DNA and cell biology最新文献

MicroRNAs (miRNAs) are short non-coding RNAs that bind to the 3' untranslated region (3'' UTR) of target mRNAs to control gene expression post-transcriptionally. Recent indications have highlighted their important roles in a variety of pathophysiological conditions as well as human malignancies. Dysregulated miRNAs act as tumor suppressor genes or oncogenes in a variety of cancers. MiR-491 has been shown to have a major effect on tumorigenesis in multiple malignancies through binding to specific genes and signaling cascades, thereby preventing cancer progression. This review provides an overview of miR-491 expression in regulatory mechanisms and biological procedures of tumor cells, as well as the prospective possible treatment effects of various types of human cancers.

Atherosclerosis is a complex vascular inflammatory disease in which multiple cell types are involved, including vascular smooth muscle cells (VSMCs). In response to vascular injury and inflammatory stimuli, VSMCs undergo a "phenotypic switching" characterized by extracellular matrix secretion, loss of contractility, and abnormal proliferation and migration, which play a key role in the progression of atherosclerosis. DNA methylation modification is an important epigenetic mechanism that plays an important role in atherosclerosis. Studies investigating abnormal DNA methylation in patients with atherosclerosis have determined a specific DNA methylation profile, and proposed multiple pathways and genes involved in the etiopathogenesis of atherosclerosis. Recent studies have also revealed that DNA methylation modification controls VSMC function by regulating gene expression involved in atherosclerosis. In this review, we summarize the recent advances regarding the epigenetic control of VSMC function by DNA methylation in atherosclerosis and provide insights into the development of VSMC-centered therapeutic strategies.

Dihydroartemisinin (DHA) is a traditional antimalarial drug. DHA plays a crucial role in preventing pulmonary hypertension (PH); however, its regulatory function on microRNAs (miRNAs) in PH remains unclear. This study aimed to investigate whether DHA exerts its protective functions by regulating miR-335 in PH. Hypoxia-induced PH models were induced both in vitro and in vivo. Mice were treated with various concentrations of DHA, and pulmonary arterial smooth muscle cells (PASMCs) were treated with DHA, miR-335 inhibitor, miR-335 mimic, or Van Gogh-like 2 (Vangl2) plasmid. The expression of miR-335 and Vangl2, pulmonary arterial remodeling index; right ventricular hypertrophy index; and proliferation and migration indexes were measured. DHA improved pulmonary vascular remodeling and alleviated PH in vivo. miRNA sequencing and real-time PCR results further show that the increase in hypoxia-induced miR-335 was avoided by DHA administration, and miR-335 increased the hypoxia-induced PASMC proliferation and migration. MiRNA databases and dual-luciferase reporter assay show that miR-335 directly targets Vangl2, and Vangl2 decreased the hypoxia-induced PASMC proliferation and migration. The miR-335 inhibitor failed to inhibit hypoxia-induced proliferation and migration upregulation in Vangl2 knockdown PASMCs, and the effect of DHA can be blocked by miR-335 upregulation. In hypoxic PH, MiR-335 is increased, whereas Vangl2 is decreased. MiR-335 can significantly promote the hypoxia-induced proliferation and migration of PASMCs by targeting the Vangl2 gene. DHA effectively reverses the hypoxia-induced upregulation of miR-335 expression, avoiding the miR-335-mediated downregulation of Vangl2 and thereby promoting the expression of Vangl2 to prevent PH.

At present, severe acute respiratory syndrome coronavirus 2 is spreading and has caused over 188 million confirmed patients and more than 4,059,101 deaths. Currently, several clinical trials are done using mesenchymal stem cell (MSC) therapy in patients with coronavirus disease 2019 (COVID-19). These cells have shown safety and effectiveness, implying a promising clinical application in patients with COVID-19. Studies have shown that abnormalities in hematological measures such as white blood cells count, neutrophilia, elevated neutrophil to lymphocyte ratio, inflammatory markers, and lactate dehydrogenase can be used to assess the severity of COVID-19 disease and the response to therapy following MSC treatment. Our study has aimed to review the role of hematological factors in determination of responsiveness to MSC therapy and disease severity in COVID-19 patients.

