Cephalotaxine Inhibits the Survival of Leukemia Cells by Activating Mitochondrial Apoptosis Pathway and Inhibiting Autophagy Flow

Cephalotaxine (CET) is a natural alkaloid with potent antileukemia effects. However, its underlying molecular mechanism has not been well understood. In this study, we verified that CET significantly inhibited the viability of various leukemia cells, including HL-60, NB4, Jurkat, K562, Raji and MOLT-4. RNA-sequencing and bioinformatics analysis revealed that CET causes mitochondrial function change. Mechanism research indicated that CET activated the mitochondrial apoptosis pathway by reducing the mitochondrial membrane potential, downregulating anti-apoptotic Bcl-2 protein and upregulating pro-apoptotic Bak protein. In addition, the autophagy signaling pathway was highly enriched by RNA-seq analysis. Then, we found that CET blocked the fluorescence colocation of MitoTracker Green and LysoTracker Red and upregulated the level of LC3-II and p62, which indicated that autophagy flow was impaired. Further results demonstrated that CET could impair lysosomal acidification and block autophagy flow. Finally, inhibiting autophagy flow could aggravate apoptosis of HL-60 cells induced by CET. In summary, this study demonstrated that CET exerted antileukemia effects through activation of the mitochondria-dependent pathway and by impairing autophagy flow. Our research provides new insights into the molecular mechanisms of CET in the treatment of leukemia.

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Influence of Ca2+ on mitochondrial apoptosis activation and yak meat tenderization during postmortem aging

Canadian Journal of Animal Science ◽

10.1139/cjas-2020-0148 ◽

2021 ◽

pp. 1-12

Author(s):

Lin-lin Wang ◽

Lian-hong Chen ◽

Jian Li ◽

Rong-sheng Du ◽

Ling Han ◽

...

Keyword(s):

Molecular Mechanisms ◽

Citrate Synthase ◽

Control Group ◽

Mitochondrial Apoptosis ◽

Apoptosis Pathway ◽

Atp Production ◽

Mitochondrial Apoptosis Pathway ◽

Mitochondrial Functions ◽

Postmortem Aging ◽

Meat Tenderization

The objective of this study was to investigate the underlying molecular mechanisms of mitochondrial Ca2+ homeostasis disequilibrium in mitochondrial apoptosis and its impact on yak meat tenderness. Results indicated that CaCl2 treatment significantly promoted glycolysis by increasing lactic acid level and decreasing glycogen content, pH, and ATP production (P < 0.01 and P < 0.05). The activities of Na+-K+-ATPase pump and Ca2+-ATPase pump in the early aging stage were significantly influenced by CaCl2 treatment. The activities of synchronous digital hierarchy and citrate synthase were also significantly improved by CaCl2 treatment (P < 0.01 and P < 0.05). Mitochondrial reactive oxygen species (ROS) levels were significantly higher in the CaCl2 group than in the control group (P < 0.01); at 24 h, the value in the Ca2+ group was 64.27% higher than that in the control group. Furthermore, CaCl2 treatment significantly enhanced the mitochondrial apoptosis cascade reaction and meat tenderization by improving the myofibril fragmentation index and shear force (P < 0.01). These results demonstrated that the imbalance of mitochondrial Ca2+ homeostasis played a significant role in the mitochondrial apoptosis pathway by regulating energy metabolism factors, meat intracellular environment, mitochondrial functions, and ROS-mediated oxidative stress. These conditions further improved meat tenderization during postmortem aging.

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