Enhancement of sonodynamic treatment of ovarian cancer based on Pt-B-P ternary nanoparticles.

Sonodynamic therapy (SDT) can noninvasively focus sound energy to deep tumor tissues and activate sonosensitizer (such as chlorin e6(Ce6)) to produce antitumor effects. However, due to the hypoxic microenvironment of the tumor, the effect of sonodynamic therapy is limited. In this work, we successfully synthesized Platinum-Boron-Phosphorus ternary nanoparticles (Pt-B-P NPs) for the first time to efficiently catalyze the decomposition of hydrogen peroxide (H2O2) in tumor tissues to produce sufficient oxygen (O2) and improve the effect of sonodynamic treatment of ovarian cancer. In vitro studies, we found that compared with Platinum nanoparticles (Pt NPs), Pt-B-P NPs have the significantly increased ability to catalyze the decomposition of H2O2 to produce oxygen and thus the hypoxic environment of tumor cells could be improved efficiently. Meanwhile, the bio-distribution, therapeutic effect and bio-safety of Pt-B-P NPs in vivo were evaluated using BALB/c-nu mouse model of ovarian cancer and the desired result had been achieved.

Interferon regulatory factor 1 (IRF1) inhibits lung endothelial regeneration following inflammation-induced acute lung injury.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a respiratory condition caused by severe endothelial barrier dysfunction within the lung. In ARDS, excessive inflammation, tissue edema, and immune cell influx prevents endothelial cell regeneration that is crucial in repairing the endothelial barrier. However, little is known about the molecular mechanism that underpin endothelial cell regeneration in ARDS. METHODS: R-based bioinformatics tools were used to analyze microarray-derived transcription profiles in human lung microvascular endothelial cells (HLMVECs) subjected to non-treatment or lipopolysaccharide (LPS) exposure. We generated endothelial cell-specific interferon regulatory factor 1 (Irf1) knockout (Irf1EC-/-) and Irf1fl/fl control mice for use in an endotoxemic murine model of acute lung injury (ALI). In vitro studies (qPCR, immunoblotting, and ChIP-qPCR) were conducted in mouse lung endothelial cells (MLECs) and HLMVECs. Dual-luciferase promoter reporter assays were performed in HLMVECs. RESULTS: Bioinformatics analyses identified IRF1 as a key up-regulated gene in HLMVECs post-LPS exposure. Endothelial-specific knockout of Irf1 in ALI mice resulted in enhanced regeneration of lung endothelium, while liposomal delivery of endothelial-specific Irf1 to wild-type ALI mice inhibited lung endothelial regeneration in a leukemia inhibitory factor (Lif)-dependent manner. Mechanistically, we demonstrated that LPS-induced Stat1Ser727 phosphorylation promotes Irf1 transactivation, resulting in downstream up-regulation of Lif that inhibits endothelial cell proliferation. CONCLUSIONS: These results demonstrate the existence of a p-Stat1Ser727-Irf1-Lif axis that inhibits lung endothelial cell regeneration post-LPS injury. Thus, direct inhibition of IRF1 or LIF may be a promising strategy for enhancing endothelial cell regeneration and improving clinical outcomes in ARDS patients.

Elevated circulating GPHB5 levels in women with insulin resistance and polycystic ovary syndrome: A cross-sectional study and multiple intervention studies.

Objective: GPHB5 has been found to be associated with glucose and lipid metabolism in animal studies. However, the association of GPHB5 with IR and metabolic disorders remains unknown, and there is a lack of research in humans. Our aim in this study was to investigate the relationship between circulating GPHB5 and metabolic disorders in humans. Methods: Bioinformatics analysis was performed to understand the relationship between GPHB5 and metabolic disorders. GPHB5 mRNA expression in mice and rats was determined using RT-qPCR. Circulating GPHB5 concentrations were measured with an ELISA kit. EHC and OGTT were performed in humans. Results: Bioinformatics analysis shows that GPHB5 is associated with metabolic disorders and PCOS. GPHB5 mRNA expression levels in the metabolic-related tissues of HFD-fed mice, db/db and ob/ob mice, and PCOS rats were significantly higher than those of WT mice or rats. In human studies, we find that circulating GPHB5 levels were significantly higher in women with IR and PCOS. GPHB5 levels were positively correlated with age, BMI, WHR, BP, FBG, 2 h-BG, FIns, 2 h-Ins, TC, LDL-C, HbA1c, and FFA, but negatively correlated with adiponectin. Furthermore, GPHB5 was positively correlated with DHEAS and FAI, while negatively correlated with SHBG, FSH, SHBG and FSH. The increased GPHB5 concentration was related to IR and PCOS. After the treatment of metformin, GLP-1RA (Lira), and TZDs, circulating GPHB5 levels were decreased. Conclusions: Our results reveal that circulating GPHB5 could be a biomarker and potential therapeutic target for IR and PCOS in women.

