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The Role of Phosphatidylethanolamine Binding Protein 1/15-Lipoxygenase 2/Glutathione Peroxidase 4 Signaling Pathway in Cerebral Ischemia Reperfusion-Induced Ferroptosis; In Vitro and in Vivo Study
No full textObjective: To investigate the role of phosphatidylethanolamine binding protein 1/15-Lipoxygenase 2/Glutathione Peroxidase 4 (PEBP1/15-lox2/GPX4) signaling pathway in cerebral ischemia reperfusion (I/R)-induced ferroptosis. Methods: The expression of PEBP1, 15-lox2, GPX4 and SLC7A11 in the peripheral serum samples of stroke patients and healthy controls was detected with quantitative polymerase chain reaction (qPCR). HT22 was selected to establish the hypoxia reoxygenation model. Enzyme linked immunosorbent assay (ELISA) was applied to detect the levels of superoxide dismutase (SOD) and malondialdehyde (MDA), transmission electron microscope to observe the microstructure of mitochondria, and western blotting to detect the expression levels of SLC7A11, 15-lox2, GPX4 and PEBP1, co-immunoprecipitation (CO-IP) to verify the interaction of PEBP1 with 15-lox2. Additionally, the function of PEBP1/15-lox2/GPX4 signaling pathway was further investigated in cerebral I/R-induced injury. Results: The expression of PEBP1 and 15-lox2 was significantly higher, while the expression of GPX4 and SLC7A11 was significantly lower in stroke patients, than that in healthy controls (p < 0.05). In HT22 cells, hypoxia reoxygenation significantly promoted MDA level and significantly reduced SOD level, compared with control. Additionally, hypoxia reoxygenation significantly increased PEBP1, 15-lox2 expression and p-PEBP1 level, and significantly reduced GPX4 and SLC7A11 expression (p < 0.05). These changes were significantly relieved by PEBP1 knockdown and significantly aggravated by PEBP1 overexpression. Morphological results also showed that PEBP1 knockdown also prevented hypoxia reoxygenation-induced cell injury. Co-Immunoprecipitation (CO-IP) also indicated a direct interaction between PEBP1 and 15-lox2. In vivo data showed that cerebral I/R significantly increased the infarct size, MDA level, PEBP1 and 15-lox2 expression, p-PEBP level, and significantly reduced SOD, GPX4 and SLC7A1 expression, compared with sham group. PEBP1 knockdown significantly attenuated those changes (p < 0.05). Morphological results further indicated that PEBP1 knockdown prevented cerebral I/R-induced injury. Conclusions: PEBP1/15-lox2/GPX4 signaling pathway participates in cerebral ischemia reperfusion-induced ferroptosis
Artesunate Attenuates Interleukin-1β-Induced the Apoptosis of Chondrocytes, Oxidative Stress Injury and Inflammatory Response: Evidence of the Presence of the Wnt/β-Catenin Pathway
No full textBackground: Recently, research has borne out that artesunate (ART), an anti-malaria agent, possesses anti-osteoarthritis function, but the mechanisms whereby ART protects the progression of osteoarthritis (OA) remains to be explored. Hence, the current study was aimed at assessing the potential mechanisms of ART in protecting aginst interleukin-1β (IL-1β) -induced rat primary chondrocytes injuries, focusing on the wingless/integrated (Wnt)/β-catenin pathway. Methods: Rat primary chondrocytes isolated from SD rats (4-week-old) were treated with IL-1β to establish an OA model in vitro. Cell viability, lactate dehydrogenase (LDH) release and intracellular reactive oxygen species (ROS) generation, lipid peroxide (malondialdehyde (MDA)) content, and antioxidant enzyme (superoxide dismutase (SOD)) activity were assessed by commercial kits. Cell apoptosis was detected by flow cytometry. The protein expression were determined by western blotting. The inflammatory factors levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: ART significantly increased cell viability, decreased LDH release, and lowered apoptosis comprising apoptosis rate, caspase-3 activity and anti-apoptotic protein (Bax)/pro-apoptotic protein (Bcl-2) ratio in IL-1β-treated rat primary chondrocytes. Additionally, ART suppressed Wnt3a/β-catenin pathway by decreasing Wnt3a/β-catenin, cyclin D1, and c-Myc expressions in IL-1β-exposed rat primary chondrocytes. Furthermore, LiCl, an activator of the