Abstract Background Emerging evidence indicates carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is involved in the development of atherosclerosis (AS). However, the roles and functions of CEACAM1 in AS remain unknown. Therefore, this study aims to investigate the roles and molecular functions of CEACAM1 in AS. Methods We constructed a diabetes mellitus (DM) + high-fat diet (HFD) mouse model based on the streptozotocin (STZ)-induced apolipoprotein E-knockdown (ApopE−/−) mouse to investigate the roles and regulatory mechanism of miR-449a/CEACAM1 axis. The mRNA expression and protein levels in this study were examined using quantity PCR, western blot, immunofluorescence (IF), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry (IHC), respectively. And the lipid deposition and collagen content were detected using Oil Red O and Sirius Red staining. Cell apoptosis, migration, invasion, and tuber formation were detected by Annexin-V FITC/PI, wound healing, transwell, and tuber formation assays, respectively. The relationship between miR-449a and CEACAM1 was determined by a dual-luciferase reporter gene assay. Results miR-449a and MMP-9 were upregulated, and CEACAM1 was downregulated in the DM + HFD MOUSE model. Upregulation of CEACAM1 promoted atherosclerotic plaque stability and inhibited inflammation in the DM + HFD mouse model. And miR-449a directly targeted CEACAM1. Besides, miR-449a interacted with CEACAM1 to regulate atherosclerotic plaque stability and inflammation in DM-associated AS mice. In vitro, the rescue experiments showed miR-449a interacted with CEACAM1 to affect apoptosis, migration, invasion, and tuber formation ability in high glucose (HG)-induced HUVECs. Conclusion These results demonstrated that miR-449a promoted plaque instability and inflammation in DM and HFD-induced mice by targeting CEACAM1.

The study aimed at exploring the miR-143-3p expression and the mechanism involved in ovarian cancer development. RT-qPCR (Quantitative Real-time PCR) served for the detection of the miR-143-3p level in different ovarian carcinoma cells. Then miR-143-3p underwent transfection and presented overexpression in ovarian carcinoma cells. 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, flat cloning experiment, Transwell invasion assay and scratch test served for the evaluation of the influences of miR-143-3p on ovarian cancer cell biological behavior. The candidate target genes were screened by using bioinformatics method. The double luciferase assay and Western blot together assessed the regulatory effect of miR-1433p. Relative to the control group (NC), the overexpressed group presented significantly reduced ovarian cancer cell growth (p < 0.01). The results indicated the inhibitory impact of miR-143-3p overexpression on the invasion and migration of ovarian cancer 3AO and SKOV3 cells. Bioinformatics analysis confirmed FGF-9 (Fibroblast Growth Factor 9) as one of target gene of miR-143-3p. Double luciferase assay also attested the direct negative regulatory impact of miR-143-3p on FGF-9 (p < 0.05). The miR-1433p overexpression significantly lowered the protein level of FGF-9 in 3AO and SKOV3 cells (p < 0.001). miR-143-3p overexpression negatively regulated the proliferation, invasion and migration abilities of ovarian carcinoma cells, as well as the FGF-9 protein expression.

