Effect of Metformin Intervention on Pancreatic β-Cell Apoptosis

2022 ◽  
Vol 12 (4) ◽  
pp. 873-877
Dongqian Xie ◽  
Zhicheng Gao ◽  
Mei Liu ◽  
Defeng Wang

Metformin is shown to have hypoglycemic effects. However, the relationship between metformin’s intervention in FFA-induced endoplasmic reticulum stress-mediated insulin resistance (IR) and insulin β-cell apoptosis under high-glucose condition remains unclear. Our study intends to assess their relationship. Human pancreatic β-cells were treated with metformin and cell proliferation and IR were detected by MTT assay along with detection of Wnt/β-catenin signaling by RT-PCR, cell cycle and apoptosis by flow cytometry. Metformin inhibited β cell proliferation which was mediated by FFA-induced endoplasmic reticulum stress in a time-dependent and dose-dependent manner as well as induced cell cycle arrest at G2/M phase. In addition, metformin inhibited β-catenin signaling activation and decreased the expression of c-myc, Dvl-2, survivin, Dvl-3, GSK-3β (p-ser9) and promoted GSK-3 (p-tyr216) and Axin-2 expression. In conclusion, metformin inhibits Wnt/β-catenin signaling and promotes FFA to induce endoplasmic reticulum stress, thereby mediating pancreatic β-cells behaviors.

Hua Zhang ◽  
Xiaojin Zhao ◽  
Fajun Shang ◽  
Huan Sun ◽  
Xu Zheng ◽  

Background: Colorectal cancer (CRC) is the third-ranked malignant tumor in the world that contributes to the death of a major population of the world. Celastrol, a bioactive natural product isolated from the medicinal plant Tripterygium wilfordii Hook F, has been proved to be an effective anti-tumor inhibitor for multiple tumors. Objective: To reveal the therapeutic effect and underlying mechanisms of celastrol on CRC cells. Methods: CCK-8 and clonogenic assay were used to analyze the cell proliferation in CRC cells. Flow cytometry analysis was conducted to assess the cell cycle and cell apoptosis. Wound-healing and cell invasion assay were used to evaluate the migrating and invasion capability of CRC cells. The potential antitumor mechanism of celastrol was investigated by qPCR, western blot, and confocal immunofluorescence analyses. Results: Celastrol effectively inhibited CRC cell proliferation by activating caspase-dependent cell apoptosis and facilitating G1 cell cycle arrest in a dose-dependent manner, as well as cell migration and invasion by downregulating the MMP2 and MMP9. Mechanistic protein expression revealed that celastrol suppressed the expression of COX-2 by inhibiting the phosphorylation of NF-κB p65 and subsequently leading to cytoplasmic retention of p65 protein, thereby inhibiting its nuclear translocation and transcription activities. Conclusion: These findings indicate that celastrol is an effective inhibitor for CRC, regulating the NF-κB/COX-2 pathway, leading to the inhibition of cell proliferation characterized by cell cycle arrest and caspase-dependent apoptosis, providing a potential alternative therapeutic agent for CRC patients.

2020 ◽  
Vol 245 (12) ◽  
pp. 1009-1015
Jinhai Ren ◽  
Ying Wang ◽  
Lihua Wang ◽  
Xiaoling Guo ◽  
Xiaonan Guo

Myelodysplastic syndromes (MDSs) are a series of heterogeneous diseases affecting hematopoietic stem cells that result in hematopoiesis disturbance and leukemic transformation. As an essential cell cycle regulator, ribophorin II (RPN2) has been extensively identified as a prospective predictor of prognosis in diverse malignant tumors. However, its effects on MDS are unclear. We observed increased mRNA expression RPN2 in samples from MDS patients, compared with samples from normal healthy controls. RPN2 overexpression promoted the proliferation of Ontario Cancer Institute OCI-acute myeloid leukemia 3 (OCI-AML3) cells, whereas RPN2 silencing clearly suppressed the proliferation of OCI-AML3 cells. Furthermore, RPN2 silencing caused G1/S cell cycle arrest and cell apoptosis. In addition, RPN2 overexpression led to a higher proportion of cells in the G2/M phase and reduced cell apoptosis. RPN2 overexpression downregulated enhancer of zeste homolog-2 (EZH2) expression, whereas RPN2 downregulation increased EZH2 expression in a dose-dependent manner. Co-immunoprecipitation showed an interaction between RPN2 and EZH2. Additionally, the administration of 3-deazaneplanocin A, an EZH2 inhibitor, reversed the function of RPN2 silencing in cell cycle arrest and apoptosis induction in OCI-AML3 cells. Hence, RPN2 is an essential regulator of cell proliferation. This study described the etiology of OCI-AML3 cell proliferation regulated by RPN2 and EZH2. Impact statement This study explored the role of ribophorin II (RPN2) in myelodysplastic syndromes (MDSs) cell proliferation and growth and revealed that RPN2 knockdown suppressed OCI-AML3 cell growth and proliferation and triggered cell cycle arrest and elicited apoptosis in OCI-AML3 cells. In addition, it shed light on the etiology of RPN2’s role in MDS cell proliferation that RPN2 can negatively impact enhancer of zeste homolog-2 (EZH2) expression, which in turn is able to modulate the cell cycle location and death in OCI-AML3 cells. Hence, RPN2 expression could be a latent predictor of prognosis in patients with MDS.

2004 ◽  
Vol 134 (11) ◽  
pp. 3121-3126 ◽  
James M. Visanji ◽  
Susan J. Duthie ◽  
Lynn Pirie ◽  
David G. Thompson ◽  
Philip J. Padfield

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