Glucose-6-phosphate dehydrogenase deficiency is a genetic disorder that occurs almost exclusively in males. This condition mainly affects red blood cells, which carry oxygen from the lungs to tissues throughout the body. In affected individuals, a defect in an enzyme called glucose-6-phosphate dehydrogenase causes red blood cells to break down prematurely. This destruction of red blood cells is called hemolysis.

Glucose-6-phosphate dehydrogenase deficiency.

MicroRNAs (miRNAs) are endogenous non-coding small RNA molecules that can be secreted into the circulation and exist in remarkably stable forms. Like intercellular miRNAs, circulating miRNAs participate in numerous regulations of biological process and expressed aberrantly under abnormal or pathological status. The quality and quantity changes of circulating miRNAs are associated with the initiation and progression of cancer and can be easily detected by basic molecular biology techniques. Consequently, considerable effort has been devoted to identify suitable extracellular miRNAs for noninvasive biomarkers in cancer. However, several challenges need to be overcome before the practical application. In this review, we discuss several issues of circulating miRNAs: biological function and basic transport carriers; extracellular cell communication process; roles as reliable cancer biomarkers and usage in targeted cancer therapy; and challenges for clinical application.

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Circulating MicroRNAs in Cancer: Potential and Challenge

Cardiovascular disease (CVD) is the leading cause of death worldwide, especially in developed countries, and atherosclerosis (AS) is the common pathological basis of many cardiovascular diseases (CVDs) such as coronary heart disease (CHD). The role of the gut microbiota in AS has begun to be appreciated in recent years. Trimethylamine N-oxide (TMAO), an important gut microbe-dependent metabolite, is generated from dietary choline, betaine, and L-carnitine. Multiple studies have suggested a correlation between plasma TMAO levels and the risk of AS. However, the mechanism underlying this relationship is still unclear. In this review, we discuss the TMAO-involved mechanisms of atherosclerotic CVD from the perspective of inflammation, inflammation-related immunity, cholesterol metabolism, and atherothrombosis. We also summarize available clinical studies on the role of TMAO in predicting prognostic outcomes, including major adverse cardiovascular events (MACE), in patients presenting with AS. Finally, since TMAO may be a novel therapeutic target for AS, several therapeutic strategies including drugs, dietary, etc. to lower TMAO levels that are currently being explored are also discussed.

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Gut Microbiota-Dependent Marker TMAO in Promoting Cardiovascular Disease: Inflammation Mechanism, Clinical Prognostic, and Potential as a Therapeutic Target.

Ischemic heart disease including myocardial infarction (MI) is a major cause of mortality and morbidity worldwide. In order to manage the acute myocardial infarction (AMI) outbreaks, novel biomarkers for risk prediction are needed. Recent studies have shown that circulating microRNAs (miRNAs) are promising biomarkers for cardiovascular diseases prediction. This study aimed to determine the possibility of circulating miRNAs used as biomarkers for AMI. The dynamic expression levels of miRNAs were examined before and after percutaneous coronary intervention (PCI) in patients. Circulating miR-17-5p, miR-126-5p, and miR-145-3p were selected and validated in 29 patients with AMI and 21 matched controls by quantitative real-time PCR. The expression levels of plasma miR-17-5p, miR-126-5p, and miR-145-3p were significantly increased in AMI patients. Receiver Operating Characteristic (ROC) analysis indicated that miR-17-5p, miR-126-5p, and miR-145-3p showed considerable diagnostic efficiency for AMI. Furthermore, we demonstrated that the combination of these three miRNAs managed to provide more accurate diagnosing of AMI.

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Circulating MiR-17-5p, MiR-126-5p and MiR-145-3p Are Novel Biomarkers for Diagnosis of Acute Myocardial Infarction

