Circular RNA expression profiles and features in NAFLD mice: a study using RNA-seq data.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is primarily characterized by the hepatic cholesterol accumulation. Circular RNA (circRNA), one of noncoding RNA, involves in many liver diseases progression. However, no recent studies on circRNA expression profiles in NAFLD have been reported previously. METHODS: A NAFLD mouse model was constructed by providing high-fat diet (HFD) for 32 weeks. The circRNAs expression profile in normal mice and NAFLD mice were determined using high-output RNA sequencing method and bioinformatics methods, while the differentially expressed circRNAs were confirmed using Sanger sequencing and qRT-PCR. The circRNA-miRNA network was also predicted. The biological functions of circRNAs were annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). RESULTS: The results demonstrated the successful construction of NAFLD mice model by immunohistology and serology assay. In total, 93 dysregulated circRNAs were observed, including 57 upregulated circRNAs and 36 downregulated circRNAs, in the NAFLD group. The circRNA-miRNA network revealed the complex interaction between circRNAs and its potential miRNA targets in NAFLD. The characteristic of tissue-specific expression in circRNA was demonstrated. The differentially expressed circRNAs with important biological function were also annotated using GO and KEGG. Both DDAH1 and VAV3 genes were found to be associated with the NAFLD development. CONCLUSIONS: Taken together, this study demonstrated the circRNAs expression profile and features in NAFLD, which may provide potential biological markers for the pathogenesis of NAFLD.

Knockdown of PLCε inhibits inflammatory cytokine release via STAT3 phosphorylation in human bladder cancer cells.

Phospholipase Cε (PLCε) is a multifunctional enzyme implicated in inflammatory functions. There are limited data, however, on how PLCε can alter inflammatory cytokine by affecting downstream pathways. Recent studies suggest that inflammation is likely to have an important role in transitional cell carcinoma of bladder (TCCB) and cancer disease progression. Here, we showed that PLCε and p-STAT3 expression were both elevated in TCCB tissues compared to adjacent tissues, and the increase of PLCε level was associated with the increase of p-STAT3 level. Then, knockdown of PLCε using adenovirus-shPLCε significantly decreased inflammatory cytokine (IL-6, TNF-α, IL-1ß) expression and inflammation-associated gene (TLR4, MyD88, p-STAT3) expression. Furthermore, we demonstrated that PLCε knockdown blocked LPS-induced inflammatory cytokine and p-STAT3 expression. Additionally, we found that combined treatment of STAT3 inhibitor S3I-201 with adenovirus-shPLCε exhibited synergistic inhibitory effects on expression of p-STAT3. Our results suggested that STAT3 phosphorylation is involved in PLCε-mediated inflammatory cytokine release. Our research is of potential importance in drug development programs using PLCε as a therapeutic target for TCCB.

Diagnostic Value of Pulmonary Ultrasound and Arterial Blood Gas Analysis in Acute Patients with Severe Injuries Complicated by Respiratory Failure-A Retrospective Study.

Background: To investigate the early application of pulmonary ultrasonography and arterial blood gas analysis in critical patients with severe multiple injuries exacerbated by respiratory failure. Patients and Methods: The retrospective selection was performed on 81 patients admitted to our critical care unit between January 2020 and January 2021 with severe multiple injuries rendered worse by respiratory failure. Based on the different examination procedures, the patients were categorised into three groups (n=27): group A; diagnosed with pulmonary ultrasonography, group B; diagnosed with arterial blood gas; and group C; diagnosed with both pulmonary ultrasonography and arterial blood gas analyses. Patients were subsequently divided into a survival group (n = 65) and a death group (n = 16). On an annual basis, patients' prognoses were examined in relation to the predictive value of pulmonary ultrasound. Results: Initial diagnosis, diagnosis, and initial correct treatment times were significantly shorter in groups B and C than group A (P<0.05). In contrast, initial diagnosis time, diagnosis time, and initial correct treatment times were potentially shorter in group C than in group B (P<0.05). Compared to groups B and C, group A had a considerably lower diagnosis rate for the examination methods (P<0.05). The right diaphragm displacement and left diaphragm displacement in the survival group were potentially higher than the LUS score (P < 0.05). In contrast, the survival group's lung ultrasound score (LUS) was considerably lower than the death group's. Statistical analysis showed that the predictive values of right diaphragm displacement, left diaphragm displacement, and mean diaphragm displacement were significant compared with the LUS score. The findings of the receiver operating characteristic curve demonstrated that the right, left, and average diaphragm displacements had high predictive values. Conclusion: In the early evaluation of patients with severe multiple injuries complicated by respiratory failure, pulmonary ultrasonography combined with arterial blood gas analysis is crucial for the rapid diagnosis and prognosis prediction of patients.

