Apigenin Suppresses MED28-Mediated Cell Growth in Human Liver Cancer Cells.

Flavonoids exhibit health-promoting benefits against multiple chronic diseases, including cancer. Apigenin (4',5,7-trihydroxyflavone), one flavonoid present in fruits and vegetables, is potentially applicable to chemoprevention. Despite considerable progress in the therapeutic regimen of liver cancer, its prognosis remains poor. MED28, a Mediator subunit for transcriptional activation, is implicated in the development of several types of malignancy; however, its role in liver cancer is unknown at present. In liver cancer, the AKT/mammalian target of rapamycin (mTOR) is one major pathway involved in the oncogenic process. The aim of this study is to investigate the role of apigenin and MED28 in AKT/mTOR signaling in liver cancer. We first identified a connectivity score of 92.77 between apigenin treatment and MED28 knockdown in several cancer cell lines using CLUE, a cloud-based software platform to assess connectivity among compounds and genetic perturbagens. Higher expression of MED28 predicted a poorer survival prognosis; MED28 expression in liver cancer tissue was significantly higher than that of normal tissue, and it was positively correlated with tumor stage and grade in The Cancer Genome Atlas Liver Cancer (TCGA-LIHC) data set. Knockdown of MED28 induced cell cycle arrest and suppressed the AKT/mTOR signaling in two human liver cancer cell lines, HepG2 and Huh 7, accompanied by less lipid accumulation and lower expression and nuclear localization of sterol regulatory element binding protein 1 (SREBP1). Apigenin inhibited the expression of MED28, and the effect of apigenin mimicked that of the MED28 knockdown. On the other hand, the AKT/mTOR signaling was upregulated when MED28 was overexpressed. These data indicated that MED28 was associated with the survival prognosis and the progression of liver cancer by regulating AKT/mTOR signaling and apigenin appeared to inhibit cell growth through MED28-mediated mTOR signaling, which may be applicable as an adjuvant of chemotherapy or chemoprevention in liver cancer.

A meta-analysis of the association between RBP4 rs3758539 genotype and metabolic syndrome factors.

AIM: To explore the link between the RBP4 rs3758539 genotype and metabolic syndrome risk factors and whether the impact of this genetic variation displays any potential race discrepancy. MATERIALS AND METHODS: This meta-analysis followed the PRISMA guidelines and was registered with PROSPERO (registration no. CRD42023407999). PubMed, Web of Science, Embase, Cochrane Library, Google Scholar, Airiti Library and CINAHL databases were used for the study search until October 2023. We evaluated the methodological quality using the Joanna Briggs Institute checklist and determined the correlation using a random-effects meta-analysis. RESULTS: The results indicated that individuals with the rs3758539 GA/AA genotype had a higher risk profile, including lower high-density lipoprotein levels [correlation: -0.045, 95% confidence interval (CI): -0.080 to -0.009, p = .015, I2 = 46.9%] and higher body mass index (correlation: 0.117, 95% CI: 0.036-0.197, p = .005, I2 = 82.0%), body fat (correlation: 0.098, 95% CI: 0.004-0.191, p = .041, I2 = 64.0%), and low-density lipoprotein levels (correlation: 0.074, 95% CI: 0.010-0.139, p = .024, I2 = 0%), of developing metabolic syndrome than those with the GG genotype. The subgroup analysis maintained a significantly positive correlation between the rs3758539 GA/AA genotype and body mass index (correlation: 0.163, 95% CI: 0.031-0.289, p = .016, I2 = 88.9%) but a negative correlation with high-density lipoprotein levels (correlation: -0.047, 95% CI: -0.087 to -0.006, p = .025, I2 = 65.7%) in the Asian group only. CONCLUSION: The current meta-analysis supports a significant link between the RBP4 rs3758539 GA/AA genotype and the metabolic syndrome.

Dosimetry and efficiency comparison of knowledge-based and manual planning using volumetric modulated arc therapy for craniospinal irradiation.

