DNMT1 methylation of LncRNA-ANRIL causes myocardial fibrosis pyroptosis by interfering with the NLRP3/Caspase-1 pathway.

Myocardial fibrosis is a common pathological manifestation that occurs in various cardiac diseases. The present investigation aims to reveal how DNMT1/lncRNA-ANRIL/NLRP3 influences fibrosis and cardiac fibroblast pyroptosis. Here, we used ISO to induce myocardial fibrosis in mice, and LPS and ATP to induce myocardial fibroblast pyroptosis. The results showed that DNMT1, Caspase-1, and NLRP3 expression were significantly increased in fibrotic murine myocardium and pyroptotic cardiac fibroblasts, whereas LncRNA-ANRIL expression was decreased. DNMT1 overexpression decreased the level of LncRNA-ANRIL while increasing the levels of NLRP3 and Caspase-1. Contrarily, silencing DNMT1 increased the LncRNA-ANRIL and decreased the levels of NLRP3 and Caspase-1. Silencing LncRNA-ANRIL increased the levels of NLRP3 and Caspase-1. The present findings suggest that DNMT1 can methylate LncRNA-ANRIL during the development of myocardial fibrosis and CFs cell scorching, resulting in low LncRNA-ANRIL expression, thereby influencing myocardial fibrosis and cardiac fibroblast pyroptosis.

TMEM158 functions as an oncogene and promotes lung adenocarcinoma progression through the PI3K/AKT pathway via interaction with TWIST1.

Lung adenocarcinoma (LUAD) is a common and deadly form of lung cancer, with high rates of metastasis and unsatisfactory clinical outcomes. Herein, we examined the influence of TMEM158 on the LUAD progression. A combination of bioinformatic analyses was used to assess the TMEM158 expression pattern, prognostic implications, and potential function in LUAD. The levels of TMEM158 and TWIST1 were evaluated in clinical samples from LUAD patients using Western blot analysis and qRT-PCR. To discover the function and underlying molecular pathways of TMEM158 in LUAD, we employed a combination of experimental approaches in vitro, such as flow cytometry analysis and colony formation, Co-IP, CCK-8, Transwell, and wound-healing assays. Elevated expression of TMEM158 in LUAD is associated with increased cancer aggressiveness and a poor prognosis. In vitro experiments demonstrated that high levels of TMEM158 promote cell proliferation, progression through the cell cycle, migration, and invasion while suppressing apoptosis. Knockdown of TMEM158 produced opposite effects. The underlying mechanism involves TMEM158 and TWIST1 directly interacting, stimulating the PI3K/AKT signaling pathway in LUAD cells. This investigation emphasizes the molecular functions of TMEM158 in LUAD progression and proposes targeting it as a promising treatment approach for managing LUAD.

Application of double low-dose mode in left atrial-pulmonary venous computed tomography angiography.

This study adopted a 256-slice iCT scanner with the double low-dose mode in left atrial-pulmonary venous computed tomography angiography (CTA) and explored its effect on image quality. 120 patients were included and randomly classified into the Observation group and Control group. Patients in the Control group underwent routine left atrial CTA, while patients in the Observation group performed a double low-dose mode. Other scanning parameters were consistent in the two groups. The Full model-based iterative reconstruction (MBIR) technique was applied to fulfill image reconstruction in observation group. Continuous variables, ordered categorical variables were analyzed by statistical test. The CT values of left atrial in the Observation group were significantly higher than those in the Control group. The exposure doses (ED) and iodine intake were lower in the Observation group, as compared to the Control group. The left atrial-pulmonary venous CTA with the 256-slice iCT scanner in a double low-dose mode can reduce the ED of radiation and iodine contrast while providing high quality images. Comparatively, the ED in the Observation group was reduced by 13% compared with the control, and the iodine intake was reduced by approximately 33%.

IGFBP3 epigenetic promotion induced by METTL3 boosts cardiac fibroblast activation and fibrosis.

