Activation of PPAR-α attenuates myocardial ischemia/reperfusion injury by inhibiting ferroptosis and mitochondrial injury via upregulating 14-3-3η.

This study aimed to explore the effects of peroxisome proliferator-activated receptor α (PPAR-α), a known inhibitor of ferroptosis, in Myocardial ischemia/reperfusion injury (MIRI) and its related mechanisms. In vivo and in vitro MIRI models were established. Our results showed that activation of PPAR-α decreased the size of the myocardial infarct, maintained cardiac function, and decreased the serum contents of creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and Fe2+ in ischemia/reperfusion (I/R)-treated mice. Additionally, the results of H&E staining, DHE staining, TUNEL staining, and transmission electron microscopy demonstrated that activation of PPAR-α inhibited MIRI-induced heart tissue and mitochondrial damage. It was also found that activation of PPAR-α attenuated MIRI-induced ferroptosis as shown by a reduction in malondialdehyde, total iron, and reactive oxygen species (ROS). In vitro experiments showed that intracellular contents of malondialdehyde, total iron, LDH, reactive oxygen species (ROS), lipid ROS, oxidized glutathione disulphide (GSSG), and Fe2+ were reduced by the activation of PPAR-α in H9c2 cells treated with anoxia/reoxygenation (A/R), while the cell viability and GSH were increased after PPAR-α activation. Additionally, changes in protein levels of the ferroptosis marker further confirmed the beneficial effects of PPAR-α activation on MIRI-induced ferroptosis. Moreover, the results of immunofluorescence and dual-luciferase reporter assay revealed that PPAR-α achieved its activity via binding to the 14-3-3η promoter, promoting its expression level. Moreover, the cardioprotective effects of PPAR-α could be canceled by pAd/14-3-3η-shRNA or Compound C11 (14-3-3η inhibitor). In conclusion, our results indicated that ferroptosis plays a key role in aggravating MIRI, and PPAR-α/14-3-3η pathway-mediated ferroptosis and mitochondrial injury might be an effective therapeutic target against MIRI.

Development and validation of a new prediction model for calcific aortic valve stenosis.

Background: Calcific aortic valve stenosis (CAVS) is a common valvular heart disease, but there are limited reports on the construction of prediction models for CAVS. This study aimed to investigate the risk factors for CAVS and construct a predictive model for CAVS based on its common clinical features. Methods: Patients with CAVS who underwent surgical treatment in our hospital from 2016 to 2020 and those who underwent physical examination during the same period were retrospectively studied and placed in the CAVS group and normal group based on the area of aortic valve orifice less than or more than 3 cm2. A total of 548 patients were included in this study, including 106 CAVS patients and 442 normal patients. Subjects were randomly divided into training and validation sets at a 7:3 ratio. The features were dimensionally reduced using the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm in the training set, and the optimal clinical features were selected. The independent predictors of patients with CAVS were determined by univariate and multivariate logistic regression, and nomogram was constructed. The calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) were used to evaluate the model in both the training set and the validation set. Results: In this study, 11 independent predictors were distinguished by multivariate logistic regression analysis: history of hypertension, history of carotid atherosclerosis, age, diastolic blood pressure, C-reactive protein, direct bilirubin, alkaline phosphatase, low-density lipoprotein (LDL), lipoprotein(a) [Lp(a)], uric acid, and cystatin C. A nomogram was constructed using the above indicators. The model was well-calibrated and showed good discrimination and accuracy [the area under the curve (AUC) =0.981] in the training set, with a sensitivity of 91.89% and a specificity of 95.48%. More importantly, the nomogram displayed a good performance in the validation set (AUC =0.955, 95% CI: 0.925-0.985), with a sensitivity of 93.75% and a specificity of 84.09%. Additionally, DCA revealed that the nomogram had high clinical practicability. Conclusions: This study successfully established a risk prediction model for CAVS based on 11 conveniently accessible clinical indicators, which might easily be used for individualized risk assessment of CAVS.

Modification of m6A mediates tissue immune microenvironment in calcific aortic valve disease.

