Bile acid profiles and classification model accuracy for inflammatory bowel disease diagnosis.

To investigate the utility of serum bile acid profiling for the diagnosis of inflammatory bowel disease (IBD). We analyzed 15 specific bile acids in the serum of 269 IBD patients, 200 healthy controls (HC), and 174 patients with other intestinal diseases (OID) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Serum bile acid levels were compared between IBD group, HC group, and OID group. Binary logistic regression-based models were developed to model the bile acids and diagnose IBD. Furthermore, receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic accuracy of each bile acid and the model. Compared to HC group, IBD group exhibited significantly lower levels of chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), glycodeoxycholic acid (GDCA), taurodeoxycholic acid (TDCA), lithocholic acid (LCA), glycolithocholic acid (GLCA), taurolithocholic acid (TLCA), and an elevated primary-to-secondary bile acid ratio. DCA had an area under the curve (AUC) of 0.860 for diagnosing IBD, with a sensitivity of 80.67% and a specificity of 82.50%. A model Y0 combining DCA and CDCA to distinguish between IBD group and HC group further improved accuracy (AUC = 0.866, sensitivity = 76.28%, specificity = 89.37%). Compared to non-IBD group (which combined healthy controls and those with other intestinal diseases), IBD group had significantly lower levels of DCA, GDCA, TDCA, LCA, GLCA, and TLCA, and elevated levels of glycocholic acid (GCA) and glycochenodeoxycholic acid (GCDCA). A model Y1 incorporating GCDCA, DCA and TLCA to distinguish between IBD group and non-IBD group yielded an AUC of 0.792, with a sensitivity of 77.67% and specificity of 71.91%. IBD patients exhibit decreased serum secondary bile acid levels and an elevated primary-to-secondary bile acid ratio. Serum bile acid alterations are associated with the onset of IBD. A model consisting of CDCA and DCA has potential for distinguishing between IBD group and HC group, while a model incorporating GCDCA, DCA and TLCA may be suitable for distinguishing between IBD group and non-IBD group.

Exploration of the application potential of serum multi-biomarker model in colorectal cancer screening.

Analyzing blood lipid and bile acid profile changes in colorectal cancer (CRC) patients. Evaluating the integrated model's diagnostic significance for CRC. Ninety-one individuals with colorectal cancer (CRC group) and 120 healthy volunteers (HC group) were selected for comparison. Serum levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and apolipoproteins (Apo) A1, ApoA2, ApoB, ApoC2, and ApoC3 were measured using immunoturbidimetric and colorimetric methods. Additionally, LC-MS/MS was employed to detect fifteen bile acids in the serum, along with six tumor markers: carcinoembryonic antigen (CEA), carbohydrate antigens (CA) 125, CA19-9, CA242, CA50, and CA72-4. Group comparisons utilized independent sample t-tests and Mann-Whitney U tests. A binary logistic regression algorithm was applied to fit the indicators and establish a screening model; the diagnostic accuracy of individual Indicators and the model was analyzed using receiver operating characteristic (ROC) curves. The CRC group showed significantly lower levels in eight serum lipid indicators and eleven bile acids compared to the HC group (P < 0.05). Conversely, serum levels of TG, CA19-9, and CEA were elevated (P < 0.05). Among the measured parameters, ApoA2 stands out for its strong correlation with the presence of CRC, showcasing exceptional screening efficacy with an area under the curve (AUC) of 0.957, a sensitivity of 85.71%, and a specificity of 93.33%. The screening model, integrating ApoA1, ApoA2, lithocholic acid (LCA), and CEA, attained an impressive AUC of 0.995, surpassing the diagnostic accuracy of individual lipids, bile acids, and tumor markers. CRC patients manifest noteworthy alterations in both blood lipids and bile acid profiles. A screening model incorporating ApoA1, ApoA2, LCA, and CEA provides valuable insights for detecting CRC.