Background: The dominant artery blood supply is a characteristic of hepatocellular carcinoma (HCC). However, it is not known whether the blood supply can predict the post-hepatectomy prognosis of patients with HCC. This retrospective study investigated the prognostic value of the portal venous and arterial blood supply estimated on triphasic liver CT (as a portal venous coefficient, PVC, and hepatic arterial coefficient, HAC, respectively) in patients with HCC following hepatectomy. Methods: HCC patients who were tested by triphasic liver CT 2 weeks before hepatectomy and received R0 hepatectomy at the Second Affiliated Hospital, Kunming Medical University between January 1, 2016 and December 31, 2020, were retrospectively screened. Their PVC and HAC, and other variables were analyzed for the prediction of overall survival (OS) and recurrence-free survival (RFS) using the least absolute shrinkage and selection operator and Cox proportional hazard regression models. Results: Four hundred and nineteen patients (53.2 +/- 10.6 years of age and 370 men) were evaluated. A shorter OS was independently associated with higher blood albumin and total bilirubin grade [hazard ratio (HR) 2.020, 95% confidence interval (CI) 1.534- 2.660], higher Barcelona Clinic Liver Cancer (BCLC) stage (HR 1.514, 95% CI 1.290- 1.777), PVC <= 0.386 (HR 1.628, 95% CI 1.149- 2.305), and HAC > 0.029 (HR 1.969, 95% CI 1.380- 2.809). A shorter RFS was independently associated with male (HR 1.652, 95% CI 1.005- 2.716), higher serum alpha-fetoprotein >= 400 ng/mL (HR 1.672, 95% CI 1.236- 2.263), higher BCLC stage (HR 1.516, 95% CI 1.300- 1.768), tumor PVC <= 0.386 (HR 1.641, 95% CI 1.198- 2.249), and tumor HAC > 0.029 (HR 1.455, 95% CI 1.060- 1.997). Conclusion: Tumor PVC or HAC before hepatectomy is valuable for independently predicting postoperative survival of HCC patients.

The mutual regulation between hydrogen sulfide (H2S) and microRNA (miRNA) is involved in the development of many diseases, including cancer, cardiovascular disease, inflammatory disease, and high-risk pregnancy. Abnormal expressions of endogenous H2S-producing enzyme and miRNA in tissues and cells often indicate the occurrence of diseases, so the maintenance of their normal levels in the body can mitigate damages caused by various factors. Many studies have found that H2S can promote the migration, invasion, and proliferation of cancer cells by regulating the expression of miRNA, while many H2S donors can inhibit cancer progression by interfering with the proliferation, apoptosis, cell cycle, metastasis, and angiogenesis of cancer cells. Furthermore, the mutual regulation between H2S and miRNA can also prevent cell injury in cardiovascular disease and inflammatory disease through anti-inflammation, anti-oxidation, anti-apoptosis, and pro-autophagy. In addition, H2S can promote angiogenesis and relieve vasoconstriction by regulating the expression of miRNA, thereby improving fetal growth in high-risk pregnancy. In this review, we discuss the mechanism of mutual regulation between H2S and miRNA in various diseases, which may provide reliable therapeutic targets for these diseases.

BackgroundAcute Coronary Syndrome (ACS) continues to be a leading cause of death and illness worldwide. Differentiating stable from unstable coronary plaques is essential for enhancing patient outcomes. This research investigates the role of CD147 as a biomarker for plaque stability among coronary artery disease patients.MethodsThe study began with high-throughput sequencing of blood samples from six patients, divided equally between those with Stable Angina (SA) and Unstable Angina (UA), followed by bioinformatics analysis. Expanding upon these findings, the study included 31 SA patients and 30 patients with ACS, using flow cytometry to examine CD147 expression on platelets and monocytes. Additionally, logistic regression was utilized to integrate traditional risk factors and evaluate the predictive value of CD147 expression for plaque stability.ResultsInitial sequencing displayed a notable difference in CD147 expression between SA and UA groups, with a significant increase in UA patients. Further analysis confirmed that elevated platelet CD147 expression was strongly associated with unstable plaques (OR = 277.81, P < .001), after adjusting for conventional risk factors, whereas monocyte CD147 levels did not show a significant difference.ConclusionElevated CD147 expression on platelets is a crucial biomarker for identifying unstable coronary artery plaques, offering insights into patient risk stratification and the development of targeted treatment strategies. This underscores the pivotal role of molecular research in understanding and managing coronary artery disease, paving the way for improved clinical outcomes.