Exposure to organochlorines is associated with epigenetic changes, including methylation change in the promoter of tumor suppressor genes, thereby leading to cancer induction. The aim of this study was to investigate the relationship between organochlorine pesticides (OCPs) and ABL1 promoter methylation in child patients with acute lymphoblastic leukemia (ALL) and the control group. The methylation rate of the ABL1 promoter was evaluated using the methylation-specific polymerase chain reaction method, and the level of OCPs in patients with ALL and healthy children was measured using gas chromatography. ABL1 promoter hypermethylation was observed in 64% of ALL patients and 28.5% of children in the control group. The level of OCPs in children with methylated ABL1 promoters was significantly higher than that in children with nonmethylated ABL1 promoters (p < 0.05). Our findings suggest that OCPs, especially alpha-hexachlorocyclohexane, beta-hexachlorocyclohexane, gamma-hexachlorocyclohexane, 2,4 dichlorodiphenyldichloroethylene, and 4,4 dichlorodiphenyltrichloroethane may induce methylation at the ABL1 promoter level, thereby preventing the normal expression of the ABL1 gene. As a result, the reduced expression of ABL1 (a tumor suppressor) gene due to the hypermethylation of its promoter leads to the disruption of normal biological processes, thus making cells vulnerable to oncogenic factors.

The COVID-19 pandemic has highlighted the urgent need for the development of broad-spectrum antivirals to enhance preparedness against future spillover of zoonotic viruses with pandemic potential into the human population. Currently, the direct-acting orally available SARS-CoV-2 inhibitors molnupiravir and paxlovid are approved for human use under emergency use authorization. A promising next-generation therapeutic candidate is the orally available ribonucleoside analog 4'-fluorouridine (4'-FlU) that had potent antiviral efficacy against different viral targets, including SARS-CoV-2 in human organoids and animal models. Although a nucleoside analog inhibitor such as molnupiravir that targets the viral RNA-dependent RNA polymerase (RdRP) complex, 4'-FlU showed a distinct mechanism of activity, delayed chain termination, compared with molnupiravir's induction of viral error catastrophe. This review will focus on some currently approved and emerging medicines developed against SARS-CoV-2, examining their potential to form a pharmacological first-line defense against zoonotic viruses with pandemic potential.

Sulfur mustard (SM), a chemical warfare agent, can form adducts with DNA, RNA, and proteins. Reactions with DNA lead to the formation of both DNA monoadducts and interstrand cross-links, resulting in DNA damage, and is an important component of SM toxicity. Our previous in vivo studies indicated that dividing cells such as hematopoietic stem cells and intestinal villi stem cells seemed to have increased sensitivity to SM. Therefore, to compare the sensitivity of somatic and stem cells to SM and to investigate the mechanism of SM cytotoxicity, we isolated human foreskin fibroblasts, reprogrammed them into pluripotent stem cells, and then compared the DNA damage repair pathways involved upon SM treatment. Our results indicated that proliferating stem cells were more sensitive to SM-induced DNA damage, and the damage mainly comprised single-stranded breaks. Furthermore, the pathways involved in DNA repair in stem cells and somatic cells were different.

