11ß-Hydroxysteroid dehydrogenase type 1 selective inhibitor BVT.2733 protects osteoblasts against endogenous glucocorticoid induced dysfunction.

Pharmacologic glucocorticoids (GCs) inhibit osteoblast function and induce osteoporosis. 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) may play a role in osteoporosis as it regulates GC action at a pre-receptor level by converting inactive GC to its active form. Further, 11ß-HSD1 was found increasingly expressed in bone with age. In spite of these observations, its function in senile osteoporosis remains uncertain. In this study we constructed a lentiviral vector overexpressing mouse 11ß-HSD1 and then MC3T3-E1 preosteoblast cells were infected by the negative control lentivirus and 11ß-HSD1-overexpressing lentivirus, respectively. The mRNA and protein levels of 11ß-HSD1 were significantly increased in MC3T3-E1 cells that were infected by 11ß-HSD1-overexpressing lentivirus compared to the cells infected by the negative control lentivirus. The osteogenic differentiation of MC3T3-E1 preosteoblast cells was dramatically suppressed by 11ß-HSD1 overexpression under the reductase substrate dehydrocorticosterone (DHC). The inhibition effect was similar to the inhibition of osteogenesis by over-dose GCs, including ALP activity, the ultimate calcium nodus formation as well as the expression of the osteogenic genes such as ALP, BSP, OPN and OCN. However, with addition of BVT.2733, a selective inhibitor of 11ß-HSD1, all of the above osteogenic repression effects by 11ß-HSD1 overexpression were reversed. Furthermore, a GC receptor antagonist RU486 also showed the similar effect, preventing inhibition of osteogenesis by 11ß-HSD1 overexpression. These results demonstrated that the specific 11ß-HSD1 inhibitor BVT.2733 can reverse the suppression effect towards osteogenic differentiation in 11ß-HSD1 overexpressed MC3T3-E1 cells. Inhibition of 11ß-HSD1 can be a new therapeutic strategy for senile osteoporosis.

Enhanced Flame Retardancy of Styrene-Acrylic Emulsion Based Damping Composites Based on an APP/EG Flame-Retardant System.

Developing flame-retarded styrene-acrylic emulsion (SAE) based damping composites is a challenging task because of their very high flammability. A promising approach is the synergistic combination of expandable graphite (EG) and ammonium polyphosphate (APP). In this study, the surface modification of APP was modified by commercial titanate coupling agent ndz-201 through ball milling, and the SAE-based composite material was prepared with SAE and different ratios of modified ammonium polyphosphate (MAPP) and EG. The surface of MAPP was successfully chemically modified by NDZ-201 through scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction analysis (XRD), Energy Dispersion Spectroscopy (EDS), and contact angle. The effects of different ratios of MAPP and EG on the dynamic and static mechanical properties and flame retardancy of composite materials were explored. The results showed that when MAPP:EG = 1:4, the limiting oxygen index (LOI) of the composite material was 52.5%, and the vertical burning test (UL-94) was at the V0 level. Its LOI increased by 141.9% compared to the composite materials without flame retardant. The optimized formulation of MAPP and EG in SAE-based damping composite materials showed a significant synergistic effect on the flame retardancy of the composite material.

Predictive value of cardiac magnetic resonance mechanical parameters for myocardial fibrosis in hypertrophic cardiomyopathy with preserved left ventricular ejection fraction.

Objective: Myocardial fibrosis leads to systolic dysfunction in hypertrophic cardiomyopathy (HCM) patients. This study aims to investigate the relationship between cardiac magnetic resonance mechanical parameters for evaluating the left ventricular function in HCM with preserved left ventricular ejection fraction (LVEF ≥50%) and the association between myocardial fibrosis defined by late gadolinium enhancement (LGE). Methods: This study was a retrospective analysis of CMR images of 93 patients with HCM with preserved ejection fraction (HCMpEF) and 96 controls diagnosed by cardiac magnetic resonance (CMR) at our hospital from July 2019 to January 2022. The myocardial contraction fraction (MCF) was calculated, and myocardial mechanical parameters, including global myocardial longitudinal strain (GLS), circumferential strain (GLS), and myocardial strain (GLS), were obtained by tissue tracking and LGE quantitative modules of dedicated software, respectively. The correlation between myocardial strain and LGE was analyzed, and a multivariate logistic regression model was developed to discuss the risk predictors of LGE. Results: Compared to the control group, the left ventricular mechanical parameters GLS (-13.90 ± 3.80% versus -18.20 ± 2.10%, p < 0.001), GCS (-16.62 ± 3.50% versus -18.4 ± 2.69%, p < 0.001), GRS (28.99 ± 10.38% versus 33.02 ± 6.25%, p < 0.01), and MCF (64 ± 16% versus 99 ± 18%, p < 0.001) were found significantly lower in HCM group. Moreover, even in LGE-negative HCM patients, GLS (-16.3 ± 3.9%) and MCF (78 ± 19%) were significantly lower compared to the control group. Left ventricular GLS [OR = 1.61, (1.29, 2.02), p = 0.001] and MCF [OR = 0.90, (0.86, 0.94), p = 0.001] independently predicted myocardial late gadolinium enhancement (LGE). Conclusion: In participants of HCM with preserved ejection fraction, the early onset of reduced left ventricular GLS and MCF in patients with HCMpEF may provide new evidence for evaluating impaired myocardial systolic function. The reduction of myocardial mechanical indexes may reflect the presence and extent of myocardial fibrosis, and the more significant the reduction, the more severe the myocardial fibrosis; GLS and MCF may be ideal predictors for LGE.