Background: Several human diseases are associated with aberrant expression of regulators involved in N6-methyladenosine (m6A) RNA modification. However, their role in aortic valve calcification (AVC) is largely unknown. The aim of this study was to determine the general expression pattern and potential function of m6A regulators in AVC by bioinformatics methods. Methods: We obtained AVC datasets from the Gene Expression Omnibus (GEO). The identification of m6A-related differentially expressed genes (DEGs) and the Consensus Clustering method was performed to type AVC individuals based DEGs. Then, we quantified the effect of typing by principal component analysis (PCA). Next, we performed the weighted gene co-expression network analysis (WGCNA) and identified the main modules as well as functional analysis. Additionally, the key genes were screened by protein-protein interaction network (PPIN) analysis and identifying important genes of important modules. We again typed AVC individuals by the same method using key genes. Finally, we evaluated the link between key genes and immune infiltration. Results: We discovered that METTL14, ZC3H13, FTO, FMR1, HNRNPA2B1, HNRNPC, LRPPRC, YTHDC1, YTHDC2, and YTHDF1 expression levels decreased considerably in AVC tissues. Based on 10 genes, we typed 240 AVC samples as clusters A and B. We assessed the immune cell content in 240 samples using Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) and found that B cell memory, CD8 T cells, T follicular helper cells, monocytes, M0 macrophages, resting dendritic cells (DCs), and interleukin-10 (IL-10) were concentrated in the cluster A group. Additionally, based on the important WGCNA modules, we identified 7 key genes. Next, 240 samples were retyped based on 7 key genes; we found that T cells CD8, T cells CD4 memory activated, T cells follicular helper, and macrophages M1 were significantly increased in gene cluster-1. Finally, we performed functional enrichment of gene cluster-typed samples, showing potential functional differences between different types. Conclusions: Our study provides a review of the m6A regulators' expression pattern and functional importance in human AVC. The data from this study might serve as a significant resource for future mechanistic and therapeutic investigations into the role of critical m6A regulators in AVC.

The Role of Primary Tumor Resection in Patients With Pancreatic Neuroendocrine Tumors With Liver Metastases.

Background: Liver metastases (LMs) are common in advanced pancreatic neuroendocrine tumor (PNET) patients. Currently, the benefit of primary tumor resection (PTR) in the setting of PNET patients with liver metastases is still controversial in several guidelines. Methods: Data were extracted from the Surveillance, Epidemiology and End Results (SEER) database to evaluate this issue. The main index of interest in our study was overall survival time. Results: Information on 536 PNET patients with liver metastases from the SEER database was identified. A total of 214 patients (PTR group) received primary tumor resection, and more than half of them (132 patients) had synchronous LM resection. The other 322 PNET patients (non-PTR group) with liver metastases did not receive primary tumor resection. A significant survival benefit was gained from PTR when compared with non-PTR patients, both in OS (72.93 ± 2.7 vs. 36.80 ± 2.22 months) and 3- or 5-year survival rates (75.1% vs. 28.9% and 67.9% vs. 22.3%, respectively). No difference was found between PTR alone and PTR with synchronous LM resection. From univariate and multivariate analyses, younger age (<65 years) and good or moderate tumor differentiation may be more important when considering primary tumor resection. However, we found that all grades of tumor differentiation could result in a better overall survival time after primary tumor resection. Conclusion: Our study suggested that primary tumor resection in pancreatic neuroendocrine patients with liver metastases could result in a longer survival time. Primary tumor resection with synchronous liver metastasis resection was not related to a better survival benefit. This treatment strategy may routinely be taken into consideration in these patients.

Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) in non-small cell lung cancer.

Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor that can regulate downstream target gene expression. Kelch-like ECH-associated protein 1 (Keap1) negatively regulates Nrf2 activation and translocation to target its 26S proteasomal degradation. It has been widely reported that the Keap1/Nrf2 pathway is associated with tumorigenesis, chemotherapy resistance and progression and development of non-small cell lung cancer (NSCLC). High expression of Nrf2 and low abundance of Keap1 contribute to the abnormalities and unrealistic treatment prognosis of NSCLC. Therefore, elucidating the role and potential mechanism of Nrf2 in NSCLC is essential for understanding tumorigenesis and for the development of strategies for effective clinical management. Here, we summarize current knowledge about the molecular structure and biological function of Nrf2, and we discuss the roles of Nrf2 in tumorigenesis, which will further provide a possible therapeutic strategy for NSCLC.

Co-disposition of chitosan nanoparticles by multi types of hepatic cells and their subsequent biological elimination: the mechanism and kinetic studies at the cellular and animal levels.