Cardiac fibrosis remains an unresolved problem in heart disease. Its etiology is directly caused by the activation and proliferation of cardiac fibroblasts (CFs). However, there is limited information regarding the biological role of cardiac fibroblasts in cardiac fibrosis. Herein, we screened out a gene, IGFBP3, whose expression significantly increased in TGF-ß1-stimulated human primary CFs by mining RNA-Seq data for differential and WGCNA. We verified the IGFBP3's expression in transverse aortic constriction (TAC) surgery, isoproterenol (ISO)-induced cardiac fibrosis models, and TGFß1-stimulated mouse primary CFs. We also found that the knockdown of IGFBP3 could inhibit the migration and proliferation ability of CFs. Furthermore, we found that aberrant N6-methyladenosine(m6A) mRNA modifications in the animal model and activated CFs may regulate the expression of IGFBP3 in developing cardiac fibrosis. Silencing METTL3 could downregulate the expression of IGFBP3 and inhibit the activation of CFs and the degree of cardiac fibrosis both in vitro and in vivo. Indeed, we also verified the expression of METTL3 and IGFBP3 in the atrial tissues of patients with atrial fibrillation (AF). Thus, METTL3 may regulate IGFBP3's expression and CFs activation via RNA epigenetic modifications, laying the foundation for a specific and novel therapeutic target in cardiac fibrosis.

Epigenetic control of LncRNA NEAT1 enables cardiac fibroblast pyroptosis and cardiac fibrosis.

Cardiac fibroblasts (CFs) drive extracellular matrix remodeling after inflammatory injury, leading to cardiac fibrosis and diastolic dysfunction. Recent studies described the role of epigenetics in cardiac fibrosis. Nevertheless, detailed reports on epigenetics regulating CFs pyroptosis and describing their implication in cardiac fibrosis are still unclear. Here, we found that DNMT3A reduces the expression of lncRNA Neat1 and promotes the NLRP3 axis leading to CFs pyroptosis, using cultured cells, animal models, and clinical samples to shed light on the underlying mechanism. We report that pyroptosis-related genes are increased explicitly in cardiac fibrosis tissue and LPS-treated CFs, while lncRNA Neat1 decreased. Mechanistically, we show that loss of DNMT3A or overexpression of lncRNA Neat1 in CFs after LPS treatment significantly enhances CFs pyroptosis and the production of pyroptosis-related markers in vitro. It has been demonstrated that DNMT3A can decrease lncRNA Neat1, promoting NLRP3 axis activation in CFs treated with LPS. In sum, this study is the first to identify that DNMT3A methylation decreases the expression of lncRNA Neat1 and promotes CFs pyroptosis and cardiac fibrosis, suggesting that DNMT3A and NEAT1 may function as an anti-fibrotic therapy target in cardiac fibrosis.

The effect of telemedicine on secondary prevention of atherosclerotic cardiovascular disease: A systematic review and meta-analysis.