BACKGROUND: Craniospinal irradiation (CSI) poses a challenge to treatment planning due to the large target, field junction, and multiple organs at risk (OARs) involved. The aim of this study was to evaluate the performance of knowledge-based planning (KBP) in CSI by comparing original manual plans (MP), KBP RapidPlan initial plans (RPI), and KBP RapidPlan final plans (RPF), which received further re-optimization to meet the dose constraints. PATIENTS AND METHODS: Dose distributions in the target were evaluated in terms of coverage, mean dose, conformity index (CI), and homogeneity index (HI). The dosimetric results of OARs, planning time, and monitor unit (MU) were evaluated. RESULTS: All MP and RPF plans met the plan goals, and 89.36% of RPI plans met the plan goals. The Wilcoxon tests showed comparable target coverage, CI, and HI for the MP and RPF groups; however, worst plan quality was demonstrated in the RPI plans than in MP and RPF. For the OARs, RPF and RPI groups had better dosimetric results than the MP group (P < 0.05 for optic nerves, eyes, parotid glands, and heart). The planning time was significantly reduced by the KBP from an average of 677.80 min in MP to 227.66 min (P < 0.05) and 307.76 min (P < 0.05) in RPI, and RPF, respectively. MU was not significantly different between these three groups. CONCLUSIONS: The KBP can significantly reduce planning time in CSI. Manual re-optimization after the initial KBP is recommended to enhance the plan quality.

Effect of FADS1 rs174556 Genotype on Polyunsaturated Fatty Acid Status: A Systematic Review and Meta-Analysis.

PUFA status is highly implicated in cognitive development and metabolic disorder-related diseases. Genetic variants of FADS genes encoding enzymes that catalyze the rate-limiting steps of PUFA biosynthesis appear to be associated with n-3 and n-6 PUFA contents. Therefore, we conducted the first systematic review and meta-analysis to explore the association of the A-allele carriers of the FADS1 rs174556 with PUFA status. The PRISMA guidelines were followed. The literature search was conducted up to November 2022 in PubMed, Web of Science, Embase, Cochrane Library, Airiti Library, and CINAHL. The Joanna Briggs Institute checklists were used to assess the methodological quality. The correlation with 95% CIs was determined by a random-effect meta-analysis. Eleven studies that met the inclusion criteria and acceptable quality were included in this systematic review. The data on PUFA contents were collected when they were mainly analyzed using blood samples and breast milk. Results of the meta-analysis on eight studies (one randomized controlled trial, one cohort study, and six cross-sectional studies) showed that the A-allele carriers of rs174556 were significantly negatively correlated with the concentrations of AA (P = 0.001), EPA (P = 0.004), and DHA (P = 0.025). However, ALA and LA were not associated with the A-allele carriers. To clarify the discrepancy, we further divided the studies into blood samples and breast milk subgroups. The subgroup analysis revealed that the A-allele carriers of rs174556 were significantly positively correlated with LA (P = 0.031) and negatively correlated with AA (P = 0.001), EPA (P = 0.036), and DHA (P < 0.001) in the blood sample group, but not in the breast milk group. The current meta-analysis proved that the A-allele carriers of the FADS1 rs174556 appeared to be highly associated with lower concentrations of AA, EPA, and DHA but higher LA in the blood samples. The study has been registered on the International Prospective Register of Systematic Reviews (PROSPERO:CRD42022363978). Adv Nutr 2023;x:xx-xx.

Bioactive Vitamin D Attenuates MED28-Mediated Cell Growth and Epithelial-Mesenchymal Transition in Human Colorectal Cancer Cells.

