Prevalence of prediabetes and risk of CVD mortality in individuals with prediabetes alone or plus hypertension in Northeast China: insight from a population based cohort study.

BACKGROUND: To evaluate the current prevalence of prediabetes in northeast China, and further determine the association between prediabetes alone or coexistent with hypertension and cardiovascular disease (CVD) mortality. METHODS: In the prospective study, 15,557 participants without diabetes among aged ≥40 years in northeast China, were followed for a median of 5.5 years. Following the American Diabetes Association, prediabetes was defined as fasting plasma glucose (FPG) range of 5.6-6.9 mmol/L or glycated hemoglobin (HbA1c) range of 5.7-6.4% in people without diabetes. RESULTS: The prevalence of prediabetes was 44.3% among population aged ≥40 years in northeast China. Prediabetes alone did not promote risk of CVD mortality. However, when the subgroups were stratified by hypertension, the CVD mortality risk in prediabetes plus hypertension subjects increased significantly compared with population without prediabetes and hypertension. Multivariate-adjusted hazard ratios for CVD mortality in prediabetes subgroups plus hypertension were 2.28 (95% CI: 1.50, 3.47) for those diagnosed by FPG < 5.6 mmol/L & HbA1c 5.7-6.4%, 2.18 (95% CI: 1.53, 3.10) for those diagnosed by FPG 5.6-6.0 mmol/L & HbA1c < 6.5% and 2.35 (95% CI: 1.65, 3.35) for those diagnosed by FPG 6.1-6.9 & HbA1c < 6.5% compared with the reference group. Moreover, the percentage of hypertension in prediabetes subjects was high (60.4%), but the awareness, treatment and control rates were far from satisfactory (45.3, 35.1 and 4.8%, respectively). CONCLUSIONS: The prevalence of prediabetes remains high in northeast China, and the CVD mortality was elevated significantly in prediabetes coexistent with hypertension. Considering the high percentage and low control rate of hypertension in prediabetes, strategies focused on HbA1c screening, FPG lowering and blood pressure management should be emphasized in northeast China.

Structural basis of nucleosomal H4K20 recognition and methylation by SUV420H1 methyltransferase.

Histone lysine methyltransferase SUV420H1, which is responsible for site-specific di-/tri-methylation of histone H4 lysine 20 (H4K20), has crucial roles in DNA-templated processes, including DNA replication, DNA damage repair, and chromatin compaction. Its mutations frequently occur in human cancers. Nucleosomes containing the histone variant H2A.Z enhance the catalytic activities of SUV420H1 on H4K20 di-methylation deposition, regulating early replication origins. However, the molecular mechanism by which SUV420H1 specifically recognizes and deposits H4K20 methyl marks on nucleosomes remains poorly understood. Here we report the cryo-electron microscopy structures of SUV420H1 associated with H2A-containing nucleosome core particles (NCPs), and H2A.Z-containing NCPs. We find that SUV420H1 makes extensive site-specific contacts with histone and DNA regions. SUV420H1 C-terminal domain recognizes the H2A-H2B acidic patch of NCPs through its two arginine anchors, thus enabling H4K20 insertion for catalysis specifically. We also identify important residues increasing the catalytic activities of SUV420H1 bound to H2A.Z NCPs. In vitro and in vivo functional analyses reveal that multiple disease-associated mutations at the interfaces are essential for its catalytic activity and chromatin state regulation. Together, our study provides molecular insights into the nucleosome-based recognition and methylation mechanisms of SUV420H1, and a structural basis for understanding SUV420H1-related human disease.

Idarubicin-loaded biodegradable microspheres enhance sensitivity to anti-PD1 immunotherapy in transcatheter arterial chemoembolization of hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is an image-guided locoregional therapy used for the treatment of patients with primary hepatocellular carcinoma (HCC). However, conventional TACE formulations such as epirubicin-lipiodol emulsion are rapidly dissociated due to the instability of the emulsion, resulting in insufficient local drug concentrations in the target tumor. To overcome these limitations, we used biodegradable Idarubicin loaded microspheres (BILMs), which were prepared from gelatin and carrageenan and could be loaded with Idarubicin (IDA-MS). The morphology and the ability to load and release IDA of BILMs were characterized in vitro. We evaluated tumor changes and side effects after TACE treatment with IDA-MS in VX2 rabbit and C57BL/6 mice HCC models. In addition, the effect of IDA-MS on the tumor immune microenvironment of HCC tumors was elucidated via mass spectrometry and immunohistochemistry. Result showed that IDA-MS was developed as a new TACE formulation to overcome the poor delivery of drugs due to rapid elimination of the anticancer drug into the systemic circulation. We demonstrated in rabbits and mice HCC models that TACE with IDA-MS resulted in significant tumor shrinkage and no more severe adverse events than those observed in the IDA group. TACE with IDA-MS could also significantly enhance the sensitivity of anti-PD1 immunotherapy, improve the expression of CD8+ T cells, and activate the tumor immune microenvironment in HCC. This study provides a new approach for TACE therapy and immunotherapy and illuminates the future of HCC treatment. STATEMENT OF SIGNIFICANCE: Conventional transarterial chemoembolization (TACE) formulations are rapidly dissociated due to the instability of the emulsion, resulting in insufficient local drug concentrations in hepatocellular carcinoma (HCC). To overcome these limitations, we used biodegradable microspheres called BILMs, which could be loaded with Idarubicin (IDA-MS). We demonstrated in rabbits and mice HCC models that TACE with IDA-MS resulted in significant tumor shrinkage and no more severe adverse events than those observed in the IDA group. TACE with IDA-MS could also significantly enhance the sensitivity of anti-PD1 immunotherapy, improve the expression of CD8+ T cells, and activate the tumor immune microenvironment in HCC. This study provides a new approach for TACE therapy and immunotherapy and illuminates the future of HCC treatment.