Background: B-cell receptor-associated protein 31 (BCAP31) has protective effects against alveolar epithelial type II cells (AECII) damage by inhibiting mitochondrial injury in acute lung injury (ALI) induced by lipopolysaccharide (LPS), whereas the precise mechanism is still unclear. It is known that PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy can remove damaged mitochondria selectively, which may be involved in BCAP31 protection against mitochondrial injury. Methods: In the current study, ALI mice models were established by using surfactant protein C (Sftpc)-BCAP31 transgenic mice (BCAP31TG mice) and AECII-specific BCAP31 knockout mice (BCAP31CKO mice) treated with LPS. Results: BCAP31 expression in lung tissue and AECII were inhibited in ALI mice. Under LPS challenge, lower level of BCAP31 was found to correlate positively with pathological injury of the lung, respiratory dysfunction, mortality rates, inflammation response, and AECII damage. Further study showed that down-regulation of BCAP31 induced decreased phosphorylation of PINK1 via reduced binding to PINK1, thereby restraining PINK1/Parkin-mediated mitophagy. Down-regulation of mitophagy promoted mitochondrial injury, as shown by the increase in mitochondrial permeability transition pore opening rate, together with enhanced mitochondrial reactive oxygen species (mROS), which were accompanied by increased cellular apoptosis and reactive oxygen species (ROS). The increased cellular ROS contributed to the inflammatory response via activation of nuclear factor κB (NF-κB). In contrast, BCAP31 overexpression promoted phosphorylation of PINK1 and PINK1/Parkin-mediated mitophagy, thus blocking the mROS/ROS/NF-κB pathway, favoring a protective condition that ultimately led to the inhibition of AECII apoptosis and inflammatory response in LPS-induced ALI. Conclusion: Ultimately, BCAP31 alleviated ALI by activating PINK1/Parkin-mediated mitophagy and blocking the mROS/ROS/NF-κB pathway in AECII.

Cardiac Vascular disease particularly myocardial infarction (MI) is a threat to health worldwide. microRNAs (miRNAs) have been shown to regulate myocardial fibrosis. Therefore, it is potential to investigate the mechanism of miRNA and fibrosis following myocardial infarction. Hypoxia human cardiac microvascular endothelial cells (HCMECs) were selected for the vitro experimental model. The miR-146a-5p expression was tested via RT-qPCR. The level of endothelial-to-mesenchymal transition (EndMT) and fibrosis markers were detected by Western blotting and immunofluorescence. Then, the inflammation, cell viability and apoptosis were investigated. The target was predicted by an online database and verified by a dual-luciferase activity assay. An MI mouse model was created to validate that miR-146a-5p regulates cardiac fibrosis in vivo. MI mouse was transfected with miR-146a-5p lentivirus. Subsequently, its effect on cardiac fibrosis of infarcted hearts was assessed by In situ hybridization (ISH), Immunohistochemistry (IHC), Triphenylterazolium chloride (TTC) staining and Masson staining. Herein, we confirmed that miR-146a-5p was down-regulated in hypoxia HCMECs. Overexpression of miR-146a-5p inhibited hypoxia-induced cardiac fibrosis following myocardial infarction by inhibiting EndMT in HCMECs. Thioredoxin-interacting protein (TXNIP) was a target that was negatively regulated by miR-146a-5p. Up-regulation of miR-146a-5p inhibited cardiac fibrosis via regulating EndMT by targeting TXNIP, and it also regulated EndMT to inhibit cardiac fibrosis in vivo.

Background Lung cancer causes significant mortality, with invasion and metastasis being the main features that cause most cancer deaths. Lymph node metastasis is the primary metastatic route in non-small cell carcinoma (NSCLC) and influences the staging and prognosis of NSCLC. Cumulative studies have reported that Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is involved in the progression of various cancers. However, few studies have discussed the function of CEACAM1 in lymphangiogenesis in NSCLC. Here, we examined how CEACAM1 influences lymphangiogenesis in NSCLC. Methods A total of 30 primary squamous cell carcinoma (LUSC) patients diagnosed with LN metastasis were prospectively selected. LUSC tumor tissues, para-cancerous tissues, and positive lymph node tissues were harvested. The expression and subcellular location of CEACAM1, CD31, and LVYE1 in clinical samples were detected by immunohistochemistry. Next, the CEACAM1 and hsa-miR-423-5p expressions were detected by qPCR. The protein expression of lymphangiogenesis-associated proteins and critical cytokines of the NF–κB pathway in HDLECs was detected by Western blot. A tube formation assay was performed to detect the lymphangiogenesis in different groups. The interaction between CEACAM1 and hsa-miR-423-5p was verified using a dual luciferase assay. Results CEACAM1 was found to be a potential gene associated with lung cancer prognosis. It was positively correlated with angiogenesis and lymphangiogenesis. Then, we detected the function of CEACAM1 in lymphangiogenesis and found that CEACAM1 promoted lymphangiogenesis. hsa-miR-423-5p overexpression inhibited lymphangiogenesis via targeting CEACAM1. Finally, we observed that CEACAM1 can activate the NF–κB pathway and, therefore, promote lymphangiogenesis. Conclusion We found that CEACAM1 enhanced lymphangiogenesis in NSCLC via NF-kB activation and was repressed by miR-423-5p. This suggests the value of CEACAM1 as a new therapeutic marker in NSCLC.

