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Li W.,Key Laboratory of Laboratory Medicine | Li W.,Zhejiang Provincial Key Laboratory of Medical Genetics | Li W.,Wenzhou University | Wen C.,Key Laboratory of Laboratory Medicine | And 7 more authors.
Molecular and Cellular Biochemistry | Year: 2015

Mitochondrial diabetes originates mainly from mutations located in maternally transmitted, mitochondrial tRNA-coding genes. In a genetic screening program of type 2 diabetes conducted with a Chinese Han population, we found one family with suggestive maternally transmitted diabetes. The proband’s mitochondrial genome was analyzed using DNA sequencing. Total 42 known nucleoside changes and 1 novel variant were identified, and the entire mitochondrial DNA sequence was assigned to haplogroup M11b. Phylogenetic analysis showed that a homoplasmic mutation, 10003T>C transition, occurred at the highly conserved site in the gene encoding tRNAGly. Using a transmitochondrial cybrid cell line harboring this mutation, we observed that the steady-state level of tRNAGly significantly affected and the amount of tRNAGly decreased by 97 %, production of reactive oxygen species was enhanced, and mitochondrial membrane potential, mtDNA copy number and cellular oxygen consumption rate were remarkably decreased compared with wild-type cybrid cells. The homoplasmic 10003T>C mutation in the mitochondrial tRNAGly gene suggested to be as a pathogenesis-related mutation which might contribute to the maternal inherited diabetes in the Han Chinese family. © 2015, Springer Science+Business Media New York. Source


Yang Y.,Wenzhou University | Meng H.,Wenzhou University | Peng Q.,Wenzhou University | Yang X.,Wenzhou University | And 7 more authors.
Cancer Gene Therapy | Year: 2015

Preliminary studies showed that miR-21 is overexpressed in some human cancers. However, the role of miR-21 in cancer is still unclear and even controversial. Our purpose was to investigate the biological effects of miR-21 on A549 non-small cell lung cancer (NSCLC) cells and the underlying mechanisms of those effects. The expression of miR-21 was quanti fied in serum samples from patients with NSCLC. A549 cells were transfected with miR-NC-sponge or miR-21-sponge only, or with miR-21-sponge plus PDCD4 small-interfering RNA (siRNA). The expression of miR-21 and PDCD4 mRNA in transfected cells was quantified by real-time polymerase chain reaction and the expression of PDCD4 protein by Western blot. Cell proliferation, apoptosis, migration, and invasion assays were performed to determine the biological effects of miR-21 expression and PDCD4 inhibition. miR-21 was overexpressed in serum from patients with NSCLC. Reduced miR-21 expression was observed following transfection with miR-21-sponge in A549 NSCLC cells. Co-transfection of miR-21-sponge with PDCD4 siRNA upregulated miR-21 expression in these cells. PDCD4 mRNA and protein levels were increased 2.14-fold and 2.16-fold, respectively, following inhibition of miR-21 expression. Inhibition of miR-21 expression following transfection of miR-21-sponge reduced cell proliferation, migration, and invasion of A549 cells. Depletion of PDCD4 by siRNA transfection reversed the reduction of cell proliferation, migration, and invasion induced by inhibition of miR-21 in A549 cells. It indicates that miR-21 is highly expressed in patients with NSCLC and inhibition of miR-21 expression reduces proliferation, migration, and invasion of A549 cells by upregulating PDCD4 expression. Modulation of miR-21 or PDCD4 expression may provide a potentially novel therapeutic approach for NSCLC. © 2015 Nature America, Inc. Source


Gan R.,Wenzhou University | Yang Y.,Wenzhou University | Yang X.,Wenzhou University | Zhao L.,Wenzhou University | And 4 more authors.
Cancer Gene Therapy | Year: 2014

