microbiota and altered lipid metabolites. Moreover, they were also closely associated with the bioactivities of BYHWD to reduce the blood lipid and blood glucose levels. Collectively, these results suggest that BYHWD could meliorate gut microbiota dysbiosis and lipid metabolite alterations induced by the HFD in diabetic rats. These results not only provide a novel perspective on understanding the mechanisms underlying BYHWD bioactivity against T2DM but also suggest the use of advanced systems biology methods to reveal some unknown scientific laws in TCM theories.

Development of Glycyrrhetinic Acid and Folate Modified Cantharidin Loaded Solid Lipid Nanoparticles for Targeting Hepatocellular Carcinoma.

Cantharidin (CTD) is the major component of anticancer drugs obtained from Mylabris Cichorii and has a good inhibitory effect on several cancers, including hepatocellular carcinoma (HCC) and breast cancer. However, due to its toxicity, oral administration can cause various adverse reactions, limiting its clinical application. The aim of this work was to design glycyrrhetinic acid (GA)- and/or folate (FA)-modified solid lipid nanoparticles (SLNs) for the encapsulation of CTD to target HCC. Four CTD-loaded SLNs (cantharidin solid lipid nanoparticles (CSLNs), glycyrrhetinic acid-modified cantharidin solid lipid nanoparticles (GA-CSLNs), folate-modified cantharidin solid lipid nanoparticles (FA-CSLNs), and glycyrrhetinic acid and folate-modified cantharidin solid lipid nanoparticles (GA-FA-CSLNs)) were prepared by the emulsion ultrasonic dispersion method, and their physicochemical parameters were determined (particle size and distribution, morphology, zeta-potential, entrapment efficiency, drug loading, and hemolysis). Additionally, the antitumor activities of the four SLNs were evaluated comprehensively by tests for cytotoxicity, cell migration, cell cycle, apoptosis, cellular uptake, competition suppression assay, and in vivo tumor suppression assay. Four SLNs showed spherical shapes and mean diameters in the range of 75-110 nm with size dispersion (PDI) within the range of 0.19-0.50 and zeta-potential approximately -10 mV. The entrapment efficiency of CTD in SLNs was higher than 95% for all tested formulations, and no hemolysis was observed. Compared to GA-CSLNs or CSLNs, GA-FA-CSLNs and FA-CSLNs showed stronger cytotoxicity on hepatocellular carcinoma cells (HepG2), and the cytotoxicity of GA-FA-CSLNs on hepatocyte cells (L-02) was remarkably reduced compared with other formulations. GA-FA-CSLNs and FA-CSLNs also increased the inhibition of HepG2 cell migration, and FA-CSLNs had the highest apoptosis rate. The cell cycle results indicated that HepG2 cells were arrested mainly in the S phase and G2/M phase. Analysis of competition inhibition experiments showed that GA and FA ligands had targeted effects on HepG2 cells. The in vivo tumor inhibition experiment showed that GA-FA-CSLNs and FA-CSLNs had excellent tumor inhibition ability-their tumor inhibition rates were 96.46% and 89.92%, respectively. Our results indicate that GA-FA-CSLNs and FA-CSLNs have a promising future in the therapeutic intervention of HCC.

Nano Drug Delivery System for Tumor Immunotherapy: Next-Generation Therapeutics.

Tumor immunotherapy is an artificial stimulation of the immune system to enhance anti-cancer response. It has become a powerful clinical strategy for treating cancer. The number of immunotherapy drug approvals has been increasing in recent years, and many treatments are in clinical and preclinical stages. Despite this progress, the special tumor heterogeneity and immunosuppressive microenvironment of solid tumors made immunotherapy in the majority of cancer cases difficult. Therefore, understanding how to improve the intratumoral enrichment degree and the response rate of various immunotherapy drugs is key to improve efficacy and control adverse reactions. With the development of materials science and nanotechnology, advanced biomaterials such as nanoparticle and drug delivery systems like T-cell delivery therapy can improve effectiveness of immunotherapy while reducing the toxic side effects on non-target cells, which offers innovative ideas for improving immunity therapeutic effectiveness. In this review, we discuss the mechanism of tumor cell immune escape and focus on current immunotherapy (such as cytokine immunotherapy, therapeutic monoclonal antibody immunotherapy, PD-1/PD-L1 therapy, CAR-T therapy, tumor vaccine, oncolytic virus, and other new types of immunity) and its challenges as well as the latest nanotechnology (such as bionic nanoparticles, self-assembled nanoparticles, deformable nanoparticles, photothermal effect nanoparticles, stimuli-responsive nanoparticles, and other types) applications in cancer immunotherapy.

