Angiopoietin-like protein 4 induces growth hormone variant secretion and aggravates insulin resistance during pregnancy, linking obesity to gestational diabetes mellitus.

Angiopoietin-like protein 4 (ANGPTL4) is a secretory glycoprotein involved in regulating glucose homeostasis in non-pregnant subjects. However, its role in glucose metabolism during pregnancy and the pathophysiology of gestational diabetes mellitus (GDM) remains elusive. Thus, this study aimed to clarify the relationship between ANGPTL4 and GDM and investigate the pathophysiology of placental ANGPTL4 in glucose metabolism. We investigated this issue using blood and placenta samples in 957 pregnant women, the human 3A-sub-E trophoblast cell line, and the L6 skeletal muscle cell line. We found that ANGPTL4 expression in the placenta was higher in obese pregnant women than in lean controls. Palmitic acid significantly induced ANGPTL4 expression in trophoblast cells in a dose-response manner. ANGPTL4 overexpression in trophoblast cells resulted in endoplasmic reticulum (ER) stress, which stimulated the expression and secretion of growth hormone-variant (GH2) but not human placental lactogen. In L6 skeletal muscle cells, soluble ANGPTL4 suppressed insulin-mediated glucose uptake through the epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinases 1/2 (ERK 1/2) pathways. In pregnant women, plasma ANGPTL4 concentrations in the first trimester predicted the incidence of GDM and were positively associated with BMI, plasma triglyceride, and plasma GH2 in the first trimester. However, they were negatively associated with insulin sensitivity index ISI0,120 in the second trimester. Overall, placental ANGPTL4 is induced by obesity and is involved in the pathophysiology of GDM via the induction of ER stress and GH2 secretion. Soluble ANGPTL4 can lead to insulin resistance in skeletal muscle cells and is an early biomarker for predicting GDM.

Isoxanthohumol reduces neointimal hyperplasia through the apelin/AKT pathway.

The abnormal proliferation, migration, and inflammation of vascular smooth muscle cells (VSMCs) play crucial roles in the development of neointimal hyperplasia and restenosis. Exposure to inflammatory cytokines such as platelet-derived growth factor (PDGF)-BB and tumour necrosis factor-alpha (TNF-α) induces the transformation of contractile VSMCs into abnormal synthetic VSMCs. Isoxanthohumol (IXN) has significant anti-inflammatory, antiproliferative, and antimigratory effects. This study aimed to explore the therapeutic impact and regulatory mechanism of IXN in treating neointimal hyperplasia. The present findings indicate that IXN effectively hinders the abnormal proliferation, migration, and inflammation of VSMCs triggered by PDGF or TNF-α. This inhibition is primarily achieved through the modulation of the apelin/AKT or AKT pathway, respectively. In an in vivo model, IXN effectively reduced neointimal hyperplasia in denuded femoral arteries. These results suggest that IXN holds promise as a potential and innovative therapeutic candidate for the treatment of restenosis.

Inhibition of monoamine oxidase B reduces atherosclerosis and fatty liver in mice.

Oxidative stress is vital for pathophysiology of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Monoamine oxidase (MAO) is an important source of oxidative stress in the vascular system and liver. However, the effect of MAO inhibition on atherosclerosis and NAFLD has not been explored. In the present study, MAO A and B expressions were increased in atherosclerotic plaques in human and apolipoprotein E (ApoE)-deficient mice. Inhibition of MAO B (by deprenyl), but not MAO A (by clorgyline), reduced the atheroma area in the thoracic aorta and aortic sinus in ApoE-deficient mice fed the cholesterol-enriched diet for 15 weeks. MAO B inhibition attenuated oxidative stress, expression of adhesion molecules, production of inflammatory cytokines, and macrophage infiltration in atherosclerotic plaques and decreased plasma triglyceride and low-density lipoprotein (LDL) cholesterol concentrations. MAO B inhibition had no therapeutic effect on restenosis in the femoral artery wire-induced injury model in C57BL/6 mice. In the NAFLD mouse model, MAO B inhibition reduced lipid droplet deposition in the liver and hepatic total cholesterol and triglyceride levels in C57BL/6 mice fed high-fat diets for 10 weeks. Key enzymes for triglyceride and cholesterol biosynthesis (fatty acid synthase and 3-hydroxy-3-methylglutaryl-CoA reductase, HMGCR) and inflammatory markers were inhibited, and cholesterol clearance was up-regulated (increased LDL receptor expression and reduced proprotein convertase subtilisin/kexin type 9, PCSK9, expression) by MAO B inhibition in the liver. These results were also demonstrated in the HepG2 liver cell model. Our data suggest that MAO B inhibition is a potential and novel treatment for atherosclerosis and NAFLD.

