Targeted delivery of MerTK protein via cell membrane engineered nanoparticle enhances efferocytosis and attenuates atherosclerosis in diabetic ApoE-/- Mice.

BACKGROUND: Clearance of apoptotic cells by efferocytosis is crucial for prevention of atherosclerosis progress, and impaired efferocytosis contributes to the aggravated atherosclerosis. RESULTS: In this study, we found that diabetic ApoE-/- mice showed aggravated atherosclerosis as hyperglycemia damaged the efferocytosis capacity at least partially due to decreased expression of Mer tyrosine kinase (MerTK) on macrophages. To locally restore MerTK in the macrophages in the plaque, hybrid membrane nanovesicles (HMNVs) were thus developed. Briefly, cell membrane from MerTK overexpressing RAW264.7 cell and transferrin receptor (TfR) overexpressing HEK293T cell were mixed with DOPE polymers to produce nanovesicles designated as HMNVs. HMNVs could fuse with the recipient cell membrane and thus increased MerTK in diabetic macrophages, which in turn restored the efferocytosis capacity. Upon intravenous administration into diabetic ApoE-/- mice, superparamagnetic iron oxide nanoparticles (SMN) decorated HMNVs accumulated at the aorta site significantly under magnetic navigation, where the recipient macrophages cleared the apoptotic cells efficiently and thus decreased the inflammation. CONCLUSIONS:  Our study indicates that MerTK decrease in macrophages contributes to the aggravated atherosclerosis in diabetic ApoE-/- mice and regional restoration of MerTK in macrophages of the plaque via HMNVs could be a promising therapeutic approach.

Supplementation of Clostridium butyricum Alleviates Vascular Inflammation in Diabetic Mice.

Background: Gut microbiota is closely related to the occurrence and development of diabetes and affects the prognosis of diabetic complications, and the underlying mechanisms are only partially understood. We aimed to explore the possible link between the gut microbiota and vascular inflammation of diabetic mice. Methods: The db/db diabetic and wild-type (WT) mice were used in this study. We profiled gut microbiota and examined the and vascular function in both db/db group and WT group. Gut microbiota was analyzed by 16s rRNA sequencing. Vascular function was examined by ultrasonographic hemodynamics and histological staining. Clostridium butyricum (CB) was orally administered to diabetic mice by intragastric gavage every 2 days for 2 consecutive months. Reactive oxygen species (ROS) and expression of nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were detected by fluorescence microscopy. The mRNA expression of inflammatory cytokines was tested by quantitative polymerase chain reaction. Results: Compared with WT mice, CB abundance was significantly decreased in the gut of db/db mice, together with compromised vascular function and activated inflammation in the arterial tissue. Meanwhile, ROS in the vascular tissue of db/db mice was also significantly increased. Oral administration of CB restored the protective microbiota, and protected the vascular function in the db/db mice via activating the Nrf2/HO-1 pathway. Conclusion: This study identified the potential link between decreased CB abundance in gut microbiota and vascular inflammation in diabetes. Therapeutic delivery of CB by gut transplantation alleviates the vascular lesions of diabetes mellitus by activating the Nrf2/HO-1 pathway.

Heart failure-related genes associated with oxidative stress and the immune landscape in lung cancer.

Background: Lung cancer is a common comorbidity of heart failure (HF). The early identification of the risk factors for lung cancer in patients with HF is crucial to early diagnosis and prognosis. Furthermore, oxidative stress and immune responses are the two critical biological processes shared by HF and lung cancer. Therefore, our study aimed to select the core genes in HF and then investigate the potential mechanisms underlying HF and lung cancer, including oxidative stress and immune responses through the selected genes. Methods: Differentially expressed genes (DEGs) were analyzed for HF using datasets extracted from the Gene Expression Omnibus database. Functional enrichment analysis was subsequently performed. Next, weighted gene co-expression network analysis was performed to select the core gene modules. Support vector machine models, the random forest method, and the least absolute shrinkage and selection operator (LASSO) algorithm were applied to construct a multigene signature. The diagnostic values of the signature genes were measured using receiver operating characteristic curves. Functional analysis of the signature genes and immune landscape was performed using single-sample gene set enrichment analysis. Finally, the oxidative stress-related genes in these signature genes were identified and validated in vitro in lung cancer cell lines. Results: The DEGs in the GSE57338 dataset were screened, and this dataset was then clustered into six modules using weighted gene co-expression network analysis; MEblue was significantly associated with HF (cor = -0.72, p < 0.001). Signature genes including extracellular matrix protein 2 (ECM2), methyltransferase-like 7B (METTL7B), meiosis-specific nuclear structural 1 (MNS1), and secreted frizzled-related protein 4 (SFRP4) were selected using support vector machine models, the LASSO algorithm, and the random forest method. The respective areas under the curve of the receiver operating characteristic curves of ECM2, METTL7B, MNS1, and SFRP4 were 0.939, 0.854, 0.941, and 0.926, respectively. Single-sample gene set enrichment analysis revealed significant differences in the immune landscape of the patients with HF and healthy subjects. Functional analysis also suggested that these signature genes may be involved in oxidative stress. In particular, METTL7B was highly expressed in lung cancer cell lines. Meanwhile, the correlation between METTL7B and oxidative stress was further verified using flow cytometry. Conclusion: We identified that ECM2, METTL7B, MNS1, and SFRP4 exhibit remarkable diagnostic performance in patients with HF. Of note, METTL7B may be involved in the co-occurrence of HF and lung cancer by affecting the oxidative stress immune responses.