[Retracted] FAM172A modulates apoptosis and proliferation of colon cancer cells via STAT1 binding to its promoter.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that lanes 1­3 of the EMSA results shown in Fig. 6 on p. 1278 were strikingly similar to data that had already appeared in a different form in the following publication by different authors at different research institutes: Qiu K, Li Z, Chen J, Wu S, Zhu X, Gao S, Gao J, Ren G and Zhou X: EIN3 and ORE1 accelerate degreening during ethylene­mediated leaf senescence by directly activating chlorophyll catabolic genes in Arabidopsis. PLoS Genet 11: e1005399, 2015. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 35: 1273­1280, 2016; DOI: 10.3892/or.2015.4485.

The Long Noncoding RNA RP11-728F11.4 Promotes Atherosclerosis.

OBJECTIVE: Noncoding RNAs are emerging as important players in gene regulation and cardiovascular diseases. Their roles in the pathogenesis of atherosclerosis are not fully understood. The purpose of this study was to determine the role played by a previously uncharacterized long noncoding RNA, RP11-728F11.4, in the development of atherosclerosis and the mechanisms by which it acts. Approach and Results: Expression microarray analysis revealed that atherosclerotic plaques had increased expression of RP11-728F11.4 as well as the cognate gene FXYD6 (FXYD domain containing ion transport regulator 6), which encodes a modulator of Na+/K+-ATPase. In vitro experiments showed that RP11-728F11.4 interacted with the RNA-binding protein EWSR1 (Ewings sarcoma RNA binding protein-1) and upregulated FXYD6 expression. Lentivirus-induced overexpression of RP11-728F11.4 in cultured monocytes-derived macrophages resulted in higher Na+/K+-ATPase activity, intracellular cholesterol accumulation, and increased proinflammatory cytokine production. The effects of RP11-728F11.4 were enhanced by siRNA-mediated knockdown of EWSR1 and reduced by downregulation of FXYD domain containing ion transport regulator 6. In vivo experiments in apoE knockout mice fed a Western diet demonstrated that RP11-728F11.4 increased proinflammatory cytokine production and augmented atherosclerotic lesions. CONCLUSIONS: RP11-728F11.4 promotes atherosclerosis, with an influence on cholesterol homeostasis and proinflammatory molecule production, thus representing a potential therapeutic target. Graphic Abstract: A graphic abstract is available for this article.

Emerging Roles of Circular RNAs in Vascular Smooth Muscle Cell Dysfunction.

Atherosclerosis is the major pathophysiological basis of cerebrovascular and cardiovascular diseases. Vascular smooth muscle cells (VSMCs) constitute the main structure of vasculature and play important roles in maintaining vascular tone and blood pressure. Many biological processes and cellular signaling events involved in atherosclerogenesis have been shown to converge on deregulating VSMC functions. However, the molecular mechanisms underlying dysfunctional VSMC in atherosclerosis are still poorly defined. Recent evidence revealed that circular RNAs (circRNAs) are closely related to diseases such as degenerative diseases, tumor, congenital diseases, endocrine diseases and cardiovascular diseases. Several studies demonstrated that circRNAs (e.g., circACTA2, Circ-SATB2, circDiaph3, circ_0020397, circTET3, circCCDC66) played critical roles in the regulation of VSMC proliferation, migration, invasion, and contractile-to-synthetic phenotype transformation by sponging microRNAs (e.g., miR-548f-5p, miR-939, miR-148a-5p, miR-138, miR-351-5p, miR-342-3p). This review describes recent progress in the profiling of circRNAs by transcriptome analysis in VSMCs and their molecular functions in regulating VSMC proliferation and migration.

Characteristic and Mechanism of Drug-Herb Interaction Between Acetylsalicylic Acid and Danhong Injection Mediated by Organic Anion Transporters.