Aim: The purpose of this systematic review was to evaluate the efficiency of telemedicine on the secondary level of prevention of patients with arteriosclerotic cardiovascular disease (ASCVD), provide evidence for the application of telemedicine in secondary prevention and promote the development of telemedicine in secondary prevention. Methods: A computer-based search was conducted in MEDLINE, Embase, Pubmed, EBSCO, CINAHL, the Cochrane Library, and Web of Science. Randomized controlled trials regarding the effect of telemedicine on secondary prevention of ASCVD were included from inception to May, 2022. Meta-analysis was used to compare the results of the included studies by RevMan5.4 software. The Cochrane Collaboration bias risk tool was used to perform risk of bias assessment in this study. Outcomes included risk factors, physical activity and exercise, muscle function, exercise compliance, medication adherence, healthy diet, depression and anxiety, self-efficacy, knowledge score, economy, and safety endpoints. Subgroup analysis was carried out for different main intervention measures included in the literature. Results: A total of 32 randomized clinical studies (n = 10 997 participants) were included in the meta-analysis. Compared with usual secondary prevention (USP) group, participants in telemedicine of secondary prevention (TOSP) group showed significant improvement in some risk factors including BMI (MD -0.87, p = 0.002), SBP (MD -4.09, p = 0.007) and DBP (MD -2.91, p = 0.0002) when they use the telephone as the intervention. In physical activity and exercise, Patients in TOSP showed an improvement in VO2 Peak (mL⋅kg-1⋅min-1) (OR 1.58, p = 0.02), 6MWT (MD 21.41, p = 0.001), GSLTPA score (MD 2.89, p = 0.005). Effects on medication adherence, exercise compliance, muscle function, healthy diet, economy and self-efficacy were synthesized narratively. Patients in TOSP did not show a reduction in knowledge score, depression, anxiety and safety endpoints. Conclusion: There is a net benefit of secondary prevention supported by telemedicine (especially when using the telephone as an intervention) in patients with ASCVD in the terms of some risk factors, physical activity and exercise. There are still controversies in the improvement of medication adherence, exercise compliance, muscle function, healthy diet, knowledge score, self-efficacy and economy via telemedicine, which is worth exploring. Larger samples size and longer-term follow-ups are needed in future studies. Systematic review registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=330478], identifier [CRD42022330478].

Silencing of integrin subunit α3 inhibits the proliferation, invasion, migration and autophagy of esophageal squamous cell carcinoma cells.

Esophageal squamous cell carcinoma (ESCC) is a deadly disease that seriously affects global public health. The aim of the present study was to explore the role of integrin subunit α3 (ITGA3) in ESCC and investigate its detailed molecular mechanisms. Using reverse transcription-quantitative PCR (RT-qPCR) and western blotting, the mRNA and protein expression of ITGA3 in cell lines was detected. In addition, a series of cellular biological experiments, including Cell Counting Kit-8, wound-healing, Transwell and TUNEL assays, were used to evaluate proliferation, migration, invasion and apoptosis, respectively. Furthermore, western blotting was used to measure the expression of corresponding proteins. ITGA3 was found to be upregulated in ESCC cell lines (ECA109 and TE1). It was also found that ITGA3 silencing inhibited the proliferation, migration, invasion and autophagy of ECA109 and TE1 cells but promoted their apoptosis. In addition, ITGA3 silencing was found to inhibit the FAK/PI3K/AKT signaling pathway. In conclusion, ITGA3 knockdown suppressed cell proliferation, invasion, migration and autophagy in ECA109 and TE1 cells, suggesting that ITGA3 may be a potential therapeutic target for the treatment of ESCC.

Mechanism of Action of Zhi Gan Cao Decoction for Atrial Fibrillation and Myocardial Fibrosis in a Mouse Model of Atrial Fibrillation: A Network Pharmacology-Based Study.

Atrial fibrillation (AF), a commonly seen cardiac disease without optimal curative treatment option, is usually treated by traditional Chinese medicine in China. The Zhi-Gan-Cao decoction (ZGCD) is an alternative medicine for clinical use and has definitive effects. It remains to be defined regarding the specific components and related mechanisms of ZGCD for the treatment of AF. We determined the primary constituents and major targets of the herbs in ZGCD using the TCMSP, HERB, and BATMAN-TCM databases. The UniProt databank database amended and combined the prospective names to supply objective data and records. Every target connected to AF was generated using the GeneCards databank, Drugbank database, TTD, Disgenet database, and OMIM. After identifying possible common targets between ZGCD and AF, the interface network illustration "ZGCD component-AF-target" was created using Cytoscape. We obtained 175 constituents and 839 targets for seven herbal drug categories in the ZGCD and identified 1008 targets of AF. After merging and removing repetitions, 136 collective targets between the ZGCD and AF were removed using the Cytoscape system. These renowned targets were generated from 38 suitable components from among the 157 components. GO enhancement examination and KEGG enrichment analysis by Metascape identified the close connection between the critical target genes and 20 signaling pathways. Then, we injected isoproterenol subcutaneously into the mouse and gave gavage with roasted licorice soup. Two weeks later, mouse were processed and sampled for testing. The results of HE and Masson staining showed that ZGCD effectively alleviated the degree of myocardial fibrosis. As indicated by qRT-PCR and Western blotting, ZGCD significantly reduced COL1A1, COL1A2, COL3A1, and TGF-ß1 in myocardial fibrotic tissue to reduce myocardial fibrosis and treat AF by interfering with the expression of COL1A1, COL1A2, COL3A1, and TGF-ß1 in myocardial tissue. ZGCD may treat AF by lowering the degree of myocardial fibrosis.