The flavonoid corylin exhibits lifespan extension properties in mouse.

In the long history of traditional Chinese medicine, single herbs and complex formulas have been suggested to increase lifespan. However, the identification of single molecules responsible for lifespan extension has been challenging. Here, we collected a list of traditional Chinese medicines with potential longevity properties from pharmacopeias. By utilizing the mother enrichment program, we systematically screened these traditional Chinese medicines and identified a single herb, Psoralea corylifolia, that increases lifespan in Saccharomyces cerevisiae. Next, twenty-two pure compounds were isolated from Psoralea corylifolia. One of the compounds, corylin, was found to extend the replicative lifespan in yeast by targeting the Gtr1 protein. In human umbilical vein endothelial cells, RNA sequencing data showed that corylin ameliorates cellular senescence. We also examined an in vivo mammalian model, and found that corylin extends lifespan in mice fed a high-fat diet. Taken together, these findings suggest that corylin may promote longevity.

Consumption of Non-Nutritive Sweetener, Acesulfame Potassium Exacerbates Atherosclerosis through Dysregulation of Lipid Metabolism in ApoE-/- Mice.

Obesity is associated with the risk of cardiovascular disease, and non-nutritive sweetener, such as acesulfame potassium (AceK) has been used to combat obesity. However, the effects of AceK on cardiovascular disease are still unclear. In this study, high cholesterol diet (HCD)-fed ApoE-/- mice had dysregulated plasma lipid profile, and developed atherosclerosis, determined by atherosclerotic plaque in the aorta. Supplement of AceK in HCD worsened the dyslipidemia and increased atherosclerotic plaque, as compared with HCD-fed ApoE-/- mice. Since treatment of AceK in RAW264.7 macrophages showed no significant effects on inflammatory cytokine expressions, we then investigated the impacts of AceK on lipid metabolism. We found that AceK consumption enhanced hepatic lipogenesis and decreased ß-oxidation in ApoE-/- mice. In addition, AceK directly increased lipogenesis and decreased ß-oxidation in HepG2 cells. Taken together, a concurrent consumption of AceK exacerbated HCD-induced dyslipidemia and atherosclerotic lesion in ApoE-/- mice, and AceK might increase the risk of atherosclerosis under HCD.

Corylin reduces obesity and insulin resistance and promotes adipose tissue browning through SIRT-1 and ß3-AR activation.

Brown adipose tissue (BAT) activation or beige adipocytes in white adipocytes (WAT) (browning) is a novel strategy against obesity. Corylin, a flavonoid compound extract from Psoralea corylifolia L., has been shown to exert anti-inflammatory, anticancer, and anti-atherosclerotic effects and ameliorate hyperlipidemia and insulin resistance. However, the therapeutic effect of corylin on obesity remains unknown. The objective of this study was to evaluate the effect of corylin on browning or obesity. Here, we report that corylin induced browning by elevating the expression levels of beige- or browning-specific marker genes, including cited1, hoxc9, pgc1α, prdm16, and ucp1, in 3T3-L1 adipocytes, WAT and BAT. Moreover, corylin also strikingly reduced body weight and fat accumulation and increased insulin sensitivity, mitochondrial biogenesis, and ß-oxidation in HFD- and DIO-treated mice. The browning and lipolysis effects of corylin were abolished by sirtuin 1 (SIRT1) inhibitor (EX527) and ß3-adrenergic receptor (ß3-AR) antagonist (L-748,337) treatment. The possible molecular mechanism of corylin on the browning and lipolysis of adipocytes is through SIRT1- or ß3-AR-dependent pathways. The study suggested that corylin exerts anti-obesity effects through the browning of white adipocytes, activating of BAT and promoting of lipid metabolism. Therefore, corylin may be a helpful therapeutic candidate for treating obesity.