The mixture of Salvia miltiorrhiza and Carthamus tinctorius (Danhong injection, DHI) is widely prescribed in China for the treatment of cardiovascular and cerebrovascular diseases. In most cases, DHI is used in combination with acetylsalicylic acid (aspirin, ASA). However, the interaction between DHI and ASA remains largely undefined. The purpose of this study is to explore the interaction profile and mechanism between DHI and ASA. The frequency of drug combination of DHI and ASA was analyzed based on 5,183 clinical cases. The interaction characteristics were evaluated by analyzing the pharmacokinetics and disposition profile of salicylic acid (SA, the primary metabolite of ASA) in rats. The interaction mechanisms were explored through evaluating the hydrolysis of ASA regulated by ASA esterase, the tubular secretion of SA mediated by influx and efflux transporters, and the tubular reabsorption of SA regulated by urinary acidity-alkalinity. The inhibitory potential of DHI on organic anion transporters (OATs) was further verified in aristolochic acid I (AAI) induced nephropathy. Clinical cases analysis showed that DHI and ASA were used in combination with high frequency of 70.73%. In drug combination of DHI and ASA, the maximum plasma concentration of SA was significantly increased by 1.37 times, while the renal excretion of SA was significantly decreased by 32.54%. The mechanism study showed that DHI significantly inhibited the transport function, gene transcription and protein expression of OATs. In OATs mediated AAI nephropathy, DHI significantly reduced the renal accumulation of AAI by 55.27%, and alleviated renal damage such as glomerulus swelling, tubular blockage and lymphocyte filtration. In drug combination of DHI and ASA, DHI increased the plasma concentration of SA not through enhancing the hydrolysis of ASA, and the tubular reabsorption of SA was not significantly affected. Inhibition of tubular secretion of SA mediated by OATs might be the reason that contributes to the decrease of SA renal excretion.

Targeting the gut microbial metabolic pathway with small molecules decreases uremic toxin production.

Uremic toxins are a class of toxins that accumulate in patients with chronic kidney disease (CKD). Indoxyl sulfate (IS), a typical uremic toxin, is not efficiently removed by hemodialysis. Modulation of IS production in the gut microbiota may be a promising strategy for decreasing IS concentration, thus, delaying CKD progression. In the present study, we identified isoquercitrin (ISO) as a natural product that can perturb microbiota-mediated indole production without directly inhibiting the growth of microbes or the indole-synthesizing enzyme TnaA. ISO inhibits the establishment of H proton potential by regulating the gut bacteria electron transport chain, thereby inhibiting the transport of tryptophan and further reducing indole biosynthesis. This non-microbiocidal mechanism may enable ISO to be used as a therapeutic tool, specifically against pathologies triggered by the accumulation of the microbial-produced toxin IS, as in CKD. Herein, we have shown that it is possible to inhibit gut microbial indole production using natural components. Therefore, targeting the uremic toxin metabolic pathway in gut bacteria may be a promising strategy to control host uremic toxin production.

TTDA inhibited apoptosis by regulating the p53-Bax/Bcl2 axis in glioma.

The trichothiodystrophy group A protein (TTDA) functions in nucleotide excision repair and basal transcription. TTDA plays a role in cancers and serves as a prognostic and predictive factor in high-grade serous ovarian cancer; however, its role in human glioma remains unknown. Here, we found that TTDA was overexpressed in glioma tissues. In vitro experiments revealed that TTDA overexpression inhibited apoptosis of glioma cells and promoted cell growth, whereas knockdown of TTDA had the opposite effect. Increased TTDA expression significantly decreased the Bax/Bcl2 ratio and the level of cleaved-caspase3. TTDA interacted with the p53 gene at the -1959 bp and -1530 bp region and regulated its transcription, leading to inhibition of the p53-Bax/Bcl2 mitochondrial apoptosis pathway in glioma cells. These results indicate that TTDA is an upstream regulator of p53-mediated apoptosis and acts as an oncogene, suggesting its value as a potential molecular target for the diagnosis and treatment of glioma.

The association of elevated serum ferritin concentration in early pregnancy with gestational diabetes mellitus: a prospective observational study.