Myocardial ischemia/reperfusion (I/R) injury is a common condition. This study aimed to investigate the potential mechanisms of circ_Ddx60 in the mouse model of I/R injury. Cardiac tissues were used to extract RNA for subsequent RNA sequencing analysis. Bioinformatic analysis was performed and circ_Ddx60 and Bcl2a1a (B cell leukemia/lymphoma 2 related protein A1a) were selected for further validation. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was used to detect the gene expression level. The effect of circ_Ddx60 on cardiac cell apoptosis was examined. The function of miR-302a-3p in cell apoptosis was further explored in circ_Ddx60-overexpressed HL-1 cells under hypoxia/reoxygenation (H/R) treatment. We have revealed a number of differentially expressed circRNAs and mRNAs between the I/R group and sham groups, with circ_Ddx60 being among them. Treatment of HL-1 cells with hypoxia/reoxygenation (H/R) led to an overexpression of circ_Ddx60, which then inhibited apoptosis and promoted the Bcl2a1a expression. Furthermore, circ_Ddx60 directly binds with miR-302a-3p, which could reverse the effect of circ_Ddx60 overexpression on cellular apoptosis and Bcl2a1a expression. Our study revealed that circ_Ddx60 inhibits apoptosis in myocardial cells by regulating the miR-302a-3p/Bcl2a1a axis, which provides novel insights into the prevention of myocardial I/R injury.

Introduction: Atherosclerosis (AS) is a common cardiovascular disease with high morbidity and mortality globally. Circular RNAs (circRNAs) have been shown to regulate AS progression. However, the biological role of circ_0,003,423 in AS pathology and its associated mechanism is still unclear. Methods: Oxidized low-density lipoprotein (ox-LDL) induced human umbilical vein endothelial cells (HUVECs) were used as an AS cell model in vitro. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot assays were conducted to measure ribonucleic acid (RNA) and protein expression. Cell proliferation was analyzed by Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assays. Cell apoptosis, migration, and angiogenesis were analyzed by flow cytometry, wound healing, and Matrigel tube formation assays. The oxidative stress factors were detected using reactive oxygen species activity (ROS) assay kit, malondialdehyde (MDA) assay kit, and superoxide dismutase (SOD) assay kit. The interaction between microRNA-142-3p (miR-142-3p) and circ_0,003,423 or sirtuin 3 (SIRT3) was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Results: Ox-LDL exposure dose-dependently reduced circ_0,003,423 expression in HUVECs. Ox-LDL suppressed the proliferation, migration, and angiogenesis and induced the apoptosis and oxidative stress of HUVECs, which were offset by circ_0,003,423 overexpression. miR-142-3p is a direct target of circ_0,003,423, and circ_0,003,423 overexpression-mediated protective effects in ox-LDL-induced HUVECs were largely reversed by the addition of miR-142-3p mimic. miR-142-3p directly interacted with the 3'UTR of SIRT3 and SIRT3 knockdown reversed anti-miR-142-3p-mediated protective effects in HUVECs upon ox-LDL exposure. Circ_0,003,423 positively regulated SIRT3 expression by sponging miR-142-3p in HUVECs. In addition, circ_0,003,423 could regulate the SIRT3/SOD2 signaling pathway in HUVECs. Conclusions: Circ_0,003,423 protected HUVECs from ox-LDL-induced dysfunction by sponging miR-142-3p and activating SIRT3/SOD2 signaling, which provided new potential targets for AS intervention and treatment. (C) 2022 Elsevier Inc. All rights reserved.