Inadequate vitamin D status may increase the risk of developing multiple types of cancer. Epidemiological studies suggest an inverse association between 25-hydroxyvitamin D3 (25(OH)D3) and malignancy, including colorectal cancer. Previous studies have suggested that MED28, a Mediator subunit involved in transcriptional regulation, is associated with the growth of colorectal cancer cells; however, its role in the progression of metastasis such as epithelial-mesenchymal transition (EMT) and cell migration of colorectal cancer is unclear at present. The aim of this study was to investigate a potentially suppressive effect of calcitriol, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), a bioactive form of vitamin D, and the role of MED28 in the progression of EMT in human colorectal cancer cells. Suppression of MED28 increased the expression of E-cadherin and reduced the expression of several mesenchymal and migration biomarkers and Wnt/ß-catenin signaling molecules, whereas overexpression of MED28 enhanced the EMT features. Calcitriol suppressed the expression of MED28, and the effect of calcitriol mirrored that of MED28 silencing. Our data indicate that calcitriol attenuated MED28-mediated cell growth and EMT in human colorectal cancer cells, underlining the significance of MED28 in the progression of colorectal cancer and supporting the potential translational application of calcitriol.

Calcitriol Suppresses Warburg Effect and Cell Growth in Human Colorectal Cancer Cells.

Increasing lines of evidence indicate that the biologically active form of vitamin D, calcitriol (1,25-dihydroxyvitamin D3), prevents cancer progression by reducing cell proliferation, increasing cell differentiation, and inhibiting angiogenesis, among other potential roles. Cancer cells in solid tumors preferably undergo the "Warburg effect" to support cell growth by upregulating glycolysis, and the glycolytic intermediates further serve as building blocks to generate biomass. The objective of the current study is to investigate whether calcitriol affects glucose metabolism and cell growth in human colorectal cancer cells. Calcitriol reduced the expression of cyclin D1 and c-Myc. In addition, calcitriol reduced the expression of glucose transporter 1 (GLUT1) and key glycolytic enzymes and decreased extracellular acidification rate but increased oxygen consumption rate in human colorectal cancer cells. In a subcutaneous HT29 xenograft NOD/SCID mouse model, the volume and weight of the tumors were smaller in the calcitriol groups as compared with the control group, and the expression levels of GLUT1 and glycolytic enzymes, hexokinase 2 and lactate dehydrogenase A, were also lower in the calcitriol groups in a dose-responsive manner. Our data indicate that calcitriol suppresses glycolysis and cell growth in human colorectal cancer cells, suggesting an inhibitory role of the biologically active form of vitamin D in colorectal cancer progression.

Pterostilbene Sensitizes Cisplatin-Resistant Human Bladder Cancer Cells with Oncogenic HRAS.

Analysis of various public databases revealed that HRAS gene mutation frequency and mRNA expression are higher in bladder urothelial carcinoma. Further analysis revealed the roles of oncogenic HRAS, autophagy, and cell senescence signaling in bladder cancer cells sensitized to the anticancer drug cisplatin using the phytochemical pterostilbene. A T24 cell line with the oncogenic HRAS was chosen for further experiments. Indeed, coadministration of pterostilbene increased stronger cytotoxicity on T24 cells compared to HRAS wild-type E7 cells, which was paralleled by neither elevated apoptosis nor induced cell cycle arrest, but rather a marked elevation of autophagy and cell senescence in T24 cells. Pterostilbene-induced autophagy in T24 cells was paralleled by inhibition of class I PI3K/mTOR/p70S6K as well as activation of MEK/ERK (a RAS target) and class III PI3K pathways. Pterostilbene-induced cell senescence on T24 cells was paralleled by increased pan-RAS and decreased phospho-RB expression. Coadministration of PI3K class III inhibitor 3-methyladenine or MEK inhibitor U0126 suppressed pterostilbene-induced autophagy and reversed pterostilbene-enhanced cytotoxicity, but did not affect pterostilbene-elevated cell senescence in T24 cells. Animal study data confirmed that pterostilbene enhanced cytotoxicity of cisplatin plus gemcitabine. These results suggest a therapeutic application of pterostilbene in cisplatin-resistant bladder cancer with oncogenic HRAS.