BACKGROUND/OBJECTIVES: The results linking body iron stores to the risk of gestational diabetes mellitus (GDM) are conflicting. We aimed to measure the serum ferritin level of women in early pregnancy and evaluate the risk of GDM in a Chinese urban population. SUBJECTS/METHODS: In total, 851 pregnant women between 10 and 20 weeks of gestation took part in the prospective, observational study conducted. The women were divided into four groups by quartiles of serum ferritin levels (Q1-4). Their blood samples were collected and assayed for several biochemical variables at the beginning of the study, and the women were followed up with a 75-g oral glucose tolerance test at 24-28 weeks of gestation. RESULTS: The participants had an average serum ferritin concentration of 65.67 µg/L. GDM prevalence within each serum ferritin quartile was 9.4%, 14.6%, 18.8% and 19.3%, respectively, (P = 0.016). The odds ratio for GDM in the ferritin Q2-4 was 1.64 (CI: 0.90-2.99), 2.23 (CI: 1.26-3.96) and 2.31 (CI: 1.30-4.10), compared with Q1, respectively. This association persisted after adjusting for potential confounders factors. In addition, in Q4, pregnant women with a pre-pregnancy body mass index ≥24 kg/m2, maternal age ≤35 years old or haemoglobin≥ 110 g/L did have an increased risk of developing GDM. CONCLUSIONS: Elevated serum ferritin concentrations in early gestation are associated with an increased risk of GDM, especially in pregnant women who have a high baseline iron storage status with no anaemia or who are overweight/obese. Individual iron supplementation should be considered to minimize the risk of GDM.

Microarray profiling analysis and validation of novel long noncoding RNAs and mRNAs as potential biomarkers and their functions in atherosclerosis.

Long noncoding (lnc)RNAs have been implicated in the development and progression of atherosclerosis. However, the expression and mechanism of action of lncRNAs in atherosclerosis are still unclear. We implemented microarray analysis in human advanced atherosclerotic plaques and normal arterial intimae to detect the lncRNA and mRNA expression profile. Gene Ontology functional enrichment and pathway analyses were applied to explore the potential functions and pathways involved in the pathogenesis of atherosclerosis. A total of 236 lncRNAs and 488 mRNAs were selected for further Ingenuity Pathway Analysis. Moreover, quantitative RT-PCR tests of most selected lncRNAs and mRNAs with high fold changes were consistent with the microarray data. We also performed ELISA to investigate the corresponding proteins levels of selected genes and showed that serum levels of SPP1, CD36, ATP6V0D2, CHI3L1, MYH11, and BDNF were differentially expressed in patients with coronary heart disease compared with healthy subjects. These proteins correlated with some biochemical parameters used in the diagnosis of cardiovascular diseases. Furthermore, receiver operating characteristic analysis showed a favorable diagnostic performance. The microarray profiling analysis and validation of differentially-expressed lncRNAs and mRNAs in atherosclerosis not only provide new insights into the pathogenesis of this disease but may also reveal new biomarkers for its diagnosis and treatment.

Forkhead Box C2 Attenuates Lipopolysaccharide-Induced Cell Adhesion via Suppression of Intercellular Adhesion Molecule-1 Expression in Human Umbilical Vein Endothelial Cells.

Atherosclerosis is a chronic vascular inflammatory disease that involves diverse cell types and circulating regulatory factors, including intercellular adhesion molecule (ICAM)-1, a proinflammatory cytokine. Lipopolysaccharides (LPS) increase ICAM-1 expression and promote cell adhesion, but the mechanism is not clear. We found that LPS induced time- and dose-regulated upregulation of ICAM-1 expression and downregulation of forkhead box protein C2 (Foxc2) expression in human umbilical vein endothelial cells (HUVECs). Overexpression of Foxc2 significantly inhibited both LPS-induced ICAM-1 expression in HUVECs and LPS-induced adhesion of THP-1 cells to HUVECs. Foxc2 siRNA dramatically increased both LPS-induced ICAM-1 expression and LPS-induced adhesion of THP-1 human monocytes cells to HUVECs. We conclude that Foxc2 inhibited LPS-induced adhesion of THP-1 cells to HUVECs by suppressing ICAM-1 expression in HUVECs.