Esmolol inhibits cognitive impairment and neuronal inflammation in mice with sepsis-induced brain injury.

Sepsis is a potentially fatal organ failure resulting from a dysregulated host response to infection. It can be a substantial financial burden on families and society due to the high cost of medical care. The study aims to investigate the protective roles of Esmolol in mice with sepsis-induced brain injuries against cognitive dysfunction and neuronal inflammation. Male C57BL/6J mice were intraperitoneally injected with LPS (10 mg/kg, L2630, Sigma) to establish a septic encephalopathy model. Esmolol (15 mg/kg/h, HY-B1392, MedChemExpress) was subcutaneously infused using osmotic mini-pumps for 6 h before LPS injection. Morris water maze and novel object recognition tests evaluated LPS-induced cognitive impairment and behavioral phenotypes. Cytokines and protein expression were assessed using ELISA assay and RT-qPCR. Esmolol treatment potentially improved cognitive impairment in septic mice. Esmolol administration markedly diminished the abnormal hippocampal neuronal structure, and the expression of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α was significantly downregulated in the hippocampal tissue. Esmolol treatment significantly reduced apoptotic TUNEL-positive cells and reversed the related gene expression (BAX and BCL-2). The effects of esmolol on the reactive oxidative species and oxidative stress markedly reduce malondialdehyde MDA content and increase superoxide dismutase and catalase in hippocampal tissues. In addition, esmolol significantly reduced the percentage and density of Iba-1 + microglia in septic mice. Our results demonstrated that esmolol potentially improved cognitive impairment and neuronal inflammation in mice with sepsis-induced brain injury.

Association between plasma homocysteine levels and pancreatic islet beta-cell function in the patients with type 2 diabetes mellitus: a cross-sectional study from China.

BACKGROUND: This study sought to investigate the association between plasma homocysteine (HCY) levels and pancreatic islet beta-cell function in type 2 diabetes mellitus (T2DM) patients. METHODS: 430 hospitalized T2DM patients were enrolled in this cross-sectional study from December 2013 to December 2016. All participants were requested to complete a detailed questionnaire and undergo anthropometric measurements. Blood samples were collected from all participants. A 75-g oral glucose tolerance test (OGTT) was performed to diagnose T2DM in each individual, and an insulin releasing test (IRT) was used to calculate selected parameters for glucose, insulin, and C-peptide. Linear correlation and multivariate regression analyses were performed to assess the association between serum HCY concentration and these parameters. RESULTS: Patients were divided into the following subgroups based on quartiles of serum HCY levels: Group Q1: <17.03 µmol/L; Group Q2: 17.03-19.50 µmol/L; Group Q3: 19.5-24.7 µmol/L; and Group Q4: >24.7 µmol/L. The levels of fasting blood glucose (FBG), 2 h postprandial blood glucose (2hPBG), glycated hemoglobin A1c (HbA1c), fasting C-peptide and fasting insulin increased significantly as HCY levels increased (P<0.05). The area under the curves (AUCs) of serum glucose and insulin in IRT increased significantly and that of serum C-peptide decreased as HCY levels increased (P<0.05). The levels of Homeostasis Model Assessment-ß (HOMA-ß), Modified Beta-cell function Index (MBCI), Disposal Index (DI), C-peptide immunoreactivity (CPR), Insulinogenic Index 30 (IGI 30), and Secretory Units of Islets in Transplantation (SUIT) decreased as HCY levels increased. An inverse linear correlation was found between HOMA-ß, MBCI, DI, CPR, IGI 30, SUIT 0 h, and HCY plasma concentration (R2, 0.539, 0.569, 0.500, 0.676, 0.579, and 0.588, respectively; P<0.001), and this association was independent of many confounders, such as age, gender, body mass index, glucose and insulin levels, and HbA1c. CONCLUSIONS: Serum HCY levels were inversely related to the parameters for pancreatic islet beta-cell function. Thus, the insulin releasing function of beta cells in the pancreas can be well elucidated by plasma HCY concentration.