Relationship between serum insulin-like growth factor 1 levels and ischaemic stroke: a systematic review and meta-analysis.

OBJECTIVE: To assess the association of insulin-like growth factor 1 (IGF-1) with the risk of incident ischaemic stroke and outcome after ischaemic stroke. DESIGN: A systematic review of primary studies. SETTING: Hospitals in Western Sweden, Italy, China and Denmark. METHODS: A search was carried out in eligible studies in electronic databases (PubMed, Scopus, Embase, China National Knowledge Infrastructure and Web of Science) updated to 29 December 2020. The relevant data were extracted in order to conduct the meta-analysis. Review Manager V.5.2 was used to pool data and calculate the mean difference (MD) and its 95% CI. Heterogeneity, subgroup analysis, sensitivity analysis and publication bias were also performed in this meta-analysis. RESULTS: A total of 2277 patients were included in 17 studies. This meta-analysis indicated that higher serum IGF-1 levels were significantly correlated with less risk of ischaemic stroke (MD=-45.32 95% CI -63.70 to -26.94], p < 0.00001, I2=99%) and better improvement of outcome after ischaemic stroke (MD=27.52, 95% CI 3.89 to 51.14, p=0.02, I2=96%). According to subgroup analysis, heterogeneity comes from country, sample size, male and the time from symptom onset to blood collection. Sensitivity analysis showed that there was no significant influence of any individual study on the pooled MD. The effect of high heterogeneity on result credibility was eliminated when four included studies were merged (MD=-30.32, 95% CI -36.52 to -24.11, p< 0.00001, I2=0%). Moreover, no potential publication bias was discovered in this meta-analysis. CONCLUSION: Higher serum IGF-1 was significantly correlated with a lower risk of ischaemic stroke. In view of the high degree of heterogeneity, it may need more studies to confirm the prognostic value of serum IGF-1 levels in ischaemic stroke and explore the sources of heterogeneity.

Chinese parents' willingness to vaccinate their children against COVID-19: A systematic review and meta-analysis.

Introduction: To evaluate Chinese parents' willingness to vaccinate their children against COVID-19, identify its predictors, and provide a reference for raising the COVID-19 vaccination rate for children. Method: PubMed, Cochrane Library, Embase, and the databases in Chinese, including CNKI, WanFang, VIP, CBM, were searched from December 2019 to June 2022, and citation tracking was used to identify relevant studies. To calculate the rate with 95% confidence intervals (CI), a random-effects model was used. To explore sources of heterogeneity, sensitivity analysis and subgroup analysis were conducted. This analysis was registered on PROSPERO (CRD42022346866) and reported in compliance with the PRISMA guidelines. Result: Overall, 80 studies were screened, and 13 studies with 47994 parents were included after removing duplicates and excluding 19 studies that did not meet the selection criteria by title, abstract and full-text screening. The pooled willingness rate of Chinese parents to vaccinate their children against COVID-19 was 70.0% (95% CI: 62.0~78.0%). Level of education, perceived susceptibility of children infected with COVID-19, and parental attitudes toward vaccination (such as perceived efficacy and safety of the COVID-19 vaccines, parental willingness to vaccinate themselves, parental vaccination hesitancy, and the history of children's vaccination against influenza) were the main predictors of parents' intention to vaccinate their children. Discussion: Chinese parents' willingness to vaccinate their children against COVID-19 is moderate, and factors including parental education level, perceived susceptibility of children infected with COVID-19, and parental attitudes toward vaccination affect this decision. Fully identifying these factors and their mechanism will be essential to further raise the willingness rate. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022346866.

Status of hypoxia-inducible factor-1α expression in non-small cell lung cancer.

According to the latest statistics from WHO for all cancers, lung cancer tops the list with a 14.5% prevalence and a 22% death rate in men, similar to the prevalence in women, which is 13.8%. It is also the number one killer of cancer in China, with 40 in every 100,000 people suffering from lung cancer. HIF-1α is widely present in human cells in hypoxic environments. It regulates the body's response to hypoxia, cell oxygen balance, and hypoxia gene expression; participates in the proliferation and apoptosis of non-small cell lung cancer cells; participates in the invasion, metastasis, and neovascularization of tumor tissues; and affects the treatment and prognosis of non-small cell lung cancer. In view of the role of HIF-1α in the occurrence and development of non-small cell lung cancer, blocking HIF-1α by use of a single medication or combination chemotherapy has become a research hotspot. This review summarizes the role of HIF-1α in non-small cell lung cancer and provides new ideas for the treatment of this cancer type by synthesizing the research results of various authors.