Astragaloside IV attenuates hypoxia/reoxygenation injury-induced apoptosis of type II alveolar epithelial cells through miR-21-5p.

We aimed to explore the role of miR-21-5p in the inhibitory effects of astragaloside IV (As-IV) on hypoxia/reoxygenation injury-induced apoptosis of type II alveolar epithelial cells. Rat type II alveolar epithelial cells RLE-6TN were cultured in vitro and randomly divided into control (C), hypoxia/reoxygenation injury (H/R), As-IV and miR-21-5p-siRNA + As-IV groups (n = 6). H/R model was established by 24 h of hypoxia and 4 h of reoxygenation. As-IV group was given 1 nmol/L As-IV and incubated for 1 h before modeling. MiR-21-5p-siRNA + As-IV group was transfected with 50 nmol/L miR-21-5p-siRNA. After 48 h, they were incubated with 1 nmol/L As-IV for 1 h before modeling. Cell viability was detected by cell counting kit-8 assay, and apoptosis rate was detected by flow cytometry. The expression levels of TLR4 and NF-κB were measured by immunofluorescence assay. The targeting relationship between miR-21-5p and TLR4 was determined by luciferase assay. Compared with H/R group, the cell viability, miR-21-5p, bax and cleaved caspase-3 expressions of As-IV group increased, apoptosis rate and Bcl-2 expression decreased, and TLR4 and NF-κB expressions were down-regulated (P < 0.05). Compared with As-IV group, the cell viability, miR-21-5p, bax and cleaved caspase-3 expressions of miR-21-5p-siRNA + As-IV group decreased, apoptosis rate and Bcl-2 expression increased, and the expressions of TLR4 and NF-κB were up-regulated (P < 0.05). As-IV up-regulates miR-21-5p expression, inhibits the TLR4/NF-κB signaling pathway and suppresses the apoptosis of type II alveolar epithelial cells during hypoxia/reoxygenation injury.

DNMT1-Induced miR-152-3p Suppression Facilitates Cardiac Fibroblast Activation in Cardiac Fibrosis.

Novel insights into epigenetic control of cardiac fibrosis are now emerging. Cardiac fibroblasts (CFs) activation into myofibroblasts and the production of extracellular matrix (ECM) is the key to cardiac fibrosis development, but the specific mechanism is not fully understood. In the present study, we found that DNMT1 hypermethylation reduces the expression of microRNA-152-3p (miR-152-3p) and promotes Wnt1/ß-catenin signaling pathway leading to CFs proliferation and activation. Cardiac fibrosis was produced by ISO, and the ISO was carried out according to the method described. CFs were harvested and cultured from SD neonatal rats and stimulated with TGF-ß1. Importantly, DNMT1 resulted in the inhibition of miR-152-3p in activated CFs and both DNMT1 and miR-152-3p altered Wnt/ß-catenin downstream protein levels. Over expression of DNMT1 and miR-152-3p inhibitors promotes proliferation of activating CFs. In addition, decreased methylation levels and over expression of miR-152-3p inhibited CFs proliferation. We determined that DNMT1 can methylate to miR-152-3p and demonstrated that expression of miR-152-3p inhibits CFs proliferation by inhibiting the Wnt1/ß-catenin pathway. Our results stand out together DNMT1 methylation regulates miR-152-3p to slow the progression of cardiac fibrosis by inhibiting the Wnt1/ß-catenin pathway.