Breast cancer (BC) is one of the most common causes of cancer in women worldwide and it is found to be associated with an increased level of Nicotinamide phosphoribosyltransferase (NAMPT), which plays an important role in nicotinamide adenine dinucleotide (NAD) pathway, both in blood and tumor tissues. This enzyme is also essential for the growth and survival of cancer cells. The short noncoding RNA microRNAs miR-26b is an important gene regulator and a tumor suppressor in different human cancers, including BC. In this study, bioinformatics analysis was evaluated to find the miRNAs targeting NAMPT 3' untranslated regions (3' UTRs), which was confirmed by luciferase assay. Next, we evaluate NAMPT and microRNA-26b (miR-26b) expression by using polymerase chain reaction (PCR) in BC. miR-26b effect on cell viability was also evaluated by Cell Counting Kit-8 (CCK-8). Following transfection with miR-613 mimic, the expression of miR-613 was elevated in the BC cells leading to inhibition of NAMPT expression at both mRNA and protein level as measured by real-time PCR and western blotting. Our result identified a significant tumor suppressor role of miR-26b on NAMPT, NAD concentration, and cell viability in BC. Overall, based on our finding, miR-26b mimic transfection could elevate miR-26b levels in BC cells via downregulating the NAMPT expression, NAD expression levels, and cell growth, whereas miR-26b inhibitor had the opposite function. In conclusion, miR-26b can become a promising target for BC treatment through targeting NAMPT and inhibiting the NAD production.

The immune response mediated by Th17 cells is essential in the pathogenesis of periodontitis. Emerging evidence has demonstrated that lipopolysaccharide from Porphyromonas gingivalis (Pg-LPS) could promote Th17-cell differentiation directly, while the downstream signaling remains elusive. This study was aimed to explore the role of JMJD3 (a JmjC family histone demethylase) and signal transducers and activators of transcription 3 (STAT3) in Th17-cell differentiation triggered by Pg-LPS and clarify the interaction between them. We found that the expression of JMJD3 and STAT3 was significantly increased under Th17-polarizing conditions. Pg-LPS could promote Th17-cell differentiation from CD4⁺ T cells, with an increased expression of JMJD3 and STAT3 compared to the culture without Pg-LPS. The coimmunoprecipitation results showed that the interactions of JMJD3 and STAT3, STAT3 and retinoid-related orphan nuclear receptor γt (RORγt) were enhanced following Pg-LPS stimulation during Th17-cell differentiation. Further blocking assays were performed and the results showed that inhibition of STAT3 or JMJD3 both suppressed the Th17-cell differentiation, JMJD3 inhibitor could reduce the expression of STAT3 and p-STAT3, while JMJD3 expression was not affected when STAT3 was inhibited. Taken together, this study found that JMJD3 could promote Pg-LPS induced Th17-cell differentiation by modulating the STAT3-RORc signaling pathway.

Plasma cell-free DNA (cfDNA) was elevated in patients with acute myocardial infarction (AMI) or heart failure (HF). However, whether cfDNA could serve as a predictor for risk of HF after AMI remains unknown. In this study, we conducted a pilot prospective cohort study in which 98 AMI patients were enrolled from a single center to assess the association between cfDNA levels at admission and risk of HF in an AMI population. Patients with cfDNA above the median level (14.39 ng/mL) showed higher low-density lipoprotein cholesterol, cardiac troponin I (cTnI), and soluble suppression of tumorigenicity 2 (sST2) levels compared with patients below the median. cfDNA was positively correlated with cTnI (r = 0.377, p < 0.001) and sST2 (r = 0.443, p < 0.001). Within a median follow-up of about 345 days, 46 patients (52.6%) developed HF. Multivariate Cox analysis showed that a higher cfDNA (above the cutoff value: 9.227 ng/mL) was an effective risk predictor (C-index = 0.74, 95% confidence interval [CI]: 0.733-0.748) for HF incidence after AMI (adjusted hazard ratio [HR]: 2.805; 95% CI: 1.087-7.242; p = 0.033). Moreover, a linear association was observed between cfDNA and risk of HF incidence adjusted for by age, gender, and history of chronic kidney disease (p for linear trend = 0.044). Taken together, the cfDNA levels at admission are associated with the incidence of HF in AMI patients. A positive correlation between cfDNA and the fibrotic factor sST2 was proved, but the underlying mechanisms require further study.