EXPERIMENTAL PHYSIOLOGY
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2020
·Vol. 105
·期 11
·1918-1927
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IF 2.431
Manfeng Wang,Xiaowei Wu,Lu Gan,Zongyan Teng,Haijin Zhang,Yina Zhang
New Findings What is the central question of this study? Does Dnmt3a play a crucial role in regulating diabetic muscle atrophy? What is the main finding and its importance? Muscle atrophy is one of the major long-term complications of diabetes mellitus. However, little is known about the molecular mechanism involved. In this paper, we demonstrated that Dnmt3a overexpression effectively improves the diabetic muscle health in mice and documented the underlying mechanisms. DNMT3A might become a promising target to prevent muscle atrophy in patients with diabetes. Muscle atrophy is one of the major long-term complications of diabetes mellitus, which greatly affects the mobility of patients. Epigenetic processes mediated by DNA methyltransferases (DNMTs) play crucial roles in the locomotor system, but little is known about the functions of DNMTs in diabetic muscle atrophy. Here, we investigated the function of Dnmt3a in diabetic muscle atrophy and explored the mechanisms involved. Adeno-associated virus AAV2 overexpressing Dnmt3a or its vector control was injected into the tibialis anterior muscle of streptozotocin-induced diabetic mice. Muscle mass and muscle cross-sectional area were used to evaluate muscle atrophy. In vitro , adeno-associated virus AAV2 overexpressing Dnmt3a or its vector control was transfected into C2C12 myoblasts. Horse serum was used to induce differentiation and palmitate to stimulate the C2C12 myoblasts. The expressions of myogenic regulatory factors were examined by real-time PCR and western blot analysis. Overexpression of Dnmt3a attenuated muscle atrophy in diabetic mice and promoted myotube formation of C2C12 myoblasts. Overexpression of Dnmt3a restored the expressions of myogenic regulatory factors atrogin-1, MuRF1, Pax7, Myod1 and myogenin, both in vivo and in vitro . Moreover, overexpression of Dnmt3a activated the phosphorylation of Akt by inhibiting the activation of Pten. This study demonstrates that overexpression of Dnmt3a prevents diabetic muscle atrophy by modulating the Pten/Akt pathway.
研究领域:
分子生物学
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糖尿病
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肌肉生理学
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表观遗传学
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DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
·
2019
·Vol. 18
·期 4
·3117-3124
·
IF 1.448
Qiurong Zhang,Xiao Wu,Jing Cao,Feng Gao,Kun Huang
A total of 133 patients with acute myeloid leukemia (AML) were enrolled in the current study and were subdivided into 4 groups: 34 harboring DNA methyltransferase 3 α (DNMT3A) + fms related tyrosine kinase 3‑internal tandem duplication (FLT3‑ITD) mutations, 37 harboring only FLT3‑ITD mutation, 32 harboring only DNMT3A mutation and 30 harboring no mutations in DNMT3A and FLT3‑ITD (control). Patients in all groups were administered daunorubicin and cytarabine chemotherapy regimens. The rates of complete remission (CR), 1‑year relapse (RR) and 3‑year overall survival (OS) were compared. Patients in the DNMT3A + FLT3‑ITD mutation group exhibited higher proportions of peripheral white blood cells (WBCs) and myeloid progenitor cells compared with those in DNMT3A mutation only, FLT3‑ITD mutation only and control groups (P<0.05). The rates of CD15+ and HLA‑DR+ in the DNMT3A + FLT3‑ITD mutation and DNMT3A mutation only groups were significantly higher than those in the FLT3‑ITD mutation only and control groups (P<0.05); in addition, the rate of CD38+ in the DNMT3A + FLT3‑ITD mutation and FLT3‑ITD mutation only groups was significantly higher compared with that in the DNMT3A mutation only and control groups (P<0.05). The overall chemotherapy effectiveness rate, CR, 1‑year RR and the 3‑year OS rates of patients in the DNMT3A + FLT3‑ITD mutation group were significantly worse compared with FLT3‑ITD mutation only, DNMT3A mutation only and control groups (P<0.05). The results of this study indicated that increased mutation rates in DNMT3Α and FLT3‑ITD may be associated with increased WBC and myeloid progenitor cell counts, an inferior chemotherapy efficacy and prognosis, a lower CR rate, and higher 1‑year RR and mortality rate.