Phylogeography of the mediterranean green seaweed Halimeda tuna (Ulvophyceae, Chlorophyta).

Populations of many Mediterranean marine species show a strong phylogeographic structure, but the knowledge available for native seaweeds is limited. We investigated the genetic diversity of the green alga Halimeda tuna based on two plastid markers (tufA gene and a newly developed amplicon spanning five ribosomal protein genes and intergenic spacers, the rpl2-rpl14 region). The tufA sequences showed that Mediterranean H. tuna represents a single, well-defined species. The rpl2-rpl14 results highlighted a genetic separation between western and eastern Mediterranean populations; specimens collected from widely scattered locations in the Adriatic/Ionian region shared a haplotype unique to this region, and formed a group separated from all western Mediterranean regions. Specimens from Sardinia also formed a unique haplotype. Within the western Mediterranean basin, a gradual shift in the frequency of haplotypes was apparent along a West-East gradient. Our results represent the first clear evidence of an East-West genetic cleavage in a native Mediterranean macroalga and offer an interesting perspective for further research into fine-scale seaweed population structure in the NW Mediterranean Sea.

MED28 and forkhead box M1 (FOXM1) mediate matrix metalloproteinase 2 (MMP2)-dependent cellular migration in human nonsmall cell lung cancer (NSCLC) cells.

Non-small-cell lung cancer (NSCLC) accounts for the majority of the lung cancer cases that have become a leading cause of cancer deaths worldwide. Overexpression of transcription factor forkhead box M1 (FOXM1) is involved in the inauspicious development of several types of cancer, including lung tumor aggressiveness. Our laboratory has previously found that MED28, a Mediator subunit for transcriptional activation, modulates cell growth, epithelial-mesenchymal transition, migration, and invasion in human breast cancer cells. The objective of the current study is to investigate the potential role of MED28 and FOXM1 in NSCLC. In addition to A549 and PC9 cells, we also used a doxycycline-inducible system to generate FOXM1-overexpressed A549-DN cells, and we explored the connection of MED28 with FOXM1 and their effect on migration. Herein, we report that the increased expression levels of both MED28 and FOXM1 elevated the expression of matrix metalloproteinase 2 (MMP2), a metastasis marker, which enhanced cell migration and matrigel invasion of NSCLC cells. Furthermore, MED28 interacted with FOXM1, and both exhibited a mutual effect on the expression and subcellular localization. Moreover, MED28 small interfering RNA-mediated MMP2 gene suppression could be attenuated by inducible expression of a constitutively active form of FOXM1, which consequently restored the migration and invasion ability of NSCLC cells. Our data indicate that MED28 interacts with FOXM1, and each affects the expression and localization of the other, and, more importantly, both regulate MMP2-dependent migration and invasion in human lung cancer cells.

Dietary and nutrient status of children with attention-deficit/ hyperactivity disorder: a case-control study.

BACKGROUND AND OBJECTIVES: Nutritional and dietary habits may affect children's behaviors and learning. The etiology of attention-deficit/hyperactivity disorder (ADHD), a common neurodevelopmental disorder in children, may be associated with unhealthy diets or nutrients deficiencies. The purpose of this study was to examine whether children with ADHD exhibited different dietary habits or nutrient profiles from healthy control subjects. METHODS AND STUDY DESIGN: We recruited 42 patients with ADHD (mean age: 8.1 years) and 36 healthy children as the control group (mean age: 9.8 years). We adopted the ADHD Rating Scale and the Swanson, Nolan, and Pelham Version IV Scale to interview both the ADHD patients and the control subjects and then evaluated participants' dietary intake with a food frequency questionnaire. Logistic regression models were utilized to produce a composite dietary/nutrient score, while receiver operating characteristic (ROC) was adopted to differentiate between the two participant groups. RESULTS: Compared to the control children, children with ADHD demonstrated a higher intake proportion of refined grains (p=0.026) and a lower proportion of dairy (p=0.013), calcium (p=0.043), and vitamin B-2 (p=0.024). We observed that the composite score of dietary and nutrient could significantly distinguish patients with ADHD from healthy controls (p<0.001). The composite dietary/nutrient score demonstrated a significant correlation with the severity of ADHD clinical symptoms (p<0.05). CONCLUSIONS: ADHD children and healthy controls have different dietary patterns and that dietary and nutrient factors may play a role in the pathophysiology of ADHD. Clinicians should consider dietary habits and specific nutrients in the routine assessment of children with ADHD.