Germacrone induces lung cancer cell apoptosis and cell cycle arrest via the Akt/MDM2/p53 signaling pathway.

Germacrone (GM) displays a wide range of antitumor, antioxidant and anti­inflammatory effects; however, to the best of our knowledge, the effects of GM on lung cancer cell apoptosis and cell cycle arrest have not been previously reported. The aim of the present study was to investigate discussed the effects of GM on the apoptosis and cycle arrest of lung cancer cells. Cell viability, proliferation and apoptosis were assessed by performing Cell Counting Kit­8, colony formation and TUNEL assays, respectively. Western blotting was performed to detect the expression levels of apoptosis­, cell cycle­ and Akt/MDM2 proto­oncogene (MDM2)/p53 signaling pathway­related proteins. Compared with the control group, 50, 100 and 200 µM GM significantly inhibited lung cancer cell proliferation, but significantly induced cell apoptosis and G1/S cell cycle arrest. GM also significantly altered the expression levels of Akt/MDM2/p53 signaling pathway­related proteins compared with the control group. Administration of Akt activator SC79 significantly reversed GM­mediated antiproliferative, proapoptotic and pro­cell cycle arrest effects in lung cancer cells. Therefore, the results of the present study demonstrated that GM induced lung cancer cell apoptosis and cell cycle arrest via the Akt/MDM2/p53 signaling pathway.

MiR-21-3p triggers cardiac fibroblasts pyroptosis in diabetic cardiac fibrosis via inhibiting androgen receptor.

AIMS/HYPOTHESIS: MicroRNA-21 has been implicated in diabetic complication, including diabetic cardiomyopathy. However, there is limited information regarding the biological role of the miR-21 passenger strand (miR-21-3p) in diabetic cardiac fibrosis. The aim of this study was to investigate the role of miR-21-3p and its target androgen receptor in STZ-induced diabetic cardiac fibrosis. METHODS: The pathological changes and collagen depositions was analyzed by HE, Sirius Red staining and Masson's Trichrome Staining. MiR-21-3p, AR, NLRP3, caspase1 and collagen I expression were analyzed by western blotting, immunohistochemistry, immunofluorescence, qRT-PCR, miR one step qRT-PCR, respectively. A luciferase reporter assay was used to verify the interaction between miR-21 and the 3' untranslated region (3'UTR) of AR. RESULTS: Our results indicated that miR-21-3p level was up-regulated, while AR was decreased in STZ-induced diabetic cardiac fibrosis tissues and cardiac fibroblast. High glucose triggers cardiac fibroblasts pyroptosis and collagen deposition. Gain-of-function and loss-of-function assays demonstrated that miR-21-3p mediated the crucial role in diabetic cardiac fibrosis. Our results show that miR-21-3p bound to the 3'UTR of AR post-transcriptionally repressed its expression. We also found AR, which regulates cardiac fibroblasts pyroptosis and collagen deposition through caspase1 signaling. CONCLUSIONS: /interpretation: Taken together, our study showed that miR-21-3p aggravates STZ-induced diabetic cardiac fibrosis through the caspase1 pathways by suppressing AR expression.

TIMP-1 and MMP-9 expressions in COPD patients complicated with spontaneous pneumothorax and their correlations with treatment outcomes.