The role of the LncRNA-FA2H-2-MLKL pathway in atherosclerosis by regulation of autophagy flux and inflammation through mTOR-dependent signaling.

Atherosclerosis is a progressive, chronic inflammation in arterial walls. Long noncoding RNAs (lncRNAs) participate in inflammation, but the exact mechanism in atherosclerosis is unclear. Our microarray analyses revealed that the levels of lncRNA-FA2H-2 were significantly decreased by oxidized low-density lipoprotein (OX-LDL). Bioinformatics analyses indicated that mixed lineage kinase domain-like protein (MLKL) might be regulated by lncRNA-FA2H-2. In vitro experiments showed that lncRNA-FA2H-2 interacted with the promoter of the MLKL gene, downregulated MLKL expression, and the binding sites between -750 and 471 were necessary for lncRNA-FA2H-2 responsiveness to MLKL. Silencing lncRNA-FA2H-2 and overexpression of MLKL could activate inflammation and inhibited autophagy flux. Both lncRNA-FA2H-2 knockdown and overexpression of MLKL could significantly aggravate inflammatory responses induced by OX-LDL. We found that the 3-methyladenine (3-MA) and Atg7-shRNA enhanced inflammatory responses induced by knockdown of lncRNA-FA2H-2 and overexpression of MLKL. We demonstrated that the effects of MLKL on autophagy might be associated with a mechanistic target of rapamycin (mTOR)-dependent signaling pathways. In vivo experiments with apoE knockout mice fed a western diet demonstrated that LncRNA-FA2H-2 knockdown decreased microtubule-associated expression of microtubule-associated protein 1 light chain 3 II and lysosome-associated membrane protein 1, but increased expression of sequestosome 1 (p62), MLKL, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, and interleukin-6 in atherosclerotic lesions. Our findings indicated that the lncRNA-FA2H-2-MLKL pathway is essential for regulation of autophagy and inflammation, and suggested that lncRNA-FA2H-2 and MLKL could act as potential therapeutic targets to ameliorate atherosclerosis-related diseases.

LncRNA-RP11-714G18.1 suppresses vascular cell migration via directly targeting LRP2BP.

Atherosclerotic cardiovascular disease is considered as the leading cause of mortality and morbidity worldwide. Accumulating evidence supports an important role for long noncoding RNA (lncRNA) in the pathogenesis of atherosclerosis. Nevertheless, the role of lncRNA in atherosclerosis-associated vascular dysfunction and the underlying mechanism remain elusive. Here, using microarray analysis, we identified a novel lncRNA RP11-714G18.1 with significant reduced expression in human advanced atherosclerotic plaque tissues. We demonstrated in both human vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) that RP11-714G18.1 impaired cell migration, reduced the adhesion of ECs to monocytes, suppressed the neoangiogenesis, decreased apoptosis of VSMCs and promoted nitric oxide production. Mechanistically, RP11-714G18.1 could directly bind to its nearby gene LRP2BP and increased the expression of LRP2BP. Moreover, we showed that RP11-714G18.1 impaired cell migration through LRP2BP-mediated downregulation of matrix metalloproteinase (MMP)1 in both ECs and VSMCs. In atherosclerotic patients, the serum levels of LRP2BP were positively correlated with high-density lipoprotein cholesterol, but negatively correlated with cardiac troponin I. Our study suggests that RP11-714G18.1 may play an athero-protective role by inhibiting vascular cell migration via RP11-714G18.1/LRP2BP/MMP1 signaling pathway, and targeting the pathway may provide new therapeutic approaches for atherosclerosis.

Disorder of gut amino acids metabolism during CKD progression is related with gut microbiota dysbiosis and metagenome change.