A study on distribution and stability of drugs at the interface of a scutellarin-loaded emulsion.

This work mainly studies the interfacial behaviors of scutellarin on a newly developed emulsion and establishes a three-phase distribution model. The results showed that the concentration of scutellarin could decrease the interfacial tension and the gel-liquid crystal phase transition temperature of phospholipids. By observing the micromorphology of the emulsion, it is inferred that the drug exists on the emulsion interface. The distribution of drugs in three phases at different pH was calculated. The results showed that when pH was in the range of 3.0-8.0, the content of scutellarin in the oil phase was less than 0.25%; when pH < 7.4, more than 88% of the drugs were on the interface; when pH > 7.4, the drugs were mainly distributed in the aqueous phase. Therefore, the behavior of emulsions (pH 6.0) in vitro and in vivo is mainly composed of the behavior of drugs on the interface. The study above can explain some properties of the emulsions after loading scutellarin. Including the decrease of particle size and stability constant Ke, the increase of zeta potential, and the decreased chemical stability after the pH value went higher.

Phloroglucinols with Immunosuppressive Activities from the Fruits of Eucalyptus globulus.

Five new phloroglucinol derivatives, eucalyptins C-G (1-5), together with 13 known analogues (6-18) were isolated from the fruits of Eucalyptus globulus. The structures and absolute configurations of 1-5 were established by means of spectroscopic data analysis, computational calculation methods, and single-crystal X-ray diffraction. Compounds 1-18 were investigated for their immunosuppressive effects in vitro, and 1, 2, 6, and 7 displayed moderate inhibitory activities with IC50 values of 11.8, 10.2, 18.2, and 19.1 µM, respectively. The stimulation index (SI) of 1 was 64.2 and was compared to that of cyclosporine A (SI = 149.57). Further study demonstrated that 1 exhibited an immunosuppressive effect through inducing apoptosis and inhibiting cytokine secretion.

Identification of amentoflavone as a potent highly selective PARP-1 inhibitor and its potentiation on carboplatin in human non-small cell lung cancer.

BACKGROUND: Nuclear protein poly (ADP-ribose) polymerase-1 (PARP-1) is a key enzyme in the repair of DNA and is a promising target in the development of chemosensitizers. This study first investigated the inhibitory effects of amentoflavone (AMF) and its derivatives on PARP-1 and the potentiation of AMF on carboplatin (CBP) in non-small cell lung cancer (NSCLC). PURPOSE: This study aims to evaluate the inhibitory effect of AMF against PARP-1 and its potentiation on CBP in lung cancer both in vitro and in vivo. STUDY DESIGN: The inhibitory effect of AMF on PARP-1 was investigated using molecular docking and cell-free model of PARP-1 assay. Its potentiation on CBP in lung cancer was also evaluated. METHODS: Fluorescence resonance energy transfer assay was used to detect the inhibitory effects of AMF and its analogues on PARP-1. Molecular docking was employed to predict the binding mode of AMF and PARP-1. MTT assay, isobologram analysis, Hoechst staining, and Annexin V-PI double staining were used to confirm the potentiation of AMF on CBP in vitro. siRNA (PARP-1)-A549 cells were used to reveal the action target of AMF. Western blot analysis, immunohistochemistry, and Tunnel assay were employed to evaluate the potentiation of AMF on CBP in A549 xenograft mice. RESULTS: AMF and its analogues exerted excellent inhibitory effects on PARP-1 with IC50 values ranging from 0.198  µM to 0.409  µM. Docking experiment showed that AMF can stably bind to PARP-1 with a comparable binding energy to olaparib. AMF can decrease the expression of PAR induced by H2O2in vitro. AMF synergistically increased the CBP anti-proliferative effect in A549. However, its potentiation nearly disappeared when the cells were transfected with siRNAs against PARP-1. Oral administration of AMF (100  mg/kg), combined with CBP, remarkably inhibited A549 tumor growth and ki67 expression, and increased apoptosis compared with CBP-alone group. CONCLUSION: All results suggest that AMF can be a potential PARP-1 inhibitor and a candidate adjuvant agent to boost the anticancer effect of CBP in NSCLC.