Background: The clearance of nanomaterials (NMs) from the liver is essential for clinical safety, and their hepatic clearance is primarily determined by the co-disposition process of various types of hepatic cells. Studies of this process and the subsequent clearance routes are urgently needed for organic NMs, which are used as drug carriers more commonly than the inorganic ones. Materials and methods: In this study, the co-disposition of chitosan-based nanoparticles (CsNps) by macrophages and hepatocytes at both the cellular and animal levels as well as their subsequent biological elimination were investigated. RAW264.7 and Hepa1-6 cells were used as models of Kupffer cells and hepatocytes, respectively. Results: The cellular studies showed that CsNps released from RAW264.7 cells could enter Hepa1-6 cells through both clathrin- and caveolin-mediated endocytosis. The transport from Kupffer cells to hepatocytes was also studied in mice, and it was observed that most CsNps localized to the hepatocytes after intravenous injection. Following the distribution in hepatocytes, the hepatobiliary-fecal excretion route was shown to be the primary elimination route for CsNps, besides the kidney-urinary excretion route. The elimination of CsNps in mice was a lengthy process, with a half time of about 2 months. Conclusion: The demonstration in this study of the transport of CsNps from macrophages to hepatocytes and the subsequent hepatobiliary-fecal excretion provides basic information for the future development and clinical application of NMs.

[Regulation of SIRT1 by SREBP-1 in Adipogenic Differentiation of Mesenchymal Stem Cells].

OBJECTIVE: To study the regulation of SIRT1 by transcription factor SREBP-1 in adipogeneic differentiation of bone marrow mesenchymal stem cells (BMMSC). METHODS: Oil red O staining was used to identify the adipogenic differentiation of BMMSC; the mRNA transcription levels of AP2, LPL, SREBF-1, SIRT1 gene were detected by RT-PCR; the expession level of SREBP-1 was determined by Western-blot. The chromatin immunoprecipitation (ChIP) assay was used to investigate the binding of SREBP-1 to SIRT1 promoter. RESULTS: BMMSC exposed to adipogenesis inducing medium become mature adipocytes at day 14; the mRNA transcription levels of AP2, LPL, SREBF-1, SIRT1 genes were up-regulated in adipocyte differentiation of BMMSC; the protein level of SREBP-1 was higher obviously; SIRT1 gene sequences was succesfully amplified from the genomic DNA immunoprecipitated by SREBP-1 antibody. CONCLUSION: SREBP-1 can bind to the promoter region of the SIRT1 gene in adipogenesis of BMMSC, and may be involved in the transcriptional regulation of the SIRT1 gene.

[Influences of shallow groundwater on sap flow of riparian poplar plantations in northern China.] / æµ å±‚åœ°ä¸‹æ°´å¯¹åŽåŒ—åœ°åŒºæ²³å²¸æ¨æ ‘æž—æ ‘å¹²æ¶²æµçš„å½±å“.

Water use strategy in growing seasons plays a great role in the management of riparian poplar plantations in northern China. The research was conducted on a poplar (Populus × euramericana cv. '74/76') plantation located near the floodplain of Chaobai River in the northeastern su-burb of Beijing. The influencing factors of poplar sap flow (SF) were presented based on the measurements on the stem SF with thermal dissipation sap flow probe (TDP), soil volumetric water content (VWC) with time-domain-reflectometer (TDR) and environmental factors with eddy cova-riance system from June to July, 2014, to explore the impact of shallow ground water on SF. The results showed that the diurnal variation of SF presented single or double peaks depending on the varia-tion of solar radiation (R). The SF density decreased in soil water relative deficient period (RDP), and the peak time advanced to 12:30 from 14:00, while the time lag between the SF density and R showed no obvious change. The solar radiation and air vapor pressure deficit were the predominant factors of SF during soil water relative sufficient period (RSP), while soil water became the limiting factor in RDP. During the RDP, the daily water consumption of individual poplar tree was significantly negatively correlated with soil VWC at the depth of 100 cm, and significantly positively correlated with soil VWC of the other depths. The shallow ground water (at the depth of ≥150 cm where the soil water content showed little change) might move to the upper soil layer controlled by the capillary force and supply for poplar growth during the soil water-relatively deficient period.