OBJECTIVE: To study the expressions of TIMP-1 and MMP-9 in patients with chronic obstructive pulmonary disease (COPD) complicated with spontaneous pneumothorax, and their correlations with treatment outcomes. METHODS: A total of 80 COPD patients complicated with spontaneous pneumothorax treated in our hospital from December 2015 to December 2017. The serum expressions of TIMP-1 and MMP-9 in 80 COPD patients complicated with spontaneous pneumothorax (COPD group) and 52 healthy volunteers (control group) were detected by ELISA. The correlations of TIMP-1 and MMP-9 expressions with arterial blood gas parameters as well as scores of MRC breathlessness scale and St. George's Respiratory Questionnaire (SGRQ) were analyzed. RESULTS: The serum expressions of TIMP-1 and MMP-9 of COPD group were significantly higher than those of control group (P<0.05), but the two groups had similar MMP-9/TIMP-1 ratios (P>0.05). For COPD group, TIMP-1 expression, MMP-9 expression, MMP-9/TIMP-1, Sa(O2) and p(O2) were not correlated (P>0.05). TIMP-1 expression was significantly positively correlated with MRC scale and SGRQ scores (P<0.05). Sa(O2), p(O2) and MRC scale score of low MMP-9 expression, low TIMP-1 expression and low MMP-9/TIMP-1 group were significantly improved compared with those of high MMP-9 expression, high TIMP-1 expression and high MMP-9/TIMP-1 group (P<0.05). MMP-9 expression, TIMP-1 expression or MMP-9/TIMP-1 was not correlated with improvement of SGRQ score. Pulmonary function improvement (Sa(O2) improvement rate ≥5% and/or p(O2) improvement rate ≥10%) was correlated with serum MMP-9 expression, baseline Sa(O2) and p(O2). CONCLUSION: Increase of serum TIMP-1 and MMP-9 expressions in COPD patients was correlated with symptoms and scores of quality of life, and the expressions were also correlated with short-term treatment reactivity.

DNMT1 Methylation of LncRNA GAS5 Leads to Cardiac Fibroblast Pyroptosis via Affecting NLRP3 Axis.

Cell death and inflammation play critical roles in cardiac fibrosis. During the fibrosis process, inflammation and tissue injury were triggered; however, the mechanisms initiating cardiac fibrosis and driving fibroblast pyroptosis remained largely unknown. In this study, we identified long non-coding RNA (LncRNA)-GAS5 as the key onset of cardiac fibroblast pyroptosis and cardiac fibrosis. Here, we detected ISO-induced cardiac fibrosis models and cardiac fibroblast pyroptosis model by stimulating with LPS. We found that the expression of pyroptosis-related proteins such as caspase 1, NLRP3, and DNMT1 was increased in cardiac fibrosis tissue, while the expression of GAS5 was decreased. The overexpressing of LncRNA GAS5 was shown to increase and inhibit cardiac fibroblast pyroptosis, as well as attenuate caspase 1 and NLRP3 expression in cardiac fibroblast. However, the silencing of GAS5 was also observed; it shows the opposite situation. Furthermore, further studies revealed that treatment of DNMT inhibitor, 5-aza-2-deoxycytidine, or downregulation of DNMT1 led to increased GAS5 expression by reversion of promoter hypermethylation in cardiac fibroblast. Importantly, we have demonstrated that DNMT1 methylation of LncRNA GAS5 leads to cardiac fibroblast pyroptosis via affecting NLRP3 axis. Our findings indicate a new regulatory mechanism for cardiac fibroblast pyroptosis under LPS stress, providing a novel therapeutic target for cardiac fibrosis. Graphical Abstract.

Epigenetic aberrations of miR-369-5p and DNMT3A control Patched1 signal pathway in cardiac fibrosis.

Modulation of epigenetic marks has promised efficacy for treating fibrosis. Cardiac fibroblast is the primary source of activated myofibroblasts that produce extracellular matrix (ECM) in cardiac fibrosis, but the mechanisms underlying this process are incompletely understood. Here we show that microRNA-369-5p (miR-369-5p) through DNMT3A hypermethylation and suppression of the Patched1 pathway leads to fibroblast proliferation in cardiac fibrosis. Forty adult male Sprague-Dawley (SD) rats were randomly divided into two groups (sham and AAC group), cardiac fibrosis was produced by abdominal aortic constriction, and the operation of abdominal aortic constriction was carried out according to the method described. Cardiac fibroblasts (CFs) were harvested from SD neonate rats and cultured. Importantly, miR-369-5p bind directly to DNMT3A with high affinity. MiR-369-5p leads to inhibition of DNMT3A enzyme activity. Exogenous miR-369-5p in cells induces aberrant DNA methylation of the Patched1, resulting in hypermethylation of low to moderately methylated regions. Moreover, Overexpression of miR-369-5p in cardiac fibroblast cells inhibits proliferation. We identify DNMT3A as miR-369-5p target genes and demonstrate that inhibition of miR-369-5p expression augments cell proliferation by activating DNMT3A and suppression of the Patched1 pathway. Together, our results highlight miR-369-5p mediated DNMT3A epigenetic silencing of Patched1 as a mechanism of fibroblast proliferation in cardiac fibrosis.