Corylin Inhibits Vascular Cell Inflammation, Proliferation and Migration and Reduces Atherosclerosis in ApoE-Deficient Mice.

Atherosclerosis is a complex disease that includes several events, including reactive oxygen species (ROS) stress, inflammation, endothelial dysfunction, lipid deposition, and vascular smooth muscle cell (VSMC) proliferation and migration, which result in atherosclerotic plaque formation. Corylin, a flavonoid compound, is known to exhibit antioxidative, anti-inflammatory and antiproliferative effects. However, it remains unknown whether corylin could modulate atherogenesis. Here, we identified the anti-inflammatory effect of corylin in tumor necrosis factor-α (TNF-α)-induced vascular cells. In human umbilical vein endothelial cells (HUVECs), corylin suppressed TNF-α-induced monocyte adhesion to the HUVECs and transmigration by downregulating the ROS/JNK/nuclear factor-kappa beta (NF-κB) p65 pathway. In VSMCs, corylin inhibited TNF-α-induced monocyte adhesion by suppressing ROS production, mitogen-activated protein kinase (MAPK) phosphorylation and NF-κB p65 translocation. In platelet-derived growth factor-BB (PDGF-BB)-induced VSMCs, corylin inhibited PDGF-BB-induced VSMC proliferation and migration through regulating the mammalian target of rapamycin (mTOR)/dynamin-1-like protein 1 (Drp1) signaling cascade. In addition, corylin treatment not only attenuated atherosclerotic lesions, ROS production, vascular cell adhesion protein-1 (VCAM-1) expression, monocyte adhesion and VSMC proliferation in apolipoprotein E (ApoE)-deficient mice but also inhibited neointimal hyperplasia in endothelial-denuded mice. Thus, corylin may be a potential prevention and treatment for atherosclerosis.

Serum Angiopoietin-like Protein 6, Risk of Type 2 Diabetes, and Response to Hyperglycemia: A Prospective Cohort Study.

CONTEXT: Angiopoietin-like protein 6 (ANGPTL6) is a hepatokine that improves insulin sensitivity in animals. However, serum ANGPTL6 concentration was found to be higher in human participants with diabetes or metabolic syndrome in cross-sectional studies, implying that ANGPTL6 may be induced to counteract hyperglycemia. OBJECTIVE: To investigate whether serum ANGPTL6 can predict incident diabetes and explore whether glucose or insulin can regulate ANGPTL6 expression and secretion. DESIGN: This cohort study included adults without diabetes at baseline who were followed every 2 years for incident diabetes. Serum ANGPTL6 concentrations were measured at baseline and during oral glucose tolerance tests (OGTTs). A hepatic cell line, HepG2, and diet-induced obesity mouse model were used to evaluate the response of ANGPTL6 expression and secretion to hyperglycemia and the metabolic syndrome. RESULTS: We recruited 1103 participants without diabetes at baseline. During the 4.22-year follow-up, 113 (10.2%) participants developed incident diabetes. Serum ANGPTL6 was negatively associated with the incidence of diabetes (adjusted hazard ratio, 0.77; P = 0.042). However, serum ANGPTL6 level was higher in participants with prediabetes (P = 0.018) and was elevated during OGTT. In HepG2 cells, treatment with glucose, but not insulin, induced ANGPTL6 expression. Hepatic ANGPTL6 expression and serum ANGPTL6 concentrations were significantly higher in mice fed with a high-fat diet than in those fed with a standard chow (both P < 0.05). CONCLUSION: A high serum ANGPTL6 level is associated with a low incidence of diabetes in humans. ANGPTL6 is expressed and secreted in response to hyperglycemia to maintain glucose homeostasis.