[Mechanism of Huangjing Qianshi Decoction in treatment of prediabetes based on network pharmacology and molecular docking].

This study analyzed the molecular mechanism of Huangjing Qianshi Decoction(HQD) in the treatment of prediabetes based on network pharmacology and molecular docking. The active components of HQD were identified and screened based on Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP, http://Lsp.nwu.edu.cn/tcmsp.php) and then the targets of the components and the genes related to prediabetes were retrieved, followed by identifying the common targets of the decoction and the disease. The medicinal component-target network was constructed by Cytoscape to screen key components. The protein-protein interaction(PPI) network was established by STRING and hub genes were identified by Cytoscape-CytoNCA, followed by Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) of the hub genes with R-clusterProfi-ler. Thereby, the possible signaling pathways were predicted and the molecular mechanism was deduced. A total of 79 active components of HQD and 785 diabetes-related targets of the components were screened out. The hub genes mainly involved the GO terms of tricarboxylic acid cycle, peptide binding, amide binding, hydrolase activity, and kinase activity regulation, and the KEGG pathways of AGE-RAGE signaling pathway, TNF signaling pathway, AMPK signaling pathway, IL-17 signaling pathway, and insulin signaling pathway. Western blot result showed that HQD-containing serum significantly reduced the expression of AKT1, AGE, and RAGE proteins in insulin resistance model cells. HQD's treatment of prediabetes is characterized by multiple pathways, multiple targets, and multiple levels. The main mechanism is that the components zhonghualiaoine, baicalein, kaempferol, and luteolin act on AKT1 and inhibit the AGE-RAGE axis.

Constructing and validating of m6a-related genes prognostic signature for stomach adenocarcinoma and immune infiltration: Potential biomarkers for predicting the overall survival.

Background: Stomach adenocarcinoma (STAD) arises from the mutations of stomach cells and has poor overall survival. Chemotherapy is commonly indicated for patients with stomach cancer following surgical resection. The most prevalent alteration that affects cancer growth is N6-methyladenosine methylation (m6A), although the possible function of m6A in STAD prognosis is not recognized. Method: The research measured predictive FRGs in BLCA samples from the TCGA and GEO datasets. Data on the stemness indices (mRNAsi), gene mutations, copy number variations (CNV), tumor mutation burden (TMB), and corresponding clinical characteristics were obtained from TCGA and GEO. STAD from TCGA and GEO at 24 m6A was investigated. Lasso regression was used to construct the prediction model to assess the m6A prognostic signals in STAD. In addition, the correlation between m6a and immune infiltration in STAD patients was discussed using GSVA and ssGSEA analysis. Based on these genes, GO and KEGG analyses were performed to identify key biological functions and key pathways. Result: A significant relationship was discovered between numerous m6A clusters and the tumor immune microenvironment, as well as three m6A alteration patterns with different clinical outcomes. Furthermore, GSVA and ssGSEA showed that m6A clusters were significantly associated with immune infiltration in the STAD. The low-m6Ascore group had a lower immunotherapeutic response than the high-m6Ascore group. ICIs therapy was more effective in the group with a higher m6Ascore. Three writers (VIRMA, ZC3H13, and METTL3) showed significantly lower expression, whereas five authors (METTL14, METTL16, WTAP, RBM15, and RBM15B) showed considerably higher expression. Three readers (YTHDC2, YTHDF2, and LRPPRC) had higher levels of expression, whereas eleven readers (YTHDC1, YTHDF1, YTHDF3, HNRNPC, FMR1, HNRNPA2B1, IGFBP1, IGFBP2, IGFBP3, and RBMX) had lower levels. As can be observed, the various types of m6 encoders have varied ramifications for STAD control. Conclusion: STAD occurrence and progression are linked to m6A-genes. Corresponding prognostic models help forecast the prognosis of STAD patients. m6A-genes and associated immune cell infiltration in the tumor microenvironment (TME) may serve as potential therapeutic targets in STAD, which requires further trials. In addition, the m6a-related gene signature offers a viable alternative to predict bladder cancer, and these m6A-genes show a prospective research area for STAD targeted treatment in the future.

Pressure injury prevalence and risk factors in Chinese adult intensive care units: A multi-centre prospective point prevalence study.