A novel SGLT2 inhibitor, SU-011, improves glycaemic control in rodents without the risk of hypoglycaemia and weight gain.

OBJECTIVE: To evaluate the pharmacological characteristics of SU-011, a novel sodium-dependent glucose co-transporter 2 (SGLT2) inhibitor. METHODS: The in vitro activities of SU-011 were investigated in cell-based assays. The urinary glucose excretion, glucose tolerance and the risk of hypoglycaemia were evaluated in mice. Moreover, the dose-response relationship and chronic pharmacological studies of SU-011 were assessed in streptozotocin (STZ)-induced diabetic model, a STZ-treated model with impaired insulin secretion. KEY FINDINGS: SU-011 is a potential SGLT2 inhibitor with 5.6 nm inhibitory activity for SGLT2 and 1137-fold selectivity for SGLT1. In healthy mice, SU-011 improves the tolerance to a glucose load and promotes the urinary glucose excretion. Besides, SU-011 (10 mg/kg) still exhibited less risk of hypoglycaemia. During chronic treatment, SU-011 exhibited sustained glucose-lowering effect without the side effect of weight gain in STZ-induced diabetic mice. The levels of non-fasting and fasting plasma glucose, glycosylated haemoglobin, food and water intake were significantly decreased in SU-011-treated group. Moreover, SU-011 decreases the plasma levels of interleukin-1ß, tumour necrosis factor-α and C-reactive protein even better than that of dapagliflozin. CONCLUSIONS: All of these results indicated that SU-011 may be effective for the management of diabetes.

Glucocorticoids transcriptionally regulate miR-27b expression promoting body fat accumulation via suppressing the browning of white adipose tissue.

Long-term glucocorticoid (GC) treatment induces central fat accumulation and metabolic dysfunction. We demonstrate that microRNA-27b (miR-27b) plays a central role in the pathogenesis of GC-induced central fat accumulation. Overexpression of miR-27b had the same effects as dexamethasone (DEX) treatment on the inhibition of brown adipose differentiation and the energy expenditure of primary adipocytes. Conversely, antagonizing miR-27b function prevented DEX suppression of the expression of brown adipose tissue-specific genes. GCs transcriptionally regulate miR-27b expression through a GC receptor-mediated direct DNA-binding mechanism, and miR-27b suppresses browning of white adipose tissue (WAT) by targeting the three prime untranslated region of Prdm16. In vivo, antagonizing miR-27b function in DEX-treated mice resulted in the efficient induction of brown adipocytes within WAT and improved GC-induced central fat accumulation. Collectively, these results indicate that miR-27b functions as a central target of GC and as an upstream regulator of Prdm16 to control browning of WAT and, consequently, may represent a potential target in preventing obesity.

Essential roles of 11ß-HSD1 in regulating brown adipocyte function.

Brown adipose tissue (BAT) increases energy expenditure and is an attractive therapeutic target for obesity. 11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1), an amplifier of local glucocorticoid activity, has been shown to modulate white adipose tissue (WAT) metabolism and function. In this study, we investigated the roles of 11ß-HSD1 in regulating BAT function. We observed a significant increase in the expression of BAT-specific genes, including UCP1, Cidea, Cox7a1, and Cox8b, in BVT.2733 (a selective inhibitor of 11ß-HSD1)-treated and 11ß-HSD1-deficient primary brown adipocytes of mice. By contrast, a remarkable decrease in BAT-specific gene expression was detected in brown adipocytes when 11ß-HSD1 was overexpressed, which effect was reversed by BVT.2733 treatment. Consistent with the in vitro results, expression of a range of genes related to brown fat function in high-fat diet-fed mice treated with BVT.2733. Our results indicate that 11ß-HSD1 acts as a vital regulator that controls the expression of genes related to brown fat function and as such may become a potential target in preventing obesity.