Role of placental fibrinogen-like protein 1 in gestational diabetes.

In view of the increasing prevalence of gestational diabetes mellitus (GDM) and the increased risks of delivering a macrosomic infant, developing preeclampsia, and suffering a perinatal death due to GDM, GDM has emerged as a growing public health problem. Although the placenta was suggested to play a crucial role in the pathology of GDM, the mechanisms that induce the development of GDM are still obscure. Fibrinogen-like protein (FGL)-1 is a hepatokine that plays an important role in hepatogenesis, as well as in nonalcoholic fatty liver disease and diabetes. Although FGL-1 is also expressed by the placenta, the pathophysiological role of FGL-1 in GDM is still unknown. In this study, FGL-1 levels were evaluated in 45 subjects with (n = 16) or without (n = 29) GDM. We found that FGL-1 was mainly expressed by placental trophoblasts, and FGL-1 expression was significantly higher in subjects with GDM. FGL-1 increased trophoblast proliferation through an extracellular signal-regulated kinase 1/2-dependent pathway. In addition, plasma concentrations of FGL-1 were higher in subjects with GDM, and the increased circulating FGL-1 might contribute to systemic insulin resistance. FGL-1 disrupted the gluconeogenic action of insulin in HepG2 cells, and decreased insulin-induced glucose uptake by L6 myotubes. Taken together, placental FGL-1 possibly plays a role in the impairment of insulin function in the development of GDM, and it might be a novel biomarker for diagnosing GDM.

Targeting fibrinogen-like protein 1 is a novel therapeutic strategy to combat obesity.

Fibrinogen-like-protein 1 (FGL1) is a novel hepatokine that plays an important role in hepatic steatosis and insulin resistance. Although FGL1 expression can be detected in adipose tissues, the functions of FGL1 in adipose tissues are still unknown. In this study, 356 participants with (body mass index (BMI) ≥25 kg/m2 ; n = 134) or without obesity (BMI <25 kg/m2 ; n = 222) were recruited, and we found that the plasma FGL1 concentrations were significantly higher in obese group than those of in the normal weight group, and were positively correlated with age, BMI, waist circumference, fat content, plasma glucose at 2 hours during an oral glucose tolerance test, and the insulin sensitivity index. In univariate analyses, BMI, waist circumference, total fat, visceral fat, and subcutaneous fat areas were positively correlated with FGL1 levels. After adjusting for age and gender, obesity indices, including the BMI and different fat areas, remained significantly associated with FGL1 levels. In order to investigate the causal relationship between FGL1 and obesity, animal and cell models were used. Overexpression of FGL1 in epididymal adipose tissue by lentiviral vector encoding FGL1 increased the fat pad size, whereas FGL1-knockdown by lentiviral vector encoding short-hairpin RNA targeted to FGL1 decreased high-fat diet-induced adiposity. In addition, 3T3-L1 adipocytes were used to clarify the possible mechanism of FGL1-induced adipogenesis. FGL1 induced adipogenesis through an ERK1/2-C/EBPß-dependent pathway in 3T3-L1 adipocytes. These findings highlight the pathophysiological role of FGL1 in obesity, and FGL1 might be a novel therapeutic target to combat obesity.

A Web-Based Virtual Microscopy Platform for Improving Academic Performance in Histology and Pathology Laboratory Courses: A Pilot Study.