Wnt3a/β-catenin pathway, remarkably blocked the beneficial effects of ART during IL-1β injury. In addition, ART attenuated IL-1β-stimulated oxidative stress by reducing ROS generation and MDA content and increasing antioxidant enzyme SOD activity, while these functions of ART were blocked by LiCl. Also, LiCl reversed the anti-inflammatory activity of ART during IL-1β stimulation as illustrated by the increased in nitric oxide level and pro-inflammatory factors including tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) secretion in rat primary chondrocytes. Conclusions: These findings demonstrated that ART attenuates apoptosis, oxidative stress and inflammation through suppressing the Wnt3a/β-catenin pathway in IL-1β-treated chondrocytes
Integrated Analysis of lncRNA-miRNA-mRNA Associated ceRNA Networks Involved in Cystic Echinococcosis-Induced Fibrogenesis in Vitro
No full textBackground: The primary pathological features of cystic echinococcosis (CE) are the formation of fibrotic pericytes and space-occupying lesions in the liver, but fibrogenesis has received little attention in CE. This study aimed to investigate the possible mechanisms underlying CE-induced fibrogenesis from the perspective of competing endogenous RNAs (ceRNAs). Methods: Hydatid fluid was collected from sheep livers infected with Echinococcus granulosus and was used to treat rat hepatic stellate cells (HSC-T6) to establish a fibrotic cell model. Next, RNA sequencing and bioinformatic analyses were conducted. Finally, two important ceRNA axes were chosen for quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Results: After hydatid fluid treatment, the both mRNA and protein expression levels of fibrosis-related factors (anti-alpha-smooth muscle actin, type III collagen, and transforming growth factor-β receptor II) were significantly higher than those in control cells. After sequencing, 569 differentially expressed (DE) mRNAs, 151 DE long non-coding RNAs (lncRNAs), and 14 DE miRNAs were identified in infected cells. Next, ceRNA regulatory networks consisting of 207 mRNAs, 13 miRNAs, and 54 lncRNAs were constructed. Based on the comparative toxicogenomics database, 8 fibrosis-related pathways were identified, including focal adhesion, extracellular matrix-receptor interaction, the hypoxia-inducible factor 1 signaling pathway, and pathways in cancer, as well as disease pathway-related regulatory networks associated with 38 DE lncRNAs, 43 DE mRNAs, 11 DE miRNAs, and 8 pathways. The qRT-PCR results of LNC_003335-novel_559-TNC and LNC_002273-miR-125-2-3p-PDGFD were consistent with the RNA sequencing results. Conclusions: Our study showed that the two ceRNA axes LNC_003335-novel_559-TNC and LNC_002273-miR-125-2-3p-PDGFD may be potential critical targets for CE-induced fibrogenesis
Schisandrin A Has an Antibacterial Effect on Escherichia coli by Affecting Ribosome Function
No full textBackground: Escherichia coli pollution is a significant microbial pollutant that affects human and animal health and is an important factor that restricts the development of the poultry industry. This study aimed to investigate the antibacterial effect of Schisandrin A on Escherichia coli. Methods: Escherichia coli was divided into a control group and a Schisandrin A treatment group. The minimal inhibitory concentration (MIC) of Schisandrin A on Escherichia coli was determined. The growth curve was drawn by measuring absorbance values at 600 nm at 0 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 12 h, and the antibacterial effect of Schisandrin A on Escherichia coli was observed. The integrity of the cell membrane and cell wall of Escherichia coli was detected using an electron microscope. The permeability of the Escherichia coli wall was measured using Alkaline phosphatase (AKP) activity and Propidium Iodide (PI) staining. Transcriptome sequencing was carried out to explore the antibacterial mechanism of Schisandrin A on Escherichia coli. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to detect the expression of virulence genes in Escherichia coli. Results: The study found that Schisandrin A has a minimum inhibitory concentration (MIC) of 3.13 mg/mL against Escherichia coli. When added at a concentration of ½ MIC, Schisandrin A can slow down the growth rate of Escherichia coli, damage the cell structure, and significantly downregulate the virulence genes ferric aerobactin receptor IutA (iutA), yersiniabactin non-ribosomal peptide synthetase HMWP2 (irp2) and type 1 fimbriae periplasmic chaperone (fimC) (p < 0.05). Transcriptome results showed that Schisandrin A could downregulate the expression of 50S ribosomal subunit protein L24 (rplX), 30S ribosomal subunit protein S12 (rpsL), 50S ribosomal subunit protein L13 (rplM), 50S ribosomal subunit protein L5 (rplE) and 30S ribosomal subunit protein S5 (rpsE) in ribosomes and upregulate 50S ribosomal subunit protein L31B (ykgM) expression. Conclusions: Schisandrin A has an inhibitory effect on Escherichia coli. It can destroy the bacterial structure and affect bacterial colonization and metabolism. Its bacteriostatic mechanism is related to the damage to ribosome function
OM-85 in the Prevention of Recurrent Respiratory Infections in Children: State of the Art
No full textRecurrent Respiratory Infections (RRIs) in the pediatric population have an important clinical and economic impact, which can be reduced through appropriate preventive measures, including immunomodulating agents, like bacterial lysates. This manuscript aimed to provide an overview of the clinical evidence on the efficacy and safety of bacterial lysates in the prevention of RRIs in children, with a particular focus on OM-85 (Broncho Vaxom®) as well as to shed light on the concomitant use of OM-85 and vaccines as a successful strategy for reducing respiratory morbidity in the pediatric population. In children with RRIs, OM-85 treatment significantly reduce the number and duration of Respiratory Tract Infections (RTIs), antibiotic courses and wheezing respiratory illnesses in young children. Its efficacy seemed to be more pronounced in children with more respiratory infections. Moreover, OM-85 was effective and well tolerated when administered concomitantly with inactivated influenza vaccine. Due to its long-term efficacy and good safety profile, OM-85 can be recommended as a valid prophylactic approach for preventing RTIs in children, especially in cases where the incidence of the disease is high and attempts to eliminate contributing environmental factors have proven unsuccessful
The Effect and Mechanism of Action of Oridonin on Carbon Tetrachloride-Induced Liver Injury; An Animal Study
No full textPurpose: The aim of this study was to look into the effect and mechanism of action of oridonin (Ori) in carbon tetrachloride (CCL4)-induced liver injury in rats. Methods: 24 adult male Sprague Dawley (SD) rats were divided into four groups at random: Control, Ori, CCL4, and CCL4 + Ori. In addition to body and liver weights as well as blood tests, real-time quantitative reverse transcription PCR (qRT-PCR) was used to detect the mitochondrial deoxyribonucleic acid (DNA) level in the liver tissue of rats, and the protein expression levels of NAD (P) H quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1) and the nuclear erythroid-2-related factor 2 (Nrf2) in the liver tissues of the rats were checked for using western blot. Results: Ori showed antioxidant and hepatoprotective effects in rats with CCL4-induced liver injury and significantly improved mitochondrial function in rats with CCL4-induced liver injury. Additionally, Ori significantly alleviated CCL4-induced liver injury in rats, by activating the Nrf2/HO-1/NQO1 pathway. Conclusions: Ori may attenuate CCL4-induced liver injury in rats via improving mitochondrial function and activating the Nrf2/HO-1/NQO1 pathway, as well as having hepatoprotective and anti-oxidative effects
NAC Attenuated NEC-Induced Lung Injury Caused by ROS Released from Neutrophils by Regulating the Keap1-Nrf2 Pathway