Exosomes are essential for tumor growth, metastasis, and are used as novel signaling molecules in targeted therapies. Therefore, exosomal miRNAs can be used in new diagnostic and therapeutic approaches due to their involvement in the development of cancers. However, the detailed biological function, potential molecular mechanism and clinical application of exo-miR-15b-3p in gastric cancer (GC) remains unclear. miR-15b-3p mRNA levels in tissues, serum, cells and exosomes were analyzed using qRT-PCR assays. qRT-PCR, immunohistochemical and western blotting analyses were utilized for the determination of DYNLT1 expression. The interrelationship connecting miR-15b-3p with DYNLT1 was verified using Dual-luciferase report, western blotting and qRT-PCR assays. Fluorescent PKH-26 or GFP-Lv-CD63 labeled exosomes, as well as Cy3-miR-15b-3p, were utilized to determine the efficacy of the transfer of exo-miR-15b-3p between BGC-823 and recipient cells. Several in vitro assays and xenograft tumor models were conducted to determine exo-miR-15b-3p impact on GC progression. This is the first study to confirm high miR-15b-3p expression in GC cell lines, tissues and serum. Exosomes obtained from 108 GC patient serum samples and GC cell-conditioned medium were found to show upregulation of exo-miR-15b-3p, with the area under the ROC curve (AUC) being 0.820 [0.763–0.876], which is superior to the AUC of tissues and serum miR-15b-3p (0.674 [0.600–0.748] and 0.642 [0.499–0.786], respectively). In addition, high exo-miR-15b-3p expression in serum was found to accurately predict worse overall survival. SGC-7901 and GES-1 cells are capable of internalizing BGC-823 cell-derived exosomes, allowing the transfer of miR-15b-3p. Migration, invasion, proliferation and inhibition of apoptosis in vitro and in vivo were enhanced by exo-miR-15b-3p, by restraining DYNLT1, Cleaved Caspase-9 and Caspase-3 expression. This study identified a previously unknown regulatory pathway, exo-miR-15b-3p/DYNLT1/Caspase-3/Caspase-9, which promotes GC development and GES-1 cell malignant transformation. Therefore, serum exo-miR-15b-3p may be a potential GC diagnosis and prognosis biomarker, which can be used in precise targeted GC therapy.

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Exosomal transfer of miR-15b-3p enhances tumorigenesis and malignant transformation through the DYNLT1/Caspase-3/Caspase-9 signaling pathway in gastric cancer.

Despite significant advances in the management of acute coronary syndromes (ACS), there are still plenty of patients undergoing percutaneous coronary intervention (PCI) and stent implantation suffered poor prognosis and high treatment expenditure. Evidence increasingly suggests that the ratio of low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio might be a novel marker for the risk of atherosclerotic cardiovascular disease, but the impact of LDL-C/HDL-C ratio on 1-year prognosis of drug-eluting stent (DES) implantation patients after PCI is still not reported. Our aim of the study was to investigate the impact of LDL-C/HDL-C ratio on 1-year prognosis of DES implantation patients after PCI. Between May 2014 and July 2016, 1937 patients who were underwent primary PCI and DES implantation and achieving LDL-C with statins were enrolled and divided into two groups based on the ratio of LDL-C/HDL-C. The entire occurrence of adverse cardiovascular events according to the ratio of LDL-C/HDL-C showed that there were no significant differences in 1-year cardiovascular death (hazard ratio [HR]: 1.97, 95% confidence interval [CI]: 0.49 to 7.84, P = 0.329), myocardial infarction (MI) (HR: 1.66, 95% CI: 0.84 to 3.28, P = 0.172) and bleeding events (HR: 1.08, 95% CI: 0.83 to 1.41, P = 0.598) The cumulative incidence of target lesion revascularization (TLR) (HR: 1.43, 95% CI: 1.10 to 1.86, P = 0.007), stent thrombosis (ST) (HR: 2.04, 95% CI: 1.06 to 3.93, P = 0.037) and major adverse cardiac events (MACE) (HR: 1.54, 95% CI: 1.24 to 1.91, P <  0.001) were significantly higher in high group than in low group. Multivariate Cox regression analysis revealed that age (HR: 1.556, 95%, CI: 1.198 to 2.021, P <  0.001), together with diabetes mellitus (HR: 1.490, 95% CI: 1.142 to 1.945, P = 0.003), and ratio of LDL-C/HDL-C (HR: 1.638, 95% CI: 1.260 to 2.218, P <  0.001) were independent predictors of 1-year MACE. The Kaplan-Meier cumulative MACE-free survival curves with a log-rank test showed that the presence of high ratio of LDL-C/HDL-C was associated with higher incidences of MACE after PCI with DES implantation. The high LDL-C/HDL-C ratio was associated with cardiovascular events in patients with ACS after PCI and DES implantation.

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Assessment of the LDL-C/HDL-C ratio as a predictor of one year clinical outcomes in patients with acute coronary syndromes after percutaneous coronary intervention and drug-eluting stent implantation

BACKGROUND Cytochrome P450 (CYP) 2C19 is an enzyme involved in the bioactivation of various important therapeutic drugs, from pro-drugs to an active inhibitor of platelet action. Variants in the CYP2C19 gene influence the pharmacokinetics and clinical response to antiplatelet drugs such as clopidogrel; however, there is no available data about the genetic variation of CYP2C19 in the Hakka population in China. MATERIAL AND METHODS A total of 6686 unrelated participants (ages 17-98 years) of self-reported Hakka ancestry admitted at an inpatient department in a hospital in southern China were successfully genotyped by the gene chip platform. RESULTS The identified allele frequencies were CYP2C19*1 (64.33%), *2 (31.06%) and *3 (4.61%). The major prevalent genotype combinations were CYP2C19 *1/*1 (41.73%) and *1/*2 (39.65%). The distribution of CYP2C19 phenotypes was divided into extensive metabolizers (EM) (41.73%), intermediate metabolizers (IM) (45.21%), and poor metabolizers (PM) (13.06%). In the Hakka population, frequencies of the CYP2C19 *2 and *3 variants were observed to be close to those previously identified in Chinese and several other Asian populations. CONCLUSIONS Our study is the first to report on CYP2C19 polymorphisms in the Hakka population, and may help to optimize pharmacotherapy effectiveness by providing personalized medicine to this ethnic group in the near future.