Virtual microscopy (VM) has been utilized to improve students' learning experience in microscope laboratory sessions, but minimal attention has been given to determining how to use VM more effectively. The study examined the influence of VM on academic performance and teacher and student perceptions and compared laboratory test scores before and after VM incorporation. A total of 662 third-year students studying histology and 651 fourth-year students studying pathology were divided into two groups. The light microscopy (LM) group used a light microscope in 2014 and 2015, while the LM + VM group used the VM platform and a light microscope in 2016 and 2017. Four factors positively predict laboratory scores (R square, 0.323; P < 0.001): (i) the pathology course and test-enhanced learning, (ii) the VM platform and experience, (iii) medical students and lecture scores, and (iv) female students. The LM + VM group exhibited less score variability on laboratory examinations relative to their mean than the LM group. The LM + VM group was also associated with fewer failing grades (F grade; odds ratio, 0.336; P < 0.001) and higher scores (A grade; odds ratio, 2.084; P < 0.001) after controlling for sex, school, course, and lecture grades. The positive effect of the VM platform on laboratory test grades was associated with prior experience using the VM platform and was synergistic with more interim tests. Both teachers and students agreed that the VM platform enhanced laboratory learning. The incorporation of the VM platform in the context of test-enhanced learning may help more students to master microscopic laboratory content.

A novel DNA repair inhibitor, diallyl disulfide (DADS), impairs DNA resection during DNA double-strand break repair by reducing Sae2 and Exo1 levels.

Combining natural products with chemotherapy and/or radiotherapy may increase the efficacy of cancer treatment. It has been hypothesized that natural products may inhibit DNA repair and sensitize cancer cells to DNA damage-based cancer therapy. However, the molecular mechanisms underlying these activities remain unclear. In this study, we found that diallyl disulfide (DADS), an organosulfur compound, increased the sensitivity of yeast cells to DNA damage and has potential for development as an adjuvant drug for DNA damage-based cancer therapy. We induced HO endonuclease to generate a specific DNA double-strand break (DSB) by adding galactose to yeast and used this system to study how DADS affects DNA repair. In this study, we found that DADS inhibited DNA repair in single-strand annealing (SSA) system and sensitized SSA cells to a single DSB. DADS impaired DNA repair by inhibiting the protein levels of the DNA resection-related proteins Sae2 and Exo1. We also found that the recruitment of MRX and the Mec1-Ddc2 complex to a DSB was prevented by DADS. This result suggests that DADS counteracts G2/M DNA damage checkpoint activation in a Mec1 (ATR)- and Tel1 (ATM)-dependent manner. Only by elucidating the molecular mechanisms by which DADS influences DNA repair will we be able to discover new adjuvant drugs to improve chemotherapy and/or radiotherapy.

Pigment epithelium-derived factor inhibits adipogenesis in 3T3-L1 adipocytes and protects against high-fat diet-induced obesity and metabolic disorders in mice.

Obesity is a major cause of metabolic syndrome and type II diabetes, and it presents with metabolic disorders, such as hyperglycemia, hyperlipidemia, and insulin resistance. Pigment epithelium-derived factor (PEDF), a protein isolated from retinal pigment epithelial cells, has multiple functions, including neuronal protection, antineoplastic effects, and anti-inflammatory activity. The aim of this study is to investigate the antiobesity effects of PEDF. The antiobesity effects of PEDF on fat accumulation, inflammation, energy expenditure, insulin resistance, and obesity-related physiological parameters and protein levels were assessed in high-fat diet (HFD)-induced obese mice in vivo and in 3T3-L1 adipocytes, palmitate (PA)-treated HepG2 cells, and C2C12 myotubes in vitro. In an in vivo assay, PEDF effectively decreased body weight gain, white adipose tissue mass, and inflammation and improved insulin resistance, dyslipidemia, and hyperglycemia in HFD-induced mice. In liver tissue, PEDF decreased lipid accumulation and fibrosis. In an in vitro assay, PEDF diminished the differentiation of 3T3-L1 preadipocytes. We also determined that PEDF promoted lipolysis and prolonged cell cycle progression, through the mTOR-S6K pathway and downstream transcription factors, such as peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein α (CEBP-α), and CEBP-ß. In addition, PEDF decreased reactive oxygen species production in PA-induced HepG2 cells and improved glucose uptake ability in PA-induced HepG2 cells and C2C12 myotubes. In the present study, PEDF protected against HFD-induced obesity and metabolic disorders in mice, inhibited adipogenesis, and improved insulin resistance. These results provide a new potential treatment for obesity in the future.