No full textBackground: Necrotizing Enterocolitis (NEC) is a critical illness commonly seen in premature and diseased neonates, characterized by mucosal necrosis of the small intestine and colon, which seriously affects the life and health of patients. Objective: The aim of the research was to investigate the role and mechanism of neutrophils in lung injury in mice with NEC. Methods: Combinational treatment with formula milk, hypoxia, and lipopolysaccharide (LPS) was performed to establish NEC in 5-day-old C57BL/6J mice. These mice were divided into 4 groups (20 mice in each group) by random number table method: Ctrl group, NEC group, NEC + phosphate-buffered saline (PBS) group, NEC + N-acetyl-L-cysteine (NAC) group. The pathological changes in intestinal and lung tissues were examined through Hematoxylin and Eosin (HE) staining. Lymphocyte antigen 6complex, locus g (Ly6G), neutrophil elastase (NE), myeloperoxidase (MPO) immunohistochemistry (IHC), and flow cytometry were used for qualitative and quantitative analysis of neutrophils in lung tissues respectively. The messenger ribonucleic acid (mRNA) relative expression levels of inflammatory factors in intestinal and lung tissues were detected using Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR). The reactive oxygen species (ROS) release level in neutrophils stimulated by N-formyl-methionyl-leucy1-phenylalanine (fMLP) was detected using an enzyme-labeled instrument. The expression levels of genes in the Kelch-like enoyl-CoA hydratase (ECH)-associated protein 1-nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) pathway were determined using RT-qPCR. Results: Compared to the Ctrl group, the intestinal and lung tissues of the mice in the NEC group were significantly damaged (p < 0.0001). However, NAC could significantly relieve the damage (p < 0.0001). Compared to Ctrl group, the mRNA relative expression levels of inflammatory factors and anti-oxidant genes were significantly upregulated (p < 0.05), while the expression levels of anti-ROS genes were significantly downregulated in the NEC group (p < 0.05), and NAC could significantly reverse this result. Mice lung tissue RNA-seq results indicated a significant enrichment in the neutrophil degranulation pathway. The levels of NE, MPO, and ROS released by neutrophils were significantly higher than those in the Ctrl group (p < 0.05). The ROS released by neutrophils is involved in NEC-induced lung injury by regulating the Keap1-Nrf2 pathway, as the inhibition of the release of ROS can alleviate the injury of intestinal and lung tissues. Conclusions: Neutrophils play an important role in NEC-induced lung injury and NAC has therapeutic potential for NEC-induced lung injury
Salvianolic Acid B Facilitates Endothelial Differentiation of Human Induced Pluripotent Stem Cells via Piezo1/MEK/Erk
No full textBackground: Piezo1 is a mechanosensitive Ca2+ channel protein that participates in stem cells fate. Salvianolic acid B (Sal-B) is a polyphenolic compound that promotes endothelial differentiation. This study aims to assess the role of Sal-B in facilitating endothelial differentiation by regulating the activity of Piezo1. Methods: The system of human-induced pluripotent stem cells (iPSCs) differentiating into endothelial cells (ECs) in vitro was established to study the role and underlying mechanism of Piezo1 and Sal-B in the regulation of endotheliogenesis. Human iPSCs were divided into four groups, including the normal Sal-B shPiezo1, shPiezo1+Sal-B, shNT and shNT+Sal-B. Fura2-AM was used to record intracellular calcium ion changes. The relative mRNA levels of Piezo1, CD144, endothelial Nitric Oxide Synthase (eNOS), mitogen-activated protein kinase (MAPK) kinase (MEK) and extracellular signal-regulated kinase1/2 (Erk1/2) were identified by Quantitative Reverse Transcription-Polymerase Chain Reaction (RT-qPCR) while the protein levels were measured by Western blotting (WB). Results: The addition of 50 μM Sal-B significantly increased the differentiation of ECs. WB and RT-qPCR results showed that Sal-B increased the relative levels of eNOS mRNA, CD144 mRNA, CD144 protein and the tube formation in vitro. Sal-B treatment enhanced Piezo1 expression and Yoda1 activated Ca2+ influx, and amplified MEK/Erk1/2 phosphorylation of endothelial cells (ECs) derived from iPSCs (iPSC-ECs). Silencing of Piezo1 impeded the effect of Sal-B on increasing the rate of endotheliogenesis, as well as the MEK/Erk1/2 phosphorylation of iPSC-ECs. Conclusions: The results indicate that Sal-B promotes endothelial differentiation of iPSCs through Piezo1 by triggering the internal flow of Ca2+ and thus further amplifying MAPK/Erk1/2 signaling. Here, we found that Sal-B allows the increase in the number and quality of ECs differentiated from iPSCs. These in-vitro studies constitute a starting point for the future use of this compound in regenerative medicine