Transcription factor HMG box-containing protein 1 (HBP1) modulates mitotic clonal expansion (MCE) during adipocyte differentiation.

Transcription factor HMG box-containing protein 1 (HBP1) has been found to be up-regulated in rat adipose tissue and differentiated preadipocyte; however, how HBP1 is involved in adipocyte formation remains unclear. In the present study, we demonstrated that under a standard differentiation protocol HBP1 expression fluctuates with down-regulation in the mitotic clonal expansion (MCE) stage followed by up-regulation in the terminal differentiation stage in both 3T3-L1 and MEF cell models. Also, HBP1 knockdown accelerated cell cycle progression in the MCE stage, but it impaired final adipogenesis. To gain further insight into the role of HBP1 in the MCE stage, we found that the HBP1 expression pattern is reciprocal to that of C/EBPß, and ectopic expression of HBP1suppresses C/EBPß expression. These data indicate that HBP1 functions as a negative regulator of MCE. In contrast, when HBP1 expression was gradually elevated along with a concomitant induction of C/EBPα at the end of the MCE, HBP1 knockdown leads to a significant reduction of C/EBPα expression, suggesting that HBP1-mediated C/EBPα expression may be needed for the termination of the cell cycle at the end of MCE for terminal differentiation. All told, our findings show that HBP1 is a key transcription factor in the already complicated regulatory cascade during adipocyte differentiation.

Simvastatin induces G1 arrest by up-regulating GSK3ß and down-regulating CDK4/cyclin D1 and CDK2/cyclin E1 in human primary colorectal cancer cells.

Simvastatin (SIM), a widely used cholesterol-lowering drug, also exhibits tumor-suppressive potentials in several types of malignancy. Colorectal cancer (CRC), the third most common malignant neoplasm, accounts for the second most leading cause of cancer-related deaths worldwide. In the present study, we investigated the anticancer effects of SIM on CRC using primary cancer cells lines (CPs: CP1 to CP5) isolated from five Taiwanese colorectal cancer patients as a model for colorectal cancer. We treated all five CPs with SIM for 24-72 hr and observed the respective cell viability by an MTT assay. SIM increased DNA content of the G1 phase, but did not induce apoptosis/necrosis in CPs as shown by flow cytometry with propidium iodide (PI)/annexin V double staining and PI staining. The expression of G1 phase-related proteins was analyzed by RT-PCR and Western blotting. SIM suppressed cell growth and induced cell cycle G1 -arrest by suppressing the expression of CDK4/cyclin D1 and CDK2/cyclin E1, but elevating the expression of glycogen synthase kinase 3ß in CPs. Our findings indicate that SIM may have antitumor activity in established colorectal cancer.

Ursolic acid suppresses leptin-induced cell proliferation in rat vascular smooth muscle cells.