Melatonin Inhibits in Vitro Smooth Muscle Cell Inflammation and Proliferation and Atherosclerosis in Apolipoprotein E-Deficient Mice.

Chronic inflammation and proliferation play important roles in atherosclerosis progression. This study aimed to identify the mechanisms responsible for the anti-inflammatory and antiproliferative effects of melatonin on tumor necrosis factor-α (TNF-α)- and platelet-derived growth factor-BB (PDGF-BB)-treated rat aortic smooth muscle cells (RASMCs). Melatonin reduced TNF-α-induced RASMC inflammation by decreasing vascular cell adhesion molecule-1 (VCAM-1) expression and nuclear factor-kappa B (NF-κB) P65 activity by inhibiting P38 mitogen-activated protein kinase phosphorylation ( P < 0.05). Additionally, melatonin inhibited PDGF-BB-induced RASMC proliferation by reducing mammalian target of rapamycin (mTOR) phosphorylation ( P < 0.05) but not migration in vitro. Melatonin also reduced TNF-α- and PDGF-BB-induced reactive oxygen species (ROS) production ( P < 0.05). Furthermore, melatonin treatment (prevention and treatment groups) significantly repressed high cholesterol diet-stimulated atherosclerotic lesions in vivo (19.59 ± 4.11%, 20.28 ± 5.63%, 32.26 ± 12.06%, respectively, P < 0.05). Taken together, the present study demonstrated that melatonin attenuated TNF-α-induced RASMC inflammation and PDGF-BB-induced RASMC proliferation in cells and reduced atherosclerotic lesions in mice. These results showed that melatonin has anti-inflammatory and antiproliferative properties and may be a novel therapeutic target in atherosclerosis.

Serum vascular adhesion protein-1 is up-regulated in hyperglycemia and is associated with incident diabetes negatively.

BACKGROUND/OBJECTIVES: Vascular adhesion protein-1 (VAP-1) can enhance tissue glucose uptake in cell studies and normalize hyperglycemia in animal studies. However, serum VAP-1 concentration (sVAP-1) is higher in subjects with diabetes in cross-sectional studies. In this cohort study, we test our hypothesis that sVAP-1 is increased in prediabetes to counteract hyperglycemia and is associated with incident diabetes negatively. SUBJECTS/METHODS: From 2006 to 2012, 600 subjects without diabetes from Taiwan Lifestyle Study were included and followed regularly. Diabetes was diagnosed if FPG ≥ 126 mg/dL (7 mmol/L), 2-h plasma glucose (2hPG) during an oral glucose tolerance test (OGTT) ≥ 200 mg/dL (11.1 mmol/L), or hemoglobin A1c (HbA1c) ≥ 6.5%, or if the subject received anti-diabetic medications. Abdominal fat areas were measured by abdominal computed tomography and sVAP-1 was analyzed by ELISA. RESULTS: sVAP-1 was higher in subjects with prediabetes (p < 0.05) and increased during an OGTT (p < 0.001). Fasting sVAP-1 was associated with the response of sVAP-1 during an OGTT (p < 0.001). Besides, sVAP-1 was associated negatively with body mass index (BMI, r = -0.1449, p = 0.003), waist circumference (r = -0.1425, p = 0.004), abdominal visceral (r = -0.1457, p = 0.003), and subcutaneous (r = -0.1025, p = 0.035) fat areas, and serum high-sensitivity C-reactive protein (hsCRP) concentration (r = -0.2035, p < 0.0001), and positively with plasma adiponectin concentration (r = 0.2086, p < 0.0001), adjusted for age and gender. After 4.7 ± 2.6 years, 73 subjects (12.2%) developed incident diabetes. High sVAP-1 predicted a lower incidence of diabetes, adjusted for age, gender, BMI, family history of diabetes, HbA1c, HOMA2-%B and HOMA2-IR (HR = 0.66, 95% CI = 0.50-0.88, p < 0.01). CONCLUSIONS: sVAP-1 is increased in response to hyperglycemia. It is associated with obesity and serum hsCRP concentration negatively, and plasma adiponectin concentration positively. Besides, a high sVAP-1 is associated with a lower incidence of diabetes in human.