Hypothalamic BMP9 suppresses glucose production by central PI3K/Akt/mTOR pathway.

Bone morphogenetic proteins (BMPs) are secreted ligands that belong to the transforming growth factor-ß (TGF-ß) superfamily. BMP7 has been reported to play a role in reversing obesity and regulating appetite in the hypothalamus. Whether BMP9 plays a central role in regulating glucose metabolism and insulin sensitivity remains unclear. Here, we investigated the impact of central BMP9 signaling and possible route of transmission. We performed intracerebroventricular (ICV) surgery and injected adenovirus expressing BMP9 (Ad-BMP9) into the cerebral ventricle of mice. Metabolic analysis, hyperinsulinemic-euglycemic clamp test, and analysis of phosphatidylinositol 3,4,5-trisphosphate (PIP3) formation were then performed. Real-time PCR and Western blotting were performed to detect gene expression and potential pathways involved. We found that hypothalamic BMP9 expression was downregulated in obese and insulin-resistant mice. Overexpression of BMP9 in the mediobasal hypothalamus reduced food intake, body weight, and blood glucose level, and elevated the energy expenditure in high-fat diet (HFD)-fed mice. Importantly, central treatment with BMP9 improved hepatic insulin resistance (IR) and inhibited hepatic glucose production in HFD-fed mice. ICV BMP9-induced increase in hepatic insulin sensitivity and related metabolic effects were blocked by ICV injection of rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) signaling. In addition, ICV BMP9 promoted the ability of insulin to activate the insulin receptor/phosphoinositide 3-kinase (PI3K)/Akt pathway in the hypothalamus. Thus, this study provides insights into the potential mechanism by which central BMP9 ameliorates hepatic glucose metabolism and IR via activating the mTOR/PI3K/Akt pathway in the hypothalamus.

Several Circulating Biomarkers for PCOS Diagnosis.

AIMS: Irisin, Betatrophin and Zinc-α2-glycoprotein (ZAG) have been shown to be associated with insulin resistance (IR) and polycystic ovary syndrome (PCOS), respectively. The purpose of this study is to explore the potential accuracy of this combination of three cytokines in screening PCOS. METHODS: 186 individuals were recruited for this study. Circulating Irisin, Betatrophin and ZAG concentrations were measured by enzyme-linked immunosorbent assay. The association between these serum biomarkers and PCOS was assessed by logistic regression analysis. Receiver operating curve (ROC) analysis was performed to evaluate the diagnostic value of these biomarkers for PCOS women. RESULTS: In women with PCOS, serum Irisin and Betatrophin levels were markedly elevated compared to those in healthy controls (p<0.01), while ZAG levels were lower (p<0.01). PCOS women with IR (M-value<6.28) had lower circulating ZAG concentrations, and higher circulating Irisin and Betatrophin levels relative to PCOS women without IR (M-value ≥ 6.28). ROC curve analyses showed that the AUC for Irisin, ZAG and Betatrophin for predicting PCOS were 0.77, 0.83 and 0.85, respectively. In a joint ROC curves analysis of these serum markers and other parameters, the results showed that the AUC was 0.93, and the sensitivity and specificity were 82.1 % and 92.3 %, respectively. CONCLUSIONS: When compared to using single cytokine, the analysis of Irisin, ZAG and Betatrophin elevates the accuracy in diagnosing PCOS.

Ultrasensitive aptasensor for isolation and detection of circulating tumor cells based on CeO2@Ir nanorods and DNA walker.

Herein, based on dual signal amplification by CeO2@Ir nanorods (Ce@IrNRs) and enzyme-free DNA walker, a novel electrochemical aptasensor was developed for simultaneous isolation and detection of circulating tumor cells (CTCs). A membrane protein MUC1-targeting aptamer was used to specifically recognize and capture MCF-7 cells. Uracil DNA glycosylase could hydrolyze deoxyuracils of the aptamer to isolate the captured cells. Novel Ce@IrNRs with large surface area and high peroxidase activity were synthesized to amplify the signal, and the enzyme-free DNA walker was applied to release more signal probes combined with Ce@IrNRs. Furthermore, to reduce steric hindrance by cells, the signal probes rather than the target cells, were directly combined with the electrode. The aptasensor could detect CTCs in the range of 2 to 2 × 106 cells mL-1 with a limit of detection 1 cell mL-1. The developed aptasensor, which can simultaneously isolate and detect CTCs, has great application potential in the early monitoring of tumor metastasis and in individualized treatment.

Serum Fetuin-A levels are increased and associated with insulin resistance in women with polycystic ovary syndrome.