Accumulating lines of evidence indicate that high leptin levels are associated with adverse cardiovascular health in obese individuals. Proatherogenic effects of leptin include endothelial cell activation and vascular smooth muscle cell proliferation and migration. Ursolic acid (UA) has been reported to exhibit multiple biological effects including antioxidant and anti-inflammatory properties. In this study, we investigated the effect of UA on leptin-induced biological responses in rat vascular smooth muscle cells (VSMCs). A-10 VSMCs were treated with leptin in the presence or absence of UA. Intracellular reactive oxygen species (ROS) was probed by 2',7'-dichlorofluorescein diacetate. The expression of extracellular signal-regulated kinase (ERK)1/2, phospho-(ERK)1/2, nuclear factor-kappa B (NF-κB) p65 and p50, and matrix metalloproteinase-2 (MMP2) was determined by Western blotting. Immunocytochemistry and confocal laser scanning microscopy were also used for the detection of NF-κB. The secretion of MMP2 was detected by gelatin zymography. UA exhibited antioxidant activities in vitro. In rat VSMCs, UA effectively inhibited cell growth and the activity of MMP2 induced by leptin. These suppressive effects appeared by decreasing the activation of (ERK)1/2, the nuclear expression and translocation of NF-κB, and the production of ROS. UA appeared to inhibit leptin-induced atherosclerosis, which may prevent the development of obesity-induced cardiovascular diseases.

Transcription factor HBP1 is a direct anti-cancer target of transcription factor FOXO1 in invasive oral cancer.

Either FOXO1 or HBP1 transcription factor is a downstream effector of the PI3K/Akt pathway and associated with tumorigenesis. However, the relationship between FOXO1 and HBP1 in oral cancer remains unclear. Analysis of 30 oral tumor specimens revealed that mean mRNA levels of both FOXO1 and HBP1 in non-invasive and invasive oral tumors were found to be significantly lower than that of the control tissues, and the status of low FOXO1 and HBP1 (< 0.3 fold of the control) was associated with invasiveness of oral tumors. To investigate if HBP1 is a direct transcription target of FOXO1, we searched potential FOXO1 binding sites in the HBP1 promoter using the MAPPER Search Engine, and two putative FOXO1 binding sites located in the HBP1 promoter -132 to -125 bp and -343 to -336 bp were predicted. These binding sites were then confirmed by both reporter gene assays and the in cellulo ChIP assay. In addition, Akt activity manipulated by PI3K inhibitor LY294002 or Akt mutants was shown to negatively affect FOXO1-mediated HBP1 promoter activation and gene expression. Last, the biological significance of the FOXO1-HBP1 axis in oral cancer malignancy was evaluated in cell growth, colony formation, and invasiveness. The results indicated that HBP1 knockdown potently promoted malignant phenotypes of oral cancer and the suppressive effect of FOXO1 on cell growth, colony formation, and invasion was alleviated upon HBP1 knockdown in invasive oral cancer cells. Taken together, our data provide evidence for HBP1 as a direct downstream target of FOXO1 in oral cancer malignancy.

MED28 Regulates Epithelial-Mesenchymal Transition Through NFκB in Human Breast Cancer Cells.

MED28, a mammalian Mediator subunit, was found highly expressed in several types of malignancy, including breast cancer. Recently, we have identified a role of MED28 in regulating both cell growth and migration in human breast cancer cells. In epithelium-derived solid tumor, migration and invasion are preceded by the progression of epithelial-mesenchymal transition (EMT) which calls for downregulation of epithelial markers as well as upregulation of mesenchymal markers, among other features. The objective of this study was to investigate a putative role of MED28 in the progression of EMT in human breast cancer cells. In fibroblast-like MDA-MB-231 cells, suppression of MED28 attenuated the mesenchymal morphology, concomitantly with a reduction of several mesenchymal biomarkers and Snail, a transcriptional repressor of E-cadherin. The suppression effect was also accompanied by downregulation of p-NFκB/p65. However, overexpression of MED28 exhibited in an opposite manner. In epithelial MCF7 cells, administration of Adriamycin®, an experimental EMT induction system, led to a mesenchyme-like appearance correlated with increased expression of MED28, p-p65, and Snail, and a reciprocal change of epithelial and mesenchymal markers. Furthermore, suppression of MED28 attenuated the experimental EMT effect and restored the original expression status of E-cadherin and MMP9 in MCF7 cells. Our data indicate that MED28 modulates the development of EMT through NFκB in human breast cancer cells, further reinforcing the significance of MED28 in the progression of breast cancer on top of its role in cell growth and migration. J. Cell. Physiol. 232: 1337-1345, 2017. © 2016 Wiley Periodicals, Inc.