BackgroundThe aim of the present study was to investigate the correlation between the elevated uric acid (UA) levels and activation of the circulating renin-angiotensin-aldosterone system (RAAS) in patients with atrial fibrillation (AF).MethodsA total of 233 outpatients and inpatients of the Cardiology Department from January 1, 2019, to December 31, 2019, were selected and divided into the sinus rhythm group (SR) with 84 cases, the paroxysmal AF group (pAF) with 76 cases, and the persistent AF group (PAF) with 73 patients. The general clinical data and the serum levels of UA of the enrolled patients were collected, and the radioimmunoassay was adopted to detect the levels of renin (Renin), angiotensin II (Ang II), and aldosterone (Ald).ResultsRenin, AngII, Ald, and UA in the PAF group were significantly higher than those in the pAF group, and the levels of the above indicators in the pAF group were significantly higher than those in the SR group (P<0.001). The left atrium anteroposterior diameter (LAD) and the left ventricular end-diastolic diameter (LVEDD) were significantly increased in the PAF group (P<0.001). The Pearson correlation analysis showed that the levels of the high sensitivity C-reactive protein (hsCRP), AngII Renin, Ald, LVEDD, and LAD were positively correlated with the serum levels of UA (r=0.174, 0.273, 0.34, 0.385, 0.138, respectively, P<0.05 in all). The left ventricular ejection fraction (LVEF) was negatively correlated with the UA level (r=-0.177, P<0.05). Multiple linear regression analysis showed that UA (β=0.103) and LAD (β=2.162) were independent risk factors for Renin. The independent risk factor for Ang II was UA (β=0.167). The independent risk factor for Ald was UA (β=0.283) and LAD (β=8.721) (P<0.05).ConclusionsElevated UA might cause excessive activation of the RAAS, aggravate the oxidative stress, and participate in the atrial remodeling, thereby promoting the occurrence and persistence of AF.

Abstract Background Epigenetic reprogramming plays an important role in the occurrence, development, and prognosis of hepatocellular carcinoma (HCC). DNA methylation is a key epigenetic regulatory mechanism, and DNA methyltransferase 1 (DNMT1) is the major enzyme responsible for maintenance methylation. Nevertheless, the role and mechanism of DNMT1 in HCC remains poorly defined. Methods In the current study, we conducted pan-cancer analysis for DNMT1’s expression and prognosis using The Cancer Genome Atlas (TCGA) data set. We conducted gene Set Enrichment Analysis (GSEA) between high-and-low DNMT1 expression groups to identify DNMT1-related functional significance. We also investigated the relationship between DNMT1 expression and tumor immune microenvironment, including immune cell infiltration and the expression of immune checkpoints. Through a combination series of computer analyses (including expression analyses, correlation analyses, and survival analyses), the noncoding RNAs (ncRNAs) that contribute to the overexpression of DNMT1 were ultimately identified. Results We found that DNMT1 was upregulated in 16 types of human carcinoma including HCC, and DNMT1 might be a biomarker predicting unfavorable prognosis in HCC patients. DNMT1 mRNA expression was statistically associated with age, histological grade, and the level of serum AFP. Moreover, DNMT1 level was significantly and positively linked to tumor immune cell infiltration, immune cell biomarkers, and immune checkpoint expression. Meanwhile, Gene Set Enrichment Analysis (GSEA) revealed that high-DNMT1 expression was associated with epithelial mesenchymal transition (EMT), E2F target, G2M checkpoint, and inflammatory response. Finally, through a combination series of computer analyses the SNHG3/hsa-miR-148a-3p/DNMT1 axis was confirmed as the potential regulatory pathway in HCC. Conclusion SNHG3/miR-148a-3p axis upregulation of DNMT1 may be related to poor outcome, tumor immune infiltration, and regulated malignant properties in HCC.