Despite increasing preventive efforts, pressure injury still occurs in intensive care patients. This study was aimed to describe pressure injury prevalence, risk factors, and prevention practices in adult intensive care patients. This was a multi-centre, one-day, prospective point prevalence study in which a total of 198 intensive care units from 21 provinces in China participated. Overall and ICU-acquired prevalence in intensive care patients were 12.26% and 4.31%, respectively. Consistent with earlier reports, almost half of the ICU-acquired pressure injuries were at stage I, one-fourth were at stage 2, and the most common body sites for pressure injuries were sacral and heel region. Risk factors identified were consistent with prior studies. Repositioning was the most commonly used pressure injury prevention strategy, followed by alternating pressure mattresses/overlays, floating heels, and air-filled mattresses/overlays. These reflect a good level of adherence to recommended international pressure injury prevention clinical practice guidelines. The results provide a baseline reference for overall and ICU-acquired prevalence among adult intensive care patients in China. Future research on what contributed to the lower pressure injury incidence in China needs to be conducted to inform healthcare organisations on their future preventive strategies for pressure injury prevention.

Polygonatum sibiricum polysaccharides (PSP) improve the palmitic acid (PA)-induced inhibition of survival, inflammation, and glucose uptake in skeletal muscle cells.

Polygonatum sibiricum polysaccharides (PSP) can decrease the levels of fasting blood glucose, total cholesterol, and triglyceride (TG) in hyperlipidemic and diabetic animals. It can also reduce inflammatory cytokines and promote glucose uptake in adipocytes. However, the underlying molecular mechanisms of PSP in improving insulin resistance (IR) in skeletal muscle remain unclear. In this study, palmitic acid (PA) induced an IR model in L6 myotubes. After treatment, cell proliferation was measured using the CCK8. miR-340-3p, glucose transporter 4 (GLUT-4), and interleukin-1 receptor-associated kinase 3 (IRAK3) expression was measured by qRT-PCR. IRAK3 protein levels were measured by Western blotting. Glucose in the cell supernatant, TG concentration in L6 myotubes, and the levels of IL-1ß, IL-6, and TNF-α were measured by an ELISA. We found that cell survival, glucose uptake, and GLUT-4 expression in L6 myotubes were significantly suppressed, while lipid accumulation and inflammatory factor levels were enhanced by PA stimulation. Furthermore, PSP treatment markedly alleviated these effects. Interestingly, PSP also significantly reduced the upregulated expression of miR-340-3p in the L6 myotube model of IR. Furthermore, overexpression of miR-340-3p reversed the beneficial effects of PSP in the same IR model. miR-340-3p can bind to the 3'-untranslated regions of IRAK3. Additionally, PA treatment inhibited IRAK3 expression, whereas PSP treatment enhanced IRAK3 expression in L6 myotubes. Additionally, miR-340-3p also inhibited IRAK3 expression in L6 myotubes. Taken together, PSP improved inflammation and glucose uptake in PA-treated L6 myotubes by regulating miR-340-3p/IRAK3, suggesting that PSP may be suitable as a novel therapeutic agent for IR.

Clinical Value of Serum Thrombospondin-2 Combined with CA19-9 in Early Diagnosis of Gastric Cancer.

Gastric cancer (GC) is a kind of common cancer worldwide. Too late in diagnosis results in poor prognosis of patients with GC. Thrombospondin-2 (THBS2) is a type of secreted protein that has been found to be a diagnostic biomarker in a variety of cancers. Our study aimed to uncover the clinical value of THBS2 in early detection for patients with gastric cancer. THBS2 was upregulated in gastric cancer tissue compared with normal tissue via analyzing data obtained from The Cancer Genome Atlas (TCGA) database. Additionally, the enzyme-linked immunosorbent assay revealed that the level of serum THBS2 and carcinoembryonic antigen, CA19-9, was higher dramatically in patients with early gastric cancer (EGC) than that in healthy control (HC) in addition to patients with benign gastric tumor (BGT), which suggested that THBS2 indeed associated with GC. Receiver operator characteristic (ROC) curve assay was conducted to demonstrate that serum THBS2 was similar to CA19-9 to distinguish patients with early gastric cancer from healthy control and patients with benign gastric tumor and that THBS2 combined with CA19-9 improved the detective performance of THBS2 for early gastric cancer. Furthermore, we applied the gene set enrichment analysis assay to analyze signaling pathways related to THBS2. We found that THBS2 positively controlled MAPK and WNT signaling pathways, which indicated that THBS2 might exert its functions via the pathway mentioned above. Thus, our study expounded that serum THBS2 could serve as a vital early diagnostic marker for patients with gastric cancer.

Pemafibrate suppresses oxidative stress and apoptosis under cardiomyocyte ischemia-reperfusion injury in type 1 diabetes mellitus.