PolyMet-HA nanocomplexs regulates glucose uptake by inhibiting SHIP2 activity.

Metformin, the first-line drug to treat type 2 diabetes, inhibits mitochondrial glycerolphosphate dehydrogenase in the liver to suppress gluconeogenesis. The major adverse effects caused by metformin were lactic acidosis and gastrointestinal discomfort. Therefore, there is need to develop a strategy with excellent permeability and appropriate retention effects.In this study, we synthesized a simple and biocompatible PolyMetformin (denoted as PolyMet) through conjugation of PEI1.8K with dicyandiamide, and then formed PolyMet-hyaluronic acid (HA) nanocomplexs by electrostatic self-assembly of the polycationic PolyMet and polyanionic hyaluronic acid (HA). Similar to metformin, the PolyMet-HA nanocomplexs could reduce the catalytic activity of the recombinant SHIP2 phosphatase domain in vitro. In SHIP2-overexpressing myotubes, PolyMet-HA nanocomplexes ameliorated glucose uptake by downregulating glucose transporter 4 endocytosis. PolyMet-HA nanocomplexes also could restore Akt signaling and protect the podocyte from apoptosis induced by SHIP2 overexpression. In essence, the PolyMet-HA nanocomplexes act similarly to metformin and increase glucose uptake, and maybe have a potential role in the treatment of type 2 diabetes.

The effects of dehydroepiandrosterone (DHEA) supplementation on body composition and blood pressure: A meta-analysis of randomized clinical trials.

Dehydroepiandrosterone (DHEA) supplementation has been anecdotally considered as a tool to improve body composition and health status. We aimed to verify the impact of DHEA supplementation on traditional measurements of body composition and blood pressure (BP) due to their clinical applicability. A meta-analysis of randomized clinical trials was conducted based on the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Regarding anthropometric characteristics, DHEA supplementation did not change body weight (weighted mean difference (WMD): -0.16 kg, 95% CI: -1.02 to 0.70, p = 0.72) or body mass index (WMD: -0.18 kg/m2, 95% CI: -0.48 to 0.12, p = 0.24), but increased lean body mass (WMD: 0.45 kg, 95% CI: 0.15 to 0.75, p = 0.004) and decreased fat mass (WMD: -0.85%, 95% CI: -1.18 to -0.51, p = 0.000), when compared to control groups. Neither systolic (WMD: 0.98 mm Hg, 95% CI: -2.31 to 4.29, p = 0.56) nor diastolic BP were significantly changed (WMD: -1.62 mm Hg, 95% CI: -5.49 to 2.24, p = 0.49). Our findings demonstrate that DHEA supplementation increased lean body mass and decreased fat mass, but debate persists when translating the results into clinical benefit. Lastly, DHEA supplementation had a neutral effect on BP.

Exosomal Hsp70 mediates immunosuppressive activity of the myeloid-derived suppressor cells via phosphorylation of Stat3.

Myeloid-derived suppressor cells (MDSCs), one of the main cell populations, are responsible for regulating the immune response, which accumulates in tumor-bearing mice and humans contributing to cancer development. Exosomes produced by tumor cells have been involved in tumor-associated immune suppression. However, the role of exosomes is unclear in the activation of MDSCs. Here, we have purified tumor-derived exosomes from the supernatants of Renca cell cultures. Transmission electron microscopy was used to confirm their morphology, and Western blot analysis showed that Hsp70 was rich in these isolated exosomes compared with the whole-cell lysates of Renca cells. Then, we demonstrated that there was a more powerful activity of exosomal Hsp70-mediated induction of proinflammation cytokines, tumor growth factors of MDSCs and tumor progression than exosomes pre-incubated with anti-Hsp70 antibody. Furthermore, we show that an interactive exosomal HSP70 and MDSCs determine the suppressive activity of the MDSCs via phosphorylation of Stat3 (p-Stat3). Finally, we show that exosomal Hsp70 triggers p-Stat3 in MDSCs in a TLR2-MyD88-dependent manner. Meanwhile, we also find that there is a more significant increase in the percentage of CD11b+Gr-1+ cells in the mice, which are treated with exosomal Hsp70 than that exosomes pre-incubated with anti-Hsp70 antibody. Hence, we believe that the signaling pathway activation by exosomal Hsp70 within MDSCs may be a significant target in future treatment of renal cell carcinoma.