BACKGROUND:Type 2 diabetes mellitus (T2DM) is a major cause of death with an increasing incidence at an epidemic rate. The existing treatments for T2DM lack long-term effective blood glucose control. In this study, the effects of miR-21 antagomir on T2DM and the related mechanism were investigated using streptozotocin (STZ)-induced T2DM rats.METHODS:30 T2DM rats were randomly divided into 3 groups (n=10): T2DM group, T2DM rats with miR-21 antagomir group, T2DM rats with NC antagomir group. The expression of miR-21 in rats was detected by qRT-PCR. blood glucose, triacylglycerol (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-Cho), insulin, adiponectin, ITT and GTT were detected. The expression of TIMP3 in si-TIMP3 rats and the expression of TIMP3 in T2DM rats with miR-21 antagomir and si-TIMP3 was detected by Western blotting.RESULTS:We found that miR-21 antagomir reduced blood glucose concentration in T2DM rats. MiR21 antagomir improved lipid metabolic disorder by decreasing the levels of triacylglycerol (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-Cho) and increasing the level of high-density lipoprotein cholesterol (HDL-Cho). Also, miR-21 antagomir reduced the value of homeostasis model assessment of insulin resistance (HOMA-IR), hemoglobin A1c (HbAc1), plasma insulin, and up-regulated the plasma adiponectin. These results, combined with insulin tolerance tests (ITT) and glucose tolerance tests (GTT) results, showed that miR-21 improved insulin resistance in STZ-induced T2DM rats. Then the target relationship between miR-21 and tissue inhibitor of metalloproteinases 3 (TIMP3) was proved by luciferase reporter assay. More impressively, miR-21 significantly increased the expression level of TIMP3 in STZ-induced T2DM rats.CONCLUSIONS:Our study taken together has shown that miR-21 antagomir improved insulin resistance and lipid metabolism disorder in STZ-induced T2DM rats by up-regulating the expression level of TIMP3. This study suggested that miR-21 antagomir could be used as an effective therapeutic strategy and the underlying mechanism was revealed.

BACKGROUND AND PURPOSE:Sunitinib is a small-molecule TK inhibitor associated with hepatotoxicity. The mechanisms of its toxicity are still unclear. EXPERIMENTAL APPROACH:In the present study, mice were treated with 60, 150, and 450 mg·kg-1 sunitinib to evaluate sunitinib hepatotoxicity. Sunitinib metabolites and endogenous metabolites in liver, serum, faeces, and urine were analysed using ultra-performance LC electrospray ionization quadrupole time-of-flight MS-based metabolomics. KEY RESULTS:Four reactive metabolites and impaired clearance of sunitinib in liver played a dominant role in sunitinib-induced hepatotoxicity. Using a non-targeted metabolomics approach, various metabolic pathways, including mitochondrial fatty acid β-oxidation (β-FAO), bile acids, lipids, amino acids, nucleotides, and tricarboxylic acid cycle intermediates, were disrupted after sunitinib treatment. CONCLUSIONS AND IMPLICATIONS:These studies identified significant alterations in mitochondrial β-FAO and bile acid homeostasis. Activation of PPARα and inhibition of xenobiotic metabolism may be of value in attenuating sunitinib hepatotoxicity.

MicroRNAs participate in the regulation of abnormal cardiomyocyte apoptosis and autophagy, which leads to heart failure (HF). Lower miR-29b-3p levels were found in HF patients in this study. However, the role of miR-29b-3p in the molecular pathogenesis of HF remains unclear. Hypoxia-stimulated H9c2 cells were used an in vitro model of HF. It was found that hypoxia stimulation decreased the miR-29b-3p expression and enhanced cell apoptosis and autophagy response in H9c2 cells. While the effects of hypoxia on cell apoptosis and autophagy were reversed by miR-29b-3p transfection, especially 100 nM. The secreted protein acidic and rich in cysteine (SPARC), predicted as a direct target of miR-29b-3p, aggravated the hypoxia-induced cells apoptosis, autophagy, and TGFβ1/Smad3 activation. While the changes were dramatically reversed by miR-29b-3p. Taken together, our data suggest that miR-29b-3p plays an important role in the progression of HF through targeting SPARC and regulating TGFβ1/Smad3 pathway.