Melatonin Sensitizes Hepatocellular Carcinoma Cells to Chemotherapy Through Long Non-Coding RNA RAD51-AS1-Mediated Suppression of DNA Repair.

DNA repair systems are abnormally active in most hepatocellular carcinoma (HCC) cells due to accumulated mutations, resulting in elevated DNA repair capacity and resistance to chemotherapy and radiotherapy. Thus, targeting DNA repair mechanisms is a common treatment approach in HCC to sensitize cancer cells to DNA damage. In this study, we examined the anti-HCC effects of melatonin and elucidated the regulatory mechanisms. The results of functional assays showed that in addition to inhibiting the proliferation, migration, and invasion abilities of HCC cells, melatonin suppressed their DNA repair capacity, thereby promoting the cytotoxicity of chemotherapy and radiotherapy. Whole-transcriptome and gain- and loss-of-function analyses revealed that melatonin induces expression of the long noncoding RNA RAD51-AS1, which binds to RAD51 mRNA to inhibit its translation, effectively decreasing the DNA repair capacity of HCC cells and increasing their sensitivity to chemotherapy and radiotherapy. Animal models further demonstrated that a combination of melatonin and the chemotherapeutic agent etoposide (VP16) can significantly enhance tumor growth inhibition compared with monotherapy. Our results show that melatonin is a potential adjuvant treatment for chemotherapy and radiotherapy in HCC.

Association of Interleukin-10 Methylation Levels With Gestational Diabetes in a Taiwanese Population.

Objective: Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset during pregnancy, which is also associated with future metabolic diseases in both patients and their offspring. The mechanisms underlying this condition remain largely unknown and may be partly related to epigenetics. The aim of this study was to compare the methylation levels of the cytokine interleukin-10 (IL-10) in pregnant women and their fetuses under both hyperglycemic and euglycemic environments, as those levels may be a clue to the epigenetic mechanisms underlying pathogenesis of GDM. Methods: We analyzed the methylation levels of the IL-10 gene in maternal blood, cord blood, and placental tissue in both a GDM group (n = 8) and a control group (n = 24) using a LightCycler LC480 (Roche, Rotkreuz, Switzerland). IL-10 concentrations in maternal blood and THP-1 cells were measured by enzyme-linked immunosorbent assay (ELISA) using BD OptEIA Human IL-10 ELISA kits (BD Biosciences Pharmingen, San Diego, CA, United States). Results: The maternal blood IL-10 methylation levels in the GDM group and the control group were 0.23 ± 0.04 and 0.26 ± 0.04, respectively (p = 0.03), but there were no significant differences between the levels of the two groups in the cord blood or placental tissue. Increased IL-10 plasma concentrations were discovered under hyperglycemic environments and were confirmed via the THP-1 cell line. Conclusion: Hypomethylation of maternal blood and increased plasma IL-10 concentrations before birth were found in the GDM group.

Inhibition of Semicarbazide-sensitive Amine Oxidase Reduces Atherosclerosis in Cholesterol-fed New Zealand White Rabbits.