Diabetes mellitus accelerates the hyperglycemia susceptibility-induced injury to cardiac cells. The activation of peroxisome proliferator-activated receptor α (PPARα) decreases ischemia-reperfusion (IR) injury in animals without diabetes. Therefore, the present study hypothesized that pemafibrate may exert a protective effect on the myocardium in vivo and in vitro. A type 1 diabetes mellitus (T1DM) rat model and H9c2 cells exposed to high glucose under hypoxia and reoxygenation treatments were used in the present study. The rat model and the cells were subsequently treated with pemafibrate. In the T1DM rat model, pemafibrate enhanced the expression of PPARα in the diabetic-myocardial ischemia-reperfusion injury (D-IRI) group compared with the D-IRI group. The infarct size in the D-IRI group was reduced following pemafibrate treatment relative to the untreated group. The disruption of the mitochondrial structure and myofibrils in the D-IRI group was partially recovered by pemafibrate. In addition, to evaluate the mechanism of action of pemafibrate in the treatment of diabetic myocardial IR injury, an in vitro model was established. PPARα protein expression levels were reduced in the high glucose and hypoxia/reoxygenation (H/R) groups compared with that in the control or high glucose-treated groups. Pemafibrate treatment significantly enhanced the ATP and superoxide dismutase levels, and reduced the mitochondrial reactive oxygen species and malondialdehyde levels compared with the high glucose combined with H/R group. Furthermore, pemafibrate inhibited the expression of cytochrome c and cleaved-caspase-3, indicating its involvement in the regulation of mitochondrial apoptosis. Pemafibrate also reduced the expression of nuclear factor-κB (NF-κB), the activation of which reversed the protective effects of pemafibrate on diabetic myocardial IR injury in vitro. Taken together, these results suggested that pemafibrate may activate PPARα to protect the T1DM rat myocardium against IR injury through inhibition of NF-κB signaling.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside, a major bioactive component from Polygoni multiflori Radix (Heshouwu) suppresses DSS induced acute colitis in BALb/c mice by modulating gut microbiota.

BACKGROUND: Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn's disease (CD), which is a common idiopathic digestive disease without a specific cure or treatment for improvement. Because Polygoni multiflori Radix has a traditional medicinal use to treat intestinal diseases, and the water extract of this herbal medicine had a positive influence on dextran sulfate sodium (DSS) induced UC model in our study. Meanwhile 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) as the major component of the water extract of Polygoni multiflori Radix with yield of more than 10% exhibited the remarkable anti-inflammatory activity in vivo and in vitro, we predicted that TSG may contribute to benefit intestinal tract presented by the water extract of Polygoni multiflori Radix. Therefore, the present study aims to explore the pharmacological effect of this compound on UC model and its possible mechanism to regulate intestinal function through gut microbiota. METHODS: Ulcerative colitis model was established in BALb/c mice by continuously administrating 3% (w/v) DSS aqueous solution for one week. The disease activity index (DAI), colon length, histopathological examination by H&E and the levels of tight junction proteins (TJP) by immunofluorescence staining were performed in ulcerative colitis model following the protocol. Furthermore, the levels of main inflammatory factors like TNF-α, IL-ß, IL-6, and IL-10 were analyzed by the ELIZA kits for the further confirmation of anti-inflammatory activity of TSG on ulcerative colitis model. Finally, 16S rDNA sequencing technology was conducted to explore the composition and relative abundance of gut microbiota of different treatment groups. RESULTS: TSG treatments effectively increased body weight about 5% of those in DSS group (p < 0.001) as well remarkably reduced the DAI scores to the 50% of those in DSS group (p < 0.001) in the UC model. TSG treatments of either 25 mg/kg (TSG-25) or 100 mg/kg (TSG-100) dosage restored epithelial barrier structure and exhibited obviously intact colon histology with reduced signs of inflammatory cells infiltration, preserved epithelia barrier, restored crypt structure, and increased numbers of goblet cells. TSG treatments could markedly lessen the histopathologic score two or three times than those in DSS group (p < 0.001). Especially for TSG-100 treatment, the fluorescence intensity of ZO-1 and Occludin were nearly back to 80% of those in normal group, and were 1.5 times more than those in the DSS group (p < 0.001). Additionally, direct evidence pointed to TSG as a therapeutically active molecule in the prevention and treatment of UC by significantly reducing the production of these pro-inflammatory cytokines like TNF-α, IL-1ß, and IL-6 (p < 0.05-0.001) and increasing the levels of anti-inflammatory cytokine IL-10 (p < 0.05-0.001). Finally, it was found TSG treatments significantly raised the relative abundances of Firmicutes and Bacteroidetes with a dose-dependently and improved the homeostasis of the gut microbiota composition which disrupted by DSS through increasing genus level Lachnospiraceae_NK4A136 and decreasing genus level of Helicobacter, Bacteroides, Parabacteroides. CONCLUSION: The present results suggested that TSG treatments had a desirable pharmacological effect on acute colitis induced by DSS in the mice as well showed the possible mechanism relate to improve the intestinal function through balancing the gut microbiota of intestinal flora.