BACKGROUND: Insulin resistance (IR) is a common characteristic of women with polycystic ovary syndrome (PCOS). It has been reported that circulating Fetuin-A levels were associated with IR and type 2 diabetes mellitus (T2DM). However, previous reports were inconsistent. METHODS: Two hundred seven subjects were screened for PCOS according to the diagnostic guideline of the Rotterdam consensus criterion. Serum Fetuin-A levels were measured using an ELISA kit. An independent t-test or Nonparametric test was used to detect differences between PCOS and control groups. Spearman's correlation analysis was used to examine the association of the serum Fetuin-A with other parameters. RESULTS: Our findings showed that circulating Fetuin-A concentration ranged from 196.6 to 418.2 µg/L for most women without PCOS (95%). Women with PCOS had higher circulating Fetuin-A levels than healthy women (437.9 ± 119.3 vs. 313.8 ± 60.5 µg/L; p <  0.01). Serum Fetuin-A was positively correlated with BMI, WHR, TG, TC, LDL-C, HOMA-IR, LH, T, and DHEA-S. Multivariate regression analysis showed that WHR, TG, HOMA-IR, and DHEA-S were independent predictors of the levels of circulating Fetuin-A. Binary logistic regression revealed that serum Fetuin-A was associated with the occurrence of PCOS. In addition, our ROC curve analysis found that the cutoff values for Fetuin-A to predict PCOS and IR were 366.3 and 412.6 µg/L. CONCLUSION: Blood Fetuin-A may be a useful biomarker for screening women for PCOS and IR.

Adipose Insulin Resistance and Circulating Betatrophin Levels in Women with PCOS.

The role of IR and metabolic disorders has become a crucial topic of study in the pathogenesis of PCOS. Adipose tissue is an important target organ of insulin, and adipose IR plays an important role in the occurrence and development of PCOS. This study seeks to investigate the role of adipose IR in the development of PCOS and to examine its relationship with circulating betatrophin levels in women with PCOS. A cross-sectional analysis of a cohort of women with PCOS and healthy women was performed in this study. Serum betatrophin concentrations were measured by ELISA. Adipose IR was calculated using the product of fasting insulin and FFA concentrations, and the relationship between adipose IR, circulating betatrophin, and other parameters was analyzed. Adipose IR in women with PCOS was significantly higher than that in controls. We found that women with PCOS who have adipose IR (adipose IR ≥ 55) have a higher BMI and higher blood glucose, insulin, PRL, FFA, TG, HOMA-IR, AUCglucose, AUCinsulin, VAIfemale, and BAI levels than PCOS-afflicted women without adipose IR, while M-values, and SHBG and LH levels were lower. In women with PCOS, serum betatrophin levels were significantly increased compared with controls. Adipose IR negatively correlated with M values and positively with circulating betatrophin levels in the study population. After metformin treatment, circulating betatrophin levels and adipose IR in women with PCOS were significantly decreased compared with pretreatment. Adipose IR is associated with betatrophin levels in women with PCOS. The combination of adipose IR and circulating betatrophin measurements may be significant for screening patients with PCOS.

Role of bone morphogenetic protein-9 in the regulation of glucose and lipid metabolism.

Bone morphogenetic protein (BMP)-9 has been reported to regulate energy balance in vivo. However, the mechanisms underlying BMP9-mediated regulation of energy balance remain incompletely understood. Here, we investigated the role of BMP9 in energy metabolism. In the current study, we found that hepatic BMP9 expression was down-regulated in insulin resistance (IR) mice and in patients who are diabetic. In mice fed a high-fat diet (HFD), the overexpression of hepatic BMP9 improved glucose tolerance and IR. The expression of gluconeogenic genes was down-regulated, whereas the level of insulin signaling molecule phosphorylation was increased in the livers of Adenovirus-BMP9-treated mice and glucosamine-treated hepatocytes. Furthermore, BMP9 overexpression ameliorated triglyceride accumulation and inhibited the expression of lipogenic genes in both human hepatocellular carcinoma HepG2 cells treated with a fatty acid mixture as well as the livers of HFD-fed mice. In hepatocytes isolated from sterol regulatory element-binding protein (SREBP)-1c knockout mice, the effects of BMP9 were ablated. Mechanistically, BMP9 inhibited SREBP-1c expression through the inhibition of liver X receptor response element 1 activity in the SREBP-1c promoter. Taken together, our results show that BMP9 is an important regulator of hepatic glucose and lipid metabolism.-Yang, M., Liang, Z., Yang, M., Jia, Y., Yang, G., He, Y., Li, X., Gu, H. F., Zheng, H., Zhu, Z., Li, L. Role of bone morphogenetic protein-9 in the regulation of glucose and lipid metabolism.