Inflammation, oxidative stress, and the formation of advanced glycated end-products (AGEs) are important components of atherosclerosis. Vascular adhesion protein-1 (VAP-1) participates in inflammation. Its enzymatic activity, semicarbazide-sensitive amine oxidase (SSAO), can catalyze oxidative deamination reactions to produce hydrogen peroxide and aldehydes, leading to the subsequent generation of AGEs. This study aimed to investigate the effect of VAP-1/SSAO inhibition on atherosclerosis. In our study, immunohistochemical staining showed that atherosclerotic plaques displayed higher VAP-1 expression than normal arterial walls in apolipoprotein E-deficient mice, cholesterol-fed New Zealand White rabbits and humans. In cholesterol-fed rabbits, VAP-1 was expressed on endothelial cells and smooth muscle cells in the thickened intima of the aorta. Treatment with PXS-4728A, a selective VAP-1/SSAO inhibitor, in cholesterol-fed rabbits significantly decreased SSAO-specific hydrogen peroxide generation in the aorta and reduced atherosclerotic plaques. VAP-1/SSAO inhibition also lowered blood low-density lipoprotein cholesterol, reduced the expression of adhesion molecules and inflammatory cytokines, suppressed recruitment and activation of macrophages, and decreased migration and proliferation of SMC. In conclusion, VAP-1/SSAO inhibition reduces atherosclerosis and may act through suppression of several important mechanisms for atherosclerosis.

Inhibition of semicarbazide-sensitive amine oxidase reduces atherosclerosis in apolipoprotein E-deficient mice.

Inflammation, oxidative stress, and formation of advanced glycated end products (AGEs) and advanced lipoxidation end products (ALEs) are important for atherosclerosis. Vascular adhesion protein-1 (VAP-1) participates in inflammation and has semicarbazide-sensitive amine oxidase (SSAO) activity, which catalyzes oxidative deamination to produce hydrogen peroxide and aldehydes, leading to generation of AGEs and ALEs. However, the effect of VAP-1/SSAO inhibition on atherosclerosis remains controversial, and no studies used coronary angiography to evaluate if plasma VAP-1/SSAO is a biomarker for coronary artery disease (CAD). Here, we examined if plasma VAP-1/SSAO is a biomarker for CAD diagnosed by coronary angiography in humans and investigated the effect of VAP-1/SSAO inhibition by a specific inhibitor PXS-4728A on atherosclerosis in cell and animal models. In the study, VAP-1/SSAO expression was increased in plaques in humans and in apolipoprotein E (ApoE)-deficient mice, and colocalized with vascular endothelial cells and smooth muscle cells (SMCs). Patients with CAD had higher plasma VAP-1/SSAO than those without CAD. Plasma VAP-1/SSAO was positively associated with the extent of CAD. In ApoE-deficient mice, VAP-1/SSAO inhibition reduced atheroma and decreased oxidative stress. VAP-1/SSAO inhibition attenuated the expression of adhesion molecules, chemoattractant proteins, and proinflammatory cytokines in the aorta, and suppressed monocyte adhesion and transmigration across human umbilical vein endothelial cells. Consequently, the expression of markers for macrophage recruitment and activation in plaques was decreased by VAP-1/SSAO inhibition. Besides, VAP-1/SSAO inhibition suppressed proliferation and migration of A7r5 SMC. Our data suggest that plasma VAP-1/SSAO is a novel biomarker for the presence and the extent of CAD in humans. VAP-1/SSAO inhibition by PXS-4728A is a potential treatment for atherosclerosis.

Corylin Suppresses Hepatocellular Carcinoma Progression via the Inhibition of Epithelial-Mesenchymal Transition, Mediated by Long Noncoding RNA GAS5.

Corylin is a flavonoid extracted from the nuts of Psoralea corylifolia L. (Fabaceae), which is a widely used anti-inflammatory and anticancer herb in China. Recent studies revealed antioxidant, anti-inflammatory, and bone differentiation-promoting effects of corylin. However, there are no studies examining the anticancer activity of corylin. In this study, we used cells and animal models to examine the antitumor effects of corylin on hepatocellular carcinoma (HCC) and then studied its downstream regulatory mechanisms. The results showed that corylin significantly inhibited the proliferation, migration, and invasiveness of HCC cells and suppressed epithelial-mesenchymal transition. We found that the anti-HCC mechanism of corylin's action lies in the upregulation of tumor suppressor long noncoding RNA growth arrest-specific transcript 5 (GAS5) and the activation of its downstream anticancer pathways. In animal experiments, we also found that corylin can significantly inhibit tumor growth without significant physiological toxicity. The above results suggest that corylin has anti-HCC effects and good potential as a clinical treatment.