LncRNAs and miRs as epigenetic signatures in diabetic cardiac fibrosis: new advances and perspectives.

PURPOSE: Diabetic cardiomyopathy (DCM) is a serious cardiac complication of diabetes, which further lead to heartfailure. It is known that diabetes-induced cardiac fibrosis is a key pathogenic factor contributing topathological changes in DCM. However, pathogenetic mechanisms underlying diabetes cardiac fibrosis arestill elusive. Recent studies have indicated that noncoding RNAs (ncRNAs) play a key role in diabetescardiac fibrosis. The increasing complexity of epigenetic regulator poses great challenges to ourconventional conceptions regarding how ncRNAs regulate diabetes cardiac fibrosis. METHODS: We searched PubMed, Web of Science, and Scopus for manuscripts published prior to April 2018 using keywords "Diabetic cardiomyopathy" AND " diabetes cardiac fibrosis " OR " noncoding RNAs " OR " longnoncoding RNAs " OR " microRNAs " OR "epigenetic". Manuscripts were collated, studied and carriedforward for discussion where appropriate. RESULTS: Based on the view that during diabetic cardiac fibrosis, ncRNAs are able to regulate diabetic cardiac fibrosisby targeting genes involved in epigenetic pathways. Many studies have focused on ncRNAs, an epigeneticregulator deregulating protein-coding genes in diabetic cardiac fibrosis, to identify potential therapeutictargets. Recent advances and new perspectives have found that long noncoding RNAs and microRNAs,exert their own effects on the progression of diabetic cardiac fibrosis. CONCLUSION: We firstly examine the growing role of ncRNAs characteristics and ncRNAs-regulated genes involved indiabetic cardiac fibrosis. Then, we provide several possible therapeutic strategies and highlight the potentialof molecular mechanisms in which targeting epigenetic regulators are considered as an effective means of treating diabetic cardiac fibrosis.

DNMT3A controls miR-200b in cardiac fibroblast autophagy and cardiac fibrosis.

AIM AND OBJECTIVE: Regulation of microRNA gene expression by DNA methylation may represent a key mechanism to drive cardiac fibrosis progression. Cardiac fibroblast autophagy is the primary source of cardiac fibrosis, but the mechanisms underlying this process are incompletely understood. Here we found that DNMT3A suppression of the microRNA-200b (miR-200b) through pathway leads to cardiac fibroblast autophagy in cardiac fibrosis. METHODS: To understand the impact of DNMT3A on miR-200b at cardiac fibrosis, the rat cardiac fibrosis model was established via the abdominal aortic coarctation. Cardiac fibroblasts (CFs) were harvested from SD neonate rats and cultured. The expression of DNMT3A, miR-200b, collagen I was measured by western blotting, immunohistochemistry and qRT-PCR. Gain- or loss-of-function approaches were used to manipulate DNMT3A and miR-200b. RESULTS: DNMT3A level was upregulated and negatively correlated with miR-200b expression in fibrosis tissues and cardiac fibroblast. We found that autophagy was activated by miR-200b inhibitor and inactivated by miR-200b mimic in the rat cardiac fibroblast. Knockdown of DNMT3A notably increased the expression of miR-200b. CONCLUSIONS: Taken together, these findings indicate that DNMT3A regulation of miR-200b controls cardiac fibroblast autophagy during cardiac fibrosis and provide a basis for the development of therapies for cardiac fibrosis.

Epigenetic signatures in cardiac fibrosis, special emphasis on DNA methylation and histone modification.