研究领域:
血液学
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肿瘤学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE
·
2024
·
IF 3.3
Mangmang Feng,Xiaxia Fan,Jiangying Shi,Shuhua Shan,Songtao Li,Shuiling He,Man Ding,Zhuoyu Li
BACKGROUND Quinoa contains far more nutrients than any traditional grain crop. It is known that terpenoids in quinoa have anti-inflammatory and antitumor effects, but their role in reversing drug resistance remains unclear. RESULTS Our previous studies showed that quinoa-derived terpenoid compounds (QBT) can inhibit the occurrence and development of colon cancer. This study further indicates that QBT markedly reverse drug resistance of colon cancer. The results showed that QBT combined with 5-fluorouracil (5-Fu) treatment significantly enhanced the chemotherapy sensitivity of HCT-8/Fu, compared with 5-Fu treatment alone. Moreover, we found that QBT significantly reduced the expression of drug-resistant proteins (P-gp, MRP1, BCRP), and increased the accumulation of chemotherapy drugs. Taking P-gp as the target for biogenesis prediction analysis, results showed that upregulation of miR-495-3p enhanced the chemosensitivity of drug-resistant HCT-8/Fu cells. Besides, the results showed that miR-495-3p was abnormally methylated in HCT-8/Fu compared with HCT-8 colon cancer cells. The expression of methyltransferases DNMT1, DNMT3a and DNMT3b was abnormal. After QBT treatment, the expression level of methyltransferases returned to normal. In addition, the QBT + 5Fu group showed inhibition of tumors in nude mice. CONCLUSION QBT treatment downregulated the expression of drug-resistant protein P-gp by inhibiting the methylation of miR-495-3p, and enhanced the accumulation of 5-Fu in vivo , which in turn reversed its chemoresistance. This suggests that QBT has potential ability as a new drug-resistance reversal agent in colorectal cancer. © 2024 Society of Chemical Industry.
研究领域:
癌症生物学
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药理学
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分子生物学
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营养科学
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PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2026
·
IF 4.7
Hou Xiaoxiao,Chen Ying,Xu Qixun,Zhong Jiaxin,Long Yudan,Liu Kai
Myocardial ischemia-reperfusion (I/R) injury is a complex condition characterized by oxidative stress, inflammation, and mitochondrial dysfunction. Ferroptosis, an iron-dependent form of regulated cell death, plays a critical role in cardiomyocyte damage during I/R. Inhibiting ferroptosis has been shown to reduce myocardial injury and improve cardiac function, making it a promising therapeutic target for enhancing clinical outcomes. An in vivo I/R model was established, and infarct size was assessed using triphenyltetrazolium chloride (TTC) staining. Histological changes were analyzed using hematoxylin and eosin (H&E) staining, Masson, immunohistochemistry (IHC), and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays. Cellular experiments included analyses of reactive oxygen species (ROS), lipid peroxidation, and iron content using specific fluorescent probes, as well as enzymatic markers measured with commercial assay kits. Cell viability and senescence were evaluated using the Cell Counting Kit-8 (CCK-8) assay and senescence-associated β-galactosidase (SA–β-gal) staining, respectively. Mitochondrial ultrastructure was examined using transmission electron microscopy (TEM), while molecular mechanisms, including DNA methylation, were investigated using methylation-specific polymerase chain reaction (MSP). Interactions among pleckstrin homology-like domain family A member 3 (PHLDA3), DNA (cytosine-5)-methyltransferase 3 A (DNMT3a), and polypyrimidine tract binding protein 1 (PTBP1) were evaluated using chromatin immunoprecipitation (ChIP) and RNA pull-down assays. Silencing of PHLDA3 demonstrated protective effects against I/R injury by attenuating cardiomyocyte ferroptosis and cardiac microvascular endothelial cells (CMECs) senescence under hypoxia/reoxygenation (H/R) conditions in vitro and I/R injury in vivo. Mechanistically, downregulated DNMT3a was responsible for PHLDA3 hypomethylation. Furthermore, PTBP1 was identified as an upstream RNA-binding protein that destabilized DNMT3a mRNA during H/R injury, indirectly enhancing PHLDA3 expression. Our findings suggest that PTBP1-mediated DNMT3a downregulation contributes to PHLDA3 hypomethylation, which may promote cardiomyocyte ferroptosis and subsequent microvascular endothelial cell senescence during I/R injury.
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PubMed
高影响因子
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