Background: It is well known that AMP-activated protein kinase (AMPK) is a key factor affecting the development of type 2 diabetes mellitus (T2DM). The single nucleotide polymorphism (SNP) rs2746342 in the AMPK alpha 2 subunit gene (PRKAA2) has been found to be associated with susceptibility to T2DM in the Chinese Han population. The present study further investigates the association of PRKAA2 genotypes with susceptibility to T2DM and its complication, diabetic nephropathy. Methods: The PRKAA2 genotypes of 406 T2DM patients and 214 controls from the Chinese Han population were determined with regard to SNPs rs10789038, rs2796498 and rs2746342. The association between these SNPs and susceptibility to T2DM and diabetic nephropathy was evaluated. The clinical characteristics differed significantly between T2DM patients and controls. Results: After adjustment for age, sex and body mass index, there was an obvious relationship between T2DM and both rs10789038 (odds ratio [OR] 1.634; P = 0.015) and rs2796498 (OR 0.656; P = 0.030), but not rs2746342. There was haplotype association of PRKAA2 rs10789038-rs2796498-rs2746342 with T2DM susceptibility. In addition, rs2796498 was found to be related to the susceptibility to diabetic nephropathy. Conclusions: Polymorphisms in rs10789038 and rs2796498 are associated with the susceptibility to T2DM, and rs2796498 may be related to diabetic nephropathy.
Heterotopic ossification (HO), the pathologic formation of extraskeletal bone, can be disabling and lethal. However, the underlying molecular mechanisms were largely unknown. The present study aimed to clarify the involvement of secreted protein acidic and rich in cysteine (SPARC) and the underlying mechanism in rat model of HO. The mechanistic investigation on roles of SPARC in HO was examined through gain- and loss-of-function approaches of SPARC, with alkaline-phosphatase (ALP) activity, mineralized nodules, and osteocalcin (OCN) content measured. To further confirm the regulatory role of SPARC, levels of mitogen-activated protein kinase (MAPK) signaling pathways-related proteins (extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), p38, nuclear factor κ-B (NF-κB), and IkB kinase β (IKKβ)) were determined. Bone marrow mesenchymal stem cells were treated with pathway inhibitor to investigate the relationship among SPARC, MAPK signaling pathway, and HO. The results suggested that SPARC expression was up-regulated in Achilles tendon tissues of HO rats. Silencing of SPARC could decrease phosphorylation of ERK, JNK, p38, NF-κB, and IKKβ. Additionally, silencing of SPARC or inhibition of MAPK signaling pathway could reduce the ALP activity, the number of mineralized nodules, and OCN content, thus impeding HO. To sum up, our study identifies the inhibitory role of SPARC gene silencing in HO via the MAPK signaling pathway, suggesting SPARC presents a potential target for HO therapy.
Metformin is a classical oral antidiabetic drug, often recommended to be the first-choice treatment of type 2 diabetes mellitus (T2DM). Based on the previous research on STK11 and diabetes, we aimed to investigate the distributive characteristic of STK11 rs2075604 polymorphism and the potential influence of STK11 rs2075604 polymorphism on metformin efficacy among Chinese T2DM patients. There was no significant difference between T2DM patients (G = 64.8%, T = 35.2%) and healthy subjects (G = 62.7%, T = 37.2%) in STK11 rs2075604 genotype and allele frequencies. After 12 weeks of treatment, 62 patients were defined as the responders and 32 patients as nonresponders according to the decrease of HbA1c level. And the GT + TT genotype in STK11 rs2075604 can decrease HbA1c level more significantly than the GG genotype. Furthermore, the allele frequency of T in the STK11 rs2075604 was higher in the responders than the nonresponders (43.55% versus 26.56%). The T allele in the STK11 rs2075604 had a 2.133 times great chance of responding to metformin treatment. In conclusion, this study suggested that the STK11 rs2075604 genetic polymorphism was significantly associated with metformin efficacy in Chinese T2DM patients and the carriers of the T allele may gain a better therapeutic metformin efficacy compared with the G allele. This trial is registered with clinical study registration number NCT03155087.
Circular RNA 40S ribosomal protein S28 (circRPS28; hsa_circ_0049055) is upregulated in papillary thyroid carcinoma (PTC) patients. However, its role remained uncovered in the progression of PTC. Above all, expression of circRPS28 was determined in PTC samples by real-time quantitative PCR and circRPS28 was highly expressed in tumor tissues and cells. Besides, circRPS28 was predominantly distributed in the cytoplasm. Functional experiments were launched using colony formation assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, 5-ethynyl-2-deoxyuridine (EdU) assay, transwell assays, scratch wound assay, and flow cytometry. As a result, blocking circRPS28 restrained PTC cell viability, EdU positive cell rate, colony formation number, wounding healing rate, and numbers of migration and invasion cells, accompanied with apoptosis rate promotion. These effects paralleled with low B-cell lymphoma (Bcl)-2 level and high Bcl-2-associated X protein (Bax), matrix metalloproteinase-2 (MMP2), and MMP9 levels, as analyzed by western blotting. Overexpressing microRNA (miR)-345-5p exerted similar roles to circRPS28 silencing. Notably, dual-luciferase reporter assay and RNA immunoprecipitation confirmed the target relationship between circRPS28 and miR-345-5p, miR-345-5p and frizzled family receptor 8 (FZD8). Downregulating miR-345-5p abrogated effects of circRPS28 blockage in PTC cells, and restoring FZD8 counteracted miR-345-5p roles, either. Furthermore, xenograft tumor model was established in mice, and exhausting circRPS28 delayed the growth of PTC cells in vivo by regulating miR-345-5p and FZD8. In conclusion, we demonstrated that blocking circRPS28 and/or promoting miR-345-5p suppressed PTC cell growth and motility via regulating FZD8. This study might suggest a novel circRPS28/miR-345-5p/FZD8 competing endogenous RNA pathway in PTC.
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