Analysis of CYP2C19 Genetic Polymorphism in a Large Ethnic Hakka Population in Southern China.

Circulating microRNA expression profiling and bioinformatics analysis of dysregulated microRNAs of patients with coronary artery disease.

Objective Acute Myocardial Infarction (AMI) is the most severe type of coronary atherosclerotic heart diseases. MiRNA is a class of endogenous noncoding small molecule RNA, which plays an important regulatory role in the development of some diseases. Methods We examined the miRNA expression profiles in 16 patients with AMI compared with 6 non-AMI controls using RNA sequencing. Results Compared with the miRNA expression profiles of non-AMI controls, a total of 181 differentially expressed miRNAs were discriminated in AMI patients, of which 96 upregulated miRNAs and 85 downregulated miRNAs. The top ten upregulated miRNAs were as follows: miR-449a-5p, miR-126-5p, miR-93-5p, miR-199a-3p, miR-4454, miR-6880-3p, miR-3135a, miR-548ad-5p, miR-4508, and miR-556-5p; while the top ten downregulated were as follows: miR-6805-5p, miR-1228-5p, miR-939-5p, miR-615-3p, miR-6780a-5p, miR-6857-3p, miR-5088-55p, miR-7155-3p, miR-184, and miR-4525. And the qRT-PCR results of differentially expressed miRNAs showed the same result as high-throughput sequencing data. For these 181 differentially expressed miRNAs, 19 841 target genes were predicted by GO analysis. The enrichment analysis revealed 2061 involved in biological processes, 353 in molecular function and 303 in cellular components. To identify biological pathways in AMI as compared to non-AMI, the target genes of differentially expressed miRNAs were mapped to the classical signal transduction pathway in KEGG, indicating that 214 classes were enriched. ROC analysis showed that the circulating miRNAs had the important value for AMI diagnosis and supported the previous conclusions that circulating miRNAs were effective to diagnose the AMI as a novel biomarker. Conclusions Our findings require further research to confirm. It may provide a meaningful reference for the diagnosis and treatment of AMI.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcla.23099

Expression profiling and bioinformatics analysis of circulating microRNAs in patients with acute myocardial infarction.

Little is known about serum lipid levels comparison of patients with acute myocardial infarction (AMI) in Hakka patients in southern China. To estimate the prevalence lipid profiles in Hakka patients with AMI in southern China. We analyzed 1382 patients with a first AMI in Hakka patients in southern China between Jan. 2015 and Dec. 2015. Our findings demonstrated that low-density lipoprotein cholesterol (LDL), total cholesterol (TC), and triglyceride (TG) were higher in nonelderly than in elderly for males. There were significant differences in TC, LDL, HDL, and TG among various age groups for both males and female patients (P < .05). TC, LDL, HDL, and TG were higher in females than males for the elderly, and the LDL levels of females were higher in 70–79,80–89 year age groups than males. The HDL level of female patients was higher than males in those 50–59, 60–69, and 70–79 year age groups. Compared with males, females had higher level of TG in the 60–69, 70–79, and 80–89 year age groups and had higher level of TC in the 50–59, 70–79, and 80–89 year age groups, respectively. Isolated high TG (normal LDL + normal HDL+ high TG) was most common type of combined dyslipidemia for female elderly (22.2%), female nonelderly (23.2%) and male elderly (24.1%) patients. Our results confirmed that serum lipid levels varied in age and gender in Hakka patients with acute myocardial infarction. Dyslipidemia is more prevalent in the non-elderly than in the elderly for males. Levels of TC, LDL, HDL, and TG were higher in females than males for the elderly Hakka population in southern China.

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Qifeng Zhang

Papers

Assessment of the LDL-C/HDL-C ratio as a predictor of one year clinical outcomes in patients with acute coronary syndromes after percutaneous coronary intervention and drug-eluting stent implantation

Analysis of CYP2C19 Genetic Polymorphism in a Large Ethnic Hakka Population in Southern China.

Circulating microRNA expression profiling and bioinformatics analysis of dysregulated microRNAs of patients with coronary artery disease.

Expression profiling and bioinformatics analysis of circulating microRNAs in patients with acute myocardial infarction.

Serum lipid profiles in patients with acute myocardial infarction in Hakka population in southern China.