Aberrantly expressed microRNAs (miRNAs) are involved in breast tumorigenesis. It is still unclear if and how miRNAs-221/222 are implicated in breast cancer and the resistance to estrogen receptor modulator tamoxifen. We investigated the roles and mechanisms of miR-221/222 in breast cancer cells, particularly in modulating response to tamoxifen therapy. MCF-7 and MDA-MB-231 breast cancer cells were transfected with antisense oligonucleotides AS-miR-221 and AS-miR-222 and their expression of miR-221 and miR-222 was assessed. The correlation of miR-221/222 with tissue inhibitor of metalloproteinase-3 (TIMP 3) expression was investigated by fluorescence quantitative PCR and western blotting analysis. The therapeutic sensitivity of these cells, transfected and untransfected, to tamoxifen was determined. Transfection of AS-miR-221 and AS-miR-222 dramatically inhibited expression of miR-221 and miR-222, respectively, in both MCF-7 and MDA-MB-231 cells (P<0.05-0.01). Downregulation of miR-221/222 significantly increased the expression of TIMP 3 compared with controls (P<0.05-0.01). The viability of estrogen receptor (ER)-positive MCF-7 cells transfected with AS-miR-221 or/and AS-miR-222 was significantly reduced by tamoxifen (P<0.05-0.01). We have demonstrated for the first time that suppression of miRNA-221/222 increases the sensitivity of ER-positive MCF-7 breast cancer cells to tamoxifen. This effect is mediated through upregulation of TIMP 3. These findings suggest that upregulation of TIMP 3 via inhibition of miRNA-221/222 could be a promising therapeutic approach for breast cancer. © 2014 Nature America, Inc. Source


Bo J.,Wenzhou University | Xie S.,Wenzhou University | Guo Y.,Wenzhou University | Zhang C.,Wenzhou University | And 7 more authors.
Journal of Diabetes Research | Year: 2016

Methylglyoxal (MG) is a highly reactive glucose metabolic intermediate and a major precursor of advanced glycation end products. MG level is elevated in hyperglycemic disorders such as diabetes mellitus. Substantial evidence has shown that MG is involved in the pathogenesis of diabetes and diabetic complications. We investigated the impact of MG on insulin secretion by MIN6 and INS-1 cells and the potential mechanisms of this effect. Our study demonstrates that MG impaired insulin secretion by MIN6 or ISN-1 cells in a dose-dependent manner. It increased reactive oxygen species (ROS) production and apoptosis rate in MIN6 or ISN-1 cells and inhibited mitochondrial membrane potential (MMP) and ATP production. Furthermore, the expression of UCP2, JNK, and P38 as well as the phosphorylation JNK and P38 was increased by MG. These effects of MG were attenuated by MG scavenger N-acetyl cysteine. Collectively, these data indicate that MG impairs insulin secretion of pancreatic β-cells through increasing ROS production. High levels of ROS can damage β-cells directly via JNK/P38 upregulation and through activation of UCP2 resulting in reduced MMP and ATP production, leading to β-cell dysfunction and impairment of insulin production. © 2016 Jinshuang Bo et al. Source


Ye W.,Key Laboratory of Laboratory Medicine | Ye W.,Wenzhou University | Chen S.,Key Laboratory of Laboratory Medicine | Jin S.,Key Laboratory of Laboratory Medicine | And 2 more authors.
Molecular Medicine Reports | Year: 2013

Metabolic syndrome (MS) is a complex disorder characterized by a group of metabolic abnormalities. In the present study, the case of an 18-year-old male who presented with MS characteristics with central obesity (overweight and a waist circumference of 95 cm) and dyslipidemia (high TG, low HDL levels and low apoA-I/apoB-100) was reported. The patient's family has maternally inherited diabetes and a number of the patient's maternal relatives present MS features. For the investigation of the mitochondrial DNA variants in the patient and the patient's family, genomic DNA of all the family members were extracted from peripheral blood using routine methods. Amplification of mitochondrial DNA in 24 overlapping fragments by PCR, direct sequencing and denaturing high-performance liquid chromatography was utilized for genetic analysis. Sequences were compared to the reference sequence to identify variants. Bioinformatic methods and databases were used to analyze conservation of the variants and to predict the protein secondary structure. With the exception of the patient, five relatives were diagnosed with MS. Moreover, 5 of the 8 family members had been diagnosed with diabetes, hearing loss and mild kidney impairment according to serum biochemical analysis. Further molecular genetic analysis indicated that the MS-associated variant T16189C was detected in this family. Notably, a heteroplasmic mutation A8890G was detected in the patient in the mitochondrial ATP6 gene, which codes the ATP synthase subunit 6 (ATPase6). A8890G changed the highly conserved ATPase6 Lys122 into Glu122 in the mitochondrial inner membrane. However, this mutation was not detected in other family members. In conclusion, the mutation A8890G may affect the function of ATPase 6 and the production of ATP, thus contributing to juvenile-onset MS. It was not detected in other family members possibly due to the mitochondrial genetic segregation or production of a new germline mutation in the juvenile-onset patient. Source

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