Chronic kidney disease (CKD) is a worldwide public health problem. Uremic retention solutes such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are accumulated in CKD patients and are associated with the incidence of CKD progression. Amino acids are the major precursors of uremic retention solutes in gut. The dynamic change of amino acid metabolism in the gut during CKD progression has not been reported previously. In this paper, we studied the dynamic change of gut IS/PCS precursor and amino acid metabolism profile during CKD progression in 5/6 nephrectomized (5/6Nx) rats model. The related gut microbiota and metagenome profile was also studied. Rat plasma, urine and feces were collected at different time points after nephrectomization. Plasma IS and PCS, fecal indole (the precursor of IS), p-cresol (the precursor of PCS) and 19 kinds of amino acids were analyzed by LC-MS. During CKD progression, 5/6 Nx rats showed increased plasma IS, PCS concentration and increased fecal indole, p-cresol concentration. 5/6 Nx rats also showed disordered gut amino acids metabolism profile which became more significant along with the progession of CKD. The abundance of some specific gut bacteria also changed significantly in 5/6 Nx rats. The 16S rDNA sequencing data of gut microbiota was further analyzed by an online tool PICRUSt, a large-scale computational method for metagenomes prediction with 16S rDNA sequencing data. The content of each gene was compared between the two groups by Mann-Whitney U test, and then the significantly regulated genes in 5/6 Nx group were subjected to KEGG website. The amino acid metabolism related genes were picked out. Most of these genes are more abundant in 5/6 Nx groups. Our study showed that gut amino acids metabolism profile was disordered with CKD progression, which was highly related to the gut microbiota dysbiosis and metagenome change. And that regulation of gut amino acids metabolism pathway may be a possible way to intervene the progression of CKD.

[Carotid artery stenosis treated with modified carotid endarterectomy: report of two cases].

OBJECTIVE: Based on standard carotid endarterectomy, we performed modified carotid endarterectomy in two cases of carotid artery stenosis by changing the direction of the carotid artery incision to avoid restenosis of the internal carotid artery without using a patch. The two patients recovered smoothly without any complications. Compared with eversion or patch endarterectomy, this modified carotid endarterectomy avoids restenosis of the carotid artery and shortens operation time.

Automated antinuclear immunofluorescence antibody analysis is a reliable approach in routine clinical laboratories.

BACKGROUND: Indirect immunofluorescence (IIF) assays are recommended as the gold standard method for the detection of antinuclear antibodies (ANAs). This study aimed to investigate the reliability of an automated system. METHODS: We compared 3745 serum samples using NOVA View archived images with manual analysis via microscopy. A custom cutoff value was established to distinguish ANA titers and was validated in two clinical laboratories. The automatic ANA pattern recognition system was evaluated, and all ANA-positive sera were subjected to two commercial ANA IIF kits to compare the consistency of the pattern interpretation results. For inconsistent patterns, a third ANA IIF testing kit was utilized. RESULTS: Agreement of the interpretation of the ANA IIF test using the platform of NOVA View and manual microscopy was 96.9%. The local cutoff value to discriminate ANA titers in four main ANA patterns was calculated based on 1390 serum samples. In our laboratory, the titer prediction accuracy was superior to the preset cutoff in NOVA View (p<0.01); the performance was similar in another laboratory (p=0.11). The automatic pattern recognition accuracies of speckled, homogeneous, centromere, nucleolar and nuclear dot patterns were 62.7%, 57.4%, 92.6%, 30.5% and 27.3%, respectively. The consistency of the pattern interpretation results between INOVA and MBL kits was 95.3%. CONCLUSIONS: It is necessary to establish a custom value-added ANA report. However, confirmation of the digital immunofluorescence images by expert technicians was essential, and suspect results of an ANA pattern should be reconfirmed by another commercial ANA IIF kit to achieve more reliable results.

Hairy/enhancer of Split Homologue-1 Suppresses Vascular Endothelial Growth Factor-induced Angiogenesis via Downregulation of Osteopontin Expression.