Integrated Bioinformatics Analysis of the IRF5 Signalling Pathway in Children with Systemic Lupus Erythematosus
No full textBackground: Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that affects multiple organs and is characterised by various symptoms such as fatigue, fever, joint pain and swelling, skin rashes, and inflammation of the kidneys or brain. Children with SLE may experience additional symptoms, such as delayed puberty. The main objective of the study is to perform an integrated bioinformatics analysis of the interferon regulatory factor 5 (IRF5) signalling pathway in children with SLE. Methods: We obtained two microarray datasets from the Gene Expression Omnibus (GEO) database. The Gene Set Enrichment (GSE17926) dataset, based on the GPL9059 platform, consists of 13 and 37 IRF5 samples. The GSE81622 dataset was based on the GPL10558 platform and consisted of 30 SLE patients and 25 controls. Data normalisation and relevant plots were produced in R software. We visualized the protein-protein interaction (PPI) networks using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and performed gene ontology and pathway enrichment analysis using ShinyGO. Results: We identified 357 differentially expressed genes (DEGs), of which 190 were downregulated while 167 were upregulated. Using the STRING tool, we constructed a PPI network and identified 10 hub genes (interleukin 1 receptor associated kinase 1 (IRAK1), Cyclic adenosine monophosphate-response element binding protein (CREBBP), signal transducer and activator of transcription 1 (STAT1), myeloid differentiation factor 88 (MyD88), interferon simulated gene 15 (ISG15), signal transducer and activator of transcription 2 (STAT2), interferon beta 1 (IFNB1), tumour necrosis receptor-associated factor 6 (TRAF6), rel-associated protein (RELA), and interferon regulatory factor 3 (IRF3) associated with IRF5 signalling in SLE. We also identified three Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in IRF5 and the hub genes: the Janus Kinase-signal transducer and activator of transcription (JAK-STAT) signalling pathway, the Toll-like receptor signalling pathway, and the cellular differentiation of T helper cells. Furthermore, we found that IRF5 signalling was enriched in pathways such as response to peptidoglycans, muramyl dipeptide and regulation of interferons. Conclusions: The dysregulation of the IRF5 signalling pathway can contribute to the development of SLE by promoting inflammation and activating the immune system. This can lead to tissue damage and the production of autoantibodies
Cardiovascular Toxicity Risks of Sunitinib in Cancer Patients: A Meta-Analysis
No full textBackground: At present, no research has systematically integrated existing data to assess the risks of cardiovascular toxicity caused by sunitinib. The goal of this study was to evaluate the risks of cardiovascular toxicity in patients with cancer who were taking sunitinib. Methods: Randomized controlled trials which used sunitinib to treat cancer patients and were published before 15 November 2021, were searched in Embase, Web of Science, and PubMed. Outcomes included cardiovascular toxicities such as hypertension, bleeding, and thromboembolism. Meta-analysis was performed using Stata (15.0, STATA Corp., College Station, TX, USA). Results: Eleven studies encompassing 5875 patients were included. Use of sunitinib was found to increase cardiovascular toxicity in patients, including all-grade hypertension (RR (relative risk) = 4.74, 95% CI 3.24–6.92), high-grade hypertension (RR = 4.13, 95% CI 2.95–5.76), and all-grade bleeding (RR = 3.16, 95% CI 2.38–4.20). However, sunitinib did not increase risks of all-grade thromboembolism in cancer patients compared to controls (RR = 1.45, 95% CI 0.44–4.79). Conclusions: This meta-analysis showed that use of sunitinib increases cardiovascular toxicity in patients with cancer. Doctors should understand these clinical risks and regularly perform cardiovascular monitoring