Quercetin suppresses cellular migration and invasion in human head and neck squamous cell carcinoma (HNSCC).

Head and neck squamous cell carcinoma (HNSCC) with aberrant epidermal growth factor receptor (EGFR) signaling is often associated with a poor prognosis and a low survival rate. Hence, efficient inhibition of the EGFR signaling-mediated malignancy would improve survival rate. In a previous study, we demonstrated that quercetin appears to be a potent anti-tumorigenic agent through its inhibition of the EGFR/Akt pathway in oral cancer, but its anti-metastatic potential in HNSCC remains unclear [1]. Here, we have hypothesized that quercetin might be effective in metastatic inhibition in EGFR-overexpressing HNSCC cells. Quercetin treatment with 10 µM (half concentration of IC50) suppressed cell migration and invasion in EGFR-overexpressing HSC-3 and FaDu HNSCC cells. Quercetin also inhibited the colony growth of HSC-3 cells embedded in a Matrigel matrix. Among matrix metalloproteinases (MMPs), the secreted gelatinases MMP-2 and MMP-9 are responsible for the degradation of gelatin in the extracellular matrix and type IV collagen in the basement membrane; and this degradation event is crucial for the migration from the origin and the invasion into the bone in HNSCC. Quercetin (10 µM) treatment also suppressed the expression and proteolytic activity of MMP-2 and MMP-9. Taken together, our data indicate that quercetin is an effective anti-cancer agent against MMP-2- and MMP-9-mediated metastasis in EGFR-overexpressing HNSCC.

Ursolic acid plays a protective role in obesity-induced cardiovascular diseases.

The metabolic disturbance of obesity is one of the most common risk factors of atherosclerosis. Resistin, an obesity-induced adipokine, can induce the expression of cell adhesion molecules and the attachment of monocytes to endothelial cells, which play an important role in the development of atherosclerosis. Ursolic acid, a pentacyclic triterpenoid found in fruits and many herbs, exhibits an array of biological effects such as anti-inflammatory and antioxidative properties. The aim of this study was to investigate the potential underlying mechanisms of the effect of ursolic acid on resistin-induced adhesion of U937 cells to human umbilical vein endothelial cells (HUVECs). Our data indicated that ursolic acid suppressed the adhesion of U937 to HUVECs and downregulated the expression of adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1), intracellular cell adhesion molecule-1 (ICAM-1), and E-selectin, in resistin-induced HUVECs by decreasing the production of intracellular reaction oxygen species (ROS) and attenuating the nuclear translocation of NFκB. Ursolic acid appeared to inhibit resistin-induced atherosclerosis, suggesting that ursolic acid may play a protective role in obesity-induced cardiovascular diseases.

Thymol reduces oxidative stress, aortic intimal thickening, and inflammation-related gene expression in hyperlipidemic rabbits.

Atherosclerosis plays a key role in the development of cardiovascular diseases, and is often associated with oxidative stress and local inflammation. Thymol, a major polyphenolic compound in thyme, exhibits antioxidant and anti-inflammatory properties. In this study, we measured the in vitro antioxidant activity of thymol, and investigated the effect of thymol on high-fat-diet-induced hyperlipidemia and atherosclerosis. New Zealand white rabbits were fed with regular chow, high-fat and high-cholesterol diet (HC), T3, or T6 (HC with thymol supplementation at 3 mg/kg/d or 6 mg/kg/d, respectively) for 8 weeks. Aortic intimal thickening, serum lipid parameters, multiple inflammatory markers, proinflammatory cytokines, and atherosclerosis-associated indicators were significantly increased in the HC group but decreased upon thymol supplementation. In summary, thymol exhibits antioxidant activity, and may suppress the progression of high-fat-diet-induced hyperlipidemia and atherosclerosis by reducing aortic intimal lipid lesion, lowering serum lipids and oxidative stress, and alleviating inflammation-related responses.