Angiogenesis plays a critical role in the progression and vulnerability of atherosclerotic plaques; however, the orchestration of angiogenesis in atherosclerotic plaque formation remains unclear. The results of microarray analysis, real-time PCR and immunohistochemical analyses showed that Hairy/enhancer of split homologue-1 (Hes-1) expression was significantly decreased, while that of osteopontin (OPN) was increased, in atherosclerotic plaques. Meanwhile, immunofluorescence results demonstrated that both Hes-1 and OPN were expressed in endothelial cells (ECs) of neovessels in atherosclerotic plaques. The results of an in vitro study showed that Hes-1 was downregulated, while OPN was upregulated, in a time- and dose-dependent manner in human umbilical vein endothelial cells (HUVECs) by VEGF treatment. In addition, Hes-1 knockdown was found to have transcriptional promotion effect on OPN expression in HUVECs and enhance OPN-induced angiogenesis in response to VEGF. On the contrary, Hes-1 overexpression inhibited OPN expression in HUVECs and reduced angiogenesis in vitro and in vivo. The results of this study suggest that decreased Hes-1 expression in atherosclerotic plaques exaggerate VEGF-induced angiogenesis by upregulating OPN. Therefore, restoring Hes-1 expression and inhibiting OPN expression may be a promising strategy to prevent vulnerable plaque formation in patients with atherosclerosis.

Long Noncoding RNA HOXC-AS1 Suppresses Ox-LDL-Induced Cholesterol Accumulation Through Promoting HOXC6 Expression in THP-1 Macrophages.

Atherosclerosis is a common pathological basis of cardiovascular disease, which remains the leading cause of mortality. Long noncoding RNAs (lncRNAs) are newly studied non-protein-coding RNAs involved in gene regulation, but how lncRNAs exert regulatory effect on atherosclerosis remains unclear. In this study, we found that lncRNA HOXC cluster antisense RNA 1 (HOXC-AS1) and homeobox C6 (HOXC6) were downregulated in carotid atherosclerosis by performing microarray analysis. The results were verified in atherosclerotic plaques and normal arterial intima tissues by quantitative reverse transcription PCR and western blot analysis. Lentivirus-mediated overexpression of HOXC-AS1 induced HOXC6 expression at mRNA and protein levels in THP-1 macrophages. Besides, oxidized low-density lipoprotein (Ox-LDL) decreased expression of HOXC-AS1 and HOXC6 in a time-dependent manner. Induction of cholesterol accumulation by Ox-LDL could be partly suppressed by overexpression of HOXC-AS1.

mTORC1 promotes aging-related venous thrombosis in mice via elevation of platelet volume and activation.

Aging is associated with an increased incidence of venous thromboembolism (VTE), resulting in significant morbidity and mortality in the elderly. Platelet hyperactivation is linked to aging-related VTE. However, the mechanisms through which aging enhances platelet activation and susceptibility to VTE are poorly understood. In this study, we demonstrated that mechanistic target of rapamycin complex 1 (mTORC1) signaling is essential for aging-related platelet hyperactivation and VTE. mTORC1 was hyperactivated in platelets and megakaryocytes (MKs) from aged mice, accompanied by elevated mean platelet volume (MPV) and platelet activation. Inhibition of mTORC1 with rapamycin led to a significant reduction in susceptibility to experimental deep vein thrombosis (DVT) in aged mice (P < .01). To ascertain the specific role of platelet mTORC1 activation in DVT, we generated mice with conditional ablation of the mTORC1-specific component gene Raptor in MKs and platelets (Raptor knockout). These mice developed markedly smaller and lighter thrombi, compared with wild-type littermates (P < .01) in experimental DVT. Mechanistically, increased reactive oxygen species (ROS) production with aging induced activation of mTORC1 in MKs and platelets, which, in turn, enhanced bone marrow MK size, MPV, and platelet activation to promote aging-related VTE. ROS scavenger administration induced a significant decrease (P < .05) in MK size, MPV, and platelet activation in aged mice. Our findings collectively demonstrate that mTORC1 contributes to enhanced venous thrombotic susceptibility in aged mice via elevation of platelet size and activation.