Cardiac fibrosis is defined as excess deposition of extracellular matrix (ECM), resulting in tissue scarring and organ dysfunction. In recent years, despite the underlying mechanisms of cardiac fibrosis are still unknown, numerous studies suggest that epigenetic regulation of cardiac fibrosis. Cardiac fibrosis is regulated by a myriad of factors that converge on the transcription of genes encoding extracellular matrix protein, a process the epigenetic machinery plays a pivotal role. Epigenetic modifications contain three main processes: DNA methylation, histone modifications, and noncoding RNAs. Here, we review recent studies that have illustrated key roles for epigenetic events in the control of pro-fibrotic gene expression, and highlight the potential of molecule mechanisms that target epigenetic regulators as a means of treating cardiac fibrosis.

Development of a nanoliposomal formulation of erlotinib for lung cancer and in vitro/in vivo antitumoral evaluation.

The aim of this study was to develop PEGylation liposomes formulations of erlotinib and evaluate their characteristics, stability, and release characteristics. The average particle sizes and entrapment efficiency of PEGylation erlotinib liposomes are 102.4±3.1 nm and 85.3%±1.8%, respectively. Transmission electron microscopy images showed that the liposomes dispersed well with a uniform shape and no changes during the storage. The in vitro drug-release kinetic model of erlotinib release from the PEGylation liposomes in phosphate-buffered saline fit well with the Higuchi equation. In vitro anticancer activity assay showed that the blank liposomes had lower cellular cytotoxicity and that the cellular cytotoxicity of erlotinib liposomes increased significantly under the same incubation condition, which should contribute to the increase in intracellular drug concentration by the transportation of liposomes. The two liposomes of erlotinib (with and without PEGylation) exhibited similar cellular cytotoxicity with no significantly different concentrations. Pharmacokinetic results indicated that erlotinib-loaded PEGylation liposomes can significantly change the pharmacokinetic behavior of drugs and improve the drug bioavailability by nearly 2 times compared to ordinary liposomes. No sign of damages such as the appearance of epithelial necrosis or sloughing of epithelial cells was detected in histological studies.

MicroRNA-21 via Dysregulation of WW Domain-Containing Protein 1 Regulate Atrial Fibrosis in Atrial Fibrillation.

BACKGROUND: microRNAs (miRs) have been reported to regulate cell biological functions. To explore the underlying mechanism of miR-21 involvement in patients with atrial fibrosis and atrial fibrillation (AF). METHODS: In total, 49 patients (24 AF, sinus rhythm 25) aged 33-68 years old, including heart valve replacement surgery and cardiac catheterisation. The pathological changes and collagen depositions was analysed by Masson's Trichrome Staining. miR-21, TGF-ß1, Smad2, p-Smad2, WWP-1, collagen I and collagen III expression were analysed by Western blotting, qRT-PCR, miR one step qRT-PCR, respectively. Treatment human cardiac fibroblasts with TGF-ß1, qRT-PCR and Western blotting to find changes in miR-21, Smad2 and WWP-1 levels. Transfected human cardiac fibroblasts with miR-21 mimic and miR-21 inhibitor. Finally, cell proliferation ability was assessed by the MTT assay and flow cytometry. RESULTS: Compared to sinus rhythm (SR) group, the collagen volume fraction was significantly increased in AF patients. The levels of the TGF-ß1, collagen I and collagen III were significantly elevated in AF group. In AF patients, the expression of miR-21 was increased, while the expression of WWP-1 was decreased. Transfected cardiac fibroblasts with miR-21 mimic increased miR-21 expression and decreased WWP-1 expression, whereas miR-21 inhibitor causes the opposite effects. Additionally, we demonstrated that knockdown miR-21 targeted up-regulation of WWP-1 may suppress cardiac fibroblasts proliferation. CONCLUSION: These indicated that miR-21 inhibits cardiac fibroblasts proliferation by inactivating the TGF-ß1/Smad2 signaling pathway via up-regulation of WWP-1.