All Trans-Retinoic Acid Mediates MED28/HMG Box-Containing Protein 1 (HBP1)/ß-Catenin Signaling in Human Colorectal Cancer Cells.

Vitamin A is required for normal body function, including vision, epithelial integrity, growth, and differentiation. All trans-retinoic acid (ATRA), a family member of vitamin A, has been explored in treating acute promyelocytic leukemia and other types of cancer. Dysregulated Wnt/ß-catenin signaling and disrupted cadherin-catenin complex often contribute to colorectal malignancy. MED28, a mammalian Mediator subunit, is found highly expressed in breast and colorectal cancers. Our laboratory has also reported that MED28 regulates cell growth, migration, and invasion in human breast cancer cells. In the current study we investigated the effect of ATRA on MED28 and Wnt/ß-catenin signaling in colorectal cancer. HCT116, HT29, SW480, and SW620, four human colorectal cancer cell lines representing different stages of carcinogenesis and harboring critical genetic changes, were employed. Our data indicated that regardless of genetic variations among these cells, suppression of MED28 reduced the expression of cyclin D1, c-Myc, and nuclear ß-catenin, but increased the expression of E-cadherin and HMG box-containing protein 1 (HBP1) where HBP1 has been described as a negative regulator of the Wnt/ß-catenin signaling. The reporter activity of an HBP1 promoter increased upon MED28 knockdown, but decreased upon MED28 overexpression. ATRA reduced the expression of MED28 and mimicked the effect of MED28 suppression in down-regulating Wnt/ß-catenin signaling. Taken together, ATRA can reverse the suppressive effect of MED28 on HBP1 and E-cadherin and inactivate the Wnt/ß-catenin pathway in colorectal cancer, suggesting a protective effect of ATRA against colorectal cancer. J. Cell. Physiol. 231: 1796-1803, 2016. © 2015 Wiley Periodicals, Inc.

ESR1 gene and insulin resistance remission are associated with serum uric acid decline for severely obese patients undergoing bariatric surgery.

BACKGROUND: Hyperuricemia is associated with obesity. Few studies have reported the effects of different types of bariatric surgery on uric acid metabolism. The aim of our study was to determine the relationships between serum uric acid reduction and estrogen receptor-α (ESR1) gene polymorphism, as well as the type of bariatric surgery received. The potential physiological pathways involved in postsurgery serum uric acid reduction were also discussed. METHODS: A total of 508 severely obese Han Chinese patients, aged 20 to 50 years, with a body mass index (BMI)≥35 kg/m(2) were selected. Patients received either laparoscopic adjustable gastric banding (LAGB; n = 164) or laparoscopic mini-gastric bypass (LMGB; n = 344). A 12-month follow-up was performed to explore the effects of the type of bariatric surgery and ESR1 polymorphism on serum uric acid reduction. RESULTS: The rs712221 polymorphism of ESR1 affects serum uric acid reduction after bariatric surgery. The LMGB group exhibited a greater reduction in serum uric acid level compared with the LAGB counterpart after adjusting for sex, age, and metabolic confounders (-2.3 ± 2.1 mg/dL versus-1.2 ± 1.1 mg/dL; P = .002). Patients with the rs712221 genotype exhibited better glycemic control and a greater serum uric acid reduction at 12 months after surgery. The effects of the rs712221 polymorphism in LMGB patients resulted in the greatest serum uric acid reduction (-2.7 ± 1.4 mg/dL). CONCLUSIONS: For severely obese Han Chinese patients, bariatric surgery appears to reduce serum uric acid levels, potentially mediated by synergic effects of surgery type, BMI reduction, rs712221 locus, insulin sensitivity, and changed dietary factors via an unknown mechanism.